NZ613269B2 - Glucagon receptor modulator - Google Patents

Glucagon receptor modulator Download PDF

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Publication number
NZ613269B2
NZ613269B2 NZ613269A NZ61326912A NZ613269B2 NZ 613269 B2 NZ613269 B2 NZ 613269B2 NZ 613269 A NZ613269 A NZ 613269A NZ 61326912 A NZ61326912 A NZ 61326912A NZ 613269 B2 NZ613269 B2 NZ 613269B2
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New Zealand
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mmol
reaction
added
nmr
mhz
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NZ613269A
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NZ613269A (en
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Gary Erik Apnes
Mary Theresa Didiuk
Kevin James Filipski
Perez Angel Guzman
Esther Cheng Yin Lee
Jeffrey Allen Pfefferkorn
Benjamin Dawson Stevens
Meihua Mike Tu
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Pfizer Inc
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Priority claimed from PCT/IB2012/050349 external-priority patent/WO2012107850A1/en
Publication of NZ613269A publication Critical patent/NZ613269A/en
Publication of NZ613269B2 publication Critical patent/NZ613269B2/en

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Abstract

The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, A1, A2, A3, A4, L, B1, B2, B3 and B4 are as defined herein. The compounds of formula (I) have been found to act as glucagon antagonists or inverse agonists. Consequently, the compounds of formula (I) and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucagon such as Type 2 diabetes. e compounds of formula (I) and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucagon such as Type 2 diabetes.

Description

GLUCAGON RECEPTOR MODULATORS FIELD OF THE INVENTION The present invention relates to compounds that are antagonists, mixed agonists/antagonists, partial agonists, negative allosteric modulators or inverse agonists of the glucagon receptor, pharmaceutical compositions sing the compounds, and the uses of the compounds or compositions.
BACKGROUND Diabetes is a major public health concern because of its increasing prevalence and associated health risks. The disease is characterized by metabolic defects in the production and utilization of carbohydrates which result in the failure to maintain appropriate blood glucose . Two major forms of diabetes are recognized. Type I diabetes, or insulin-dependent diabetes mellitus (IDDMT1DM), is the result of an te ency of insulin. Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDMTZDM), often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues and cells to d appropriately to insulin. Aggressive control of NIDDM T2DM with medication is essential; otherwise it can progress into B-cell failure and insulin dependence. on is a twenty nine amino acid peptide which is secreted from the on cells of the pancreas into the c portal vein y exposing the liver to higher levels of this hormone than non-hepatic s. Plasma glucagon levels decrease in response to hyperglycemia, hyperinsulinemia, elevated plasma non-esterified fatty acid levels and somatostatin whereas glucagon secretion is increased in response to ycemia and elevated plasma amino acid . Glucagon, through activation of its receptor, is a potent activator of hepatic glucose production by activating glycogenolysis and gluconeogenesis.
The glucagon receptor is a 62 kDa protein that is activated by on and is a member of the class B G-protein coupled family of receptors. Other y d G-protein coupled receptors include glucagon-like peptide-1 receptor (GLP- 1), glucagon-like peptide-2 receptor (GLP-2) and gastric inhibitory ptide receptor. The glucagon receptor is encoded by the GCGR gene in humans and these receptors are mainly expressed in the liver with lesser amounts found in the kidney, heart, adipose tissue, spleen, thymus, adrenal glands, pancreas, cerebral cortex and gastrointestinal tract. Stimulation of the glucagon or results in activation of adenylate cyclase and increased levels of intracellular cAMP.
Reports have indicated that an uncommon missense on in the GCGR gene is correlated with diabetes mellitus type 2 and one reported inactivating mutation of the glucagon receptor in humans causes resistance to glucagon and is associated with pancreatic oc-cell hyperplasia, oblastosis, hyperglucagonemia and pancreatic neuroendocrine tumors. In rodent studies with GCGR ut mice and mice treated with GCGR antisense oligonucleotides the mice exhibited improved fasting glucose, glucose tolerance and pancreatic B-cell function. In both healthy control animals and animal models of type 1 and type 2 diabetes, removal of circulating on with selective and specific antibodies has ed in a reduction of the ic level. More specifically, treatment of both mice and cynomolgus monkeys with GCGR-antagonizing antibodies (mAb B and mAb Ac) has been shown to improve glycemic control without causing hypoglycemia.
Recent mice studies have further shown that antagonism of the glucagon receptor s in improved glucose homeostasis through a mechanism which requires a functional GLP-1 receptor. Antagonism of the glucagon receptor resulted in compensatory overproduction of GLP-1, likely from the pancreatic oc-cells, and this may play an important role in intraislet regulation and maintenance of B-cell function.
A promising area of diabetes research involves the use of small molecule antagonists, mixed agonists/antagonists, partial ts, negative allosteric tors or inverse agonists of the glucagon receptor to lower the level of ating glucagon and thereby lower the ic level. Therapeutically, it is anticipated that inactivation of the glucagon receptor would be an ive gy for lowering blood glucose by reducing c glucose output and normalizing glucose stimulated insulin secretion. Consequently, a glucagon antagonist, mixed agonist/antagonist, partial agonist, negative allosteric modulator or or inverse agonist may provide therapeutic treatment for NIDDM T2DM and associated complications, inter alia, hyperglycemia, dyslipidemia, insulin resistance syndrome, hyperinsulinemia, hypertension, and obesity.
Several drugs in five major categories, each acting by different mechanisms, are available for treating lycemia and subsequently, NIDDM T2DM (Moller, D. E., "New drug targets for Type 2 diabetes and the metabolic syndrome" Nature 414; 821-827, (2001)): (A) Insulin secretogogues, including sulphonyl-ureas (e.g., ide, glimepiride, glyburide) and meglitinides (e.g., nateglidine and repaglinide) enhance secretion of insulin by acting on the pancreatic beta-cells. While this therapy can decrease blood glucose level, it has limited efficacy and tolerability, causes weight gain and often induces hypoglycemia. (B) Biguanides (e.g., metformin) are t to act primarily by decreasing c glucose production.
Biguanides often cause gastrointestinal disturbances and lactic acidosis, further limiting their use. (C) Inhibitors of alpha-glucosidase (e.g., acarbose) decrease intestinal glucose tion. These agents often cause gastrointestinal disturbances. (D) Thiazolidinediones (e.g., pioglitazone, rosiglitazone) act on a specific receptor (peroxisome erator—activated receptor-gamma) in the liver, muscle and fat tissues. They regulate lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edema and anemia. (E) lnsulin is used in more severe cases, either alone or in combination with the above agents. ldeally, an effective new treatment for NIDDM T2DM would meet the following criteria: (a) it would not have significant side effects including induction of hypoglycemia; (b) it would not cause weight gain; (c) it would at least partially e insulin by acting via mechanism(s) that are independent from the actions of insulin; (d) it would desirably be metabolically stable to allow less frequent usage; and (e) it would be usable in ation with tolerable amounts of any of the categories of drugs listed .
A number of publications have ed which disclose ptide compounds which act at the glucagon receptor. For example, WO 03/048109, WO 2004/002480, , , , WO 2006/102067, , , , WO 23581 and Kurukulasuriya et aI. Bioorganic & Medicinal Chemistry s, 2004, 14(9), 2047-2050 each disclose non-peptide compounds that act as glucagon receptor antagonists. Although igations are on-going, there still exists a need for a more effective and safe therapeutic treatment for es, particularly NIDDM.
Brief Description of the Drawings Figure 1 provides the powder X—ray diffraction for the exemplified compound as noted.
SUMMARY OF THE INVENTION The present invention es compounds of Formula I that act as on receptor modulators, in particular, glucagon antagonists; therefore, may be used in the treatment of diseases mediated by such antagonism (e.g., diseases related to Type 2 diabetes, and diabetes-related and obesity-related co- morbidities). A first embodiment of the present invention are compounds of <2}%H R2/ | or a pharmaceutically acceptable salt thereof, wherein R1 is a 5 membered heteroaryl group attached through either a carbon or nitrogen atom and which is optionally fused to a (C4-Cy)cycloalkyl, phenyl or 6 membered heteroaryl; wherein the optionally fused 5 membered heteroaryl is optionally substituted with one to four substituents each independently selected from halo, -S(O)2-(C1-Cs)alkyl, -S-(C1- Cs)alkyl, hydroxy, -C(O)NRaRb, (Cs-C5)cycloalkyl, cyano, phenyl which is optionally tuted with one to three halo, cyano, )alkyl or (C1-Cs)alkoxy, 6 membered heteroaryl which is ally substituted with one to three halo, cyano, (C1-Cs)alkyl or (C1-Cs)alkoxy, (C1-Cs)alkyl ally substituted with one to three fluoro, or (C1-Cs)alkoxy optionally substituted with one to three ; R:11 and Rb are each independently H or (C1-Cs)alkyl; R2 is H or methyl; R3 is tetrazolyl, -CH2- tetrazolyl, -(CH2)2803H or —(CH2)ZCOZH, -CHZCHFCOZH or -CHZCHOHCOZH; A1, A2, A3 and A4 are each independently CR4 or N, with the proviso that no more than two of A1, A2, A3 and A4 are N; R4 at each occurrence is independently H, halo, cyano, (C1-Cs)alkyl optionally substituted with one to three fluoro, or (C1-Cs)alkoxy optionally substituted with one to three fluoro; L is —X—CH(R5)- or -CH(R5)-X-; X is CH2, 0 or NH; R5 is (C1-Cs)alkyl which is optionally substituted with one to three fluoro, hydroxy or methoxy; )cycloalkyl which is optionally tuted with one to two (C1-Cs)alkyl which are optionally substituted with one to three fluoro and wherein one to two carbons of the (Cs-Cy)cycloalkyl can be ed with a NH, N(C1-Cs)alkyl, O or S; or (Cs-Cy)cycloalkyl-(C1-Cs)alkyl wherein the (Cs-Cy)cycloalkyl group of said (Cs-Cy)cycloalkyl-(Ci-Cs)alkyl is optionally substituted with one to two (C1-Cs)alkyl which are optionally substituted with one to three fluoro; B1, BZ, B3 and B4 are each independently CR6 or N, with the proviso that no more than two of B1, BZ, 83 and B4 are N; and R6 at each occurrence is independently H, halo, (Ci- Cs)alkyl optionally substituted with one to three fluoro, or (C1-Cs)alkoxy ally substituted with one to three fluoro.
A second embodiment of the present invention is the compound of the first embodiment or a pharmaceutically acceptable salt f, wherein R1 is a 5 ed heteroaryl attached through a nitrogen atom to the carbon between A1 and A4 of the ring containing A1, A2, A3 and A4; R2 is hydrogen; and R3 is — (CH2)ZCOZH.
A third embodiment of the present invention is the compound of the first or second embodiments or a pharmaceutically acceptable salt thereof, wherein X is O.
A fourth embodiment of the present invention is the compound of the first or second embodiments or a pharmaceutically acceptable salt thereof, n X is NH. A fifth embodiment of the present invention is the compound of the first or second ments or a pharmaceutically acceptable salt f, wherein X is CH2.
A sixth embodiment of the present invention is the compound of the third or fourth embodiments or a pharmaceutically acceptable salt thereof wherein R2 is hydrogen; R3 is —(CH2)ZCOZH; L is —X-CH(R5)- ; A1, A2, A3 and A4 are each ndently CR4; or A4 is N and A1, A2 and A3 are each CR4; or A1 and A4 are each N and A2 and A3 are each CR4; or A2 and A4 are each N and A1 and A3 are each CR4; R4 at each occurrence is independently H or methyl; B1, 82, 83 and B4 are each CR6; or B1 is N and BZ, 83 and B4 are each CR6; or 82 and 83 are each N and B1 and B4 are each CR6; or B1 and B4 are each N and 82 and 83 are each CR6; and R6 at each occurrence is H.
A seventh embodiment of the present invention is the compound of the third embodiment or a pharmaceutically acceptable salt thereof wherein R2 is hydrogen; R3 is —(CH2)ZCOZH; L is —X-CH(R5)- ; A1, A2, A3 and A4 are each CR4; or A4 is N and A1, A2 and A3 are each CR4; or A1 and A4 are each N and A2 and A3 are each CR4; or A2 and A4 are each N and A1 and A3 are each CR4; R4 at each occurrence is independently H or methyl; B1, 82, 83 and B4 are each CR6; and R6 at each occurrence is ndently H or methyl.
WO 07850 An eighth embodiment of the present invention is the compound of the fourth ment or a pharmaceutically acceptable salt thereof wherein R2 is hydrogen; R3 is —(CH2)ZCOZH; L is -CH(R5)-X- ; A4 is N and A1, A2 and A3 are each CR4; or A1 and A4 are each N and A2 and A3 are each CR4; or A2 and A4 are each N and A1 and A3 are each CR4; R4 at each occurrence is independently H or methyl; B1, BZ, 83 and B4 are each CR6; and R6 at each occurrence is independently H or methyl.
A ninth embodiment of the present invention is the compound of the fourth embodiment or a pharmaceutically acceptable salt thereof wherein R2 is en; R3 is —(CH2)ZCOZH; L is -CH(R5)-X- ; A1, A2, A3 and A4 are each ndently CR4; R4 at each occurrence is independently H or methyl; one of B1, BZ, 83 and B4 is N and the others are each CR6; and R6 at each occurrence is independently H or methyl.
A tenth embodiment of the present invention is the compound of the sixth through ninth embodiments or a pharmaceutically acceptable salt thereof wherein R5 is ethyl, propyl, pyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.
An eleventh embodiment of the present invention is the compound of the tenth embodiment or a ceutically acceptable salt thereof wherein R1 is olyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each ndently selected from methyl, oromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro.
A twelth embodiment of the present invention is the compound of the first ment or a pharmaceutically acceptable salt thereof wherein R1 is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two tuents each independently selected from , trifluoromethyl, ethyl, propyl, pyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro; L is —X—CHR5-; X is O; and R5 is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.
A thirteenth embodiment of the present invention is the compound of the first embodiment or a pharmaceutically acceptable salt thereof wherein R1 is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro; L is -CHR5-X-; X is NH; and R5 is ethyl, propyl, isopropyl, isobutyl, neopentyl, ropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.
A fourteenth embodiment of the present invention is the nd of the twelth or thirteenth embodiments or a pharmaceutically acceptable salt thereof wherein R1 is 4-trifluoromethylpyrazoly| or 4-trifluoromethylimidazolyl.
A fifteenth ment of the present invention is a compound selected from the group consisting of: (+/—)(4-(1-(3-methyl(4-(trifluoromethyl)—1H-imidazolyl)phenylamino)butyl) ido)propanoic acid; (+/—)(4-(3-methyl(4-(4-(trifluoromethyl)—1 H- imidazolyl)phenyl)butoxy)benzamido)propanoic acid; (+/—)(6-(1-(4-(4- (trifluoromethyl)-1H-pyrazolyl)phenoxy)butyl) nicotinamido)propanoic acid; (+/—)(4-(4-methyl(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenyl)pentan yl)benzamido)propanoic acid; (+/—)(4-(1-(6-(4-(trifluoromethyl)-1 H-pyrazol yl)pyridineylamino)butyl) benzamido)propanoic acid; (R)—3-(4-(1-(6-(4- (trifluoromethyl)-1H-pyrazolyl)pyridineylamino)butyl)benzamido)propanoic acid; (S)(4-(1-(6-(4-(trifluoromethyl)—1H-pyrazolyl)pyridineylamino)butyl) benzamido)propanoic acid; (+/—)(4-(cyclopentyl(6-(4-(trifluoromethyl)—1 H- imidazolyl)pyridineylamino)methyl)benzamido)propanoic acid; 3-(4-(1-(6- (4-(trifluoromethyl)-1H-imidazolyl)yridineylamino)butyl)benzamido)propanoic acid; (R)—3-(4-(1-(6-(4-(trifluoromethyl)—1H-imidazolyl)pyridineylamino)butyl) benzamido)propanoic acid; (4-(1-(6-(4-(trifluoromethyl)—1H-imidazolyl) yridineylamino)butyl) benzamido)propanoic acid; (+/—)(4-(1-(4-(4- (trifluoromethyl)-1H-pyrazolyl)phenylamino) butyl)benzamido)propanoic acid; (+/—)(4-(1-(3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazolyl)phenylamino)butyl) ido)propanoic acid; (R)—3-(4-(1-(3,5-dimethyl(4-(trifluoromethyl)-1H- pyrazolyl) phenylamino)butyl)benzamido)propanoic acid; (S)(4-(1-(3,5- yl(4-(trifluoromethyl)—1H-pyrazolyl)phenylamino)butyl)benzamido) propanoic acid; (+/—)(4-(1-(4-(4-(trifluoromethyl)—1H-imidazolyl)phenylamino) butyl)benzamido)propanoic acid; (R)—3-(4-(1-(4-(4-(trifluoromethyl)-1 H-imidazol yl)phenylamino)butyl) benzamido)propanoic acid; (S)(4-(1-(4-(4-(trifluoromethyl)- 1H-imidazoly|)phenylamino) butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(4- (trifluoromethyl)-1H-imidazolyl)phenoxy)butyl)benzamido)propanoic acid; (+/—) (4-(1-(4-(4-(methylthio)-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(3-tert—butyl-1H-pyrazolyl)phenoxy)butyl) benzamido)propanoic acid; (+/—)- 3-(4-(1-(4-(4-ch|oro—3-methy|—1H-pyrazoIy|)phenoxy)buty|) benzamido)propanoic acid; (+/—)(4-(1-(4-(4-ch|oro-1H-pyrazoIy|)phenoxy) butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(4-ethy|—3-methy|—1 H-pyrazoI y|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(3,5-diethyI-1H- pyrazoIy|)phenoxy)buty|) benzamido)propanoic acid; 3-(4-(1-(4-(4-methy|— 1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)- 3-(4-(1-(4-(3- isopropyI-1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1- (4-(4-fluoro—1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1- (4-(3-methyI-1H-pyrazoIy|)phenoxy)butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(2H-1,2,3-triazoIyl)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(3-buty|—1H-pyrazoIy|)phenoxy)butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(5-ethoxymethy|—1H-pyrazoIy|)phenoxy)buty|)benzamido) propanoic acid; (+/—)(4-(1-(4-(5-methoxymethyI-1H-pyrazoIy|)phenoxy) butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(4-buty|—1 H-imidazoI noxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(2-cyano—3,4,5- trimethyI-1H-pyrroIy|)phenoxy)buty|) benzamido)propanoic acid; (+/—)(4-(1-(4- (3-cyano—2,4-dimethy|—1H-pyrroIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(2-cyano—3-methy|—1H-pyrroIy|)phenoxy)butyl)benzamido) propanoic acid; (+/—)- 1-(4-(3-propyI-1H-pyrazoIy|)phenoxy)buty|) nicotinamido)propanoic acid; (+/—)(4-(1-(4-(3,4-dimethy|—1H-pyrazoIyl) phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(1 H-pyrazoI y|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(1H-imidazo[1,2— b]pyrazoly|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(3-ethy|— 1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)- 1-(4-(4- chloromethyI-1H-imidazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(4,5-diethy|—1H-imidazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(3,5-dimethy|—1H-pyrazoIy|)phenoxy)buty|)benzamido) propanoic acid; 3-(4-(1-(4-(3-methy|—1H-1,2,4-triazoly|)phenoxy)buty|) benzamido)propanoic acid; (+/—)(4-(1-(4-(1H-1,2,4-triazoly|)phenoxy)buty|) benzamido)propanoic acid; (+/—)(4-(1-(4-(2-buty|—1H-imidazoIy|)phenoxy)buty|) benzamido)propanoic acid; (+/—)(4-(1-(4-(4,5-dimethyI-1H-imidazoIy|)phenoxy) butyl) ido)propanoic acid; (+/—)(4-(1-(4-(1-propy|-1H-pyrazoI y|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(1H-pyrazoI y|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(3,5-dimethylisoxazol- 4-yl)phenoxy)butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(1-methy|—3- (trifluoromethyI)-1H-pyrazoIy|)phenoxy) benzamido)propanoic acid; (+/—) (4-(1-(4-(1-methyI-1H-pyrazoIyl)phenoxy)butyl)benzamido) propanoic acid; (+/—)- 3-(4-(1-(4-(1,5-dimethyI-1H-pyrazoIyl)phenoxy)butyl) benzamido)propanoic acid; (+/—)- 3-(4-(1-(4-(1H-pyrazoIyl)phenoxy)butyl) benzamido)propanoic acid; (+/—)- 3-(4-(1-(4-(1-methyI-1H-pyrazoIyl) phenoxy)buty|)benzamido)propanoic acid; (+/— )(4-(1-(4-(1,3,5-trimethy|—1H-pyrazoIyl)phenoxy)buty|)benzamido)pr0panoic acid; (+/—)(4-(1-(4-(4-(trif|uoromethy|)-1H-pyrazoIy|)phenoxy)butyl) benzamido)propanoic acid; (R)—3-(4-(1-(4-(4-(trif|uoromethyl)—1 H-pyrazoI noxy)buty|)benzamido)propanoic acid; (S)(4-(1-(4-(4-(trif|uoromethyI)-1H- pyrazoIy|)phenoxy)buty|) benzamido)propanoic acid; (+/—)(4-(1-(6-(4-pheny|— 1H-pyrazoIy|)pyridine—3-y|amino)butyl) benzamido)propanoic acid; (+/—)(4-(1- (4-(4-fluoro—1H-pyrazoIy|)phenylamino)buty|)benzamido)propanoic acid; (+/—) (6-(3-methyI(4-(4-(trif|uoromethy|)-1H-pyrazoIy|)pheny|)buty|amino) nicotinamido)propanoic acid; (+/—)(4-(2—cyc|opropyl(4-(4-(trif|uoromethy|)-1 H- pyrazoIy|)phenoxy)ethy|) benzamido)propanoic acid; (+/—)(4-(cyc|openty|(4-(4- (trifluoromethyI)-1H-pyrazoIy|)phenoxy) methyl)benzamido)propanoic acid; (R)—3- (4-(cyclopentyl(4-(4-(trifluoromethyl)-1H-pyrazoIy|)phenoxy)methyl)benzamido) propanoic acid; (S)(4-(cyc|openty|(4-(4-(trifluoromethyl)-1H-pyrazoIy|)phenoxy) methyl)benzamido)propanoic acid; (+/—)(4-(cyc|obuty|(4-(4-(trifluoromethyI)-1H- pyrazoIy|)phenoxy)methyl)benzamido)propanoic acid; (+/—)- 3-(4-(1-(4-(3- (trifluoromethyI)-1H-pyrazoIy|)phenoxy)butyl)benzamido)propanoic acid; (+/—) (4-(3,3-dimethy|—1-(4-(4-(trif|uoromethy|)-1H-pyrazoIy|)phenoxy)buty|)benzamido) propanoic acid; 3-(4-(1-(4-(4-methy|—3-(trif|uoromethy|)-1H-pyrazoIyl) phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(3-(trif|uoromethy|)-1H- 1,2,4-triazoly|)phenoxy)butyl)benzamido)propanoic acid; (+/—)(4-(1-(4-(3- methyl(trifluoromethyl)-1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(2-methy|—4-(trif|uoromethy|)-1H-imidazoIy|)phenoxy) butyl)benzamido) oic acid; (+/—)(4-(cyc|opropyl(4-(4-(trifluoromethyl)-1H- pyrazoIy|)phenoxy)methy|)benzamido)propanoic acid; (+/—)(4-(2—methy|—1-(4- ifluoromethyI)-1H-pyrazoIy|)phenoxy)propy|)benzamido) propanoic acid; (+/— )(4-(1-(4-(4-(trif|uoromethy|)-1H-pyrazoIy|)phenoxy)propy|) ido) propanoic acid; (+/—)(4-(3-methy|—1-(4-(4-(trif|uoromethyl)—1 H-imidazoI nyl)butoxy)benzamido)propanoic acid; (+/—)(4-(3-methyI(4-(4- (trifluoromethy|)-1H-pyrazoIy|)phenoxy)butyl)benzamido)propanoic acid; (+/—) (4-(1-(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazoIy|)phenoxy)buty|) benzamido) propanoic acid; (S)(4-(1-(3,5-dimethyl(4-(trifluoromethy|)-1H- pyrazoIyl) phenoxy)buty|)benzamido)propanoic acid; (R)—3-(4-(1-(3,5-dimethy|—4- (4-(trifluoromethy|)-1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(5-(4-(trif|uoromethy|)-1 H-pyrazoIy|)pyridineyloxy)buty|) benzamido)propanoic acid; (+/—)(4-(1-(6-(4-(trif|uoromethy|)-1 H-pyrazoI y|)pyridineyloxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(6-(4- uoromethy|)-1H-imidazoIyl) pyridineyloxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(4-cyano-1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(4,5,6,7-tetrahydro—2H-indazoIyl)phenoxy)buty|)benzamido) propanoic acid; (+/—)(4-(1-(4-(5,6-dihydrocyclopenta[c]pyrazo|—2(4H)- noxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(2H-indazo|—2— y|)phenoxy)buty|)benzamido)propanoic acid; (+/—)(4-(1-(4-(4-methy|-1H-1,2,3- triazoIy|)phenylamino)buty|)benzamido)propanoic acid; (+/—)(2—(3-methy|—1-(4- (4-(trifluoromethy|)-1H-pyrazoIy|)phenyl)butylamino)pyrimidinecarboxamido) propanoic acid; 3-(4-(cyc|opentyl(6-(4-(trifluoromethy|)-1H-pyrazoIyl) pyridineylamino)methy|) ido)propanoic acid; (R)—3-(4-(cyc|openty|(6-(4- (trifluoromethy|)-1H-pyrazoIy|)pyridineylamino)methyl)benzamido)propanoic acid; (S)(4-(cyc|opentyl(6-(4-(trifluoromethy|)-1H-pyrazoIyl) pyridine ylamino)methy|)benzamido)propanoic acid; (4-(cyc|openty|(6-(4- (trifluoromethy|)-1H-imidazoIy|)pyridinylamino)methyl) benzamido)propanoic acid; (S)(4-(cyc|opentyl(6-(4-(trifluoromethy|)-1H-imidazoIy|)pyridin y|amino)methy|) benzamido)propanoic acid; (+/—)(2-(cyc|ohexy|(6-(4- (trifluoromethy|)-1H-imidazoIy|)pyridineyl)methylamino) nicotinamido) propanoic acid; (+/—)(4-(3,3-dimethyI(6-(4-(trif|uoromethy|)-1H-imidazoIyl) pyridineylamino)buty|) benzamido)propanoic acid; (+/—)(4-(cyc|ohexy|(6-(4- uoromethy|)-1H-pyrazoIy|)pyridineylamino)methyl)benzamido)propanoic acid; (+/—)(6-(3-methy|—1-(5-methyl(4-(trifluoromethyl)—1H-pyrazoIy|)pyridin- 3-ylamino)butyl) nicotinamido)propanoic acid; (R)—3-(4-(1-(4-(4-(trif|uoromethy|)-1H- pyrazoIy|)phenylamino)butyl) benzamido)propanoic acid; and (S)(4-(1-(4-(4- (trifluoromethy|)-1H-pyrazoIy|)pheny|amino)buty|) benzamido)propanoic acid; or a pharmaceutically acceptable salt thereof.
A sixteenth embodiment of the present invention is a nd selected from the group consisting of: (+/-)(4-(1-(3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazolyl) phenoxy)butyl) ido)propanoic acid; (S)(4-(1-(3,5-dimethyl(4-(trifluoromethyl)—1H- pyrazolyl) phenoxy)butyl) benzamido)propanoic acid; (R)—3-(4-(1-(3,5-dimethyl (4-(trifluoromethyl)-1H-pyrazolyl) phenoxy)buty|)benzamido)propanoic acid; (+/-)(4-(cyclopentyl(6-(4-(trifluoromethyl)—1H—imidazolyl)pyridin ylamino)methy|)benzamido)propanoic acid; (R)— cyclopentyl(6-(4- (trifluoromethyl)-1H-imidazolyl)pyridinylamino)methyl)benzamido)propanoic acid; and (S)(4-(cyclopentyl(6-(4-(trifluoromethyl)—1H-imidazoly|)pyridin ylamino)methyl)benzamido)propanoic acid; or a ceutically acceptable salt thereof.
A seventeenth embodiment of the present invention is the compound (-) (4-(1-(3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzamido) propanoic acid or a pharmaceutically acceptable salt thereof. An enth embodiment of the present invention is the crystalline form of the compound of the seventeenth embodiment with the powder X—ray diffraction spectrum substantially as shown in Figure 1.
Preferred R1 groups include optionally substituted pyrazolyl, olyl and indazolyl. Preferred embodiments of the ring containing A1, A2, A3 and A4 include phenyl, methyl substituted phenyl, dimethyl-substituted phenyl, nyl, pyrimidinyl and pyrazinyl. Preferred embodiments of the ring containing B1, BZ, 83 and B4 include phenyl, pyridinyl, pyrimidinyl and pyrazinyl. A preferred embodiment of R3 is —(CH2)ZCOZH.
Another embodiment of the present ion is the compound of formula I according to the first embodiment or a pharmaceutically acceptable salt thereof with the exception that R5 is (Cs-Cy)cycloalkyl which can be further substituted with one to three fluoro. Yet another embodiment of the present invention is the compound of formula I according to the first embodiment or a pharmaceutically acceptable salt thereof with the exception that R1 is a 5 ed heteroaryl which can be fused to another 5 membered heteroaryl. Yet another embodiment of the present invention are the compounds as set forth in es 105-193.
Another aspect of the present ion is a pharmaceutical composition that comprises (1) a compound of the t invention, and (2) a pharmaceutically acceptable excipient, diluent, or carrier. Preferably, the composition comprises a therapeutically effective amount of a compound of the present invention. The composition may also contain at least one additional pharmaceutical agent (described herein). Preferred agents include anti-obesity agents and/or anti- diabetic agents (described herein below).
In yet another aspect of the present invention is a method for treating a disease, condition, or disorder mediated by glucagon, in ular, deactivation of the glucagon receptor, in a mammal that includes the step of administering to a mammal, preferably a human, in need of such ent a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.
Diseases, disorders, or conditions mediated by glucagon include Type II diabetes, hyperglycemia, metabolic syndrome, impaired glucose tolerance, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslididemia, hypertension, hyperinsulinemia, and insulin resistance syndrome. Preferred diseases, disorders, or conditions include Type II diabetes, hyperglycemia, impaired glucose tolerance, obesity, and insulin resistance me. More preferred are Type II diabetes, hyperglycemia, and obesity. Most preferred is Type II diabetes.
In yet another aspect of the present invention is a method of ng the level of blood glucose in a mammal, preferably a human, which es the step of administering to a mammal in need of such treatment a therapeutically ive amount of a compound of the present ion, or a pharmaceutical composition thereof.
Compounds of the present ion may be administered in combination with other pharmaceutical agents (in particular, anti-obesity and anti-diabetic agents bed herein . The combination therapy may be administered as (a) a single pharmaceutical composition which comprises a nd of the present invention, at least one onal pharmaceutical agent described herein and a pharmaceutically able excipient, diluent, or carrier; or (b) two separate pharmaceutical itions comprising (i) a first composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier, and (ii) a second composition comprising at least one additional pharmaceutical agent bed herein and a pharmaceutically acceptable WO 07850 excipient, t, or carrier. The pharmaceutical compositions may be administered simultaneously or sequentially and in any order.
Definitions As used herein, the term “alkyl” refers to a hydrocarbon radical of the general formula CnH2n+1. The alkane radical may be straight or branched. For e, the term “(C1-Ca)alkyl” refers to a monovalent, straight, or branched aliphatic group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, yl, i- propyl, n—butyl, i-butyl, s—butyl, t—butyl, n—pentyl, 1-methylbutyl, 2-methylbutyl, 3- methylbutyl, tyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl, and the like).
Similarly, the alkyl portion (i.e., alkyl moiety) of an alkoxy, acyl (e.g., alkanoyl), alkylamino, dialkylamino, alkylsulfonyl, and alkylthio group have the same definition as above. When indicated as being “optionally substituted”, the alkane radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally, one to three tuents except in the case of halogen substituents such as perchloro or perfluoroalkyls).
The term “cycloalkyl” refers to nonaromatic rings that are fully hydrogenated and may exist as a single ring, bicyclic ring or a spiral ring. Unless specified othenNise, the carbocyclic ring is generally a 3- to 8—membered ring. For example, (Cs-Cy)cycloalkyl include groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, norbornyl (bicyclo[2.2.1]heptyl) and the like.
In certain embodiments one or more of the carbon atoms in a cycloalkyl may be replaced with a heteroatom as specified, such as with an O, 8, NH or N-alkyl.
The phrase “5 membered heteroaryl” or “6 membered heteroaryl” means a radical of a 5 or 6 membered heteroaromatic ring, respectively. The aromatic ring can contain 1 to 4 heteroatoms selected from N, O and S. 5 to 6 membered heteroaryl groups include pyrrolyl, furanyl, thienyl, olyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. Preferred to 6 membered heteroaryl groups include pyrazolyl, imidazolyl, pyridinyl, dinyl or pyrazinyl. The heteroaryl group may be fused to another ring when specified. For e, a 5 ed heteroaryl such as a pyrazole may be fused with a phenyl to provide an indazole.
The phrase “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or ts the particular disease, condition, or disorder, (ii) ates, rates, or eliminates one or more WO 07850 symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the ular disease, condition, or disorder bed herein.
The term “animal” refers to humans (male or female), companion animals (e.g., dogs, cats and horses), food-source animals, 200 animals, marine animals, birds and other similar animal species. e animals” refers to food-source animals such as cows, pigs, sheep and poultry.
The phrase “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
The terms “treating”, “treat”, or ment” embrace both tative, i.e., prophylactic, and palliative treatment.
The terms “modulated” or “modulating”, or “modulate(s)”, as used herein, unless othenNise indicated, refers to the changes in activity of the glucagon receptor as a result of action of the compounds of the present invention.
The terms ted” or “mediating” or te(s)”, as used , unless othenNise indicated, refers to the treatment or prevention the particular disease, condition, or disorder, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease, condition, or disorder, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease, condition, or disorder described herein, by modulation of glucagon.
The term “compounds of the present invention” (unless specifically fied othenNise) refer to compounds of Formula I and any pharmaceutically acceptable salts of the compounds, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers, conformational isomers, and isotopically d compounds. es and solvates of the compounds of the present invention are considered compositions of the present invention, wherein the compound is in association with water or solvent, respectively.
ED DESCRIPTION Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, ularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, ts for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or eins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also ble via the Beilstein online database)).
For illustrative purposes, the reaction s depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those d in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further ed in light of this disclosure using conventional chemistry well known to those skilled in the art.
In the ation of compounds of the t invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such tion will vary depending on the nature of the remote functionality and the ions of the preparation methods. Suitable amino- protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t—butoxycarbonyl (BOC), benzyloxycarbonyl (082) and 9-fluorenylmethyleneoxycarbonyl . rly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. le hydroxyl-protecting groups (O-Pg) include for e, allyl, acetyl, silyl, benzyl, para-methoxybenzyl, trityl, and the like. The need for such protection is readily determined by one skilled in the art.
For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
Reaction Scheme | outlines the general procedures that can be used to provide compounds of the present invention of Formula |.
Reaction Scheme | 34:33 0 A4:A3 / A4.A3 \1 2 . B ~B O R— lV R1_M + /(\ [>_Lu —> } b—L 1- 2 VII Lg A A R1 A1A2 VI V A4:A3 B4 3 o A:A4 3 B4 3 } b—L—< o / hydrolysis ( >— R1 \A1-A2 B1-BZ O—R —> 12 L \ I ”I R1 A A BLBZ OH R3 'NH, A4:A3 84:83 0 coupleanddeprotect 1/‘AI_A/2_L_<}31_BI2 : ifnecessary R N—R Reaction Scheme | provides a general route which can be employed to prepare compounds of Formula |. More specific details of the transformations depicted are provided in Reaction Schemes ll-Vll below. It is to be understood that the reaction schemes are illustrative and are not to be ued as a tion in any . In step one of Reaction Scheme | the compound R1-M of Formula VII and the compound of Formula Vl are coupled. In the nd of Formula Vll, R1 is a 5 membered optionally fused and optionally substituted heteroaryl group. The group M can represent either hydrogen when attached to nitrogen in the heteroaryl group R1 or an appropriate metal species when attached to a carbon in the heteroaryl group R1. When M is a metal attached to a carbon in the group R1 the coupling reaction can be d out using a palladium catalyzed coupling reaction.
When M represents hydrogen attached to en in the heteroaryl R1 group the philic displacement reaction to form the compound of Formula V can be carried out in an appropriate solvent in the ce of a base. In the nd of Formula Vl Lg is an appropriate leaving group, such as a halide or triflate. The compound of Formula V can then be reacted with the compound of Formula IV to provide the compound of Formula III. In the compound of Formula V L’ represents a precursor group which is, along with R” in the compound of Formula IV is ted into the linker L in the compound of Formula Ill. The compound of Formula ”I can then be hydrolyzed to provide the free acid of Formula II which can then be subjected to an amide coupling reaction with the amine R3'R2NH, followed by deprotection if necessary to provide the compound of Formula |. The group R3' in the amine R3'R2NH can represent either R3 itself or a protected version of R3 which can be uently deprotected to provide R3.
Reaction Scheme ll outlines r general procedure that can be used to provide compounds of the present invention having Formula |.
Reaction Scheme || Ri-H A4:A3 B4 3 0A A:A4 3 B~4 3 o Lg/(“A1_AIZ—L—<1 ’2 k b—L B ‘B O‘R R1 All—A2 BLBZ Illa O‘R R1_M I” hydrolysis A4=A3 84:83 0 RS'NH A4=A3 34:33 0 —> 6 /1_ />—L—< ’ ( I)_ /y A A2 \1 >—/{ —.| d \\\ L—<\ < R1 B~32 OH 323303;? R1/N-A2 BLBZ N_R3 if necessary I R2 The ester compound of Formula lll may be formed by reaction of an appropriate heteroaryl compound R1-H or a metallated heteroaryl compound R1-M with the compound of Formula llla. The reaction with R1-H can be ed when the hydrogen depicted in R1-H is attached to en in the R1 heteroaryl group.
The reaction can be carried out in an riate solvent such as dimethyl sulfoxide and a base such as potassium carbonate in the presence of copper(|) iodide. The on between the compound of Formula llla and R1-M can be carried out by a palladium catalysed coupling reaction. Preferably, the reaction is d out between the boronate ester R1-M (where M is B(OR’)2 and R’ is H or lower alkyl or both R’s er form an appropriate cyclic group) and the compound of Formula llla (wherein Lg is OSOZCFs, Cl, Br or I) using a suitable palladium st, a suitable phosphine ligand and a suitable base in the presence of a suitable solvent at a temperature of typically from room temperature up to around reflux (or at temperatures above the boiling point of the solvent e.g. 120 °C using microwave conditions).
A suitable ium catalyst is tris(dibenzylideneacetone)dipalladium, bis (dibenzylideneacetone) palladium, palladium acetate or (1 ,1’- bis(dipheny|phosphino) ferrocene) dichloropalladium. A le phosphine ligand is tricyclohexylphosphine, triphenylphosphine or 2-dicyclohexylphosphino-2’,6’- dimethoxylbiphenyl. A suitable base is sodium carbonate, potassium carbonate, potassium phosphate or sodium hydrogen ate and solvents are DME, 1,4- dioxane or TH F/water.
Alternatively, the cross coupling may be carried out between the trimethyl ne of general a R1-M (wherein M is SnMe3) and the compound of Formula Illa using a suitable st, such as tetrakis(triphenylphosphine)pa|ladium, an optional copper (I) source, such as copper (I) chloride, a suitable base, such as cesium fluoride, and a suitable solvent, such as N,N-dimethylformamide, at a temperature of lly around 80 °C to 120 °C. Further ative s using metallated compounds R1-M (where M is MgX’ or ZnX’ and X’ is a halide) with the derivative Illa using a suitable palladium catalyst, a suitable phosphine base, an optional copper (I) source, and a suitable base in the presence of a suitable solvent at a temperature of typically around reflux, can also be employed.
Suitable palladium catalysts are tris(dibenzylideneacetone)dipalladium, bis(dibenzy|idene acetone)pa||adium, palladium acetate or (1,1’- bis(diphenylphosphino) ferrocene) dichloropalladium. le phosphine bases are tricyclohexylphosphine or clohexylphosphino-2’,6’-dimethoxylbiphenyl. A suitable copper (I) source is copper (I) chloride. Suitable bases are potassium carbonate or sodium hydrogen carbonate. Suitable solvents are DME, 1,4-dioxane or TH r.
The compound of Formula III then undergoes hydrolysis to provide the compound of Formula II. Depending on which R group is present in the ester of Formula III, riate acid or base catalyzed hydrolysis can be carried out to provide the corresponding free acid in the compound of a II. For example, when R represents methyl, hydrolysis is typically carried outwith aqueous sodium hydroxide or lithium hydroxide in a mixture of methanol and tetrahydrofuran at a temperature from room temperature up to 80 °C for 15 minutes to 24 hours.
Conversion of the compound of Formula II to provide the compound of Formula I can be carried out using standard amide coupling conditions. Amide coupling is carried out using standard literature conditions. The acid of Formula II can be converted to the corresponsing acid chloride using a suitable chlorinating agent, such as oxalyl chloride or thionyl chloride, in a suitable solvent, such as romethane or toluene, optionally in the presence of catalytic DMF, at a le temperature, typically of between 0 °C and room temperature. The acid chloride can then be reacted with the amine of generic formula R3'-NH2 in the presence of a base, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as dichloromethane or toluene, at a temperature of between 0 °C and room temperature. R3 can represent either R3 itself or a protected version of R3 which can be subsequently deprotected to provide R3. Alternatively, the acid of Formula II can be converted to a suitable activated species with a ng agent, such as EDCI.HCI, HBTU, HATU, PyBop, DCC, or CDI, in a suitable solvent, such as dichloromethane, acetonitrile or DMF. In the presence of EDCI.HCI, HOBT is typically added. EDCI is 1-ethyl(3-dimethylaminopropyl)carbodiimide; HBTU is O-Benzotriazole-N,N,N’,N’-tetramethyluronium hexafluorophosphate; HATU is O-(7- Azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; PyBop is Benzotriazolyloxytripyrrolidinophosphonium hexafluorophosphate; DCC is dicyclohexylcarbodiimide; CDI is N,N’-carbonyldiimidazole and HOBT is 1-hydroxy benzotriazole. A suitable base, such as ylamine or diisopropylethylamine, is also used and the reaction is typically carried out at room temperature. In the instance where R3, represents a ted version of R3, subsequent ection can then be carried out by methods known in the art to provide R3. For example, when R3 is an ester, appropriate acid or base catalyzed hydrolysis can be carried out to provide the corresponding free acid in the compound of Formula |.
Reaction Scheme ||| outlines the general ures one could use to provide compounds of the present invention having Formula la. The compounds of Formula la are of Formula I wherein L is -C(R5)-X-, X is NH and R2 is H. on Scheme ||| 34:33 0 A4:A3 . 4. 3 Lg—<\ H Va A.A NH2 1 2 6 ’>' —N B-B o—R lVa ' _ ( / . /‘ H R1 ‘ALAZ reduction R1 ‘)_\1_A2 R5 B4__B3 O B43B3 O A4:A3 HN—<\ H A4:A3 hydrolysis HN—<\ H } H B1-BZ o—R B4~B3 o 2 A4:A3 HN—-<\ H —> 1_ 2 \ _ 3 couple and deprotect } ’>_< B B HN R R1 A A1- 2 ifnecessary R5 The nitrile of Formula Va is reacted with an appropriate rd reagent R5-M n M represents a magnesium halide such as magnesium chloride or ium bromide. The reaction is carried out in an appropriate t such as tetrahydrofuran or a mixture of tetrahydrofuran and diethyl ether. The reaction is typically carried out at 0 °C to 100 °C and microwave irradiation of the reaction mixture is preferred. Upon completion of the Grignard reaction the reaction mixture is then subjected to reduction using an appropriate reducing agent such as sodium borohydride in an riate solvent such as methanol to provide the amine compound of Formula lVa. The compound of Formula lVa is then converted to the compound of a la as previously described for Reaction Scheme ll. on Scheme lV provides the preparation of compounds where L is — XCHR5- and x is NH as depicted.
Reaction Scheme lV A4IA3 IZ—NOZ6 H 54:83 0 Weduction A4:A3 A b—NHZ R5 84:83 0 R1 ALAZ IVb A4:A3 \ I } b—NH BLBZ O—R R1 ‘I‘ALAZ lllb R5 B4:B3 O R5 84.83- 0 R -NH3. 2 A4_A3 H- \ / A'A4 3 hydrolysis H\ I (/\ b—NH 81-82 HN—R3 (/ b—NH 81-82 OH coupleand R1‘ALA2 R1 \ALAZ deprotect lb Ilb if necessary The amine of Formula lVb can be prepared by reduction, such as by hydrogenation, of the corresponding nitro derivative. The amine of Formula lVb can be converted to the compound of Formula lllb by two methods. The first method involves reaction of the amine with the de of Formula lVb’ followed by alkylation of the resulting ne with an appropriate ting reagent R5-M of Formula lVb”. The reaction of the amine of Formula lVb with the aldehyde of Formula lVb’ to provide the corresponding aldimine is carried out in an appropriate solvent, such as toluene, typically in the presence of molecular sieves, at a temperature from room temperature up to 100 °C for a period of 1 to 24 hours. The reaction mixture containing the aldimine can be filtered and concentrated. The resulting residue can then be olved in a t appropriate for the alkylation 2012/050349 reaction, such as tetrahydrofuran. Typically, an appropriate metallated alkylating agent, such as a Grignard reagent R5-M of Formula lVb” where M represents a metal such as a magnesium halide is employed. The alkylation reaction can be carried out at a temperature of 0 °C to 60 °C for a period of 1 to 24 hours to provide the compound of Formula lllb. When R5-M represents a rd reagent addition of zinc chloride to the on mixture may be desirable to increase the yield of the compound of Formula lllb (see lshihara, K. et al.; JACS, 2006, 128, 9998.
Alternatively, the compound of Formula lllb can be prepared by reaction of an amine of Formula Nb and a ketone of Formula lVb’” followed by reduction of the resulting imine. The reaction can be carried out under l reductive amination conditions to provide the nd of Formula lllb. For example, the amine of Formula Nb and ketone lVb’” in an appropriate solvent such as dimethoxyethane and in the ce of molecular sieves and para-toluene sulfonic acid can be reacted at room temperature up to 120 °C (sealed tube) for 1 to 24 hours. The reaction mixture can then be allowed to cool to room temperature and be treated with an appropriate reducing agent, such as sodium orohydride in methanol, and in the presence of acetic acid for 1 to 24 hours to provide the compound of Formula lllb.
The compound of Formula lllb can be hydrolyzed to provide the free acid compound of a llb by s as previously described for the preparation of the compound of Formula lla in on Scheme II. The free acid compound of Formula llb can then undergoe amide coupling conditions followed by deprotection if necessary to provide the compound of Formula lb as previously described for the conversion of the compound of Formula lla to Formula la in on Scheme ll.
Reaction Scheme V outlines the general procedures that can be used to provide compounds of the present invention having Formula lc. The compounds of a lc are of Formula I wherein L is —X—C(R5)-, X is O and R2 is H.
Reaction Scheme V A4:A3 H 34:33 O R5-M R5 34-33 0 } b—QH \ I I R1 ALAZ . H\ No 0 BLBZ VC O‘R HO BLBZ O—R Vc |Vc R5 34:33 0 R5 34:33 0 A4=A3 >_<\ H hydrolysis A4IA3 \ / } b—o Bi-B O-R } b—O Bi—B2 OH R1 ‘Ai-AZ R1 ‘ALAZ |||c R5 34:33 0 2 A4=A3 H / —> B1_B2 HN_R3 couple and deprotect if necessary Rl/(tAi-A/Z—O The compound of Formula NC is prepared by reaction of an aldehyde of Formula V0 with an appropriate metallated alkylating compound R5-M (Vc’).
Typically, R5-M is a Grignard reagent in which M represents a magnesium halide, such as magnesium chloride or magnesium bromide. The reaction is carried out in an appropriate solvent, such as tetrahydrofuran, at a temperature from about -78 °C to room temperature for a period of 15 minutes to 24 hours to provide the alcohol of Formula NC. The alcohol NC is then d with the phenol of Formula ch’ using phenolic ether Mitsunobu reaction conditions (see e.g Mitsunobu, 0.; Synthesis, 1981, 1; Lepore, S.D. et al. J. Org. Chem, 2003, 68(21), 8261-8263) to provide the compound of Formula lllc. This reaction is typically d out in an appropriate solvent such as tetrahydrofuran in the presence of an appropriate ng reagent such as diethylazodicarboxylate (DEAD) or diisopropylazodicarboxylate (DIAD) and a phosphine ligand such as triphenylphosphine. The reaction is typically run at a temperature from about 0 °C to room temperature for 1 to 24 hours. The compound Illc can then be yzed to the compound of a He followed by amide formation and deprotection, as necessary, to provide the compound of Formula Ic as previously described for the corresponding steps in Reaction Scheme ||.
Reaction Scheme VI outlines the general ures that can be used to provide compounds of the present ion having Formula Id. The compounds of Formula Id are of Formula I wherein L is -C(R5)-X-, X is O and R2 is H.
Reaction Scheme VI 54:53 0 4 3 , (A A O RS-M ,A4:,A3 OH 81‘82 O‘R 1‘ I: 2 ' } ’>—< lVd' R.1 )AL,A2 H Vd' R1 ALAZ R5 —> Vd IVd 54:53 0 54:53 0 A4=A3 O—<\ />—< hydrolysis A4=A3 0—<\ />—< k / BLB2 O—R } H 81-82 OH R1 ‘Ai-AZ R5 R1 ‘Ai-AZ R5 Illd 54:53 0 2 (A4:A3 o—<\ , i B 1-B2 HN_R3 couple and deprotect if necessary 1/?A1-A/2 R5 The compound of Formula Id is prepared in an analogous manner to the preparation of the compound of Formula lc in Reaction Scheme V by substituting the compounds of Formula Vd, Vd’, lVd, lVd’, Illd and Ild for the compounds Vc, Vc’, ch, ch’, lllc and lie as previously described.
Reaction Scheme Vll outlines the general procedures one could use to provide compounds of the present invention having Formula la. The compounds of Formula la are of a I wherein R1 is in the para position, L is —X-C(R5)-, X is CH2 and R2 is H.
Reaction Scheme Vll A4:A3 a) base A4:A3 L94 >—\ Ai-A2 3Br' 0 34:33 0 Lg_<\ WBLBHO_R Vlle \ H Vle R5 B1-BZ O-R Vlle' R5 34:33 R1M 0 R5 84:33 0 4 3 A4zAiNj—<\1 H hydrolySIs' A:A Vle' 1 R1—<\ HOH R—<\1 ,2 8-8 O—R ALAZ A'A lVe R5 34:33 0 R5 34:33 0 hydrogenate R3-NH2. MAW H —1> Ami—H1 HNH-R3. couple R1—<\ / 81-82 NH-RSI R _<\ / B '82 llle lle R5 84:33 0 deprotect —»R1—<\A4=A:_)_<\ HI Bi-B2 NH-R3 The phosphomium e compound of Formula Vlle may be treated with an appropriate base and then reacted with the ketone derivative of a Vlle’ to provide the olefinic compound of Formula Vle. The compound of Formula Vlle is typically treated with a base such as lithium bis(trimethylsilyl)amide (LHMDS) in an appropriate t such as toluene at -78 °C up to room temperature. Other bases that can be employed include lithium amides such as lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethyl dide (LiTMP) or lithium diethyl amide as well as alkyl lithiums such as methyl m or n-butyl lithium.
The compound of Formula Vle can then be reacted with the heteroaryl compound R1-M (Vle’ wherein M is hydrogen when attached to nitrogen or an appropriate metal when attached to carbon). When M is a metal attached to a carbon in the heteroaryl represented by R1 the reaction is typically a palladium zed coupling reaction, as was described previously for the first step in Reaction Scheme II to provide the compound of Formula Ve. When M is hydrogen attached to nitrogen in the heteroaryl R1, the nucleophilic substitution reaction is typically carried out in an appropriate solvent in the presence of a base. The compound of Formula Ve is then ted to hydrolysis, typically in ol and tetrahydrofuran using sodium hydroxide as base at 0 °C to room temperature for a period of 1 to 24 hours to provide the free acid of formula We. The free acid of Formula We can then be reacted with the amine R3'-NH2 using the amide coupling conditions usly bed for Reaction Scheme II to provide the compound of Formula llle. The compound of Formula llle is then subjected to hydrogenation to reduce the olefinic moiety and provide the compound of Formula lie. The hydrogenation is typically d out in the presence of an appropriate hydrogenation catalyst, such as 10% palladium on carbon (Pd/C), in an appropriate solvent such as methanol at a temperature from room temperature up to 50 °C.
Hydrogenation apparatus such as the ThalesNano H-Cube® hydrogenator sNano, Budapest with a 10% Pd/C cartridge can be employed for , Hungary) this step. The compound of Formula He can then be deprotected as necessary and as previously described for Reaction Scheme II to provide the compound of Formula le.
Reaction Scheme Vlll outlines another general procedure that can be used to provide compounds of the present invention having Formula lc. The compounds of Formula lc are of a I wherein L is —X—C(R5)-, X is O and R2 is H.
Reaction Scheme Vlll 34:83 0 R5-CHO R5 84:83 0 A 5—0“ 31—32 HN-R3' Vf' HO 31—32 HN—R3' Vf IVf R5 34:33 0 R5 34:33 0 A4=A3 >—<\ H hydrolysis A4=A3 >—<\ I A b—O 31—32 HN—R3' —’A 5—0 31-32 HN—R3 R1 ALAZ lllf IC The compound of Formula Vf in which Lg is an appropriate halide, preferably iodide, and R3, represents a protected R3 group (such as an ester of an appropriate R3 ylic acid group) can be treated with magnesium in an appropriate solvent to provide the corresponding Grignard reagent. The Grignard reagent can then be reacted with the aldehyde R5-CHO to provide the nd of Formula IVf. The compound of Formula |Vf can undergoe Mitsunobu coupling with the compound of Formula ch’ as previously described for Reaction Scheme V to provide the compound of a lllf. ection of the compound of Formula lllf, for example by hydrolysis of an ester as previously described, then provides the compound of a lc.
The compounds of the present invention may be isolated and used per se, or when possible, in the form of its pharmaceutically acceptable salt. The term “salts” refers to inorganic and organic salts of a compound of the present invention.
These salts can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the nd with a le organic or inorganic acid or base and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, hydroiodide, sulfate, bisulfate, e, acetate, trifluoroacetate, oxalate, besylate, palmitiate, pamoate, malonate, stearate, laurate, malate, , benzoate, lactate, ate, hexafluorophosphate, benzene sulfonate, tosylate, formate, e, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. These may include cations based on the alkali and alkaline earth , such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, mine, and the like. See, e.g., Berge, et al., J. Pharm. Sci., 66, 1-19 (1977).
The compounds of the present invention may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. Unless ied ise, it is intended that all stereoisomeric forms of the compounds of the t invention as well as es thereof, ing racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional s. For example, if a compound of the present invention incorporates a double bond or a fused ring, both the cis— and trans— forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their al chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or ’s acid chloride), separating the reoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column. Alternatively, the specific stereoisomers may be synthesized by using an optically active starting material, by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one stereoisomer into the other by asymmetric transformation.
It is also possible that the intermediates and compounds of the present ion may exist in different tautomeric forms, and all such forms are ed within the scope of the invention. The term “tautomer” or “tautomeric form” refers to ural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include onversions via migration of a proton, such as keto-enol and imine- enamine isomerizations. A specific example of a proton tautomer is the imidazole moiety where the proton may e between the two ring nitrogens. Valence tautomers include interconversions by reorganization of some of the bonding electrons. For e, the pyrimidonr ring of this invention may also exist in its hydroxy pyrimidine form. Both such forms are included in the compounds of Formula |.
Certain compounds of the t invention may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example, because of steric hindrance or ring strain, may permit separation of different conformers.
The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, 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 .
Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, , phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H, 11c, 130, 14c, 13N, 15N, 150,170, 18o, 31P, 32P, 35S, 18F, 123l,125| and 36Cl, respectively.
Certain isotopically-labeled compounds of the present ion (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) es are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as ium (i.e., 2H) may afford certain therapeutic advantages ing from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 15O, 13N, 11C, and 18F are useful for positron emission tomography (PET) studies to examine substrate occupancy. lsotopically labeled compounds of the t invention can generally be prepared by following ures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non- isotopically labeled reagent. n compounds of the present invention may exist in more than one crystal form (generally referred to as “polymorphs”). rphs may be prepared by llization under various conditions, for example, using different ts or different solvent mixtures for recrystallization; crystallization at different temperatures; and/or various modes of cooling, ranging from very fast to very slow cooling during crystallization. Polymorphs may also be obtained by heating or melting the compound of the present invention followed by gradual or fast cooling.
The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray ction or such other techniques.
Compounds of the present invention are useful for treating diseases, conditions and/or disorders modulated by on; therefore, another embodiment of the present invention is a ceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically able ent, diluent or carrier. The compounds of the present invention (including the compositions and processes used therein) may also be used in the manufacture of a medicament for the therapeutic applications described herein.
A typical ation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. Suitable carriers, ts and excipients are well known to those skilled in the art and include materials such as ydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular r, diluent or ent used will depend upon the means and purpose for which the compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., , PEG300), etc. and mixtures f. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (Le, a compound of the present invention or pharmaceutical ition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
The formulations may be ed using conventional ution and mixing procedures. For example, the bulk drug nce (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is ved in a suitable solvent in the presence of one or more of the excipients described above.
The compound of the present ion is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to give the patient an elegant and easily handleable product.
The pharmaceutical compositions also include solvates and hydrates of the compounds of Formula |. The term “solvate” refers to a lar complex of a nd represented by Formula | (including pharmaceutically acceptable salts thereof) with one or more t molecules. Such solvent molecules are those ly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, ethylene glycol, and the like, The term “hydrate” refers to the complex where the solvent molecule is water. The es and/or hydrates preferably exist in crystalline form. Other solvents may be used as intermediate solvates in the preparation of more desirable solvates, such as methanol, methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)—propylene glycol, 1,4-butyne-diol, and the like.
The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
The container may also include a -proof assemblage to t indiscreet access to the contents of the e. In addition, the ner has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
The present invention further provides a method of treating diseases, ions and/or disorders modulated by glucagon in an animal that includes administering to an animal in need of such treatment a therapeutically ive amount of a compound of the t invention or a pharmaceutical composition comprising an effective amount of a compound of the present invention and a pharmaceutically acceptable excipient, diluent, or carrier. The method is particularly useful for treating diseases, ions and/or disorders that benefit from the modulation of glucagon which include: eating disorders (e.g., binge eating disorder, anorexia, bulimia, weight loss or control and obesity), prevention of obesity and insulin resistance.
One aspect of the present ion is the treatment of obesity, and obesity- related disorders (e.g., overweight, weight gain, or weight maintenance).
Obesity and ight are generally defined by body mass index (BMI), which is correlated with total body fat and tes the relative risk of disease.
BMI is calculated by weight in ams d by height in meters d (kg/m2). Overweight is typically defined as a BMI of 25-29.9 kg/m2, and obesity is typically defined as a BMI of 30 kg/m2. See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, DC: US.
Department of Health and Human Services, NIH publication no. 98-4083 (1998).
Another aspect of the present invention is for the treatment or delaying the progression or onset of diabetes or diabetes-related disorders including Type 1 (insulin-dependent es mellitus, also referred to as “IDDM”) and Type 2 (noninsulin-dependent diabetes mellitus, also referred to as “NIDDM”) diabetes, ed glucose tolerance, insulin resistance, hyperglycemia, and diabetic complications (such as sclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and pathy).
Yet another aspect of the present invention is the treatment of diabetes- or obesity-related co-morbidities, such as metabolic syndrome. Metabolic syndrome includes diseases, conditions or disorders such as dyslipidemia, ension, insulin resistance, diabetes (e.g., Type 2 diabetes), weight gain, coronary artery disease and heart failure. For more detailed information on Metabolic Syndrome, see, e.g., Zimmet, P.Z., et al., “The Metabolic Syndrome: Perhaps an Etiologic Mystery but Far From a Myth — Where Does the ational es Federation Stand?,” Diabetes & Endocrinology, 7(2), (2005); and Alberti, K.G., et al., “The Metabolic Syndrome — A New Worldwide Definition,” m, 366, 1059-62 (2005).
Preferably, administration of the compounds of the present invention provides a statistically icant 5) reduction in at least one cardiovascular disease risk factor, such as lowering of plasma leptin, C-reactive n (CRP) and/or cholesterol, as ed to a vehicle control containing no drug. The administration of nds of the present ion may also provide a statistically significant (p<0.05) reduction in glucose serum levels.
In yet another aspect of the present invention, the condition treated is impaired glucose tolerance, hyperglycemia, diabetic complications such as sugar cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy and ic cardiomyopathy, anorexia nervosa, a, cachexia, hyperuricemia, hyperinsulinemia, hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver disease, atherosclerosis, arteriosclerosis, acute heart e, congestive heart failure, coronary artery disease, cardiomyopathy, myocardial infarction, angina pectoris, hypertension, hypotension, stroke, ischemia, ischemic reperfusion injury, aneurysm, restenosis, vascular stenosis, solid tumors, skin cancer, melanoma, lymphoma, breast cancer, lung , colorectal cancer, stomach cancer, esophageal cancer, pancreatic cancer, prostate cancer, kidney cancer, liver cancer, bladder cancer, cervical cancer, uterine cancer, testicular cancer and ovarian cancer.
The present invention also relates to eutic methods for treating the above described conditions in a mammal, including a human, wherein a compound of Formula | of this invention is stered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of formula (I) of this invention being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the conditions.
In general, an effective dosage for the compounds of the present invention is in the range of 0.01 mg/kg/day to 30 mg/kg/day, preferably 0.01 mg/kg/day to 5 day of active compound in single or divided doses. r, some variability in the l dosage range may be required depending upon the age and weight of the t being treated, the intended route of administration, the particular compound being administered and the like. The determination of dosage ranges and optimal s for a particular patient is well within the ability of one of ry skill in the art having the benefit of the instant disclosure. Practitioners will appreciate that “kg” refers to the weight of the patient measured in kilograms.
The compounds or compositions of this invention may be administered in single (e.g., once daily) or le doses or via constant infusion. The compounds WO 07850 of this invention may also be administered alone or in combination with ceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and ts include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
The compounds or compositions of the present invention may be administered to a subject in need of ent by a variety of conventional routes of administration, including orally and parenterally, (e.g., intravenously, aneously or intramedullary). Further, the pharmaceutical compositions of this invention may be administered asally, as a suppository, or using a “flash” formulation, i.e., ng the tion to dissolve in the mouth without the need to use water.
It is also noted that the compounds of the present ion can be used in sustained release, controlled release, and delayed release formulations, which forms are also well known to one of ordinary skill in the art.
The compounds of this invention may also be used in conjunction with other pharmaceutical agents for the treatment of the diseases, conditions and/or ers described . Therefore, methods of treatment that include administering compounds of the present invention in combination with other pharmaceutical agents are also provided. Suitable pharmaceutical agents that may be used in combination with the compounds of the present invention e anti- obesity agents (including appetite suppressants), anti-diabetic agents, anti- hyperglycemic agents, lipid lowering agents, and anti-hypertensive agents.
Suitable anti-diabetic agents include an acetyI-CoA carboxylase-2 (ACC-2) inhibitor, a diacylglycerol O-acyltransferase 1 1) inhibitor, a phosphodiesterase (PDE)—10 inhibitor, a sulfonylurea (e.g., examide, chlorpropamide, diabinese, glibenclamide, g|ipizide, g|yburide, glimepiride, g|ic|azide, g|ipentide, gliquidone, glisolamide, mide, and tolbutamide), a meglitinide, an ase inhibitor (e.g., tendamistat, trestatin and AL-3688), an dg |ucoside hydrolase inhibitor (e.g., acarbose), an d-glucosidase inhibitor (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), a PPARV agonist (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone and troglitazone), a PPAR d/v agonist (e.g., CLX—0940, GW—1536, 9, GW-2433, KRP-297, L-796449, LR- 90, MK-0767 and SB-219994), a biguanide (e.g., metformin), a glucagon-like peptide 1 (GLP-1) agonist (e.g., exendin-3 and exendin-4), a protein tyrosine phosphatase-1 B B) inhibitor (e.g., trodusquemine, hyrtiosal extract, and compounds sed by Zhang, S., et al., Drug Discovery Today, 12(9/10), 373- 381 (2007)), SlRT-1 inhibitor (e.g., atrol), a dipeptidyl ase IV (DPP-IV) inhibitor (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin), an SGLT1 tor, an SGLT2 inhibitor (e.g. dapagliflozin, remogliflozin, sergliflozin and AVE2268), an n secreatagogue, a fatty acid oxidation inhibitor, an A2 antagonist, a c-jun amino-terminal kinase (JNK) inhibitor, insulin, an insulin mimetic, a glycogen phosphorylase inhibitor, and a VPACZ receptor agonist. Preferred anti-diabetic agents for the combination aspects are metformin, SGLT2 inhibitors (e.g. iflozin, remogliflozin, sergliflozin and AVE2268) and DPP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin and saxagliptin). Preferred combinations include the instant compounds of Formula | with metformin and a DPP-IV tor or with metformin and an SGLT2 tor.
Suitable anti-obesity agents include 11B-hydroxy steroid dehydrogenase-1 (11B-HSD type 1) inhibitors, stearoyl-CoA desaturase—1 (SOD-1) inhibitor, MGR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors (such as sibutramine), sympathomimetic agents, [33 rgic agonists, dopamine agonists (such as riptine), melanocyte—stimulating hormone analogs, 5HT2c agonists, melanin trating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors (such as tetrahydrolipstatin, i.e. orlistat), anorectic agents (such as a bombesin agonist), neuropeptide—Y antagonists (e.g., NPY Y5 antagonists), PYY3-35 (including analogs thereof), thyromimetic agents, oepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors (such as AxokineT'VI available from Regeneron Pharmaceuticals, Inc, Tarrytown, NY and Procter & Gamble Company, Cincinnati, OH), human agouti-related protein (AGRP) inhibitors, ghrelin nists, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors, such as dirlotapide), opioid antagonist, orexin antagonist, and the like.
Preferred anti-obesity agents for use in the combination aspects of the present invention include lective MTP inhibitors (e.g., dirlotapide, mitratapide and implitapide, R56918 (CAS No. ) and CAS No. 9135416), CCKa agonists (e.g., N-benzyl-2—[4-(1H-indolylmethyl)—5-oxo—1-phenyl-4,5-dihydro— 2,3,6,10b-tetraaza-benzo[e]azulenyl]—N-isopropyl-acetamide described in PCT Publication No. or US Publication No. 2005-0267100 A1), 5HT2c agonists (e.g., lorcaserin), MCR4 agonist (e.g., compounds described in US 6,818,658), lipase inhibitor (e.g., Cetilistat), PYY3-35 (as used herein 35” includes s, such as peglated PYY3-35 e.g., those described in US Publication 2006/0178501), opioid nists (e.g., naltrexone), oleoyl-estrone (CAS No. 1800032), obinepitide (TM30338), pramlintide (Symlin®), tesofensine (N82330), leptin, liraglutide, bromocriptine, orlistat, exenatide a®), ADD-9604 (CAS No. 2212313) and sibutramine. Preferably, nds of the present invention and ation therapies are administered in conjunction with exercise and a sensible diet.
All of the above recited US. patents and publications are incorporated herein by reference.
Embodiments of the present invention are illustrated by the following Examples. It is to be understood, however, that the embodiments of the ion are not limited to the specific details of these Examples, as other variations thereof will be known, or apparent in light of the instant disclosure, to one of ordinary skill in the art.
EXAMPLES Unless specified ise, starting materials are generally available from commercial sources such as Aldrich Chemicals Co. (Milwaukee, WI), Lancaster Synthesis, lnc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), and AstraZeneca Pharmaceuticals (London, England).
General Experimental Procedures NMR a were ed on a Varian UnityT'VI 400 (available from Varian Inc, Palo Alto, CA) at room temperature at 400 MHz for proton. Chemical shifts are expressed in parts per million (8) relative to residual solvent as an internal reference. The peak shapes are denoted as follows: s, t; d, doublet; dd, doublet of doublet; t, triplet; q, t; m, let; bs, broad singlet; 2s, two singlets. Atmospheric pressure chemical ionization mass spectra (APCl) were obtained on a FisonsT'VI Platform ll Spectrometer (carrier gas: acetonitrile: ble from Micromass Ltd, Manchester, UK). Chemical ionization mass spectra (Cl) were obtained on a Hewlett-Packard“VI 5989 instrument (ammonia ionization, PBMS: available from Hewlett-Packard y, Palo Alto, CA). Electrospray ionization mass spectra (ES) were obtained on a WatersT'VI ZMD instrument (carrier gas: acetonitrile: available from Waters Corp., Milford, MA). High resolution mass spectra (HRMS) were obtained on an AgilentT'VI Model 6210 using time of flight method. Where the intensity of chlorine or bromine-containing ions are described, the expected intensity ratio was ed (approximately 3:1 for 35CI/37CI-containing ions and 1:1 for 79Br/81Br-containing ions) and the intensity of only the lower mass ion is given. In some cases only representative 1H NMR peaks are given. Optical ons were ined on a PerkinElmerT'VI 241 polarimeter (available from PerkinElmer lnc., Wellesley, MA) using the sodium D line (9» = 589 nm) at the indicated ature and are reported as follows [oc]Dtemp, concentration (c = g/100 ml), and solvent.
Column chromatography was performed with either BakerT'VI silica gel (40 um; J.T. Baker, Phillipsburg, NJ) or Silica Gel 50 (EM SciencesT'V', Gibbstown, NJ) in glass columns or in Flash 40 BiotageT'VI columns (lSC, lnc., Shelton, CT) or BiotageT'VI SNAP cartridge KPsiI or Redisep Rf si|ica (from TeledyneT'VI |scoT"") under low nitrogen pressure. Chiral SFC (supercritical fluid tography) was performed on the chiral columns as ied.
Certain ts and reagents may be referred to using common abbreviations such as DCM for romethane, DMF for dimethylformamide, EtOH for ethanol, EtOAc for ethyl acetate, and MeOH for methanol, for example.
Preparation of Starting Materials and Intermediates The following starting materials are ble from the corresponding sources: (Z)-N-(3-(dimethylamino)(trifluoromethyl)allylidene)-N-methylmethanaminium hexafluorophosphate — Anichem LLC (North Brunswick, NJ, USA); 4-phenyl-1H— pyrazole — Anichem LLC (North Brunswick, NJ, USA); tert—butyl rtbuty |amino)propanoate — Aurora Fine Chemicals LLC (San Diego, CA, USA); 2,4,5,6-tetrahydrocyclopenta[c]pyrazole — Ambinter (Paris, France); methyl 6- formylnicotinate — Ark Pharm lnc. (Libertyville, IL, USA); 4-(trifluoromethyl)-1H- le — Anichem LLC (North Brunswick, NJ, USA); 4-(trifluoromethyl)—1H— imidazole — Ark Pharm lnc. (Libertyville, IL, USA); 4-methyl(trifluoromethyl)—1H- pyrazole — ASDl lnc. (Newark, DE, USA); 3-methyl(trifluoromethyl)—1H-pyrazole — Accel Pharmtech LLC (East Brunswick, NJ, USA); 3-(trifluoromethyl)—1H-1,2,4- 2012/050349 le — Beta Pharma Inc. ord, CT, USA); 2-methyl(trifluoromethyl)—1H- imidazole — APAC Pharmaceutical LLC (Columbia, MA, USA); ethyl 2- chloropyrimidine—5-carboxylate — Ark Pharm Inc. (Libertyville, IL, USA); 2- cyclopropylacetaldehyde — Anichem LLC (North Brunswick, NJ, USA); 4-chloromethyl- 1H-pyrazole — Oakwood Products, Inc. (West Columbia, SC, USA); 2-(1H-pyrazol yl)pyridine — Oakwood Products, Inc. (West Columbia, SC, USA); and 4-ethylmethyl-1H— pyrazole — Aces , Inc. (Branford, CT, USA).
Preparation of Intermediates Intermediate 1 : 4- 4- trifluorometh I-1H- razol I hen Imethanol 9ch (1) A mixture of (4-iodophenyl)methanol (1030 mg, 4.41 mmol), 4- (trifluoromethyl)—1H-pyrazole (600 mg, 4.41 mmol), copper(|) iodide (168 mg, 0.882 mmol), transhydroxy-L-proline (231 mg, 1.76 mmol) and cesium carbonate (2900 mg, 8.82 mmol) in dimethylsulfoxide (7.5 mL) was heated to 85°C for 20 hours. The mixture was diluted with water and extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and trated.
Purification by column chromatography (0 - 45% ethyl acetate in heptane), gave (4- (4-(trifluoromethyl)—1H-pyrazoIyl)pheny|)methanol. 1H NMR (400 MHz, CDCI3, 5): 8.16 (s, 1 H), 7.89 (s, 1 H), 7.65 (d, J: 8.39 Hz, 2 H), 7.47 (d, J: 8.39 Hz, 2 H), 4.74 (d, J: 5.66 Hz, 2 H), 1.85 (t, J: 5.86 Hz, 1 H).
Intermediate 2 : 4- 4- trifluorometh I -1H- razol I deh de >LCN” (2, A mixture of Intermediate (1) (230 mg, 0.95 mmol), dimethylsulfoxide (1.35 mL) and triethylamine (0.662 mL, 4.75 mmol) in dichloromethane (3.5 mL) was cooled to 0°C. Sulfur trioxide ne complex (0.454 g, 2.85 mmol) was added in portions and the mixture stirred at 0°C for 2 hours. The reaction was diluted with ethyl acetate, washed with saturated um chloride and brine, dried over sodium sulfate, filtered and concentrated to give 4-(4-(trifluoromethyl)—1 H-pyrazol yl)benzaldehyde. 1H NMR (400 MHz, CDCI3, 5): 10.04 (s, 1 H), 8.29 (s, 1 H), 7.99 - 8.05 (m, 2 H), 7.95 (s, 1 H), 7.87 - 7.92 (m, 2 H).
Intermediate 3 : 1- 2-meth Initro hen I trifluorometh I -1H-imidazole A mixture of 4-(trifluoromethyl)—1H-imidazole (198 mg, 1.46 mmol), ro- 2-methylnitrobenzene (216 mg, 1.53 mmol) and potassium carbonate (402 mg, 2.91 mmol) in acetonitrile (1.5 mL) was heated to 85°C for 24 hours. The mixture was diluted with water and saturated um chloride and was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 - 50% ethyl acetate in e), gave 1-(2-methylnitrophenyl)(trifluoromethyl)-1H- imidazole. 1H NMR (500 MHz, CDCI3, 5): 8.30 (d, J: 2.44 Hz, 1 H), 8.21 - 8.25 (m, 1 H), 7.70 (s, 1 H), 7.45 - 7.49 (m, 2 H), 2.38 (s, 3 H).
Intermediate 4 : 3-meth I 4- trifluorometh I -1H-imidazol I benzenamine F (4) A mixture of Intermediate (3) (325 mg, 1.20 mmol) and 10 wt% palladium on carbon (40 mg) in ethanol (6 mL) was pressurized to 48 psi hydrogen and agitated for 6 hours. The mixture was filtered through celite, g with ethyl acetate and ol. The filtrate was concentrated to give 3-methyl(4-(trifluoromethyl)—1H- imidazolyl) benzenamine. 1H NMR (500 MHz, CDCI3, 6): 7.56 (s, 1 H), 7.32 (s, 1 H), 7.01 (d, J: 8.54 Hz, 1 H), 6.62 (d, J: 2.68 Hz, 1 H), 6.57 (dd, J: 8.29, 2.44 Hz, 1 H), 3.85 (br. s., 2 H), 2.08 (s, 3 H). MS (M+1): 242.3.
Intermediate (5): Ethyl 4-butyrylbenzoate WO 07850 O (5) At -40°C, isopropylmagnesium chloride lithium chloride (15.3 mL, 1.3 M in THF, 19.9 mmol) was added dropwise to a solution of ethyl 4-iodobenzoate (5000 mg, 18.11 mmol) in tetrahydrofuran (30 mL). The solution was stirred at -40°C for 40 minutes. Butyraldehyde (1830 mg, 25.4 mmol) was added. The mixture was allowed to warm to room temperature over 3 hours. The reaction was quenched with 1N HCI and extracted three times with ethyl e. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give ethyl 4-(1- hydroxybutyl)benzoate. 1H NMR (400 MHz, CDCI3, 5): 8.02 (d, J: 8.6 Hz, 2H), 7.41 (d, J: 8.0 Hz, 2H), 4.83 - 4.66 (m, 1H), 4.38 (q, J: 7.2 Hz, 2H), 1.86 (d, J: 3.7 Hz, 1H), 1.83 - 1.61 (m, 2H), 1.51 - 1.42 (m, 1H), 1.39 (t, J: 7.2 Hz,3H), 1.36 - 1.23 (m, 1H), 0.94 (t, J: 7.6 Hz, 3H).
A mixture of the crude alcohol (1.0 g, 4.5 mmol) in dichloromethane (16.7 mL), dimethylsulfoxide (4.79 mL) and ylamine (2.28 g, 22.5 mmol) was cooled to 0°C. Sulfur trioxide pyridine complex (2.15 g, 13.5 mmol) was added in portions and the mixture stirred at 0°C for 1 hour. The reaction was then allowed to warm to room temperature and stir for 2 hours. The reaction was ed with brine and diluted with dichloromethane. The layers were separated and the aqueous was ted again with romethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 - 30% ethyl acetate in heptane) gave ethyl 4-butyrylbenzoate. 1H NMR (400 MHz, CDCI3, 5): 8.05 - 8.17 (m, 2 H), 8.04 - 7.92 (m, 2 H), 4.40 (q, J = 7.15 Hz, 2 H), 2.96 (t, J: 7.22 Hz, 2 H), 1.86 - 1.69 (m, 2 H), 1.40 (t, J: 7.12 Hz, 3 H), 1.00 (t, J: 7.22 Hz, 3 H).
Intermediate 6 : 6- 4- trifluorometh l -1H-imidazol l ridinamine A mixture of 4-(trifluoromethyl)-1H-imidazole (2000 mg, 14.70 mmol), 2- chloronitropyridine (2330 mg, 14.70 mmol), and potassium carbonate (4060 mg, 29.4 mmol) in acetonitrile (14.7 mL) was heated at 85°C overnight. The reaction was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was dissolved in ethanol (20 mL) and ethyl acetate (15 mL). 10 wt% Palladium on carbon (500 mg) was added to the solution.
The mixture was pressurized to 50 psi hydrogen and was shaken for 5 hours. The reaction was filtered h celite, rinsing with methanol. The filtrate was concentrated to give trifluoromethyl)-1H-imidazolyl)pyridinamine. 1H NMR (400 MHz, CDCI3, 5): 8.15 (s, 1 H), 7.93 (d, J: 2.73 Hz, 1 H), 7.85 (s, 1 H), 7.20 - 7.15 (m, 1 H), 7.14 - 7.09 (m, 1 H), 3.13 - 2.30 (m, 2 H). MS (M+HCO2'): 273.0.
Intermediate 7A : -N- 3— dimeth lamino orometh | all lidene -N- methylmethanaminium hexafluorophosphate(V) Me N/ / NMe Phosphoryl chloride (18.0 mL, 200 mmol), was added in an on funnel over 30 minutes to anhydrous dimethylformamide (40.0 mL) at 0°C. After completion of the addition, the light pink solution was warmed to room termperature and trifluoropropionic acid (8.90 mL, 101 mmol) was added dropwise over 10 s. The solution was then warmed to 55°C and stirred for 4 hours at 55°C. The bright yellow solution was cooled to room temperature and slowly added over 30 s to a 0°C solution of sodium hexafluorophosphate (19.0 g, 110 mmol) in water (250 mL) while maintaining the internal temperature below 10°C. The yellow precipitate was collected by vacuum filtration and washed with ice cold water (3X150 mL). The yellow solid was dried in vacuo and then azeotrophed with toluene two times and dried again in vacuo to provide (Z)—N-(3— (dimethylamino)(trif|uoromethyl)a|ly|idene)-N-methy|methanaminium hexafluorophosphate(V) as a yellow solid (22.0 g, 64%). 1H NMR (400 MHz, CD3CN, 6): 7.72 (s, 2 H), 3.41 (s, 6 H), 3.23 (d, J: 1.4 Hz, 6 H).
Intermediate 7B : 1- 4-bromo-2 6-dimeth l hen l h drazine h drochloride HIN Br In a 3L 3-neck round bottom flask equipped with a mechanical stirrer was added concentrated hydrochloric acid (125 mL) and water (250 mL). 4-Bromo-2,6- dimethylbenzenamine (100 g, 500 mmol) was added slowly at 0°C. ng was continued for an additional 15 minutes, resulting in a thick white slurry. A freshly prepared solution of sodium e (34.5 g, 500 mmol) in water (100 mL) was added to the slurry dropwise maintaining the internal temperature below 5°C. After stirring for 30 minutes, a deep orange solution was formed. Tin(|l) de dehydrate (282 g, 1250 mmol) in 1:1 concentrated hydrochloric acid:water (300 mL) was added dropwise while ining the internal temperature between 0-5°C. The resulting mixture was stirred at 0°C for 1 hour and then warmed to room ature and stirred for 15 hours. The on mixture was filtered and washed with diethyl ether. The solid was slowly added to an s 10 M solution of sodium hydroxide (1 L) between 0-10°C and extracted with ethyl acetate (3X 800 mL). The organic layer was washed with brine twice, dried over anhydrous sodium sulfate, and concentrated to give 1-(4-bromo-2,6-dimethylphenyl)hydrazine (76.0 g, 353 mmol). The hydrazine was dissolved in ethyl acetate (800 mL) to which hydrochloric acid/methanol (88.2 mL) was added. The mixture was stirred for 25 minutes. The reaction was filtered, washed with ethyl acetate until the solid is white. The white solid was dried in vacuo to afford 1-(4-bromo-2,6- dimethylphenyl)hydrazine hydrochloride (80.0 g, 64%). 1H NMR (400 MHz, DMSO-d6, 6): 9.71 (s, 3 H), 7.32 (s, 2 H), 6.78 (s, 1 H), 2.37 (s, 6 H).
Intermediate 7 : 1- 4-bromo-2 6-dimeth l hen l trifluorometh l-1H- razole F\g/N \ F (7) (Z)-N-(3-(dimethylamino)(trif|uoromethyl)a|ly|idene)-N-methyl methanaminium uorophosphate (3000 mg, 8.819 mmol) and 1-(4-bromo-2,6- dimethylphenyl)hydrazine hydrochloride (2480 mg, 9.84 mmol) were suspended in tetrahydrofuran. The suspension was cooled to 0°C. Sodium methoxide (551 mg, 9.7 mmol) was added as a solid in one portion. The ice bath was removed and the e warmed to room temperature and stirred for 48 hours. Trifluoroacetic acid (3 mL) was then added at room temperature. The reaction was heated to 80°C for 5 hours, diluted with ethyl acetate and washed with saturated sodium bicarbonate twice. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 - 20% ethyl acetate in heptane), gave 1-(4-bromo-2,6-dimethylphenyl)(trifluoromethyl)-1H-pyrazole as an oil. 1H NMR (400 MHz, CDCI3, 5): 7.93 (s, 1 H), 7.71 (s, 1 H), 7.31 (s, 2 H), 1.99 (s, 6 H). ediate 8 : 3 5-dimeth l 4- trifluorometh | -1H- razol | amine \éN/N\ NH2 F \ F (8) A vial containing Intermediate (7) (1200 mg, 3.76 mmol), copper(l) iodide (143 mg, 0.75 mmol), transhydroxy-L-proline (197 mg, 1.50 mmol) and potassium carbonate (1570 mg, 11.3 mmol) was purged with nitrogen.
Dimethylsulfoxide (7.5 mL) was added followed by ammonia (3.73 mL, ~28% aqueous). The vial was sealed and heated to 75°C for 20 hours. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl e twice. The combined organic layers were dried over sodium sulfate, filtered and trated to give 3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazolyl) benzenamine.1H NMR (400 MHz, CDCI3, 5): 7.84 (s, 1 H), 7.65 (s, 1 H), 6.37 (s, 2 H), 3.82 - 3.47 (br s, 2 H), 1.85 (s, 6 H). MS (M+H+CH3CN): 297.2. ediate 9 : +/— -meth l4- 1-h drox meth lbut lbenzoate 2012/050349 A solution of 4-formyl-benzoic acid methyl ester (1.56 g, 9.50 mmol) in tetrahydrofuran (53 mL) was cooled to 0°C. Isobutylmagnesium chloride (4.75 mL, 2M in THF) was then added dropwise over 15 minutes. The reaction was stirred at 0°C for 1 hour. The ice bath was removed and the on was allowed to warm to room temperature and stir for 1 hour. The reaction was quenched by carefully adding 1N HCI. The reaction was diluted with water and diethylether and the layers were separated. The aqueous was extracted three more times with diethyl ether. The combined organics were dried over ium sulfate, filtered, and trated. Purification by column chromatography (0 — 40% ethyl acetate in heptane) gave (+/—)-methy| 4-(1-hydroxymethylbutyl)benzoate (404.6 mg, 19%) as a clear, colorless OH. 1H NMR (400 MHz, CDCI3, 5): 7.99 (d, J = 8.2 Hz, 2H), 7.40 (d, J: 8.2 Hz, 2H), 4.79 (br. s., 1H), 3.89 (s, 3H), 1.94 (d, J: 2.73, 1H), 1.65 - 1.78 (m, 2H), 1.42 - 1.52 (m, 1H), 0.91 - 0.97 (m, 6H).
Intermediate (10): methyl 4-(3-methylbutanoyl)benzoate (10) Intermediate (9) (404.6 mg, 1.820 mmol) was dissolved in romethane (6.07 mL) and cooled to 0°C. Pyridinium chlorochromate (785 mg, 3.64 mmol) was added. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 48 hours. The on was diluted with dichloromethane and magnesium sulfate was added. This mixture was stirred for 10 minutes and was then filtered and concentrated. Purification by column chromatography (0 — % ethyl acetate in heptane) gave methyl 4-(3-methylbutanoy|)benzoate (363.7 mg, 91%) as a clear, colorless OH. 1H NMR (400 MHz, CDCI3, 5): 8.07 - 8.13 (m, 2012/050349 2H), 7.95 - 8.00 (m, 2H), 3.93 (s, 3H), 2.82 - 2.86 (m, 2H), 2.28 (dt, J = 13.4, 6.8 Hz, 1H), 0.99 (d, 6H).
Intermediate 11 :4-fluoro4-nitro hen I-1H— razole F (11) To a solution of ro-1 zole (250 mg, 2.90 mmol) and potassium carbonate (803 mg, 5.81 mmol) in acetonitrile (3 mL) was added 4- fluoronitrobenzene (430 mg, 3.05 mmol). The resulting mixture was stirred at 70°C for 2 hours. The reaction was then filtered and concentrated. cation by column chromatography gave 4-fluoro(4-nitrophenyI)-1H-pyrazole (400 mg, 67%). 1H NMR (400 MHz, CDCI3, 6): 8.34 (d, 2H), 7.91 (d, 1H), 7.81 (d, 2H), 7.67 (d, 1H).
Intermediate 12 :4- 4-fluoro-1H- razoI I aniline F (12) A mixture of Intermediate (11) (200 mg, 0.965 mmol) and 10 wt% palladium on carbon (100 mg) in ethanol (10 mL) was pressurized to 15 psi hydrogen and stirred at 35°C overnight. The reaction was filtered and concentrated. Purification by column chromatography gave 4-(4-fluoro-1H-pyrazoIyl)aniline (150 mg, 88%). 1HNMR (400 MHz, CDCI3, 6): 7.65 (d, 1H), 7.50 (d, 1H), 7.37 (d, 2H), 6.72 (d, 2H), 3.76 (br s, 2H).
Intermediate 13 :4- 4- trifluorometh I -1H- razoI I benzonitrile (13) To a 0°C solution of 4-(trifluoromethyl)—1 H-pyrazole (1 g, 7 mmol) in N,N- dimethylformamide (10 mL) was added 60 wt% sodium hydride (132 mg, 3.31 mmol). The mixture was stirred at 0°C for 30 minutes. 4-fluorobenzonitrile (979 mg, 8.08 mmol) was added and the reaction was heated to 80°C overnight. ted um chloride was added and the mixture extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. cation by column chromatography gave 4-(4-(trifluoromethyl)—1H-pyrazolyl)benzonitrile (1.2 g, 72%). 1H NMR (400 MHz, CD30D, 5): 8.84 (s, 1H), 7.96 (s, 1H), 7.95 (d, 2H), 7.78 (d, 2H).
Intermediate 14 : +/— meth l 4- 4- orometh l -1H- 1- l hen lbutanamine (14) A microwave vial was charged with Intermediate (13) (300 mg, 1.26 mmol) and tetrahydrofuran (5 mL). lsobutylmagnesium bromide (1.90 mL, 2M in THF, 3.80 mmol) was added. The resulting mixture was heated to 100°C under microwave irratiation for 1 hour. The mixture was lly added to a solution of sodium borohydride (95.7 mg, 2.53 mmol) in methanol (5 mL) at room temperature. After stirring for 5 minutes, the reaction was concentrated to dryness. Purification by column chromatography gave (+/—)methyl(4-(4-(trifluoromethyl)—1 H-pyrazol yl)phenyl)butanamine (250 mg, 67%). 1H NMR (400 MHz, CD30D, 6): 8.69 (s, 1H), 7.91 (s, 1H), 7.76 (d, 2H), 7.46 (d, 2H), 4.09 — 4.05 (m, 1H), 1.67 — 1.60 (m, 2H), 1.37 — 1.34 (m, 1H), 0.86 (d, 3H), 0.82 (d, 3H).
Intermediate 15 : +/— -z‘en‘-but l3- N-z‘ert-but l 1-h drox meth lbut l benzamido ro anoate OH (15) To a -20°C solution of Intermediate 30 (1.28 g, 4.26 mmol) in tetrahydrofuran (20 mL) was added lsobutylmagnesium bromide (2.13 mL, 2M in THF, 4.26 mmol). The reaction mixture was warmed to room temperature and stirred for 5 hours. Saturated ammonium chloride was added and the mixture was WO 07850 extracted with ethyl acetate. The combined organic layers were dried over magnesium e, filtered and concentrated. Purification by column chromatography gave (+/—)—ten‘-butyl 3-(N-tert—butyl(1-hydroxy methylbutyl)benzamido)propanoate (400mg, 24%). 1H NMR (400 MHz, CD30D, 6): 7.45 — 7.43 (m, 2H), 7.35 — 7.33 (m, 2H), 4.73 (m, 1H), 3.62 — 3.58 (m, 2H), 2.48 — 2.45 (m, 2H), 1.72 — 1.67 (m, 2H), 1.57 (s, 9H), 1.50 — 1.47 (m, 1H), 1.36 (s, 9H), 0.97 — 0.96 (m, 6H).
Intermediate 16: +/— -meth l4- 2-c clo ro lh drox eth lbenzoate (16) To a -40°C solution of methyl 4-iodobenzoate (0.39 g, 1.5 mmol) in tetrahydrofuran (7.5 mL) was added isopropylmagnesium chloride-lithium chloride (1.5 mL, 1.3 M in THF, 1.95 mmol) se. After ng for 30 minutes at -40°C, 2-cyclopropylacetaldehyde (190 mg, 2.26 mmol) was added dropwise. The resulting mixture was then stirred at room temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The layers were separated and the aqueous was extracted again with ethyl e. The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave (+/—)-methy| 4-(2- cyclopropylhydroxyethyl)benzoate (150 mg, 45%). 1HNMR (400MHz, CDCI3, 6): 7.89 (d, 2H), 7.32 (d, 2H), 4.75 — 4.72 (m, 1H), 3.79 (s, 3H), 1.60 — 1.51 (m, 2H), 0.60 — 0.51 (m, 1H), 0.49 — 0.25 (m, 2H), 0.07 — -0.12 (m, 2H). ediate 17 : +/— -ten‘-but l3- N-tert—but l 1-h drox meth | ro | benzamido ro anoate OH (17) To a -20°C solution of Intermediate (30) (100 mg, 0.3 mmol) in tetrahydrofuran (1 mL) was added isopropylmagnesium bromide (0.45 mL, 1M in THF, 0.45 mmol). The reaction mixture was stirred for 5 hours at room temperature. ted ammonium chloride was then added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography gave (+/— )-ten‘-butyl 3-(N-tert—butyl(1-hydroxymethylpropyl)benzamido)propanoate (45 mg, 40%). 1H NMR (400 MHz, CDCI3, 5): 7.26 — 7.32 (m, 4H), 4.39 — 4.41 (m, 1H), 3.53 — 3.57 (m, 2H), 2.37 — 2.41 (m, 2H), 1.93 — 1.95 (m, 1H), 1.53 (s, 9H), 1.34 (s, 9H), 0.97 (m, 3H), 0.79 (m, 3H).
Intermediate 18 : 1-azido—4-nitrobenzene (18) A solution of sodium nitrite (761 mg, 11 mmol) in water (5 mL) was added dropwise to a 0°C solution of 4-nitroaniline (508 mg, 3.68 mmol) in trifluoroacetic acid (5 mL). After stirring for 10 minutes, a solution of sodium azide (1.55 g, 23.9 mmol) was added slowly. The resulting yellow suspension was stirred at room temperature for 5 hours. The reaction mixture was ioned n water and ethyl acetate. The organic layer was dried over sodium e, filtered and concentrated. Purification by column chromatography gave 1-azido—4-nitrobenzene (600mg, 99%). 1H NMR (400 MHz, CDCI3, 5): 8.16 — 8.19 (m, 2H), 7.05 — 7.09 (m, 2H).
Intermediate 19: +/— -meth I4- c clo ro lh drox meth lbenzoate (19) The title compound was prepared by a method analogous to that bed for Intermediate (16) using cyclopropanecarbaldehyde. 1H NMR (400 MHz, CDCI3, ): 7.96 (d, J: 6.8 Hz, 2 H), 7.43 (d, J: 8.4 Hz, 2 H), 4.00 (d, J: 8.4 Hz, 1 H), 3.85 (s, 3H), 1.19-1.12 (m, 1 H), 0.59 — 0.52 (m, 2 H), 0.43 — 0.34 (m, 2 H).
Intermediate 20 : +/— -meth I4- 1-h drox but I benzoate HO I (20) A solution of methyl 4-formylbenzoate (2.092 g, 12.74 mmol) in tetrahydrofuran (50 mL) was cooled to 0°C. To this solution was added npropylmagnesium e (6.4 mL, 2.0M in THF) dropwise over 20 minutes. The reaction was stirred at 0°C for 2 hours. The reaction was then quenched by addition of saturated ammonium chloride. This mixture was extracted with ethyl acetate twice. The organics were dried over magnesium sulfate, filtered and concentrated.
Purification by column chromatography (0 — 40% ethyl e in heptanes) gave (+/—)-methy| 4-(1-hydroxybutyl)benzoate (1.252 g, 47%) as a colorless oil. 1H NMR (400 MHz, CDCI3, 6): 7.97 - 8.02 (m, 2H), 7.40 (d, J = 8.4 Hz, 2H), 4.74 (dd, J = 7.8, .7 Hz, 1H), 3.90 (s, 3H), 1.61 - 1.82 (m, 2H), 1.23 - 1.49 (m, 2H), 0.92 (t, J = 7.32 Hz, 3H).
Intermediate 21 :meth |4-but Ibenzoate (21) The title compound was ed by a method analogous to that described for Intermediate (10) using Intermediate (20). 1H NMR (400 MHz, CDCI3, 6): 8.08 - 8.13 (m, 2H), 7.97 - 8.01 (m, 2H), 3.94 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H), 1.77 (m, 2H), 1.00 (t, J = 7.41 Hz, 3H).
Intermediate 22 :4-but Ibenzoic acid (22) ediate (21) (256.1 mg, 1.242 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3.0 mL). 1N NaOH (3.73 mL) was added and the reaction was heated to 50°C for 3 hours. The reaction was then cooled to room temperature and concentrated. The crude e was taken up in water and acidified to pH = 5 with 1N HCI. A white precipitate formed. The solids were filtered off and dried under vacuum to give 4-butyrylbenzoic acid (155.4 mg, 65%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 8.16 - 8.21 (m, 2H), 8.01 - 8.05 (m, 2H), 2.98 (t, J = 7.2 Hz, 2H), 1.78 (m, 2H), 1.01 (t, J = 7.41 Hz, 3H).
Intermediate 23 : meth |3- 4-but Ibenzamido ro anoate O O N/\)]\O H | (23) 1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.801 mmol) was added to a solution of Intermediate (22) (154 mg, 0.801 mmol), methyl opropanoate hydrochloride (90.8 mg, 0.881 mmol), 1-hydroxy azabenzotriazole (109 mg, 0.801 mmol), and triethylamine (120 uL, 0.86 mmol) in dichloromethane (8.0 mL). The reaction was stirred at room temperature for 19 hours. The reaction was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium e, filtered, and concentrated. Purification by column chromatography (5 — 60% ethyl acetate in e) gave methyl 3-(4-butyrylbenzamido)propanoate (124.1 mg, 56%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 7.99 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 6.89 (br. s., 1H), 3.69 - 3.77 (m, 5H), 2.95 (t, J = 7.2 Hz, 2H), 2.66 (t, J = .8 Hz, 2H), 1.71 - 1.82 (m, 2H), 1.00 (t, J = 7.43 Hz, 3H). MS (M+1): 278.2.
Intermediate 24 :5-iodo 4- hen l-1H- razol l ridine (24) A mixture of 2-fluoroiodopyridine (368.3 mg, 1.652 mmol), 4-phenyl-1H— pyrazole (238.2 mg, 1.652 mmol), and potassium carbonate (457 mg, 3.30 mmol) in N,N-dimethylformamide (3.30 mL) was heated to 85°C for 21 hours. The reaction was then concentrated and the crude residue diluted with water and ethyl acetate.
The layers were separated and the aqueous was extracted two more times with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated to give 5-iodo(4-phenyl-1H-pyrazolyl)pyridine (537.2 mg, 94%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 8.76 (s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.09 (dd, J = 8.7, 2.2 Hz, 1H), 8.01 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.55 - 7.61 (m, 2H), 7.36 - 7.43 (m, 2H), 7.25 - 7.31 (m, 1H). MS (M+1): 348.0.
Intermediate 25 :6- 4- hen l-1H- razol | ridinamine (25) A on vial was oven-dried and cooled under nitrogen. To this vial was added Intermediate (24) (100.9 mg, 0.291 mmol), copper(l) iodide (11.0 mg, 0.058 mmol), transhydroxy-L-proline (15.2 mg, 0.116 mmol), potassium ate (122 mg, 0.873 mmol), and ylsulfoxide (0.58 mL). The vial was ,evacuated, and back-filled with nitrogen 4 times. Ammonium hydroxide (28 wt%, 0.29 mL) was then added. The reaction was heated to 80°C for 18 hours. The reaction was then cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted two more times with ethyl e.
The combined organics were washed once with brine, dried over magnesium sulfate, filtered, and concentrated. cation by column chromatography (5 — 60% ethyl acetate in heptane) gave 6-(4-phenyl-1H-pyrazoly|)pyridinamine (42.1 mg, 61%) as a pale yellow solid. 1H NMR (400 MHz, CDCI3, 5): 8.66 (s, 1H), 7.95 (s, 1H), 7.89 (d, J = 2.9 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.54 - 7.60 (m, 2H), 7.34 - 7.41 (m, 2H), 7.21 - 7.27 (m, 1H), 7.14 (dd, J = 8.7, 2.8 Hz, 1H), 3.69 (br. s., 2H).
MS (M+1): 237.2.
Intermediate 26 : 3 5-dimeth l 4- trifluorometh | - 1H- razol | henol F (26) A microwave vial was charged with tris(dibenzylideneacetone)dipalladium(0) (75.9 mg, 0.13 mmol), ‘ert—butylphosphino—2',4',6'-triisopropylbipheny| (22.1 mg, 0.051 mmol), and potassium hydroxide (113 mg, 1.92 mmol). The vial was capped, evacuated, and back-filled with nitrogen three times. A on of Intermediate (7) (204 mg, 0.64 mmol) in 1,4-dioxane (0.38 mL) was added, followed by degassed water (0.38 mL). The reaction was heated at 100°C for 2.5 hours. The reaction was quenched with 1 N HCI and extracted three times with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-15% ethyl acetate in heptane) provided 3,5-dimethyl(4- (trifluoromethyl)—(1H-pyrazolyl)phenol (120 mg, 73%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 7.94 (s, 1H), 7.72 (s, 1H), 6.50 (s, 2H), 1.92 (s, 6H). MS (M+1): 257.
Alternatively, intermediate (26) can be prepared as follows. To a flask containing Intermediate (7) (15.0 g, 47.0 mmol) in 1,4-dioxane (28.1 mL) and degassed water (28.1 mL), was added tris(dibenzylideneacetone)dipalladium(0) (557 mg, 0.94 mmol), ert—butylphosphino-2',4',6'-triisopropylbiphenyl (1.6 g, 3.76 mmol), and potassium hydroxide (3.3 g, 141.0 mmol). The reaction was purged with nitrogen and then heated at 95 °C for 1 hour. The reaction was quenched with 1 N HCI and extracted three times with ethyl acetate.The organics were dried over sodium sulfate, filtered and concentrated. The crude material was filtered h a plug of silica (5-10% ethyl acetate in heptane). The trated material was then triturated three times with heptanes to provide 3,5-dimethyl(4- (trifluoromethyl)—(1H-pyrazolyl)phenol (11 g, 91%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 7.94 (s, 1H), 7.72 (s, 1H), 6.50 (s, 2H), 1.92 (s, 6H). MS (M+H): 257.
Intermediate 27 : +/— -meth I4- 1- 4-iodophenox but I benzoate OOI (27) Diisopropyl arboxylate (880 uL, 4.47 mmol) was added to a room temperature solution of Intermediate (20) (929 mg, 4.46 mmol), 4-iodophenol (987 mg, 4.49 mmol), and triphenylphosphine (1.17 g, 4.46 mmol) in tetrahydrofuran (22 mL). The reaction was stirred at room temperature overnight. The reaction was then diluted with lether (30 mL). The mixture was washed successively with 1N NaOH and saturated ammonium chloride. The c layer was dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography gave (+/—)-methyl 4-(1-(4-iodophenoxy)butyl)benzoate (1.38 g, 75%) as a colorless oil. 1H NMR (400 MHz, CDCI3, 5): 7.95 — 8.00 (m, 2H), 7.39 — 7.45 (m, 2H), 7.32 —7.38 (m, 2H), 6.52 — 6.59 (m, 2H), 5.03 — 5.10 (m, 1H), 3.88 (s, 3H), 1.89 — 2.01 (m, 1H), 1.70 — 1.82 (m, 1H), 1.33 — 1.52 (m, 2H), 0.89 — 0.95 (m, 3H).
Intermediate 28 : Pre aration of 1- 4-methox hen l trifluorometh l -1H- pyrazole F F (28) (Z)—N-(3-(dimethylamino)(trifluoromethyl)allylidene)—N-methyl methanaminium hexafluorophosphate (4.46 g, 13.1 mmol) and 4-methoxyphenyl hydrazine hydrochloride (2.55 g, 14.6 mmol) were suspended in tetrahydrofuran (50 mL) and cooled to 0°C. Sodium methoxide (820 mg, 14 mmol) was added as a solid in one portion. The mixture was stirred at 0°C for 10 s. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. The mixture was cooled again to 0°C and trifluoroacetic acid (3 mL) was added. The ice bath was removed and the mixture heated to reflux. After 18 hours at reflux, the reaction was cooled to room ature and diluted with ethyl acetate (50 mL). The mixture was washed successively with saturated sodium bicarbonate until the washings were basic. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude material was passed through a plug of silica gel (100 g), eluting with romethane (600 mL). The filtrate was concentrated to give 1-(4-methoxyphenyl)(trifluoromethyl)-1H- pyrazole (2.7 g, 85%). 1H NMR (400 MHz, CDCI3, 6): 8.06 (s, 1H), 7.85 (s, 1H), 7.53 — 7.59 (m, 2H), 6.94 — 7.00 (m, 2H), 3.84 (s, 3H). ediate 29 :4- 4- trifluorometh l-1H- razol l henol “CON’N\ \\§VF F F (29) Intermediate (28) (2.63 g, 10.9 mmol) was dissolved in dichloromethane (50 mL). The solution was cooled to -78°C. Boron tribromide (2.0 mL, 21 mmol) was added se over 10 minutes. Following the addition, the mixture was allowed to gradually warm to room temperature and stir overnight. The resulting clear red solution was cooled to 0°C and additional boron tribromide (1 mL) was added. The ice bath was removed and the solution stirred at room temperature. After 6 hours the solution was cooled to 0°C and quenched by slow addition of anhydrous methanol (15 mL). The resulting mixture was washed with water. The aqueous layer was extracted with ethyl e. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-(4- (trifluoromethyl)—1H-pyrazolyl)phenol (2.46 g, 99%). 1H NMR (400 MHz, CDCI3, 6): 8.04 (s, 1H), 7.86 (s, 1H), .51 (m, 2H), 6.85-6.92 (m, 2H), 5.65-5.85 (br s, 1H).
Intermediate (30): utyl 3-(N-feltibutylformylbenzamido)propanoate took”; N,N-dimethylformamide (25 uL) was added to a room ature suspension of 4-carboxybenzaldehyde (2.0 g, 13 mmol) and oxalyl chloride (1.14 mL, 13.3 mmol) in dichloromethane (50 mL). The reaction was stirred at room ature 30 minutes, then heated to reflux for 5 hours. The reaction mixture was concentrated. A solution of tert—butyl t—butylamino)propanoate (2.68 g, 13.3 mmol) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (50 mL) was added to the crude acid chloride. The mixture was stirred at room temperature ght.
The reaction was washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and trated to give tert—butyl 3-(N-tert—butyl formylbenzamido)propanoate (4.47 g, 100% ). 1H NMR (400 MHz, CDCI3, 6): 10.01 (s, 1H), 7.86-7.91 (m, 2H), 7.45-7.49 (m, 2H), 3.46-3.54 (m, 2H), 2.34-2.41 (m, 2H), 1.52 (s, 9H), 1.31 (s, 9H).
Intermediate 31 :eth l4- c clo entanecarbon lbenzoate O O\/ (31) At -40°C, isopropylmagnesium chloride lithium chloride (13.9 mL, 1.3 M in THF) was added dropwise to a solution of ethyl 4-iodobenzoate (4971 mg, 18.01 mmol) in tetrahydrofuran (30 mL). The solution was stirred at -40°C for 50 minutes.
Copper(|) iodide (1.03 g, 5.4 mmol) was added. The mixture was allowed to warm to -15°C and stir for 8 minutes. The solution was cooled back to -40°C and cyclopentanecarbonyl de (3580 mg, 27.0 mmol) was added dropwise. The mixture was allowed to gradually warm to 0°C over 3 hours. The mixture was quenched with 1 N HCl (20 mL) and diluted with ethyl acetate. The e was stirred at room temperature for 5min. A white precipitate formed. The mixture was filtered through celite and the filtrate transferred to a tory funnel. The layers were separated. The aqueous was extracted twice with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, filtered and trated. Purification by column chromatography (0-20% ethyl acetate in heptane) gave ethyl 4-(cyclopentanecarbonyl)benzoate as an oil. 1H NMR (400 MHz, CDCI3, 5): 8.13 — 8.08 (m, 2 H), 8.02 — 7.97 (m, 2 H), 4.39 (q, J= 7.22 Hz, 2 H), 3.77 — 3.65 (m, 1 H), 1.99 — 1.79 (m, 4 H), 1.77 — 1.60 (m, 4 H), 1.40 (t, J: 7.22 Hz, 3 H).
Intermediate 32 :6- 4- trifluorometh I -1H- razol I ridinamine /N\ — F (32) The title nd was prepared by a method analogous to that described for Intermediate (6) using 4-(trifluoromethyl)—1H-pyrazole. 1H NMR (400 MHz, CDCI3, 5): 8.68 (s, 1H), 7.86 (d, J: 2.73 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J: 8.58 Hz, 1H), 7.13 (dd, J: 8.68, 2.83 Hz, 1H), 3.77 (br. s, 2H). MS (M+1): 229.1.
Intermediate 33: +/— 4-bromo hen Imeth Ibutanol OH (33) 4-bromo-iodobenzene (1.42 g, 5.00 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -40°C. A solution of isopropylmagnesium chloride lithium chloride (5 mL, 1.3 M in THF) was added dropwise over 5 s. The mixture was stirred at -40°C for 30 minutes, then 3-methylbutanal (0.81 mL, 7.5 mmol) was added. The reaction was allowed to warm to room temperature and stir for 1 hour.
The reaction was then quenched by addition of saturated um chloride (10 mL) and water (40 mL). The mixture was diluted with ethyl acetate (50 mL), and the layers were ted. The cs were washed with water (50 mL) and brine (25 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/—)(4-bromophenyl) methylbutanol (958 mg, 79%) as a clear oil. 1H NMR (400 MHz, CDCI3, 6): 7.47 — 7.41 (m, 2H), 7.22 — 7.17 (m, 2H), 4.68 (dd, J: 8.1, 5.4 Hz, 1H), 1.97 (br.s, 1H), 1.71 — 1.61 , 1.49 — 1.39 (m, 1H), 0.94 — 0.90 (m, 6H).
Intermediate 34: +/— -meth |4 4-bromo hen lmeth Ibutox benzoate /©)‘\O/ (34) Methyl 4-hydroxybenzoate (609 mg, 4.00 mmol), 1-(4-bromophenyl)—3- methylbutanol (1.95 g, 8.00 mmol) and triphenylphosphine (2.10 g, 8.00 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.58 mL, 8.00 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and washed with 0.1M HCI (3 x 100 mL) and brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptane) gave methy| 4-bromophenyl)methy|butoxy) benzoate (1.4 g, 93%) as a clear oil. 1H NMR (400 MHz, CDCI3, 6): 7.89 — 7.83 (m, 2H), 7.46 — 7.40 (m, 2H), 7.21 — 7.16 (m, 2H), 6.83 — 6.78 (m, 2H), 5.16 (dd, J: 9, 4.7 Hz, 1H), 3.83 (s, 3H), 1.99 — 1.91 (m, 1H), 1.88— 1.75 (m, 1H), 1.58— 1.51 (m, 1H), 0.97 (d, J: 6.6 Hz, 3H), 0.92 (d, J: 6.6 Hz, 3H).
Intermediate 35 : +/— 5-bromo ridin l 1-ol OH (35) 2,5-Dibromopyridine (1.08 g, 4.6 mmol) was azeotroped with toluene several times, then dissolved in anhydrous toluene (12 mL) under a nitrogen atmosphere. The resulting solution was cooled to -78°C and n-butyl lithium (2.4 mL, 2.1 M in hexane, 5.0 mmol) was added dropwise, maintaining an internal temperature below -70°C. The resulting orange solution was d for 30 s at -78°C, then butyraldehyde was added. The resulting solution was d for 30 minutes at -78°C then quenched by addition of saturated ammonium chloride. The resulting mixture was warmed to room temperature and diluted with ethyl acetate (25 mL) and water (25 mL). The layers were separated. The organics were washed with brine, dried over sodium sulfate, filtered and trated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/—)(5- bromopyridinyl)butano| (738 mg, 70%) as a clear oil. 1H NMR (400 MHz,CDCI3, 5): 8.57 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.3, 2.2 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 4.72-4.66 (m, 1H), 3.58 (d, J = 5.7Hz, 1H), .57 (m, 2H), 1.47- 1.35 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H).
Intermediate 36: +/— bromo—2- 1- 4-iodo henox but I ridine ' (36) Intermediate (35) (738 mg, 3.21 mmol), 4-iodophenol (1.06 g, 4.81 mmol) and triphenylphosphine (1.68 g, 6.41 mmol) were dissolved in tetrahydrofuran (10 mL). Diisopropyl azodicarboxylate (1.34 mL, 6.41 mmol) was added. The resulting on was allowed to stir at room temperature overnight. The reaction was heated to 50°C and allowed to stir for 24 hours. The reaction was concentrated. cation by column chromatography (0-100% ethyl acetate in heptane) gave (+/— )bromo(1-(4-iodophenoxy)butyl)pyridine (540 mg, 39%) as a clear oil. 1H NMR (400 MHz, CDCI3, 5): 8.61 (d, J: 2.3 Hz, 1H), 7.73 (dd, J: 8.4, 2.3 Hz, 1H), 7.48 — 7.42 (m, 2H), 7.22 (d, J: 8.4 Hz, 1H), 6.62 — 6.56 (m, 2H), 5.13 (dd, J: 8.1, 4.8 Hz, 1H), 1.99 — 1.81 (m, 2H), 1.57 — 1.36 (m, 2H), 0.94 (t, J: 7.4 Hz, 3H). MS (M+1): 432.0.
Intermediate 37 : +/— -meth I4- c clo ent lh drox meth Ibenzoate (37) The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclopentanecarbaldehyde. 1H NMR (400 MHz, CDCI3, ): 8.005 (m, 2H), 7.413 (m, 2H), 4.50 (m, 1H), 3.90 (s, 3H), 2.25 — 2.15 (m, 1H), 1.87 — 1.71 (m, 2H), 1.70 — 1.49 (m, 6H), 1.47 — 1.43 (m, 1H), 1.30 — 1.11 (m, 1H). ediate 38 :6- 4- trifluorometh I -1H- razoI I ridinol F (38) Concentrated sulfuric acid (5.5 mL) was added to water (20 mL) and cooled to 0°C. Intermediate (32) (500 mg, 2.19 mmol) was added, followed by the dropwise addition of a solution of sodium nitrite (133 mg, 1.93 mmol) in water (1.5 mL). The on was stirred at 0°C for 30 minutes. The reaction was then poured into a boiling mixture of water (29 mL) and concentrated ic acid (2.6 mL) and d for 30 minutes. The reaction was cooled to room temperature, poured onto ice, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6 -(4-(trifluoromethyI)-1H-pyrazoIy|)pyridino| (220 mg, 44%). 1H NMR (400 MHz, CD30D, 5): 8.71 (s, 1H), 7.89 (m, 1H), 7.84 (s, 1H), 7.71 (m, 1H), 7.27 — 7.24 (m, 1H).
Intermediate 39 z I-1H- razoIol OH (39) 1-benzyI(4,4,5,5-tetramethyI-1,3,2-dioxaborolanyl)—1H-pyrazole (2.0 g, 7.03 mmol) was dissolved in tetrahydrofuran (18 mL) and cooled to 0°C. 2N NaOH (7.03 mL, 14.06 mmol) and 30% peroxide (14.07 mL) were added and the reaction was stirred at room temperature for 45 minutes. The reaction was acidified to pH = 2 by addition of 2N HCI and extracted with dichloromethane. The organic layer was dried over sodium sulfate, ed and concentrated to give 1-benzyl-1H—pyrazol CI (1.54 g) as a yellow solid. 1H NMR (400 MHz, CDCI3, 6): 7.25 — 7.21 (m, 3H), 7.08 — 7.07 (m, 3H), 6.91 (s, 1H), 5.06 (s, 2H).
Intermediate 40 : 1-benz Imethox -1H- razole / (40) To a mixture of Intermediate (39) (588 mg, 3.38 mmol) and cesium carbonate (1540 mg, 4.73 mmol) in methylformamide (14.7 mL) was added iodomethane (672 mg, 4.73 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was diluted with water and extracted with ethyl acetate. The c layer was dried over sodium sulfate, filtered and concentrated.
Purification by column chromatography gave 1-benzylmethoxy-1H-pyrazole (0.586 g, 92%) as a yellow oil. 1HNMR (400 MHz, CDCI3, 5): 7.29 — 7.22 (m, 3H), 7.19 (s, 1H), 7.14 (m, 2H), 6.95 (s, 1H), 5.13 (s, 2H), 3.64 (s, 3H).
Intermediate 41 : 4-methox -1H- razole /O (41) Intermediate (40) (586 mg, 3.11 mmol) was dissolved in methanol (70 mL) and 1N HCI (7.78 mL). Palladium hydroxide on carbon (0.734 g, 4.83 mmol) was added. The mixture was rized to 50 psi hydrogen and agitated at room temperature ght. The reaction mixture was ed through celite and the filtrate concentrated to give 4-methoxy-1H—pyrazole (110 mg, 36%) as a yellow oil. 1H NMR (400 MHz, CD30D, 5): 7.64 (br s, 2H), 3.64 (s, 3H).
Intermediate 42 : +/— -meth l4- 1-h drox -3 3-dimeth lbut l benzoate (42) To a -40°C solution of methyl 4-iodobenzoate (1 g, 4 mmol) in tetrahydrofuran (10 mL) was added isopropylmagnesium chloride lithium chloride (3.82 mL, 1.3 M in THF, 4.98 mmol). The mixture was stirred at -40°C for 30 minutes. 3,3-Dimethylbutanal (573 mg, 2.86 mmol) was added. The reaction was stirred at room temperature for 4 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, ed and trated. Purification by column chromatography gave methy| 4-(1-hydroxy-3,3-dimethylbutyl)benzoate (640 mg, 95%). 1H NMR (400 MHz, CDCI3, 5): 7.93 (d, 2H), 7.34 (d, 2H), 4.81-4.84 (m, 1H), 3.84 (s, 3H), 1.70-1.61 (m, 1H), 1.53-1.49 (m, 1H), 0.94 (s, 9H).
Intermediate (43): methyl 4-(3,3-dimethylbutanoyl)benzoate (43) To a 0°C on of Intermediate (42) (0.300 g, 1.27 mmol) in tetrahydrofuran (10 mL) was added trifluoroacetic acid (261 mL, 2.29 mmol) followed by 1,1,1-Tris(acetyloxy)—1,1-dihydro-1,2-benziodoxol(1H)-one (862 mg, 2.03 mmol). The reaction was stirred at room temperature for 2 hours. The reaction mixture was quenched by addition of 1M sodium ulfite (10 mL) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by column chromatography gave methyl 4-(3,3- dimethylbutanoyl)benzoate (220 mg, 74%). 1H NMR (400 MHz, CDCI3, 5): 8.04 (d, 2H), 7.90 (d, 2H), 3.88 (s, 3H), 2.82 (s, 2H), 0.99 (s, 9H).
Intermediate (44): methyl 4-(cyclohexanecarbonyl)benzoate (44) Magnesium turnings (324 mg, 13.5 mmol) were suspended in tetrahydrofuran (20 mL). A l of iodine was added. Bromocyclohexane (2.00 g, 12.26 mmol) was added dropwise. The mixture was refluxed for 2 hours. The mixture was then added to a -5°C on of methyl 4-(methoxy(methyl)carbamoyl) benzoate (456 mg, 2.04 mmol) in tetrahydrofuran (5 mL). The reaction was stirred 1 hour, maintaining an internal temperature below 0°C. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic 2012/050349 layer was dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 4-(cyclohexanecarbonyl)benzoate (160 mg, 32%).1H NMR (400 MHz, CDCI3, 5): 8.10 — 8.12 (m, 2H), 7.96 — 7.98 (m, 2H), 3.94 (s, 3H), 3.22 — 3.25 (m, 1H), 1.90 — 1.82 (m, 4H), 1.76 — 1.72 (m, 1H), 1.25 — 1.50 (m, 5H).
Intermediate 45 : +/— -meth I4- c clobut I h drox meth I benzoate (45) The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclobutanecarbaldehyde. 1H NMR (400 MHz, CDCI3, ): 7.93 — 8.00 (m, 2H), 7.35 — 7.39 (m, 2H), 4.64 (m, 1H), 3.90 (s, 3H), 2.57 — 2.65 (m, 1H), .08 (m, 2H), 1.80— 1.91 (m, 4H).
Intermediate 46 : +/— -z‘en‘-but l3- t—but l 1-h drox ro l benzamido propanoate OH (46) The title compound was prepared by a method analogous to that described for Intermediate (17), using ethylmagnesium bromide. 1H NMR (400 MHz, CDCI3, 6): 7.29 — 7.35 (m, 4H), 4.59 — 4.62 (m, 1H), 3.53 — 3.57 (m, 2H), 2.37 — 2.41 (m, 2H), 1.71 — 1.83 (m, 2H), 1.53 (s, 9H), 1.34 (s, 9H), 0.87 — 0.91 (m, 3H).
Intermediate 47 :4- 4-meth I-1H—1 2 3-triazol I aniline (47) A solution of onitrobenzene (0.500 g, 3.05 mmol) and 3- bromopropyne (1.45 g, 12.2 mmol) in toluene (3 mL) was heated to 60°C for 24 hours in a sealed tube. Additional 3-bromoprop—1-yne (1.45 g, 12.2 mmol) was added and the solution stirred at 60°C overnight. The reaction mixture was concentrated to an orange solid. The crude residue was ved in ethanol (100 mL). 10 wt% Palladium on carbon (150 mg) was added and the mixture was pressurized to 50 psi hydrogen and stirred for 18 hours. The reaction e was filtered through celite and the filtrate was concentrated. The residue was slurried in ethyl e. The mixture was filtered, and the solid dried under vacuum to give 4- (4-methyI-1H-1,2,3-triazoly|)ani|ine (300 mg). 1HNMR (400MHz, CD30D, 5): 8.37 (s, 1H), 8.03 (m, 2H), 7.58 (m, 2H), 2.44 (s, 3H).
Intermediate 48 : +/— -ten‘-but I3- N-tert—but I 1-h drox but I benzamido propanoate O2,34%0 OH (48) The title compound was prepared by a method analogous to that described for Intermediate (17) using n-propylmagnesium bromide. 1H NMR (400 MHz, CDCI3, ): 7.33 (m, 4H), 4.59 (m, 1H), 3.55 (m, 2H), 2.41 (m, 2H), 1.77 (m, 4H), 1.52 (s, 9H), 1.42 (s, 9H), 0.90 (m, 3H).
Intermediate 49 : +/— -meth I4 5-iodo 2- on but I benzoate ' (49) The title compound was prepared by a method analogous to that described for Intermediate (27) using 2-hydroxyiodopyridine. 1H NMR (400 MHz, CDCI3, 5): 8.19 (d, J = 2.5 Hz, 1H), 7.99 — 7.94 (m, 2H), 7.73 (dd, J = 8.7, 2.4 Hz, 1H), 7.44 — 7.39 (m, 2H), 6.61 (d, J: 8.6 Hz, 1H), 6.00 (dd, J: 7.8, 5.7 Hz, 1H), 3.87 (s, 3H), WO 07850 2.03 — 1.92 (m, 1H), 1.85 — 1.74 (m, 1H), 1.49 — 1.27 (m, 2H), 0.92 (t, J = 7.41 Hz, 3H). MS (M+1): 412.1.
Intermediate 50 : 6- 4- trifluorometh I -1H-imidazol I ridinol The title compound was ed by a method analogous to that described for ediate (38) using Intermediate (6). 1H NMR (400 MHz, CD30D, 5): 8.71 (s, 1H), 7.89 (d, 1H), 7.84 (s, 1H), 7.71 (m, 1H), 7.27 — 7.24 (m, 1H).
Intermediate 51 :1- 4-nitro hen I trifluorometh I-1H- razole L/N‘Q'NOZ/N\ F3C (51) The title compound was prepared by a method analogous to that described for Intermediate (3), using 1-fluoronitrobenzene and 4-(trifluoromethyl)—1H— pyrazole. 1H NMR (400 MHz, CDCI315): 8.38 (m, 1H), 8.30 (m, 1H), 7.97 (s, 2H), 7.90 (m, 2H).
Intermediate 52 :4- 4- trifluorometh I-1H- razoI ne LNQNHZ/N\\ The title compound was prepared by a method analogous to that described for Intermediate (4) using Intermediate (51). 1H NMR (400 MHz, CDCI3, 5): 8.03 (m, 1H), 7.85 (s, 1H), 7.43 (dt, J: 9.0, 2.9 Hz, 2H), 6.75 (dt, J: 9.0, 3.1 Hz, 2H).
Intermediate 53 : 1- 4-nitro hen I trifluorometh I -1H-imidazole LNQNOZA\ F3C (53) The title compound was prepared by a method analogous to that described for Intermediate (3) using ronitrobenzene. The crude product was recrystallized from toluene and minimal ethyl acetate to afford the product as a white powder. MS (M+1): 257.0.
Intermediate 54 :4- 4- trifluorometh l -1H-imidazol laniline A solution of Intermediate (53) (3.02 g, 11.7 mmol) and di-z‘ert-butyl onate (4.05 mL, 17.6 mmol) in ethanol (117 mL) was passed through an H- Cube reactor (50°C, 50bar, 1 mL/min, 10% Pd/C dge). The reaction mixture was concentrated and the crude oil was heated at 40°C overnight. The crude oil was then treated with trifluoroacetic acid (8.7mL) in oromethane (15.6mL).
The mixture was stirred for 30min whereupon the reaction mixture was concentrated and the residual trifluoroacetic acid was removed via a toluene ope. Purification via column chromatography (0-70% ethyl acetate in heptane) gave 4-[4-(trifluoromethyl)—1H-imidazolyl]aniline (1.23 g, 46%) as a solid. 1H NMR (400 MHz, CD30D, 5): 8.15 (s, 1H), 8.02 (m, 1H), 7.48 (dd, J: 8.8, 2.9 Hz, 2H), 7.10 (dd, J: 8.6, 2.9 Hz, 2H).
Intermediate 55 :4- 2H-indazol l henol HOON’N $55) 4-Bromophenol (2.00 g, 11.6 mmol) was combined with azole (1.64 g, 13.9 mmol), copper(|) iodide (110 mg, 0.578 mmol), potassium phosphate (5.15 g, 24.3 mmol), trans-dimethylcyclohexane-1,2-diamine (0.365 mL, 2.31 mmol), and toluene (10 mL). The reaction was refluxed for 21 hours, then cooled to room temperature and partitioned between ethyl acetate and ammonium hydroxide.
The organic layer was washed with 0.5 N HCI and brine, dried over ium sulfate, filtered and concentrated. Purification by column chromatography (0 — 40% ethyl acetate in heptane) gave 4-(2H-indazolyl)phenol (0.479 g, 20%) as a tan solid. 1H NMR (400 MHz, (CD3)ZSO, 5): 9.84 (s, 1H), 8.90 (s, 1H), 7.86 (d, J: 8.8 Hz, 2H), 7.74 (d, J: 8.4 Hz, 1H), 7.68 (d, J: 8.8 Hz, 1H), 7.22 — 7.33 (m, 1H), 7.03 — 7.12 (m, 1H), 6.94 (d, J: 8.8 Hz, 2H). MS (M+1): 211.2.
Intermediate (56): hyl 4-(1-hydroxybutyl)benzoate HO O (55) A mixture of ediate (5) (30.0 g, 140 mmol) and [N-[(1R,2R)—2-(amino- KN)-1,2-diphenylethyl]—4-methylbenzenesulfonamidato-Kl\l]chloro[(1,2,3,4,5,6-r])- 1,3,5-trimethylbenzene]—ruthenium (2.12 g, 3.40 mmol) was suspended in a 5:2 azetropic mixture of formic acid and triethylamine (68.1 mL). The mixture was stirred at ambient ature for 12 hours. The reaction was quenched with water and extracted three times with ethyl acetate. The ed organic layers were washed with concentrated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was dissolved in dichloromethane (1.0 L) and silacycle Si-Thiol (90 g) was added. The mixture was slurried for twelve hours at ambient temperature. The crude mixture was filtered and concentrated in vacuo to give primarily (R)—ethyl 4-(1-hydroxybutyl)benzoate (30.0 g, 100%). 1H NMR (400 MHz, CDCI3, 5): 7.98 (d, J = 8.4 Hz, 2H), 7.38 (d, J: 8.0 Hz, 2H), 4.71 (dd, J: 7.4, 5.7 Hz, 1H), 4.34 (q, J: 7.0 Hz, 2H), 1.58 - 1.81 (m, 2H), 1.29 - 1.48 (m, 2H), 1.36 (t, J: 7.1 Hz, 3H), 0.90 (t, J: 7.3 Hz, 3H). Chiral HPLC: Chiralpak AD-H, 4.6 mm x 25 cm; SFC Mobile Phase 80:20 COZ/Methanol, 2.5 mL/min, Retention time: 3.13 min (R-ent, 92.9%), 3.41 min (S-ent, 7.1%), 86% ee. The (R)- enantiomer was further resolved by chiral SFC to give optically pure (R)—ethyl 4-(1- hydroxybutyl) te. Column: Chiralpak AD-H. Dimensions: 21 x 250mm.
Mobile Phase: 80/20 COZ/methanol. Flow Rate: in. Modifier: none.
Retention time: 2.91min.
Intermediate 57 : eth l4- 3-meth lbutano lbenzoate Step A: (+/—)—ethyl 4-(1-hydroxymethylbutyl)benzoate To a solution of ethyl 4-iodobenzoate (20 g, 72 mmol) in tetrahydrofuran (200 mL) at -40 °C was added isopropylmagnesium chloride lithium chloride (62 mL, 80 mmol, 1.3 M in THF) dropwise, maintaining the internal temperature below -30 °C. The mixture was d for 30 minutes and ylbutanal (8.68 g, 101 mmol) was then added dropwise, maintaining the al temperature below -35 °C. Following the addition, the reaction was allowed to stir for 15 s at -35 °C and was then allowed to warm to room temperature.
The reaction was ed with 1 N aqueous hydrochloric acid (400 mL), and the mixture was extracted with ethyl acetate (2 x 200 mL). The cs were washed with brine (200 mL) and water (200 mL), dried over sodium sulfate, filtered and concentrated to give ethyl 4- (1-hydroxymethylbutyl)benzoate (16 g, 93%) as an oil. 1H NMR (400 MHz, CDCI3, 6): 7.95 (d, J: 8.4 Hz, 2 H), 7.34 (d, J: 8.4 Hz, 2 H), 4.73 — 4.76 (m, 1 H), 4.28 — 4.33 (m, 2 H), 1.60 — 1.71 (m, 2 H), 1.41 — 1.46 (m, 1 H), 1.31 — 1.39 (m, 3 H), 0.87 - 0.92 (m, 6 H).
Step B: ethyl 4-(3-methylbutanoyl)benzoate A mixture of ethyl 4-(1-hydroxymethylbutyl)benzoate (15 g, 63 mmol), dichloromethane (150 mL), dimethylsulfoxide (198 g, 2540 mmol), and triethylamine (32 g, 317 mmol) was cooled to 0 °C. Sulfur trioxide pyridine complex (30 g, 190 mmol) was added in portions, maintaining the internal temperature below 50 °C. The mixture was stirred at 0 °C for 1 hour. The reaction was then allowed to warm to room temperature and stir for 36 hours. The reaction was diluted with brine (300 mL) and extracted with methyl tert-butylether (2 x 500 mL). The ed organics were washed with 1 N aqueous hydrochloric acid (500 mL), dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(3-methylbutanoyl)benzoate (12 g, 80%) as a white solid. 1H NMR (400 MHz, CDCI3, 6): 8.11 (dd, J: 1.6, 6.8 Hz, 2 H), 7.98 (d, J: 6.8 Hz, 2 H), 4.40 (q, J: 7.2 Hz, 2 H), 2.85 (d, J: 6.8 Hz, 2 H), 2.24 —2.34 (m, 1 H), 1.39 — 1.43 (t, J: 7.2 Hz, 3 H), 1.50 (d, J: 6.8 Hz, 6 H).
Intermediate 58: meth l3- 4- 3-meth lbutano lbenzamido ro anoate Ste A: 4- 3-meth lbutano Ibenzoic acid To a solution of Intermediate (57) (12 g, 51 mmol) in methanol (80 mL) was added 2 N aqueous sodium hydroxide (80 mL, 160 mmol). The reaction was stirred at room temperature for 40 minutes. The methanol was then removed in vacuo and the residue was extracted with dichloromethane. The aqueous phase was ied to pH = 4 with 3 N aqueous hydrochloric acid and extracted with ethyl acetate (2 x 200 mL). The combined organics were washed with brine, dried over sodium e, filtered and concentrated to give ethylbutanoyl)benzoic acid (9.5 g, 86%) as a white solid. 1H NMR (400 MHz, CDCI3, 6): 8.13 (d, J: 8.4 Hz, 2 H), 7.96 (d, J: 8.0 Hz, 2 H), 2.81 (d, J: 6.8 Hz, 2 H), 2.19 — 2.29 (m, 1 H), 0.96 (d, J: 6.8 Hz, 6 H).
Ste B: meth l 3- 4- 3-meth lbutano l ido ro anoate To a solution of 4-(3-methylbutanoyl)benzoic acid (9.5 g, 46 mmol) in N,N- dimethylformamide (80 mL) was added O-(7-Azabenzotriazoly|)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (26.3 g, 69.1 mmol) at 0 °C. The mixture was stirred for 40 minutes. Methyl 3-aminopropanoate hydrochloride (7.72 g, 55.3 mmol) and triethylamine (23.3 g, 230 mmol) were added and the reaction was allowed to warm to room ature and stir for 16 hours. The reaction mixture was extracted with ethyl acetate (3 x). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by column tography gave methyl 3-(4-(3- methylbutanoyl)benzamido)propanoate (10 g, 77%) as a pale yellow solid. 1H NMR (400 MHz, CDCI3, 6): 7.98 (d, J: 8.0 Hz, 2 H), 7.83 (d, J: 8.4 Hz, 2 H), 6.91 (s, 1 H), 3.72 — 3.76 (m, 5 H), 2.84 (d, J: 6.0 Hz, 2 H), 2.66 — 2.69 (t, J: 6.0 Hz, 2 H), 2.23 — 2.33 (m, 1 H), 0.99 (d, J: 6.4 Hz, 6 H).
Intermediate 59 : eth l4- c clobutanecarbon lbenzoate Step A: (+/—)—ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate The title compound was prepared by a method analogous to that described for Intermediate (16), using ethyl benzoate and cyclobutanecarbaldehyde. 1H NMR (400 MHz, CDCI3, 6): 7.93 (d, J: 8.0 Hz, 2 H), 7.31 (d, J: 8.0 Hz, 2 H), 4.58 (d, J: 8.0 Hz, 1 H), 4.29 (q, J: 6.8 Hz, 2 H), 2.50 — 2.58 (m, 1 H), 1.70 — 2.02 (m, 6 H), 1.34 (t, J: 7.2 Hz, 3 Step B: ethyl 4-(cyclobutanecarbonyl)benzoate Trifluoroacetic acid (613 mg, 5.38 mmol) was added se to a 0°C solution of ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (700 mg, 3 mmol) in dichloromethane (10 mL).
Then Dess-Martin periodinane (2.03 g, 4.78 mmol) was added and the reaction was warmed to room temperature and stirred for 2 hours. The reaction was quenched with 1 N aqueous sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3 x 30 mL). The ed organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave ethyl 4-(cyclobutanecarbonyl)benzoate (540 mg, 78%) as an OH. 1H NMR (400 MHz, CDCI3, 6): 8.04 (d, J: 8.4 Hz, 2 H), 7.86 (d, J: 8.4 Hz, 2 H), 4.33 (q, J: 7.2 Hz, 2 H), 3.90 — 3.99 (m, 1 H), 2.20 — 2.40 (m, 4 H), 2.00 — 2.09 (m, 1 H), 1.81 — 1.90 (m, 1 H), 1.34 (t, J: 7.2 Hz, 3 H).
Intermediate 60 : eth I 4- 2-c clo ro lacet I benzoate The title compound was ed by a method analogous to that described for Intermediate (59), using 2-cyclopropylacetaIdehyde. 1H NMR (400 MHz, CDCI3, 6): 8.15 (d, J: 7.2 Hz, 2 H), 8.01 (d, J: 7.2 Hz, 2 H), 4.44 (q, J: 7.2 Hz, 2 H), 2.94 (d, J: 6.8 Hz, 2 H), 1.45 (t, J: 7.2 Hz, 3 H), 1.10 - 1.22 (m, 1 H), 0.59 - 0.68 (m, 2 H), 0.21 - 0.26 (m, 2 H).
Intermediate 61 :3-meth I 4- trifluorometh I-1H- razol I henol HO N\%/FF Ste A: 1methox meth l hen l trifluorometh l-1H- razole \ T O N’ / F To a mixture of 1-bromomethoxymethylbenzene (1.5 g, 7.5 mmol) in N,N- dimethylformamide (15 mL) was added 4-(trifluoromethyl)-1H-pyrazole (1.12 g, 8.21 mmol), copper(ll) oxide (107 mg, 0.746 mmol), and cesium carbonate (4.86 g, 14.9 mmol). The mixture was heated in a microwave to 120 °C for 1 hour. The e was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave 1-(4-methoxymethylphenyl)(trifluoromethyl)-1H-pyrazole (550 mg, 29%) as a white solid. 1H NMR (400 MHz, CDCI3, 6): 7.81 (s, 1 H), 7.74 (s, 1 H), 7.16 (m, 1 H), 6.74 (m, 2 H), 3.77 (s, 3 H), 2.10 (s, 3 H).
Ste B: 3-meth l 4- trifluorometh l -1H- razol l henol To a 0 °C solution of 1-(4-methoxymethylpheny|)(trifluoromethy|)-1H-pyrazole (400 mg, 2 mmol) in romethane (5 mL) was added boron tribromide (1 g, 6 mmol).
The mixture was allowed to warm to room ature and stir overnight. The reaction was quenched with methanol (2 mL), diluted with water (10 mL), and extracted with dichloromethane (3 x 10 mL). The combined organics were dried over sodium sulfate, ed, and concentrated to give 3-methyl(4-(trifluoromethy|)-1H-pyrazolyl)phenol (390 mg, 99%) as a brown solid. 1H NMR (400 MHz, CDCI3, 6): 7.83 (s, 1 H), 7.74 (s, 1 H), 7.08 (d, J: 8.4 Hz, 1 H), 6.65 (s, 1 H), 6.62 (d, J: 8.4 Hz, 1 H), 5.57 (s, 1 H), 2.05 (s, 3 H).
Intermediate (62): methyl 4-butyrylfluorobenzoate F O/ Ste A: +/— ofluoro hen |butanol F Br To a -78 °C solution of 4-bromofluorobenzaldehyde (600 mg, 3 mmol) in tetrahydrofuran (10 mL) was added n-propylmagnesium chloride (2.22 mL, 4.43 mmol) dropwise over 20 minutes. The reaction was warmed to 0 °C and stirred for 2 hours. The reaction was quenched with saturated aqueous ammonium de, extracted with ethyl acetate (3 x), dried over sodium sulfate, filtered, and trated. Purification by preparatory thin layer tography gave (+/—)(4-bromof|uorophenyl)butano| (440 mg, 60%) as a colorless oil. 1H NMR (400 MHz, CDCI3, 6): 7.26 — 7.30 (m, 1 H), 7.21 (d, J: 8.0 Hz, 1 H), 7.13 (d, J: 8.0 Hz, 1 H), 4.90 (t, J: 5.6 Hz, 1 H), 1.53 — 1.79 (m, 2 H), 1.30 — 1.45 (m, 2 H), 0.85 (s, J: 5.6 Hz, 3 H).
Step B: 1-(4-bromofluorophenyl)butanone F Br Trifluoroacetic acid (366 mL, 3.21 mmol) was added dropwise to a 0 °C solution of 1-(4-bromof|uorophenyl)butano| (440 mg, 1.8 mmol) in dichloromethane (10 mL).
Added Dess-Martin periodinane (1.21 g, 2.85 mmol) and let on warm to room temperature and stir for 2 hours. The reaction was quenched with 1 N s sodium hydrosulfite (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 1-(4-bromofluorophenyl)butanone (330 mg, 75%) as a colorless oi|.1H NMR (400 MHz, CDCI3, 6): 7.65 — 7.69 (m, 1 H), 7.32 — 7.45 (m, 2 H), 2.83 — 2.87 (m, 2 H), 1.62 — 1.71 (m, 2 H), 0.90 (m, 3 H).
Step C: methyl 4-butyrylfluorobenzoate A mixture of 1-(4-bromofluorophenyl)butanone (300 mg, 11.8 mmol), (1 ,1’- bis(diphenylphosphino)ferrocene) dichloropalladium (258 mg, 0.367 mmol), and diisopropylethylamine (790 mg, 6.1 mmol) in methanol (20 mL) was pressurized to 50 psi of carbon monoxide. The on was heated to 80 °C and stirred for 10 hours. The reaction was cooled to room temperature and filtered through Celite. The filtrate was trated and purified by flash column chromatography to give methyl 4-butyrylfluorobenzoate (260 mg, 87%) as a pale yellow solid. 1H NMR (400 MHz, CDCI3, 6): 7.81 (d, J: 8.4 Hz, 1 H), 7.79 (d, J: 8.4 Hz, 1 H), 7.73 (d, 1 H), 3.88 (s, 3 H), 2.88 —2.92 (m, 2 H), 1.64 — 1.73 (m, 2 H), 0.92 (t, J: 7.6 Hz, 3 H).
Intermediate (63): methyl 4-butyrylmethylbenzoate Step A; (+/—)—methyl 4-(1-hydroxybutyl)—3-methylbenzoate The title compound was prepared by a method analogous to that described for ediate (16), using methyl 4-iodomethylbenzoate and ldehyde. 1H NMR (400 MHz, CDCI3, 6): 7.87 (d, J: 8.4 Hz, 1 H), 7.81 (s, 1 H), 7.56 (d, J: 8.4 Hz, 1 H), 4.98 (q, J = 4.4 Hz, 1 H), 3.90 (s, 3 H), 2.37 (s, 3 H), 1.63 — 1.72 (m, 2 H), 1.50 — 1.54 (m, 1 H), 1.39 — 1.43 (m, 1 H), 0.98 (t, J: 7.6 Hz, 3 H).
Step B: methyl 4-butyrylmethylbenzoate To a solution of (+/—)-methyl 4-(1-hydroxybutyl)methy|benzoate (0.8 g, 4 mmol) in dichloromethane (15 mL) was added manganese dioxide (3.13 g, 36.0 mmol). The reaction was stirred at 30 °C overnight. TLC showed ng material remained and the reaction was heated to reflux for 5 hours. The reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography to give methyl 4-butyrylmethylbenzoate (290 mg) as an oil. 1H NMR (400 MHz, CDCI3, 6): 7.90 (d, J: 7.6 Hz, 2 H), 7.59 (d, J: 7.6 Hz, 1 H), 3.93 (s, 3 H), 2.86 (t, J: 7.6 Hz, 2 H), 2.49 (s, 3 H), 1.69 — 1.78 (m, 2 H), 0.99 (t, J: 7.6 Hz, 3 H). ediate 64: 2- 4- trifluorometh l-1H- razol l rimidinamine Ste A: 5-nitro 4- trifluorometh l-1H- 1- l rimidine To a solution of 2-chloronitropyrimidine (1.5 g, 9.4 mmol) and 4-(trifluoromethyl)- 1H-pyrazole (1.41 g, 10.3 mmol) in acetonitrile (40 mL) was added ium carbonate (2.60 g, 18.8 mmol). The reaction was heated to 80 °C and stirred overnight. The reaction was concentrated and the residue was diluted with water and extracted with ethyl acetate (2 x 40 mL). The combined cs were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 5-nitro(4- (trifluoromethyl)-1H-pyrazolyl)pyrimidine (1.5 g, 62%) as a yellow solid. 1H NMR (400 MHz, CDCI3, 6): 9.48 (s, 2 H), 8.92 (s, 1 H), 8.05 (s, 1 H).
Ste B: 2- 4-trifluorometh l-1H- razol l rimidinamine 2012/050349 Glacial acetic acid (2.78 g, 46.3 mmol) was slowly added to a solution of 5-nitro (4-(trifluoromethyl)-1H-pyrazolyl)pyrimidine (1.5 g, 5.8 mmol) and iron powder (1.94 g, 34.7 mmol) in methanol (30 mL). The reaction was stirred at room temperature for 3 hours.
The reaction was then diluted with ethyl acetate (50 mL) and filtered through Celite. The filtrate was lized with ted aqueous potassium carbonate. The organic layer was separated and washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 2-(4-(trifluoromethyl)-1H-pyrazolyl)pyrimidinamine (850 mg, 64%) as a yellow solid. 1H NMR (400 MHz, CDCI3, 6): 8.68 (s, 1 H), 8.16 (s, 2 H), 7.87 (s, 1 H), 3.82 (s, 2 H). ediate (65): ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate To a 0 °C solution of 3,3-dimethylcyclobutanecarboxylic acid (1.35 g, 10.5 mmol) in dichloromethane (10 mL) was slowly added oxalyl chloride (4.01 g, 31.6 mmol) and 1 drop of methylformamide. The reaction was warmed to room ature and stirred for 2 hours. The reaction was concentrated in vacuo to give crude 3,3- dimethylcyclobutanecarbonylchloride (1.54 g) as a yellow oil.
To a -40 °C solution of ethyl 4-iodobenzoate (2.30 g, 8.30 mmol) in tetrahydrofuran (20 mL) was added isopropylmagnesium chloride-lithium chloride (7.1 mL, 1.3 M in THF, 9.2 mmol) dropwise. The mixture was stirred for 1 hour at -40 °C. Copper(l) iodide (476 mg, 2.50 mmol) was then added and the reaction was allowed to warm to -10 °C and stir for 20 minutes. The solution was cooled again to -40 °C and a solution of the previously prepared 3,3-dimethylcyclobutanecarbonylchloride (1.54 g, 10.5 mmol) in tetrahydrofuran (10 mL) was added dropwise. The reaction was allowed to warm to 0 °C and stir for 2 hours. The reaction was quenched with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (3 x 15 mL). The combined organics were dried over sodium e, filtered, and concentrated. Purification by flash column chromatography gave ethyl - dimethylcyclobutanecarbonyl)benzoate (1.80 g, 83%) as a pale yellow solid. 1H NMR (400 MHz, CDCI3, 6): 8.15 (d, J: 8.4 Hz, 2 H), 7.98 (d, J: 8.4 Hz, 2 H), 4.20 — 4.47 (m, 2 H), 3.89 — 3.98 (m, 1 H), 2.22 — 2.27 (m, 2 H), 2.09 — 2.15 (m, 2 H), 1.45 (t, J: 7.2 Hz, 3 H), 1.32 (s, 3 H), 1.13 (s, 3 H).
Intermediate 66 : 4- 2H-indazol l meth l henol HO N 2012/050349 Ste A: 2- 4-methox meth l hen l -2H-indazole ,0 o3 A mixture of 4-methoxymethylaniline (1.37 g, 10.0 mmol) and 2- nitrobenzaldehyde (1.51 g, 10.0 mmol) in tetrahydrofuran (30 mL) was d at reflux for 4 hours. The reaction was concentrated. To the e was added triethyl phosphite (10 mL) and the mixture was stirred at reflux for 40 hours. The reaction was concentrated and purification by flash column chromatography gave ethoxymethylphenyl)-2H- indazole (1.5 g, 63%) as a white solid. 1H NMR (400 MHz, CDCI3, 6): 8.05 (s, 1 H), 7.80 (d, J: 8.8 Hz, 1 H), 7.74 (d, J: 8.8 Hz, 1 H), 7.31 — 7.35 (m, 2 H), 7.12 — 7.16 (m, 1 H), 6.82 — 6.88 (m, 2 H), 3.87 (s, 3 H), 2.20 (s, 3 H).
Ste B: 4- 2H-indazol l meth l henol A solution of 2-(4-methoxymethylphenyl)-2H-indazole (500 mg, 2.1 mmol) in dichloromethane (10 mL) was cooled to -78 °C. Added boron mide (2.6 g, 10.5 mmol) and reaction was stirred at -78 °C for 1 hour. Reaction was warmed to room temperature are stirred overnight. The reaction was diluted with methanol and water, and extracted with ethyl acetate (3 x 30 mL). The combined organics were washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give 4-(2H-indazolyl)methylphenol (350 mg, 74%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 6): 9.82 (s, 1 H), 8.51 (s, 1 H), 7.76 (d, J: 8.4 Hz, 1 H), 7.68 (d, J: 8.8 Hz, 1 H), 7.25 — 7.30 (m, 2 H), 7.07 — 7.11 (m, 1 H), 6.80 (d, J: 2.4 Hz, 1 H), 6.75 (dd, J: 8.4, 2.4 Hz, 1 H), 2.06 (s, 3 H).
Intermediate 67 : 2-meth l 4- trifluorometh l-1H- razol lbenzonitrile To a solution of 4-(trifluoromethyl)-1 H-pyrazole (1.0 g, 7.0 mmol) and 4-fluoro methylbenzonitrile (1.16 g, 8.50 mmol) in acetonitrile (8 mL) was slowly added potassium carbonate (1.96 g, 14.2 mmol) at room temperature. The reaction was heated to 80 °C and stirred overnight. The reaction was cooled to room temperature and poured into water. The layers were separated and the aqueous was extracted with ethyl e (3 x 15 mL). The ed organics were washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-methyl(4- (trifluoromethyl)-1H-pyrazolyl)benzonitrile (710 mg, 40%) as a yellow solid. 1H NMR (400 MHz, CDCI3, 6): 8.26 (s, 1 H), 7.94 (s, 1 H), 7.72 — 7.74 (m, 2 H), 7.61 — 7.64 (m, 1 H), 2.64 (s, 3 H).
Intermediate 68 : +/— -eth l4- c clo ent lh drox meth lbenzoate The title compound was prepared by a method analogous to that described for Intermediate (16) using cyclopentanecarbaldehyde and ethyl 4-iodobenzoate. 1H NMR (400 MHz, CDCI3, 6): 8.01 (d, J: 8.4 Hz, 2 H), 7.40 — 7.44 (m, 2 H), 4.49 (d, J: 8.0 Hz, 1 H), 4.39 (q, J: 7.2 Hz, 2 H), 2.19 —2.21 (m, 1 H), 1.82 — 1.87 (m, 2 H), 1.41 — 1.67 (m, 6 H), 1.39 (t, J: 7.2 Hz, 3 H).
Intermediate 69 : 6- 4-chloro-1H-imidazol l 3-amine Step A: 4-chloro-1H-imidazole To a solution of 1H-imidazole (10.0 g, 0.15 mol) in form (100 mL) was slowly added a solution of chlorine (2.08 g, 0.0294 mol) in chloroform (18.6 mL). The on was cooled to 0 °C, then left stirring ght, gradually warming to room temperature. Aqueous sodium bisulfite was added and the layers were separated. The aqueous was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (0 — 10% methanol / dichloromethane) gave 4-chloro-1H-imidazole (400 mg) as a light yellow solid. 1H NMR (400 MHz, CD30D, 6): 7.58 (s, 1 H), 7.05 (s, 1 H).
Ste B: 2- 4-chloro-1H-imidazol l nitro ridine A vial was charged with 4-chloro-1H-imidazole (450 mg, 4.4 mmol), 2-chloro nitropyridine (1.04 g, 6.58 mmol), potassium carbonate (1.21 g, 8.78 mmol), and acetonitrile (10 mL). The vial was capped and heated to 80 °C for 2 hours. The reaction was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column tography gave 2-(4-chloro-1H-imidazol yl)nitropyridine (675 mg, 68%) as a white solid. 1H NMR (400 MHz, CD30D, 6): 9.35 (d, J = 2.4 Hz, 1 H), 8.78 (dd, J: 9.0, 2.6 Hz, 1 H), 8.64 (d, J: 1.6 Hz, 1 H), 8.05 (d, J: 1.6 Hz, 1 H), 7.95 (d, J: 8.8 Hz, 1 H).
Ste C: 6- 4-chloro-1H-imidazol l ridinamine A vial was charged with 2-(4-chloro-1H-imidazoIy|)nitropyridine (675 mg, 3.01 mmol), tin(|l) chloride dihydrate (2.03 g, 9.02 mmol), and methanol (10 mL). The vial was sealed and heated to 90 °C and d for 16 hours. The reaction was cooled to room temperature and trated. The residue was taken up in water (20 mL) and neutralized with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column tography gave 6-(4-chloro-1H-imidazol idinamine (380 mg, 65%) as a light yellow solid. 1H NMR (400 MHz, CD30D, 6): 8.20 (d, J: 1.6 Hz, 1 H), 7.89 (d, J: 2.4 Hz, 1 H), 7.68 (d, J: 1.6 Hz, 1 H), 7.38 (d, J: 8.8 Hz, 1 H), 7.21 (dd, J: 8.8, 2.8 Hz, 1 H).
Intermediate 70 : 1-bromo-3 3-dimeth Ibutanone >003.
To a solution of 3,3-dimethylbutanone (18 g, 180 mmol) in dichloromethane (400 mL) and methanol (160 mL) was added tetrabutylammonium tribromide (95.3 g, 198mmol). The reaction mixture was d at room temperature for 2 h. The solution was concentrated under reduced re and the residue dissolved in methyl t—butyl ether (250 mL). The solution was washed with 1N aqueous HCI (250 mL * 3) and brine (250 mL * 2). The organic layer was dried over anhydrous NaZSO4 and concentrated under reduced pressure to give crude 1-bromo-3,3-dimethylbutanone (28 g) as a colorless oil which was used without further cation. 1H NMR (400 MHz, CDCI3) 6 4.17 (s, 2 H), 1.23 (s, 9 H).
Intermediate 71 t-but I-1H-imidazole XUHN A solution of intermediate (70) (3 g, 20 mmol) in formamide (15 mL) was heated to 160 °C for 5 h. The mixture was poured into 10% aqueous sodium bicarbomate (30 mL). The solution was extracted with dichloromethane (30 mL * 2). The combined organic layers were washed with 10% aqueous potassium carbonate, brine, dried over NaZSO4 and concentrated under reduced pressure to give 4-tert-butyI-1H-imidazole (1.1 g) as a brown oi|.1H NMR (400 MHz, CDCI3) 6 7.57 (s, 1 H), 6.76 (s, 1 H), 1.31 (s, 9 H).
Intermediate 72 :2- 4-tert-but I-1H-imidazol Initro ridine To a solution 2-bromonitropyridine (2.2 g, 10 mmol) in acetonitrile (15 mL) was added ediate (71) (1.5 g, 12 mmol) and potassium carbonate (3 g, 20 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL * 3). The organic layer was dried over anhydrous NaZSO4 and trated under d pressure. Purification by silica gel chromatography gave 2-(4-tert-butyI-1H-imidazoIy|)nitropyridine (1.4 g) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 9.23 (d, J=2.8 Hz, 1H), 8.53 (dd, J=9.2, 2.8 Hz, 1H), 8.33 (s, 1H), 7.39 (d, J=9.2 Hz, 1H), 7.19 (s, 1H), 1.28 (s, 9H).
Intermediate 73 : 6- 4-tert-but I-1H-imidazol I ridinamine To a solution of Intermediate (72) (1.2 g, 4.9 mmol) in ethanol (40 mL) was added % Pd/C (500 mg). The mixture was stirred under a 40 psi hydrogen atmosphere for 24 h.
The mixture was filtered and concentrated to give 6-(4-tert-butyI-1H-imidazoIyl)pyridin amine (1.1 g) as a yellow solid which was used without further purification. 1H NMR (400 MHz, CD30D) 6 8.22 (s, 1 H), 7.93 (d, J=2.8 Hz, 1H), .40 (m, 2H), 7.28 (d, J=2.4 Hz, 1H), 1.38 (s, 9H).
Intermediate 74 :4-iso ro midazole YEN)NH A on of 1-bromomethylbutanone (15 g, 9.1 mmol) in formamide (60 mL) was refluxed for 4 h. The mixture was poured into 10% aqueous sodium bicarbonate (30 mL) and adjusted to pH=9.5. The solution was extracted with dichloromethane (30 mL * 2). The combined organic layers were washed with 10% aqueous potassium carbonate, brine, dried over NaZSO4, and concentrated under d pressure to give 4-isopropyl-1H-imidazole (5.5 g) as a brown oi|.1H NMR (400 MHz, CDCI3) 6 7.51 (s, 1H), 6.70 (s, 1H), 2.92-2.85 (m, 1H), 1.22 (d, 6H).
Intermediate 75 : 2- 4-iso ro I-1H-imidazol Initro ridine To a solution 2-chloronitropyridine (1 g, 9.1 mmol) in acetonitrile (15 mL) was added Intermediate (74) (1.3 g, 8.3 mmol) and potassium carbonate (2.27 g, 16.4 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL * 3). The combined organic layers were dried over anhydrous NaZSO4 and concentrated under reduced pressure. Purification by silica gel chromatography gave 2-(4-isopropyI-1H-imidazoIy|)nitropyridine (860 mg) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 9.23 (d, J=2.4 Hz, 1H), 8.53 (dd, J=9.2, 2.8 Hz, 1H), 8.35 (d, J=0.8 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 7.31 (s, 1H), 2.94-2.87 (m, 1H), 1.27 (d, J=6.8 Hz, 6H).
Intermediate 76 : 6- 4-iso ro I-1H-imidazol I 3-amine To a solution of Intermediate (75) (800 mg, 3.44 mmol) in methanol (20 mL) was added % Pd/C (400 mg). The mixture was stirred under a 40 psi hydrogen atmosphere 12 h.
The mixture was filtered and the filtrate trated under d re to give 6-(4- isopropyI-1H-imidazoIyl)pyridinamine (600 mg) as a yellow solid which was used without further purification. 1H NMR (400 MHz, CD30D) 6 8.04 (d, J=1.2 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 7.22-7.26 (m, 2H), 7.10 (dd, J=8.4, 2.8 Hz, 1H), 2.83-2.76 (m, 1H), 1.18 (d, J=7.2 Hz, 6H). ediate 77 : +/- -eth I4- 1- 4-bromo henox but Ibenzoate COBr To a 0 °C solution of 4-bromophenol (1.87 g, 1.08 mmol), ethyl 4-(1-hydroxybutyl)benzoate (2 g, 0.9 mmol) and triphenylphosphine (2.83 g, 1.08 mmol) in THF (20 mL) was added DIAD (2.18 g, 1.08 mmol). The resulting mixture was stirred at 30 °C overnight. The on mixture was diluted with brine (20 mL) and extracted with ethyl acetate (3*25 mL). The ed organic layers were dried over NaZSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (+/-)-ethy| 4-(1-(4- bromophenoxy)butyl)benzoate (2.3 g, 67.7 %) as a yellow oil. 1HNMR (400MHz, CDCI3) 6 8.00 (d, J=8.4Hz, 2H), 7.37 (d, J=8.4Hz, 2H), 7.25 (d, J=8.8Hz, 2H), 6.67 (d, J=8.8Hz, 2H), .08 (m, 1H), 4.35 (q, J=7.2Hz, 2H), 1.98-1.94 (m, 1H), 1.80-1.74 (m, 1H), .50 (m, 1H), 1.43-1.39 (m, 1H), 1.37 (t, J=7.2Hz, 3H), 0.94 (t, J=7.2Hz, 3H). ediate 78 : 4- hen I-1H-imidazole A solution of 2-bromophenylethanone (5.56 g, 30.38 mmol) in formamide (35.4 ml, 1.04 mol) was stirred at 185 °C for 3 h. After cooling to room temperature, the reaction was washed with satured aqueous sodium chloride (100 mL) and extracted with ethyl acetate (100 mL * 4). The combined organic extracts were dried over NaZSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel tography to give 4-phenyl-1H—imidazole (4.6 g) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 8.23 (d, J=13.6 Hz, 1H), 7.72-7.75 (m, 3H), 7.34-7.42 (m 2H), 7.26-7.29 (m, 1H). ediate 79 :2-bromomethox -1 3-dimeth lbenzene To a 0 °C solution of 4-bromo-3,5-dimethylphenol (1.00 g, 4.98 mmol) in DMF (10.0 mL) was added iodomethane (1.41 g, 9.96 mmol) and potassium carbonate (1.37 g, 9.96 mmol).
The mixture was stirred for 5 h at room temperature. The mixture was poured into water and extracted with ethyl acetate (15 ml*3). The ed organic layers were dried over NaZSO4 and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 2-bromomethoxy-1,3-dimethylbenzene (1.00 g) as a yellow oil. 1H NMR (400 MHz, CDCI3) 6 6.57 (s, 2H), 3.69 (s, 3H), 2.31 (s, 6H).
Intermediate 80 :4-chloro 4-methox -2 6-dimeth I hen I-1H- razole To a -78 °C solution of Intermediate (79) (500 mg, 2.34 mmol) in THF (10 mL) was added n- BuLi (0.98 mL of a 2.5M solution in s, 2.45 mmol). The reaction e was stirred for 30 min at -78 oC. Di-t—butyl diazene-1,2-dicarboxylate (565 mg, 2.45 mmol) was added in one portion. The reaction e was allowed to warm to room temperature and stirred for min. A solution of 2-chloromalonaldehyde (260 mg, 2.45 mmol) in THF (2.0 mL) was added dropwise at 0 oC. 4M HCI in dioxane (10 mL) was added. The reaction mixture was stirred at reflux overnight. Saturated aqueous NaHC03 was added to bring the s layer to pH=7. The mixture was extracted with ethyl acetate (10 ml x 3). The combined organic layers were dried over NaZSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give compound 4-chloro(4- methoxy-2,6-dimethylphenyl)-1H-pyrazole (100 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCI3) 6 7.57 (s, 1H), 7.35 (s, 1H), 6.57 (s, 2H), 3.74 (s, 3H), 1.92 (s, 6H).
Intermediate 81 :4- 4-chloro-1H- razol I-3 5-dimeth I henol To a -10 °C solution of Intermediate (80) (850 mg, 3.60 mmol) in romethane (15.0 mL) was added boron tribromide (2.72 mg, 10.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred overngiht. The resulting mixture was quenched by addition of methanol and concentrated under d pressure to give 4-(4-chloro-1H- pyrazoIy|)-3,5-dimethy|phenol (795 mg) as a yellow solid. 1H NMR (400 MHz, Methanol- d4) 6 7.83 (d, J=0.4 Hz, 1H), 7.72 (d, J=0.4Hz, 1H), 6.60 (s, 2H), 1.94 (s, 6H). ediate 82 : 1- 2 6-dimeth Initro hen I trifluorometh I -1H-imidazole To a 0 °C solution of 2,6-dimethylnitrophenol (3 g, 17.9 mmol) and pyridine (4.25 g, 53.7 mmol) in romethane (30 mL) was slowly added c anhydride (7.6 g, 26.8 mmol).
The solution was stirred at room temperature for 2 h. The e was concentrated poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was dried over anhydrous NaZSO4 and concentrated under reduced pressure to give crude 2,6- dimethylnitrophenyl trifluoromethanesulfonate (5.5 g) as a yellow solid.
To a 0 °C solution of 4-(trifluoromethyl)-1H-imidazole (1.82 g, 13.4 mmol) in DMF (20 mL) was added sodium e (0.81 g, 20.1 mmol). The mixture was stirred at room temperature for 1 h. The crude 2,6-dimethylnitrophenyl trifluoromethanesuIfonate prepared above (4.0 g, 13.4 mmol) was added. The mixture was stirred at 80 °C for 12 h.
The reaction was diluted with water and extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous NaZSO4 and concentrated under reduced pressure.
The crude material was purified by silica gel tography to give 1-(2,6-dimethyI nitrophenyl)(trifluoromethyl)-1H-imidazole (805 mg, 21%) as a colorless solid. 1H NMR (400 MHz, CDCI3) 6 8.01 (s, 2 H), 7.47 (s, 1 H), 7.23 (s, 1 H), 2.11 (s, 6 H).
Intermediate 83 : 3 5-dimeth I 4- orometh I -1H-imidazol I henol To a solution of Intermediate (82) (470 mg, 1.65 mmol) in ethanol (40 mL) was added 10% Pd/C (150 mg). The mixture was stirred under a 40psi hydrogen atmosphere at 15 °C for 24 h. The mixture was filtered and concentrated under reduced re. The residue was added to a solution of concentrated HZSO4(5.5 mL) in water (20 mL) and cooled to 0 °C. A solution of sodium nitrite (146 mg, 2.12 mmol) in water (2 mL) was added se. The mixture was stirred for at 0 °C 30 min. The reaction was poured into a boiling mixture of concentrated H2804 (2.9 mL) and water (26 mL) and refluxed for 2 h. The on e was then cooled to room temperature and slowly added into ice water. The mixture was extracted with ethyl acetate (30 mL x 3). The ed organic layers were washed with brine, dried over NaZSO4, ed, and then concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 3,5-dimethyl(4- (trifluoromethyl)-1H-imidazolyl)phenol (330 mg) as a yellow solid. 1H NMR (400 MHz, CD30D) 6 7.80 (s, 1 H), 7.68 (s, 1 H), 6.64 (s, 2 H), 2.03 (s, 6 H).
Intermediate 84 : 6- 4- hen I-1H- razol I ridinol Intermediate 25 (400 mg, 1.69 mmol) was added to a 0 00 solution of concentrated H2804 (5.5 ml) in water (20 ml). A solution of sodium nitrite (128.5 mg, 1.86 mmol) in water (1.5 ml) was added dropwise. The reaction was stirred at 0 °C for 1h. The reaction mixture was poured into a g mixture of water (29 ml) and concentrated H2804 (2.6 ml) and ed for 1h. The mixture was cooled, poured into ice water and extracted with ethyl acetate (3 x ml).The organic layer was dried over anhydrous NaZSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to afford 6- (4-phenyI-1H-pyrazoIyl)pyridinol (200 mg) as an orange solid. 1H NMR (400 MHz, CDCI3) 68.75 (s, 1H), 8.14 (d, J=2.8 Hz, 1H), 7.99 (s, 1H), 7.93 (d, J=8.8Hz, 1H), 7.59 (d, J=7.6Hz, 2H), 7.38-7.42 (m, 3H), 7.26-7.29 (m, 1H).
Intermediate 85 : tert—but I4-tert-but I-1H- razolecarbox late A mixture of le (40 g, 0.587 mol) and 2-chloromethylpropane (81.7 g, 0.881 mol) were heated at 220 °C for 6h in an autoclave. The reaction mixture was cooled to room temperature and adjusted to ~pH 9 with saturated aqueous NaHC03. The mixture was extracted with dich|oromethane (200 mL x 3). The combined organic layers were dried over NaZSO4 and concentrated to dryness, providing a 50 g of mixture, consitsting mostly of 4- tert—butyl-1H—pyrazole and 1,4-di-tert—butyI-1H-pyrazole. 500 mg of this crude mixture was dissolved in THF (8 mL). The solution was cooled to 0 °C. LiHMDS (6 mL of a 1M solution in THF, 6.0 mmol) was added. The e was stirred at 0 °C for 45 min. Di-t—butyldicarbonate (967 mg, 4.43 mmol) was added. The resulting mixture was stirred at room temperature ght. The reaction was ed by addition of 1N aqueous HCI and extracted with romethane (10 mL x 3). The ed organic layers were washed with brine, dried over NaZSO4 and concentrated. The crude material was purified by silica gel chromatography to give tert—butyl 4-tert-butyI-1H-pyrazolecarboxylate (120 mg) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 7.82 (s, 1H), 7.63 (s, 1H), 1.64 (s, 9H), 1.26 (s, 9H).
Intermediate 86 : 4-tert-but I-1H- razole HN’N\ To a solution of Intermediate (85) (120 mg, 0.535 mmol) in dich|oromethane (5 mL) was added trifluoroacetic acid (64 mg, 1.6 mmol). The mixture was stirred at romm temperature ght. Saturated aqueous NaHC03 was added and the mixture extracted with dich|oromethane (10 mL x 3). The combined organic layers were washed with brine, dried over NaZSO4, and concentrated to give 4-tert-butyl-1H—pyrazole (80 mg) as a yellow solid. 1H NMR (400 MHz,CDCI3)611.98(brs, 1H), 7.47 (br s, 2H), 1.20 (s, 9H).
Intermediate 87 : 6- 4-tert-but I-1H- razol I ridinamine WO 07850 To a on of 4-tert-butyI-1 H-pyrazole (300 mg, 2.41 mmol) and onitropyridine in acetonitrile (15 mL) was added ium carbonate (833 mg, 6.04 mmol). The mixture was stirred at reflux overnight. The mixture was diluted with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over NaZSO4, and concentrated to give 350 mg yellow solid. The solid was dissolved in ethanol (10 mL). 10 wt% Pd/C (30 mg) was added. The mixture was stirred overnight at 30 °C under a 40 psi hydrogen atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by silica gel chromatography to give 6-(4-tert-butyI-1 H-pyrazol yl)pyridinamine (140 mg) as a yellow solid. 1H NMR (400 MHz, CD30D) 6 8.04 (s, 1H), 7.72 (d, J=2.4 Hz,1H), .47 (m, 2H), 7.09 (dd, J=8.8, 2.8 Hz, 2H), 1.19 (s, 9H).
Intermediate 88 : 4- 5-chloro-2H-indazol I henol 4-(5-chloro-2H-indazolyl)phenol was prepared using a method analogous to that described for Intermediate (Q10), starting from oxyaniline and 5-chloro nitrobenzaldehyde. Yellow solid. 1HNMR (400MHz Methanol-d4) 6 8.60 (d, J=1.6Hz, 1H), 7.71-7.75 (m, 3H), 7.65 (d, J=9.2Hz, 1H), 7.27 (dd, J=9.2, 2.0 Hz, 1H), 6.95 (d, J=8.8Hz, 2H). ediate 89 : 3-meth I 6- 4- trifluorometh I-1H- razol I ridin I butanol Ste A: 6-chloro-N-methox -N-meth Inicotinamide \ N,O\ | | CI N To a solution of 6-chloronicotinic acid (2.0 g, 12.7 mmol) in DMF (20 mL) was added TBTU ( 6.11 g, 19.0 mmol), di-iso-propylethylamine (4.9 g, 38.1 mmol), and N-methoxymethylamine hydrochloride (1.48 g, 15.2 mmol). The reaction mixture was stirred at 25 °C overnight. The reaction solution was poured into brine (40 mL) and extracted with ethyl acetate (40 mL*2).
The organic layer was dried over NaZSO4 and trated under reduced pressure. The 2012/050349 residue was purified by silica gel chromatography to give 6-chloro-N-methoxy-N- methylnicotinamide (2.3g) as an oil. 1H NMR (400 MHz, CDCI3) 6 8.70 (d, J: 2.0 Hz, 1H), 7.95 (dd, J: 2.4, 8.4 Hz, 1H), 7.32 (d, J: 8.0 Hz, 1H), 3.49 (s, 3H), 3.32 (s, 3H).
Ste B: 1- 6-chloro 3- lmeth one Cl N To a 0 00 solution of 6-chloro-N-methoxy-N-methylnicotinamide (2 g, 10 mmol) in THF (30 mL) was added the iso-butymagnesium bromide (15 mL of a 1.33M solution in THF, 20 mmol). The reaction mixture was d at 25 °C for 2 h. The reaction was quenched by addition of aqueous NH4C| (30 mL) and extracted with ethyl acetate (30 mL*2). The organic layer was washed with brine (50 mL) and water (50 mL), then dried over anhydrous NaZSO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 1-(6-chloropyridinyl)methy|butanone (1.8 g) as a colorless solid. 1H NMR (400 MHz, CDCI3) 6 8.85 (d, J=2.0 Hz, 1H), 8.12 (dd, J=2.4, 8.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 2.75 (d, J: 6.8 Hz, 2H), 2.26-2.19 (m, 1H), 0.94 (d, J: 6.8 Hz, 6H).
Ste C: 3-meth l 6- 4- trifluorometh l-1H- razol l ridin |butanone / N,N\ To a solution of 1-(6-chloropyridinyl)methy|butanone (1.0 g, 5.1 mmol) and 4- (trifluoromethyl)-1H-pyrazole (766 mg, 5.62 mmol) in anhydrous DMF (20 mL) was added potassium carbonate (2.12 g, 15.3 mmol). The mixture was stirred at 50 °C for 6 h. The reaction e was poured into brine (30 mL) and ted with ethyl acetate (30 mL*2).
The combined organic layers were dried over anhydrous NaZSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 3-methyl(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridinyl)butanone (1.4 g) as a colorless solid. 1H NMR (400 MHz, CDCI3) 6 8.92 (d, J=2.0 Hz, 1H), 8.85 (s, 1H), 8.33 (dd, J=2.0, 8.4 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 2.79 (d, J=6.8 Hz, 2H), 2.31-2.21 (m, 1H), 0.96 (d, J=6.8 Hz, 6H).
Ste D: 3-meth l 6- 4- trifluorometh l-1H- razol l ridin |butanol To a 0 00 solution of 3-methyl(6-(4-(trifluoromethyl)-1H-pyrazolyl)pyridinyl)butan one (1.4 g, 4.7 mmol) in methanol (20 mL) was added sodium borohydride (367 mg, 9.4 mmol). The resulting mixture was stirred at 20 °C for 1hour. Water was added and the mixture was extracted with ethyl acetate (40mL). The organic layer was dried over anhydrous NaZSO4, filtered, and trated to give 3-methyI(6-(4-(trifluoromethy|)-1H- pyrazoIyl)pyridinyl)butano| (1.4 g) as a colorless solid. 1H NMR (400 MHz, CDCI3) 6 8.78 (s, 1H), 8.32 (d, J: 2.0 Hz, 1H), 7.91 (d, J: 8.4 Hz, 1H), .79 (m, 2H), 4.82-4.77 (m, 1H), 1.83 (s, 1H), 1.75-1.64 (m, 2H), 1.47-1.43 (m,1H), 0.88-0.92 (m, 6H).
Intermediate 90 : meth I6- tert—butox carbon lamino nicotinate o\o/ JOLI/ Di-t—butyldicarbonate (5.0 g, 23 mmol) was added to a room temperature suspension of methyl 6-aminonicotinate (2.65g, 17.4 mmol) and N,N-dimethylaminopyridine (109 mg, 0.86 mmol) in 40 mL acetonitrile. The resulting orange mixture was stirred at room temperature overnight. The sion was filtered. The solid was washed with acetonitrile and air dried to give 2.64g methyl 6-(tert—butoxycarbonylamino)nicotinate as a ess solid. The filtrate was concentrated under reduced pressure. The residue was ed by silica gel chromatography to give an additional 1.50g methyl 6-(tert—butoxycarbonylamino)nicotinate. 1H NMR (400 MHz, CDCI3) 6 .92 (m, 1H), 8.49-8.59 (br s, 1H), 8.24 (dd, J=8.0, 2.3Hz, 1H), 8.04 (d, J=8.0 Hz), 3.89 (s, 3H), 1.54 (s, 9H).
Intermediate 91 : -N- 2-c clo ro I dimeth lamino all lidene -N- meth lmethanaminium hexafluoro hos hate V (+3/ 9 \N / N/ PFe I l (E)—N-(2-cyclopropyl(dimethylamino)allylidene)-N-methylmethanaminium uorophosphate(V) was ed using a method analogous to that described for the preparation of Intermediate (7A), starting from 2-cyclopropylacetic acid. Yellow solid. 1H NMR (400MHz, DMSO-d6) 67.38 (s, 2H), 3.42 (s, 6H), 3.25 (s, 6H), 1.80-1.78 (m, 1H), 0.89- 0.85 (m, 2H), 0.47-0.43 (m, 2H).
Intermediate 92 : 1- 4-bromo-2 6-dimeth I hen Ic clo ro I-1H- razole 1-(4-bromo-2,6-dimethylphenyl)cyclopropyI-1H-pyrazole was prepared using a method analogous to that described for the preparation of Intermediate (7), starting from Intermediate (7B) and Intermediate (91). Brown oil. 1H NMR (400MHz, CDCI3) 6 7.42 (s, WO 07850 1H), 7.19 (s, 2H), 7.10 (s, 1H), 1.91 (s, 6H), 1.72-1.67 (m, 1H), 0.85-0.80 (m, 2H), 0.52-0.48 (m, 2H).
Intermediate 93 :4- 4-c clo ro I-1H- razol I-3 5-dimeth I henol 4-(4-cyclopropyI-1H-pyrazoIy|)-3,5-dimethylphenol was prepared using a method analogous to that described for Intermediate (26), starting from Intermediate (92). Yellow solid. 1H NMR (400 MHz, CDCI3) 6 7.55 (br, 1H), 7.42 (s, 1H), 7.10 (s, 1H), 6.30 (s, 1H), 1.79 (s, 6H), 1.71-1.67 (m, 1H), 0.85-0.80 (m, 2H), 0.52-0.48 (m, 2H). ediate 94 : 1- 4-bromo-2 6-dimeth I hen I trifluorometh I -1H-1 2 3-triazole 4-bromo-2,6-dimethylaniline (302 mg, 1.51 mmol) was suspended in 4 mL 18% aqueous HCI. The mixture was cooled to 0 °C. A solution of sodium nitrite (125 mg, 1.81 mmol) in 500 uL water was added dropwise over 5 min. During addition, the suspension begins to clear, giving a yellow solution. The on was stirred at 0 °C 1h. A solution of sodium acetate (2.50 g 30.5 mmol) and sodium azide (201 mg, 3.1 mmol) in 5 mL water was added se. The mixture was stirred at 0 °C for 30 min and then warmed to room temperature. The mixture was extracted with 3x20 mL ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure, without heating, to give 520 mg brown oil. The residue was dissolved in 15 mL ethanol in a heavy walled sealable glass tube. The solution was cooled to -78 °C. 3,3,3-trifluoromethylpropyne was d through the solution for 5 min. A solution of copper (I) iodide (14 mg, 0.074 mmol) and sodium ate (30 mg, 0.15 mmol) in 500 uL water was added. The reaction vessel was sealed and allowed to warm to room temperature. After 15h at, the reaction mixture was cooled to -78°C. The vessel was opened at this temperature and then allowed to warm to room ature. The on mixture was concentrated to give 1-(4-bromo- 2,6-dimethylphenyl)(trifluoromethyl)-1H-1,2,3-triazole (447mg) as a pale yellow solid.
Recrystallization from heptane gave fine, colorless needles. 1H NMR (400 MHz, CDCI3) 6 7.89-7.92 (m, 1H), 7.38 (s, 2H), 1.98 (s, 6H).
Intermediate 95 : 3 5-dimeth I 4- trifluorometh I -1H-1 2 3-triazol I henol 3,5-dimethyl(4-(trifluoromethy|)-1H-1,2,3-triazolyl)phenol was prepared using a method analogous to that described for Intermediate (26), starting from Intermediate (94). Colorless solid. 1H NMR (400 MHz, CDCI3) 6 7.87-7.90 (m, 1H), 6.65 (s, 2H), 5.09 (s, 1H), 1.93 (s, 6H).
Intermediate 96 : eth I3- 4- 1-h drox but I ido ro anoate O O W121M“ Ste A : 4- 1-h drox but I benzoic acid The alcohol corresponding to intermediate 5 (1.0 g, 4.5 mmol) was charged with ydrofuran (10.0 mL), water (10.0 mL), and methanol (10.0 mL). Lithium hydroxide monohydrate (944 mg, 22.5 mmol) was then added. The suspension was d at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 1.4 g of crude material. Purification by silica gel flash chromatography (0 — 30% ethyl acetate in heptane) ed 4-(1- ybutyl)benzoic acid (730 mg, 83% yield) as a white solid. 1H NMR (400 MHz, CDCI3) 6 8.09 (d, J: 8.0 Hz, 2H), 7.46 (d, J: 8.2 Hz, 2H), 4.79 (dd, J: 7.6, 5.5 Hz, 1H), 1.86-1.75 (m, 1H), 1.75-1.64 (m, 1H), 1.52-1.24 (m, 2H), 0.95 (t, J: 7.4 Hz, 3H).
Ste B : eth I 3- 4- 1-h drox but I benzamido ro anoate N,N-dimethylformamide (8.60 mL) was added to a vial containing 4-(1- hydroxybutyl)benzoic acid (250 mg, 1.29 mmol), ethyl 3-aminopropanoate hydrochloride (395 mg, 2.57 mmol) and O—(7-azabenzotriazoIy|)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (979 mg, 2.57 mmol). Diisopropylethylamine (1.12 mL, 6.44 mmol) was then added. The reaction was stirred for 16 h, and was then trated. Purification by column chromatography (0 — 50% ethyl acetate in heptane) afforded ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (350 mg, 93% yield) as an oil. 1H NMR (400 MHz, CDCI3) 6 7.73 (d, J: 8.2 Hz, 2H), 7.40 (d, J: 8.0 Hz, 2H), 6.84 (br.s., 1H), 4.74 (t, J: 6.5 Hz, 1H), 4.23-4.07 (m, 2H), 3.72 (q, J: 5.9 Hz, 2H), 2.64 (t, J: 5.9 Hz, 2012/050349 2H), 1.35-1.72 (m, 1H), 1.72-1.53 (m, 1H), 1.52-1.37 (m, 1H), 1.37-1.30 (m, 1H), 1.23 (t, J: 7.2 Hz, 3H), 0.93 (t, J: 7.3 Hz, 3H). MS (M+1) 294.3.
Intermediate 97 : 5-meth l 4- orometh l-1H- razol l ridinol F3C N_ N OH Ste A : 5-bromometh l 4- trifluorometh l-1H- razol l ridine A flask was charged with 5-bromochloromethylpyridine (250 mg, 1.21 mmol), 4-(trifluoromethyl)-1H-pyrazole (165 mg, 1.21 mmol), potassium ate (512 mg, 3.63 mmol), and anhydrous dimethylformamide (1.21 mL). The reaction was heated at 85 to 130 °C for 36 h. The on was concentrated to give 690 mg of crude material. Purification by silica gel flash chromatography (0 — 5% ethyl acetate in heptane) afforded 5-bromo methyl(4-(trifluoromethyl)-1H-pyrazolyl)pyridine (containing approximately 30% starting al) was carried forth to the next reaction. MS (M+1) 308.1.
Ste B : 5-meth l 4- trifluorometh l-1H- razol l ridinol To a flask containing 5-bromomethyl(4-(trifluoromethyl)-1H-pyrazol yl)pyridine (55.0 mg, 0.180 mmol) in 1,4-dioxane (0.100 mL) and degassed water (0.100 mL), was added tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.0360 mmol), ert— butylphosphino-2',4',6'-triisopropylbiphenyl (6.10 mg, 0.014 mmol), and potassium hydroxide (31.9 mg, 0.0540 mmol). The reaction was purged with nitrogen and then heated at 100 °C for 2 hour. The reaction was quenched with 1 N HCI and extracted three times with ethyl acetate.The organics were dried over sodium sulfate, filtered and concentrated. Purification by silica gel flash tography (0 — 25% ethyl acetate in heptane) afforded impure 5- methyl(4-(trifluoromethyl)-1H-pyrazolyl)pyridinol (containing approximately 30% impurity as a solid. MS (M+H): 244.2.
Intermediate 98 : eth l3- 4- c clobut l h drox meth lbenzamido ro anoate HOEGYHN O\/ o VT Step (A): cyclobutanecarbaldehyde A flask was charged with oxalyl chloride (1.12 mL, 12.8 mmol) and anhydrous methylene de (21.0 mL). The solution was cooled to -78 °C and dimethylsulfoxide (1.82 mL, 25.5 mL) was added dropwise and the on was stirred for 30 min. at -78 °C.
A solution of cyclobutylmethanol (1.10 mL, 11.6 mmol) in methylene chloride (8.0 mL) was added dropwise and the reaction was aged for 1 h at the same temperature. Triethylamine (8.20 mL, 58.0 mL) was then added dropwise and the reaction was warmed to room temperature and aged for 18 h. The reaction was quenched with water and ted three times with methylene chloride. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give cyclobutanecarbaldehyde (2.00 g) as a crude oil containing approximately 1.0 g triethylamine. 1H NMR (400 MHz, CDCI3) 6 9.73 (d, J: 2.0 Hz, 1H), 3.18 (s, 1H), 2.34-2.22 (m, 2H), 2.22-2.11 (m, 2H), 2.11-1.99 (m, 1H), 1.99-1.84 (m, 1H).
Step (B): ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate To a solution of ethyl 4-iodobenzoate (1.45 mL, 8.69 mmol) in anhydrous tetrahydrofuran (14.5 mL) at -40 °C was added isopropyl magnesium chloride lithium chloride x (8.0 mL, 10.4 mmol) dropwise. The resulting brown solution was stirred for 40 min at -40 °C. The crude cyclobutanecarbaldehyde (1.8 g, approximately 10.5 mmol pure) was added and the reaction was warmed to room temperature and d for 18 h.
The reaction is then quenched with 1 N hydrochloric acid and extracted three times with ethyl acetate. The ed organic layers were dried over sodium sulfate, ed, and concentrated to give 2.0 g of crude material. Purification by silica gel flash chromatography (0 — 20% ethyl acetate in heptane) afforded ethyl 4-(cyclobutyl(hydroxy) methyl)benzoate (1.05 g) as an oil. 1H NMR (400 MHz, CDCI3) 6 8.01 (d, J: 8.4 Hz, 2H), 7.39 (d, J: 8.2 Hz, 2H), 4.64 (d, J: 7.6 Hz, 1H), 4.47-4.25 (m, 2H), 2.73-2.47 (m, 1H), .94 (m, 2H), 1.95-1.70 (m, 4H), 1.55 (br. s., 1H), 1.38 (t, J: 7.0 Hz, 3H).
Ste C :4- c clobut l h drox meth l benzoic acid To a flask containing ethyl 4-(cyclobutyl(hydroxy)methyl)benzoate (530 mg, 2.26 mmol) was added ydrofuran (5.60 mL), water (5.60 mL), and methanol (5.60 mL).
Lithium hydroxide monohydrate (475 mg, 11.3 mmol) was then added. The sion was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 490 mg of crude material.
Purification by silica gel flash chromatography (0 — 20% ethyl acetate in heptane) ed 4-(cyclobutyl(hydroxy)methyl)benzoic acid (360 mg, 77%) as a white solid. 1H NMR (400 MHz, CDCI3) 6 8.07 (d, J: 8.2 Hz, 2H), 7.43 (dd, J: 8.0, 1.0 Hz, 2H), 4.67 (d, J: 7.6 Hz, 1H), 2.62 (d, J: 8.0 Hz, 1H), 2.09-1.98 (m, 2H), 1.91-1.80 (m, 4H). MS (M-1): 205.2.
Ste D : eth l3- 4- c clobut l h drox meth l benzamido ro anoate N,N-dimethylformamide (9.00 mL) was added to a vial containing 4- (cyclobutyl(hydroxy)methyl)benzoic acid (370 mg, 1.79 mmol), ethyl 3-aminopropanoate hydrochloride (551 mg, 3.59 mmol) and O—(7-azabenzotriazoly|)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (1.36 g, 3.59 mmol). Diisopropylethylamine (1.56 mL, 8.97 mmol) was then added. The reaction was stirred for 1.5 h, and was then concentrated. cation by column chromatography (0 — 50% ethyl acetate in heptane) afforded ethyl 3-(4-(cyclobutyl(hydroxy)methyl)benzamido)propanoate (570 mg, 100% yield) as a white solid. 1H NMR (400 MHz, CDCI3) 6 7.73 (d, J: 8.2 Hz, 2H), 7.38 (d, J: 8.2 Hz, 2H), 4.63 (d, J: 7.8 Hz, 1H), 4.17 (q, J: 7.2 Hz, 2H), 3.72 (q, J: 6.0 Hz, 2H), 2.64 (t, J: .9 Hz, 2H), 2.61-2.54 (m, 1H), 2.08-1.95 (m, 2H), 1.88-1.75 (m, 4H), 1.27 (t, J: 7.1 Hz, 3H). MS (M+1): 306.3.
Intermediate (99): ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate Step (A) - 3,3-dimethylcyclobutanecarbonyl chloride 3,3-Dimethyl-cyclobutanecarboxylic acid (Parkway Scientific, New York, NY, USA) (500 mg, 3.90 mmol) was ved in dichloromethane (3 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room temperature for 4 h before concentrating in vacuo to provide 3,3-dimethylcyclobutanecarbonyl de which was carried on without purification. 1H NMR (400 MHz, CDCI3) 6 3.49 (quin, J=8.9 Hz, 1 H) 2.27 -2.15 (m, 2 H)2.14 -2.06 (m, 2 H) 1.18 (s, 3 H) 1.12 (s, 3 H).
Step (B): ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate In a 3-neck flask at -30 °C (monitored with thermalcouple) containing ethyl 4- iodobenzoate (25.0 g, 89.0 mmol) in anhydrous tetrahydrofuran (148 mL) was added pylmagnesium chloride (51.0 mL, 20.4 mmol) dropwise over 30 min. and then stirred at the same temperature for another 105 min. Copper iodide (5.07 g, 26.6 mmol) was then added quickly in one portion. The mixture was brought to -20 °C for 25 min. to ensure the solid has dissolved. The reaction is then brought back to -40 °C. 3,3-dimethylcyclobutane carbonyl chloride (15.6 g, 106 mmol) was then added over 5 min. the reaction was then warmed to 0 °C over 4 h. The mixture was then diluted with 1 N HCI and extracted three times with ethyl acetate. The combined c layers were then washed two times with brine and then dried over sodium sulfate, filtered, and concentrated to provide 26.6 g of crude brown oil. Purification by silica gel flash chromatography twice (0 — 5% ethyl acetate in heptane) afforded ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (17.2 g, 74% yield) as an oi|.1H NMR (400 MHz, CDCI3) 6 8.11 (d, J: 8.2 Hz, 2H), 7.93 (d, J: 8.2 Hz, 2H), 4.40 (q, J: 7.2 Hz, 2H), 3.89 (quin, J: 8.8 Hz,1H),2.27 - 2.14 (m, 2H), 2.12 - 2.02 (m, 2H), 1.41 (t, J: 7.1 Hz, 3H), 1.27 (s, 3H), 1.08 (s, 3H). MS (M+1): 261.2. ediate (100): ethyl 4-((3,3-dimethylcyclobutyl)(hydroxy)methyl)benzoate To a flask containing ediate (99) (350 mg, 1.34 mmol) was added anhydrous methanol (6.70 mL). The solution was cooled to 0 °C and sodium borohydride (152 mg, 4.00 mmol) was added. After 20 min., the reaction was quenched with saturated aqueous ammonium chloride and ted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 420 mg of crude material. Purification by silica gel flash chromatography (0 — 15% ethyl acetate in heptane) afforded impure ethyl 4-((3,3-dimethylcyclobutyl)(hydroxy)methyl)benzoate (260 mg, 73.8%) as a solid. 1H NMR (400 MHz, CDCI3) 6 8.00 (d, J: 8.6 Hz, 2H), 7.38 (d, J: 8.0 Hz, 2H), 4.60 (d, J: 7.8 Hz, 1H), 4.37 (q, J: 7.0 Hz, 2H), 2.61-2.39 (m, 1H), 1.89-1.71 (m, 2H), 1.66-1.51 (m, 2H), 1.38 (t, J: 7.2 Hz, 3H), 1.11 (s, 3H), 1.07 (s, 3H).
Intermediate 101 :eth I3- 4- 3 3-dimeth lc clobutanecarbon I benzamido ro anoate Ste A : 4- 3 3-dimeth lc clobutanecarbon I benzoic acid To a flask containing Intermediate (99) (3.00 g, 12.0 mmol) was added anhydrous tetrahydrofuran (28.8 mL), methanol (28.8 mL), and 1 N sodium ide (28.8 mL, 28.8 mmol). After 1 h, the reaction was concentrated to a white solid. The solid was the redissolved in 700 mL of water. With vigorous stirring, 1 N HCI (29.0 mL) was added dropwise and the sion was d for 30 min. at room temperature. The solid was then collected with a Buchner funnel and the solid was washed two times with water. The solid was then azeotrophed with toluene to give 4-(3,3-dimethylcyclobutanecarbonyl) benzoic acid (2.15 g, 92% yield) as a white solid. 1H NMR (400 MHz, CDCI3) 6 8.21 - 8.15 (m, 2H), 8.01- 7.94 (m, 2H), 3.91 (quin, J: 8.9 Hz, 1H), 2.28 - 2.17 (m, 2H), 2.15 - 2.04 (m, 2H), 1.28 (s, 3H), 1.09 (s, 3H). MS (M-1): 231.4.
Ste B : eth I3- 4- 3 3-dimeth lc clobutanecarbon I benzamido ro anoate 2012/050349 Tetrahydrofuran (138 mL) was added to a vial ning 4-(3,3- dimethylcyclobutanecarbonyl)benzoic acid (3.20 g, 14.0 mmol), ethyl 3-aminopropanoate hydrochloride (3.17 g, 20.7 mmol) and 1,2,3-benzotriazolol monohydrate (2.22 g, 14.5 mmol). Triethylamine (9.11 mL, 4.75 mmol) was then added. The reaction was stirred for 16 h, and was then concentrated. Purification by column chromatography (0 — 35% ethyl acetate in heptane) afforded impure ethyl 3-(4-(3,3- dimethylcyclobutanecarbonyl)benzamido)propanoate (4.22 g, approximately 8.90 mmol pure) as an oil. MS (M+1) 332.2.
Intermediate 102 : eth I 3- 4- 3 3-dimeth lc clobut I h drox meth I ido propanoate HO§@(HNWOW 0 0 To a flask containing ethyl 3,3-dimethylcyclobutanecarbonyl)benzamido) propanoate (1.21 g, approximately 2.55 mmol pure) was added anhydrous methanol (18.3 mL). The solution was cooled to 0 °C and sodium borohydride (414 mg, 11.0 mmol) was added. After 15 min., the reaction was quenched with saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 1.10 g of crude material.
Purification by silica gel flash chromatography (0 — 50% ethyl acetate in heptane) afforded impure ethyl 3-(4-((3,3-dimethylcyclobutyl)(hydroxy)methyl)benzamido)propanoate (750 mg, approximately 1.8 mmol pure) as an oil. MS (M+1): 334.3.
Intermediate 103 : 3-methox meth I 4- orometh I-1H- razol I henol EN/ OH Ste A : 1- ox meth I hen I trifluorometh I-1H- razole Intermediate 7A (1.77 g, 5.20 mmol) and 1-(2-methoxymethylphenyl)hydrazine hydrochloride (Shanghai Chempartner Co. Ltd.) (1.00 g, 5.20 mmol) were suspended in tetrahydrofuran (20.8 mL). The suspension was cooled to 0 °C. Sodium methoxide (325 mg, .72 mmol) was added as a solid in one portion. The ice bath was removed and the mixture warmed to room temperature and d for 18 hours. Trifluoroacetic acid (1.77 mL) was then added at room temperature. The reaction was heated to 80°C for 5 hours, diluted with ethyl acetate and washed with saturated sodium bicarbonate twice. The combined aqueous washings were extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 - 10% ethyl acetate in heptane), gave 1-(2-methoxymethylpheny|) (trifluoromethyl)-1H-pyrazole (810 mg, 61%) as a solid. 1H NMR (400 MHz, CDCI3) 6 7.93 (s, 1H), 7.81 - 7.71 (m, 1H), 7.33 (t, J: 8.1 Hz, 1H), 6.96 - 6.81 (m, 2H), 3.76 (s, 3H), 2.07 (s, 3H). MS (M+1): 257.2.
Ste B : 3-methox meth l 4- trifluorometh l-1H- 1- l henol To a flask containing 1-(2-methoxymethylphenyl)(trifluoromethy|)-1H-pyrazole (75.0 mg, 0.290 mmol) was added di-p-methoxobis(1,5-cyclooctadiene)diiridium(|) (2.00 mg, 0.003 mmol), bis(pinacolato)diboron (75.2 mg, 0.290 mmol), 4,4’di-tert-butyl-2,2’-dipyridy| (1.60 mg, 0.006 mmol) and degassed methyl tert-butyl ether (1.50 mL). The resulting red solution was heated to 80 °C for 18 h and then at room temperature for 3 d. The reaction was concentrated. Acetone (0.980 mL) was added to provide a nous solution followed by an aqueous solution of oxone (180 mg, 0.290 mmol), 0.98 mL of water) dropwise over 2 min. The reaction was stirred at room temperature for 18 h. The reaction was then quenched with aqueous sodium bisulfate and extracted three times with methylene de. The combined organic layers were washed with brine and water. The c layer was then dried over sodium sulfate, ed, and concentrated. Purification by column chromatography (0 - 25% ethyl acetate in heptane), gave 3-methoxymethyl(4- uoromethyl)-1H-pyrazolyl)phenol (26.0 mg, 33%) as a solid. 1H NMR (400 MHz, CDCI3) 6 7.93 (s, 1H), 7.75 - 7.70 (m, 1H), 6.27 (dd, J: 15.8, 2.5 Hz, 2H), 3.68 (s, 3H), 1.96 (s, 3H). MS (M+1): 273.2.
Intermediate (104): ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoate F F Step (A): 3,3-difluorocyclobutanecarbonyl chloride 3,3-Difluorocyclobutanecarboxylic acid ay Scientific, New York, NY, USA) (531 mg, 3.90 mmol) was dissolved in dichloromethane (3.00 mL) and oxalyl chloride (1.02 mL, 11.7 mmol) was added. The solution was stirred at room temperature for 4 h before concentrating in vacuo to provide 3,3-difluorocyclobutanecarbonyl chloride (ca. 50% pure), which was d on without purification.
Step (B): ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoate In a 3-neck flask at -30 °C containing ethyl 4-iodobenzoate (600 mg, 2.17 mmol) in anhydrous tetrahydrofuran (6.00 mL) was added isopropylmagnesium chloride lithium chloride complex (1.84 mL, 2.39 mmol) dropwise and then stirred at the same temperature for another 40 min. Copper iodide (124 mg, 0.650 mmol) was then added y in one portion. The mixture was brought to -15 °C for 20 min. to ensure the solid has dissolved.
The reaction is then brought back to -40 °C. Crude 3,3-difluorocyclobutanecarbonyl chloride (470 mg, 1.50 mmol pure) was then added and the reaction was then warmed to 0 °C over 1 h and then stirred at room temperature for 18 h. The mixture was then diluted with 1 N HCI and ted three times with ethyl e. The combined organic layers were then washed with brine and then dried over sodium sulfate, filtered, and concentrated to provide 680 mg of crude oil. Purification by silica gel flash chromatography (0 — 10% ethyl acetate in heptane) afforded impure ethyl 4-(3,3-difluorocyclobutanecarbonyl)benzoate (130 mg, approximately 0.24 mmol pure) as a solid. 1H NMR (400 MHz, CDCI3) 6 8.09 (d, J: 9.0 Hz, 2H), 7.18 (d, J: 9.2 Hz, 2H), 4.39 (q, J: 7.4 Hz, 2H), 3.34-3.15 (m, 1H), 3.12-2.78 (m, 4H), 1.40 (t, J: 7.4 Hz, 3H).
Intermediate 105 : 2- 4- trifluorometh l-1H- razol l nol EHN_/ N )m Ste A : 5-bromo 4- trifluorometh l -1H- razol l rimidine To a mixture of 5-bromochloropyrimidine (4.32 g, 21.5 mmol), fluoromethyl)- 1H-pyrazole (2.92 g, 21.5 mmol), and dried potassium carbonate (8.90 g, 64.4 mmol) was added anhydrous dimethylformamide (31.5 mL). The resulting suspension was heated at 85 °C for 4 h. The reaction was diluted with water and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate, filtered, and trated to give 12.4 g of crude yellow solid. The crude material was put through a plug of silica eluting with 15% ethyl e in heptanes to give o(4- (trifluoromethyl)-1H-pyrazolyl)pyrimidine (6.2 g, 99%) as a solid. 1H NMR (400 MHz, CDCI3) 6 8.87 (s, 1H), 8.83 (s, 2H), 8.02 (s, 1H).
Ste B : 5- 4 4 5 5-tetrameth H 3 2-dioxaborolan l 4- trifluorometh l -1H- razol yl)pyrimidine To a flask containing 5-bromo(4-(trifluoromethyl)-1H-pyrazolyl)pyrimidine (2.90 g, 9.9 mmol) was added bis(dipinacolato)borane (3.00 g, 11.9 mmol), potassium e (2.90 g, 29.7 mmol), and 1,1’-bis(diphenylphosphino)ferrocenepalladium(||)dichloride (366 mg, 0.500 mmol). After purging with nitrogen, anhydrous ylforamide (12.4 mL) was added. The reaction was heated at 80 °C. After 2h, the reaction was cooled to room temperature and partitioned between ethyl acetate and brine. The mixture was filtered through celite and eluted with ethyl acetate. The filtrate was washed twice with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 5.30 g of crude material. Purification by silica gel flash chromatography (0 — 50% ethyl acetate in heptane) afforded 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)(4-(trifluoromethy|)-1H- lyl)pyrimidine (3.22 g, 96% yield) as a yellow solid. 1H NMR (400 MHz, CDCI3) 6 9.05 (s, 2H), 9.00 — 8.89 (m, 1H), 8.02 (s, 1H), 1.38 (s, 12H).
Ste C :2- 4- trifluorometh l -1H- 1- l rimidinol To a flask containing 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)(4- (trifluoromethyl)-1H-pyrazolyl)pyrimidine (3.20 g, 9.40 mmol) was added ol (72.4 mL) and 50% aqueous hydrogen de (1.71 mL). After 2 h, the reaction was carefully concentrated and the solid was ved in diethyl ether and washed twice with water then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 880 mg of crude solid. The brown solid was suspended in water and filtered through a Buchner funnel and washed with ethyl acetate to give a white solid (580 mg). The above aqueous layer was also filtered through a Buchner funnel to provide 926 mg of white solid.
The combined batches provided pure 2-(4-(trifluoromethyl)-1H-pyrazolyl)pyrimidinol (1.50 g, 69%) as a white solid. 1H NMR (400 MHz, CDCI3) : 8.79 (s, 1H), 8.43 (s, 2H), 7.96 (s, 1H). MS (M+1)231.1.
Intermediate 106 :2- 4- trifluorometh l-1H- razol l rimidinamine EHN—/ N Nwt Ste A: 5-nitro 4- trifluorometh l-1H- razol l rimidine A round bottom flask was charged with 2-chloronitropyrimidine (2.50 g, .7 mmol), 4-(trifluoromethyl)—1H-pyrazole (2.35 g, 17.2 mmol), K2C03 (4.33 g, 31.3 mmol) and acetonitrile (39 mL). The reaction was heated at 80 °C for 2 hours.
Potassium carbonate filtered off with a biichner funnel and acetonitrile removed under reduced re. The crude material was dissolved in ethyl acetate and transferred to a separatory funnel. Organics washed with water (3X), with brine (1X), dried over sodium sulfate, filtered and concentrated to afford the raw material. cation by silica gel flash chromatography (ethyl acetate / heptane) provide 5- nitro(4-(trifluoromethyl)-1H-pyrazolyl)pyrimidine (1.95 g, 49%) as a yellow solid. MS (M+1): 259.2.
Ste B :2- 4-trifluorometh l-1H- razol l rimidinamine A Parr Shaker bottle was charged with Pd/C (10% wet; degussa type; 300 mg) and the o(4-(trifluoromethyI)-1H-pyrazoIy|)pyrimidine (1.18 g, 4.55 mmol) in ethyl acetate (91 mL). Shaked at 40 psi of H2 (g) for 8 hours. Crude mixture filtered through celite and concentrated under d pressure to afford 2- (4-(trifluoromethyl)-1H-pyrazolyl)pyrimidinamine (1.78 g, 98%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) 6 5.85 (s, 2 H) 8.15 (s, 1 H) 8.18 (s, 2 H) 8.95 (s, 1 H); MS (M+1): 230.2.
Intermediate 107: 6- 4- hen I-1H-imidazoI I ridinamine The title compound was prepared by a method analogous to that described for ediate (24), using 4-phenyl-1H—imidazole. 1H NMR (400 MHz, CDCI3, 6): 8.69 (d, J: 2.1 Hz, 1 H), 8.40 (s, 1 H), 8.11 (dd, J: 8.5, 2.2 Hz, 1 H), 7.89 (s, 1 H), 7.85 (d, J: 7.2 Hz, 2 H), 7.41 (t, J: 7.7 Hz, 2 H), 7.22 - 7.32 (m, 2 H). MS (M+1) 348.1.
Ste B: 6- 4- hen I-1H-imidazoI I ridinamine The title compound was prepared by a method analogous to that described for Intermediate (25), using 5-iodo(4-phenyI-1H-imidazoIyl)pyridine. 1H NMR (400 MHz, CDCI3, 6): 8.20 (s, 1 H), 7.94 (d, J: 2.7 Hz, 1 H), 7.79 - 7.87 (m, 3 H), 7.38 (t, J: 7.6 Hz, 2 H), 7.22 - 7.28 (m, 1 H), 7.16 - 7.21 (m, 1 H), 7.08 - 7.12 (m, 1 H), 3.72 (br. s., 2 H). MS (M+1) 237.3.
Intermediate 108: 6- 4-chloro—3-meth I-1H- razoI I ridinamine / / \ N NH The title compound was prepared by a method analogous to that described for Intermediate (107), using 4-chloromethyI-1H-pyrazole. 1H NMR (400 MHz, CDCI3, 6): 8.28 (s, 1 H), 7.82 (d, J: 2.9 Hz, 1 H), 7.62 — 7.66 (m, 1 H), 7.07 — 7.11 (m, 1 H), 3.68 (br. s., 2 H), 2.30 (s, 3 H). MS (M+1) 209.2.
Intermediate 109: 6- 4- ridin I-1H- razoI I ridinamine /N\ — \ >’NH2 The title compound was ed by a method ous to that described for Intermediate (107) using 2-(1H-pyrazolyl)pyridine. 1H NMR (400 MHz, CDCI3, 6): 8.88 — 8.90 (m, 1 H), 8.56 — 8.59 (m, 1 H), 8.19 (s, 1 H), 7.88 (d, J: 2.7 Hz, 1 H), 7.77 (d, J: 8.6 Hz, 1 H), 7.62 — 7.68 (m, 1 H), 7.50 — 7.55 (m, 1 H), 7.08 — 7.14 (m, 2 H), 3.73 (br. s., 2 H).
MS (M+1) 238.3.
Intermediate 110: 6- 4-eth Imeth I-1H- razoI I ridinamine The title compound was prepared by a method analogous to that described for Intermediate (107), using 4-ethylmethyI-1H-pyrazole. 1H NMR (400 MHz, CDCI3, 6): 8.07 (s, 1 H), 7.82 (d, J: 2.3 Hz, 1 H), 7.65 (d, J: 8.6 Hz, 1 H), 7.08 (dd, J: 8.7, 2.8 Hz, 1 H), 3.56 (br. s., 2 H), 2.44 (q, J: 7.6 Hz, 2 H), 2.26 (s, 3 H), 1.20 (t, J: 7.5 Hz, 3 H). MS (M+1) 203.3.
Intermediate 111 :3 5-dimeth I 4- trifluorometh I-1H- razoI I benzonitrile “\‘\ CF3 A microwave vial was charged with Intermediate (7) (1.00 g, 3.10 mmol), zinc cyanide (199 mg, 1.69 mmol), zinc acetate (22.9 mg, 0.125 mmol), zinc dust (8.2 mg, 0.13 mmol), bis(dibenzylideneacetone)paIladium(0) (17.8 mg, 0.0310 mmol), and 1,1’-bis(diphenylphosphino)ferrocene (52.6 mg, 0.0940 mmol). The solids were purged with dry nitrogen, and then dissolved in N,N-dimethylformamide (3.13 mL) and water (0.31 mL). The reaction was sealed and heated to 100 °C for 3 hours. The mixture was cooled to room temperature, ed by addition of sat. aq ammonium chloride, and extracted with ethyl acetate (3 x). The combined organics were dried (Na2804) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl e / heptane) gave 3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazoIyl)benzonitrile. 1H NMR (400 MHz, CDCI3, 5): 8.00 (s, 1H), 7.77 (s, 1H), 7.50 (s, 2H), 2.09 (s, 6H). MS (M+1): 266.1. ediate 112 : 3 5-dimeth I 4- trifluorometh I -1H- razol y|)benza|dehyde 1%N\ A solution of Intermediate (111) (250 mg, 0.943 mmol) in tetrahydrofuran (8.57 mL) was cooled to -78 °C. utylaluminum hydride (1.5 M in toluene, 1.57 mL, 2.36 mmol) was added dropwise. After 2 hours, the reaction was warmed to 0 °C. After 30 minutes, the mixture was quenched by addition of sat. aq ammonium chloride, allowed to warm to room temperature, and extracted with ethyl acetate (3 x). The ed organics were dried (NaZSO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) gave 3,5-dimethyl(4-(trifluoromethyl)-1H-pyrazoI y|)benza|dehyde. 1H NMR (400 MHz, CDCI3, 6): 10.04 (s, 1 H), 8.00 (s, 1 H), 7.79 (s, 1 H), 7.70 (s, 2 H), 2.13 (s, 6 H). MS (M+1): 269.2.
Intermedaite 113 : +/— -N- 3 5-dimeth I 4- trifluorometh I -1H- razol I benz lidene - ylpropanesuIfinamide t—Bu/S\|N E113)...N\ To a solution of Intermediate (112) (526 mg, 1.96 mmol) and (+/—)methyl- anesulfinamide (245 mg, 1.96 mmol) in dichloromethane (19.6 mL) was added titanium(IV) ethoxide (0.822 mL, 3.92 mmol). Reaction was refluxed for 1 hour then cooled to room temperature. ol (2 mL) was added followed by sat. aq sodium bicarbonate (1 mL). The resulting slurry was stirred for 1 hour, then concentrated under reduced pressure. After diluting with ethyl acetate (40 mL), the slurry was dried (NaZSO4) and filtered through celite (ethyl acetate eluent). The filtrate was concentrated under reduced pressure to provide (+/—)-N-(3,5-dimethyl- 4-(4-(trifluoromethyl)—1H-pyrazoly|)benzylidene)methy|propanesulfinamide. 1H NMR (400 MHz, CDCI3, 5): 8.59 (s, 1 H), 7.99 (s, 1 H), 7.78 (s, 1 H), 7.66 (s, 2 H), 2.10 (s, 6 H), 1.30 (s, 9 H). lntermedaite 114 : +/— -N- 1- 3 th l 4- trifluorometh | -1H- razol | hen | methylbutyl )—2-methylpropanesulfinamide (ls? t-Bu/ ‘NH figy}N\ A suspension of Intermediate (113) (186 mg, 0.501 mmol) in tetrahydrofuran (5.01 mL) was cooled to -78 °C. lsobutyllithium (1.7 M in heptane, 0.353 mL, 0.600 mmol) was added dropwise. After 2 hours, additional isobutyllithium (1.7 M in heptane, 0.353 mL, 0.600 mmol) was added. After 1 hour, the solution was quenched at -78 °C by addition of sat. aq ammonium chloride (6 mL). The resulting slurry was allowed to warm to room temperature. The e was diluted with 20 mL sat. aq ammonium chloride then extracted with ethyl acetate (3 x 25 mL). The combined organics were dried (NaZSO4) and filtered, and the te was concentrated under reduced re. cation by column chromatography (ethyl acetate / heptane) gave N-(1-(3,5-dimethyl(4-(trifluoromethyl)—1 H- pyrazoly|)pheny|)methy|butyl)methy|propanesulfinamide. 1H NMR (400 MHz, CDCI3, 5): 7.94 (s, 1 H), 7.75 (s, 1 H), 7.12 (s, 2 H), 4.37 (t, J: 7.4 Hz, 1 H), 2.03 (s, 6 H), 1.89 - 1.79 (m, 1 H), 1.68 - 1.45 (m, 4 H), 1.24 (s, 9 H), 0.95 (d, J: 6.6 Hz, 3 H), 0.91 (d, J: 6.6 Hz, 3 H). MS (M+1): 430.5.
Intermediate 115: +/— 3 5-dimeth l 4-trifluorometh l-1H- razol | hen l methylbutanamine hydrochloride HCI ””2 NWN\ To a solution of Intermediate (114) (226 mg, 0.525 mmol) in methanol (2.62 mL) was added hydrogen chloride (4 M in dioxane, 0.524 mL, 2.10 mmol) dropwise.
The reaction was concentrated under reduced pressure to e 1-(3,5- dimethyl(4-(trifluoromethy|)-1H-pyrazoly|)phenyl)methy|butanamine hydrochloride. 1H NMR (400 MHz, CD30D, 5): 8.33 (s, 1 H), 8.08 (s, 1 H), 7.32 (s, 2 H), 4.35 (dd, J: 9.8, 5.9 Hz, 1 H), 2.06 (s, 6 H), 1.99 - 1.87 (m, 1 H), 1.84 - 1.74 (m, 1 H), 1.50 - 1.37 (m, 1 H), 0.99 (d, J: 6.4 Hz, 3 H), 0.95 (d, J: 6.6 Hz, 3 H).
Intermediate 116 : meth l +/— 1- 3 5-dimeth l 4- orometh l -1H- razol l hen lmeth lbut lamino nicotinate fj/COZMG\ | HN N (WN\ To a mixture of Intermediate (115) (190 mg, 0.525 mmol) and potassium carbonate (296 mg, 2.10 mmol) in methylformamide (1.05 mL) was added methyl 6-f|uoronicotinate (88.1 mg, 0.551 mmol). The reaction was heated to 85 °C. After 19 h, the reaction was cooled to room temperature, diluted with water (25 mL), and extracted with ethyl acetate (3 x 25 mL). The combined organics were dried (NaZSO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (ethyl e / heptane) gave methyl (+/—)((1-(3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)pheny|) methylbutyl)amino)nicotinate. 1H NMR (400 MHz, CDCI3, 5): 8.67 (d, J: 1.8 Hz, 1 H), 8.03 (dd, J: 8.8, 2.0 Hz, 1 H), 7.94 (s, 1 H), 7.74 (s, 1 H), 7.12 (s, 2 H), 6.33 (d, J: 9.0 Hz, 1 H), 4.67 - 4.61 (m, 1 H), 3.88 (s, 3 H), 2.01 (s, 6 H), 1.89 - 1.71 (m, 2 H), 1.71 - 1.61 (m, 1 H), 1.02 (d, J: 6.4 Hz, 3 H), 0.98 (d, J: 6.4 Hz, 3 H). MS (M+1): 461.5.
Intermediate 117: +/— 1- 3 5-dimeth I 4- trifluorometh I-1H- razol I hen I methylbutyl)amino)nicotinic acid (WN\ To a solution of Intermediate (116) (197 mg, 0.428 mmol) in tetrahydrofuran (2.14 mL) and methanol (2.14 mL) was added 1 N aq sodium hydroxide (2.14 mL, 2.14 mmol). After 22 h, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 3.5. The mixture was diluted with sat. aq sodium chloride (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organics were dried 4) and filtered, and the filtrate was concentrated under reduced pressure to provide (+/—)((1-(3,5-dimethyl(4-(trifluoromethyl)—1 H-pyrazoI yl)phenyl)methylbutyl)amino)nicotinic acid. 1H NMR (400 MHz, CDCI3, 6): 8.71 (s, 1 H), 8.16 (d, J: 9.0 Hz, 1 H), 7.94 (s, 1 H), 7.75 (s, 1 H), 7.14 (s, 2 H), 6.40 (d, J: 9.2 Hz, 1 H), 4.55 - 4.48 (m, 1 H), 2.02 (s, 6 H), 1.99 - 1.91 (m, 1 H), 1.89 - 1.77 (m, 1 H), 1.71 - 1.60 (m, 1 H), 1.03 (d, J: 6.6 Hz, 3 H), 0.98 (d, J: 6.6 Hz, 3 H).
MS (M+1): 447.5.
Intermediate 118 : eth I R 6- 1- 3 5-dimeth I 4- trifluorometh I -1H- razol yl)phenyl)—3-methylbutyl)amino)nicotinamido)propanoate and edaite (119): ethyl (S)- 3- 6- 1- 3 5-dimeth I 4- trifluorometh I-1H- 1- I hen Imeth Ibut I amino)nicotinamido)propanoate O O O O HN \N (HAN/\JLOE';H HN \N fig?N‘ fig}N‘ To a mixture of Intermediate (117) (183 mg, 0.410 mmol), ine ethyl ester hydrochloride (99.4 mg, 0.615), and 1-hydroxyazabenzotriazole (69.0 mg, 0.492 mmol) in dichloromethane (4.10 mL) was added triethylamine (0.172 mL, 1.23 mmol) followed by N-(3-dimethylaminopropyl)—N’-ethylcarbodiimide hydrochloride (95.8 mg, 0.492 mmol). After 20 hours, additional B-alanine ethyl ester hydrochloride (99.4 mg, 0.615), 1-hydroxyazabenzotriazole (69.0 mg, 0.492 mmol), triethylamine (0.172 mL, 1.23 mmol), N-(3-dimethylaminopropyl)—N’- ethylcarbodiimide hydrochloride (95.8 mg, 0.492 mmol), and dichloromethane (2.10 mL) were added. After 7 hours, the mixture was diluted with dichloromethane (20 mL) and washed with water (3 x 20 mL) and sat. aq sodium chloride (20 mL). The organic layer was dried (NaZSO4) and filtered, and the filtrate was concentrated under d pressure. Purification by column chromatography (ethyl acetate/ heptane) ed by SFC (Chiralpak OD-H column, 10 mm x 250 mm, 15% 2- propanol / carbon dioxide eluent) gave ethyl (R)—3-(6-((1-(3,5-dimethyl(4- (trifluoromethyl)—1H-pyrazoly|)phenyl)methy|butyl)amino)nicotinamido) propanoate (SFC retention time 4.54 min) and ethyl (S)(6-((1-(3,5-dimethy|—4-(4- (trifluoromethyl)—1H-pyrazoly|)phenyl)methy|butyl)amino)nicotinamido) propanoate (SFC retention time 6.94 min). 1H NMR (400 MHz, CDCI3, 5): 8.49 (d, J = 1.6 Hz, 1 H), 7.92 (s, 1 H), 7.77 (dd, J: 8.8, 2.3 Hz, 1 H), 7.74 (s, 1 H), 7.09 (s, 2 H), 6.71 (t, J: 5.9 Hz, 1 H), 6.24 (d, J: 8.8 Hz, 1 H), 5.55 (br. s., 1 H), 4.68 (d, J: 6.4 Hz, 1 H), 4.16 (q, J: 7.0 Hz, 2 H), 3.67 (q, J: 5.9 Hz, 2 H), 2.60 (t, J: 5.9 Hz, 2 H), 1.98 (s, 6 H), 1.80 - 1.67 (m, 2 H), 1.67 - 1.56 (m, 1 H), 1.26 (t, J: 7.1 Hz, 3 H), 0.99 (d, J: 6.2 Hz, 3 H), 0.96 (d, J: 6.2 Hz, 3 H). MS (M+1): 546.4.
An tric synthesis of ethyl (6-((1-(3,5-dimethy|—4-(4- (trifluoromethyl)—1H-pyrazoly|)phenyl)methy|butyl)amino)nicotinamido) propanoate may also be achieved by utilizing (S)-(—)methyl propanesulfinamide and Intermediate (112), analogous to that described for the preparation of Intermediate (113). Ethyl (R)—3-(6-((1-(3,5-dimethyl(4- (trifluoromethyl)—1H-pyrazoIy|)phenyl)methy|butyl)amino)nicotinamido) propanoate may then be prepared analogous to the racemic route.
Intermediate 120 : meth I4- tetrah dro-2H- rancarbon I benzoate o o/ Step A: To a on of methyl 4-iodobenzoate (1.21 mL, 7.24 mmol) in THF (12 ml) at -40 °C was added TurboGrignard (1.3 M in THF,6.13 ml, 7.97 mmol) dropwise.
The mixture was stirred for imately 60 minutes whereupon, tetrahydro-2H- pyrancarbaldehyde (0.761 ml, 0.724 mmol) was added dropwise. The e was stirred for 15 minutes and slowly warmed to rt over 12 hours. The reaction was quenched with HCI (1 N, aq.) and the aq. layer was extracted with EtOAc (3 x 75 mL). The combined organic layers were washed with brine, dried over NaZSO4, filtered, and concentrated in vacuo to provide ethyl 4-(hydroxy(tetrahydro-2H-pyran- 4-yl)methyl)benzoate. Crude mixture used into the next step without any further purification. m: A round bottom flask was charged with ethyl 4- (hydroxy(tetrahydro-2H-pyranyl)methyl)benzoate (1.9 g, 7.2 mmol), the Dess- Martin reagent (3.66 g, 8.63 mmol) and DCM (15 mL). The reaction was stirred at room ature overnight. Reaction d with DCM and solid filtered off. The mother liquor concentrated and loaded onto a silica gel column. Purification by silica gel flash chromatography (ethyl acetate/ DCM) provide methyl 4-(tetrahydro- 2H-pyrancarbonyl)benzoate (290 mg, mmol) as a white solid. 1H NMR (400 MHz, CDCI3)51.75 - 1.96 (m, 4 H) 3.45 - 3.62 (m, 3 H) 3.97 (s, 3 H) 4.07 (dt, J=11.88, 3.25 Hz, 2 H) 7.98 - 8.02 (m, 2 H) 8.12 - 8.17 (m, 2 H); MS (M-1): 246.8.
Intermediate 121 : |+ -meth I4- tetrah dro-2H- ran I 6- 4-trifluorometh I-1H- 1- I ridin lamino meth Ibenzoate o o/ / ,N A round bottom flask was charged with methyl 4-(tetrahydro-2H-pyran carbonyl)benzoate (150 mg, 572 mmol),6-(4-(trifluoromethy|)-1H-pyrazoI idinamine (130 mg, 572 mmol) and MeOH (1.2 mL). Decaborane reagent (26.4 mg, 229 mmol) was added in one portion and the reaction stirred over the week-end. The reaction mixture was quenched with HCI solution (1 N, aq.) and extracted with EtOAc twice. The ed organic layers were washed with brine, dried over NaZSO4 and concentrated under reduced pressure. cation by silica gel flash chromatography (ethyl acetate/ heptane) e thyl 4- ((tetrahydro-2H-pyranyl)((6-(4-(trifluoromethyl)—1H-pyrazolyl)pyridin y|)amino)methyl)benzoate (206 mg, 78%) as a colorless gum. MS (M+1): 461.3.
Intermediate 122 : eth I3- 4- ivalo Ibenzamido ro anoate: O O WNJ‘“ m: A round bottom flask was charged with the ethyl 4-iodobenzoate (10 g, 36 mmol) and THF (45 mL). Solution cooled down to 0 °C. Turbo Grignard 1.3 M in THF (30.6 mL, 39.8 mmol) was then added in one portion and the reaction stirred for 30 minutes at 0 °C. Pivaloyl chloride (5.35 mL, 43.5 mmol) was then charged in a second flask in THF (10 mL) and the preformed anion transferred via canula to the acyl chloride. The on was then slowly warmed to room temperature and stirred overnight. The reaction was quenched with ammonium chloride solution (sat. aq.) and extracted with ethyl acetate (2X), washed with brine (1X), dried over sodium sulfate, filtered and concentrated to provide ethyl 4-pivaloylbenzoate as a crude yellow gum (8.50 g). Used without further purification. 1H NMR (400 MHz, CDCI3)61.30 - 1.36 (m, 9 H) 1.42 (t, J=7.04 Hz, 3 H) 4.40 (q, J=7.24 Hz, 2 H) 7.61 - 7.69 (m, 2 H) 8.04 - 8.12 (m, 2 H); MS (M): 234. m: A round bottom flask was charged with ethyl 4-pivaloylbenzoate (7.67 g, 32.7 mmol), THF (100 mL) and MeOH (100 mL). Sodium ide 1N, aq. (65.5 mL, 65.5 mmol) was then added in one portion. Reaction stirred at 40 °C for 1 hour.
Organic solvent removed under reduced pressure and water (150 mL) added to the flask. Acidification with HCI 1N aq. to ca. pH 1 followed by filtration of the solid WO 07850 formed over a er funnel provide 4-pivaloylbenzoic acid as a light yellow solid (9.25 g). 1H NMR (400 MHz, DMSO-d5)51.25 - 1.27 (m, 9 H) 7.70 - 7.74 (m, 2 H) 7.97 - 8.01 (m, 2 H) 13.00 (br. s., 1 H); MS (M-1): 205.3. m: A round bottom flask was charged with 4-pivaloylbenzoic acid (7.67 g, 37.2 mmol), ethyl opropanoate hydrochloride (6.86 g, 44.6 mmol), HOAT (5.57 g, 40.9 mmol), DCM (93 mL) and TEA (7.80 mL, 55.8 mmol). EDC hydrochloride (7.92 g, 40.9 mmol) was then added in one portion and the reaction allowed to stir at room temperature for 2 hours. DCM added to the reaction mixture and organics washed with an ammonium chloride solution (sat.aq.; 1X), water (2X), brine (1X), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude material. cation by silica gel flash chromatography (ethyl acetate / heptane) provide ethyl 3-(4-pivaloylbenzamido)propanoate as a yellow oil (4.25 g, 37.4%; over 3 steps). 1H NMR (400 MHz, CDCI3) 5 1.26 (m, J=7.02, 7.02 Hz, 3 H) 1.32 (s, 9 H) 2.63 (t, J=5.95 Hz, 2 H) 3.72 (m, J=6.05, 6.05, 6.05 Hz, 2 H) 4.16 (m, J=7.22, 7.22, 7.22 Hz, 2 H) 6.92 (br. s., 1 H) 7.64 - 7.68 (m, 2 H) 7.75 - 7.79 (m, 2 H); MS (M+1): 306.3.
Intermediate 123 |+ -eth l 3- 4- 2 2-dimeth l 6- 4- trifluorometh l -1H- razol l ridin lamino ro lbenzamido ro anoate 0 0 HNT1N/ N’N\ A round bottom flask was charged with Intermediate (32) (1.12 g, 4.91 mmol), ethyl ivaloylbenzamido)propanoate (1.50 g, 4.91 mmol), decaborane (309 mg, 2.46 mmol) and MeOH (12 mL). Reaction mixture stirred overnight at room temperature.
The mixture was ed with 1N HCl and extracted with EtOAc (2X). The combined c layers were washed with brine (1X), dried over NaZSO4, filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate / heptane) provide (i)—ethyl 3-(4- (2,2-dimethyl((6-(4-(trifluoromethy|)-1H-pyrazoly|)pyridiny|)amino)propy|) benzamido)propanoate as an orange gum (1.97 g, . 1H NMR (400 MHz, CDCI3) 5 1.05 (s, 9 H) 1.27 (t, J=7.12 Hz, 3 H) 2.59 - 2.67 (m, 2 H) 3.72 (q, J=6.18 Hz, 2 H) 4.12 - 4.21 (m, 3 H) 6.83 (t, J=5.95 Hz, 1 H) 6.90 (dd, J=8.78, 2.34 Hz, 1 H) 7.37 (d, J=8.00 Hz, 2 H) 7.65 (d, J=8.78 Hz, 1 H) 7.71 (d, J=8.58 Hz, 2 H) 7.76 (br. s., 1 H) 7.79 (s, 1 H) 8.67 (s, 1 H); MS (M+1): 518.4.
Intermediate 124 |+ -eth I 3- 4- 2 2-dimeth I 6- 4- trifluorometh I -1H-imidazol I 3- lamino ro Ibenzamido ro anoate O 0 ”$0“ HQU\I / N N /\\N A round bottom flask was charged with Intermediate (6) (747 mg, 3.28 mmol), 3-(4- pivaloylbenzamido)propanoate (1.00 g, 3.28 mmol), rane (206 mg, 1.64 mmol) and MeOH (8 mL). Reaction mixture stirred overnight at room ature. The mixture was quenched with 1N HCI and extracted with EtOAc (2X). The combined organic layers were washed with brine (1X), dried over NaZSO4, filtered and concentrated under reduced pressure to afford the crude material. Purification by silica gel flash chromatography (ethyl acetate / DCM) provide (i)—ethyl 3-(4-(2,2-dimethyI((6-(4-(trifluoromethyl)-1H-imidazol yl)pyridinyl)amino)propyl)benzamido)propanoate as an orange oil. 1H NMR (400 MHz, DMSO-dg) 6 0.99 (s, 9 H) 1.16 (m, , 6.83 Hz, 3 H) 2.54 (t, J=6.93 Hz, 2 H) 3.42 - 3.50 (m, 2 H) 4.00 - 4.08 (m, 2 H) 4.34 (d, J=8.39 Hz, 1 H) 6.55 (d, J=8.39 Hz, 1 H) 7.11 (dd, J=8.88, 2.83 Hz, 1 H) 7.42 - 7.48 (m, 3 H) 7.71 - 7.77 (m, 2 H) 7.89 (d, J=2.73 Hz, 1 H) 8.26 - 8.30 (m, 1 H) 8.38 (s, 1 H) 8.46 (t, J=5.56 Hz, 1 H); MS (M+1): 518.4.
Intermediate 125: 4- 5-fluoro-indazol l- henol 4-bromophenol (1.27 g, 7.35 mmol) was combined with 5-fluoro-1H-indazole (1.000 g, 7.35 mmol), Cul (69.9 mg, 0.367 mmol), K3PO4 (3.282 g, 15.4 mmol), toluene (15 mL), and dimethylethylenediamine (0.158 mL, 1.47 mmol). This was refluxed as a mixture for 3 d. The reaction was cooled and partitioned between ethyl acetate and sat. NH4CI. The aqueous was extracted with ethyl acetate and the combined organics were dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave 4-(5- fluoro-indazolyl)—phenol (0.114 g) impure with the indazole starting material. Used as is.
The other regioisomer was also observed but was ted by chromatography. MS (M+1): 229.2.
Intermediate 126 : 4- 6-fluoro-indazol l- henol 4-bromophenol (1.27 g, 7.35 mmol) was ed with 6-fluoro-1H-indazole (1.000 g, 7.35 mmol), Cul (69.9 mg, 0.367 mmol), K3PO4 (3.282 g, 15.4 mmol), toluene (15 mL), and dimethylethylenediamine (0.158 mL, 1.47 mmol). This was refluxed as a mixture for 3 d.
The reaction was cooled and partitioned between ethyl acetate and sat. NH4CI. The aqueous was extracted with ethyl acetate and the combined organics were dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave 4-(6- -indazolyl)—phenol (0.129 g, 8%) as a tan solid. The other regioisomer was also ed but was separated by chromatography. 1H NMR (400 MHz, DMSO-d6, 6): 9.86 (s, 1 H) 8.96 (s, 1 H) 7.75 - 7.91 (m, 3 H) 7.41 (d, J: 10.6 Hz, 1 H) 6.99 (td, J: 9.3, 2.2 Hz,1 H) 6.93 (d, J: 8.8 Hz, 2 H); MS (M+1): 229.2.
Intermediate 127. 4- 2H-indazol l -3 5-dimeth l henol Ste A: E 2- h drox meth l hen ldiazen l-3 5-dimeth l henol HO N“ (2-aminophenyl)methanol (4000 mg, 32.48 mmol) was dissolved in water (25 mL) with concentrated HCI (6 N, 7.00 mL, 42.2 mmol) and the solution was cooled in an ice/NaCl bath to -5 0C, ard sodium nitrite (2420 mg, 39 mmol) in 20 mL of water was added dropwise over 20 minutes. Solids itated out. The organic mixture/suspension was stirred at -5 0C->0 0C for 25 minutes. 5 mL CH3CN was added. The solution of 3,5-dimethylphenol (3970 mg, 32.5 mmol) in CH3CN (10 mL) was mixed with a solution of Na2C03 (13.8 g, 130 mmol) in H20 (20 mL). The mixed solution was added to the above diazonium solution slowly at -5 0C->0 0C. The mixture was stirred at at -5 0C->0 0C for 2 hours. Brownish solids precipitated out.
The e was neutralized with conc. HCI (12 N) and diluted with EtOAc. The suspension filtered through celite and washed with EtOAc which was used for tion. After four extractions, the combine dark brownish organic layers were washed with brine, dried over NaZSO4 and concentrated, leading to dark brownish solids. The crude was dissolved in EtOAc and loaded to the column and purified by ISCO (120 g silica gel, EtOAc/Heptane: 0->45%), leading the desired product as orange solids. 1H NMR (400 MHz, DMSO-da) 6 ppm 2.42 (s, 6 H) 4.96 (d, J=5.66 Hz, 2 H) 5.14 - 5.25 (m, 1 H) 6.58 (s, 2 H) 7.29 - 7.36 (m, 1 H) 7.41 - 7.50 (m, 2 H) 7.65 (d, J=0.78 Hz, 1 H) 9.92 (s, 1 H). LCMS: m/z = 257.3 [M+H].
Ste B: 4- 2H-indazol l-3 th l henol Iodine (3980 mg, 15.7 mmol) was added to the orange solution of (E)((2- xymethyl)phenyl)diazenyl)—3,5-dimethylphenol (2680 mg, 10.46 mmol), triphenylphosphine (4110 mg, 15.7 mmol) and imidazole (2140 mg, 31.4 mmol) in tetrahydrofuran (30 mL) at room temperature. The mixture was stirred for 40 minutes. The t was ated. The crude was dissolved in EtOAc/MeOH and loaded to the column and purified by ISCO (40 g silica gel, EtOAc/heptane: 0->50%), leading to the desired product as a white/pale yellow solid. 1H NMR (400 MHz, CDCI3) 6 ppm 1.85 (s, 6 H) 6.49 (s, 2 H) 7.07 - 7.21 (m, 1 H) 7.32 - 7.42 (m, 1 H) 7.75 (d, J=8.58 Hz, 1 H) 7.80 (dd, , 0.98 Hz, 1 H) 7.96 (d, J=0.78 Hz, 1 H) 7.99 (s, 1 H). LCMS: m/z = 239.2 [M+H].
Intermediate 128 : 1- 6- 4- trifluorometh l -1H- razol l ridin l butanol Ste A: 1- 6-chloro ridin l butanol To a -10 °C solution of 6-chloronicotinaldehyde (553 mg, 3.91 mmol) in 3.5 mL THF was added n-propylmagnesium bromide (2.34 mL of a 2.0 M solution in THF, 4.69 mmol). The solution was stirred at -10 °C for 10 min, and was then allowed to warm to room temperature. The reaction mixture was ed by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was concentrated. The crude residue was purified by silica gel chromatography to give 1-(6- chloropyridinyl)butano| (400 mg) as a yellow oil. 1H NMR (400 MHz, CDCI3) 6 8.24- 8.31 (m, 1H), 7.61-7.67 (m, 1H), .30 (m, 1H), 4.68-4.74 (m, 1H), 2.05-2.26 (brs, 1H), 1.69-1.82 (m, 1H), 1.57-1.68 (m, 1H), 1.19-1.49 (m, 2H), 0.91 (t, J=7.43 Hz, 3H).
Ste B: 1- 6-chloro ridin l butanone To a solution of_1-(6-chloropyridinyl)butano| (210 mg, 1.13 mmol) in 10 mL dichloromethane was added 2g of silica gel, followed by pyridinium chlorochromate (488 mg, 2.26 mmol) The mixture was stirred at room temperature 5h. The e was filtered through a plug of silica gel, eluting with 100 mL dichloromethane. The eluent was concentrated to give 1-(6-ch|oropyridinyl)butanone (210 mg). 1H NMR (400 MHz, CDCI3) 6 8.88-8.96 (m, 1H), .20 (m, 1H), 7.42 (d, J=8.4 Hz, 1H), 2.92 (t, J=7.2 Hz, 2H), .82 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).
Ste C: 1- 6- 4- trifluorometh l-1H- razol l ridin lbutanone / N’N\ F F A mixture of 4-(trifluoromethyl)pyrazole (116 mg, 0.85 mmol), 1-(6-chloropyridinyl)butan- 1-one (130 mg, 0.71 mmol), and potassium carbonate (294 mg, 2.12 mmol) was stirred 4h at 50 °C. The mixture was cooled to room temperature and stirred overnight. The e was partitioned n ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The e was purified by silica gel chromatography to give 1-(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridinyl)butanone (200 mg) as a colorless solid. 1H NMR (400 MHz, CDCI3) 6 8.97-8.99 (m. 1H), 8.90-8.91 (m, 1H), 8.39 (dd, J: 8.5, 2.4 Hz, 1H), 8.08 (dd, J=8.58, 0.78 Hz, 1H), 7.93 (s, 1H), 2.94 (t, J=7.4 Hz, 2H), 1.74-1.85 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).
Ste D: 1- 6- 4- orometh l-1H- razol l ridin lbutanol 1-(6-(4-(trif|uoromethy|)-1H-pyrazoly|)pyridinyl)butanone (140 mg, 0.49 mmol) was dissolved in 5 mL methanol. Sodium borohydride (18.7 mg, 0.494 mmol) was added. The reaction mixture was concentrated and the residue partitioned between water and ethyl acetate. The organic layer was concentrated to give 1-(6-(4-(trif|uoromethy|)-1H-pyrazol y|)pyridiny|)butano| (140 mg). 1H NMR (400 MHz, CDCI3) 6 8.84 (s, 1H), 8.34-8.40 (m, 1H), 7.96 (d, J: 8.4 Hz, 1H), 7.82-7.90 (m, 2H), 4.75-4.82 (m, 1H), 1.64-1.89 (m, 2H), 1.27- 1.53 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Intermediate 129 :2- 4- trifluorometh l-1H-imidazol l namine A mixture of 4-(trifluoromethyl)-1H-imidazole (572 mg, 4.2 mmol) 5-bromo chloropyrimidine (813 mg, 4.20 mmol) and potassium carbonate (1740 mg, 12.6 mmol) in DMF (5 mL) was heated at 85 °C for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The ed organic layers were dried over sodium sulfate and concentrated under reduced pressure. A mixture of this crude residue (376 mg), copper(|) iodide (61.1 mg, 0.32 mmol), 4-hydroxy-L-proline (84.1 mg, 0.64 mmol) and ium carbonate (537 mg, 3.85 mmol) was purged with nitrogen. Dimethyl sulfoxide (2.5 mL) was added followed by ammonium ide (1.40 mL, 28% aqueous solution).
The mixture was heated at 75 °C for 20 hours. The mixture was diluted with 1 N HCI and extracted with ethyl e. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to the provide 2-(4-(trifluoromethyl)-1H-imidazolyl)pyrimidinamine. 1H NMR (400 MHz, CDCI3) 3.86 (br s, 2H), 8.13 - 8.15 (m, 1H), 8.15 (s, 2H), 8.50 (s, 1H).
LCMS: m/z = 230.1 [M+H].
Preparation of compounds of Formula | Exam le 1: +/— 4- 1- 3-meth l 4- trifluorometh l -1H-imidazol l hen lamino but mido ro anoic acid | hen lamino but Ibenzoate WO 07850 To a solution of Intermediate (21) (248 mg, 1.2 mmol) and Intermediate (4) (290 mg, 1.2 mmol) in methanol (12 mL) was added decaborane (44.1 mg, 0.36 mmol) at room ature under nitrogen. The resulting solution was stirred at room ature overnight. The reaction was concentrated and purification by column chromatography (0 — 35% ethyl acetate in heptane), gave (+/—)-methyl(1- (3-methyl(4-(trifluoromethyl)—1H-imidazoly|)phenylamino)butyl)benzoate as a foam. 1H NMR (500 MHz, CDCI3, 5): 8.02 (d, J: 8.29 Hz, 2H), 7.48 (s, 1H), 7.42 (d, J: 8.29 Hz, 2H), 7.25 (s, 1H), 6.90 (d, J: 8.54 Hz, 1H), 6.41 (m, 1H), 6.34 (m, 1H), 4.40 (m, 2H), 3.91 (s, 3H), 1.98 (s, 3H), 1.72 — 1.87 (m, 2H), 1.34 — 1.52 (m, 2H), 0.96 (t, J = 7.32 Hz 3H). MS (M+1): 432.4.
Ste B: +/— -z‘en‘-but l 3- 4- 1- 3-meth l 4- 4- trifluorometh l -1H-imidazol | hen lamino but Ibenzamido ro anoate To a solution of (+/—)-methyl(1-(3-methyl(4-(trifluoromethyl)—1 H- imidazoly|)phenylamino)butyl)benzoate (0.100 g, 0.232 mmol) in methanol (1 mL), tetrahydrofuran (1 mL), and water (1 mL) was added lithium hydroxide (0.40 g, 9.2 mmol). The reaction was stirred at room temperature for 60 hours. The mixture was acidified with 1N HCl and extracted three times with ethyl acetate. The combined organic layers were dried over sodium e, filtered and concentrated.
To the crude residue was added N,N-dimethylformamide (2 mL), beta- alanine tert—butyl ester hydrochloride (69.8 mg, 0.384 mmol) and O—(7- Azabenzotriazoly|)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (146 mg, 0.384 mmol). Diisopropylethylamine (99.3 mg, 0.768 mmol) was then added and the reaction was stirred at room ature for 4 hours. The reaction was concentrated and purification by column chromatography (0 — 70% ethyl acetate in heptane), gave (+/—)-z‘ert—butyl 3-(4-(1-(3-methyl(4-(4-(trifluoromethy|)-1H- imidazoly|)phenylamino)buty|)benzamido)propanoate (92 mg, 88%). 1H NMR (500 MHz, CDCI3, 5): 7.73 (d, J = 8.29 Hz, 2H), 7.46 (s, 1H), 7.39 (d, J = 8.05 Hz, 2H), 7.24 (s, 1H), 6.99 — 6.93 (m, 1H), 6.89 — 6.85 (m, 1H), 6.41 — 6.39 (m, 1H), 6.34 — 6.30 (m, 1H), 4.54 — 4.43 (m, 1H), 4.41 — 4.31 (m, 1H), 3.70 — 3.62 (m, 2H), 2.57 — 2.50 (m, 2H), 1.96 (s, 3H), 1.85 — 1.70 (m, 2H), 1.45 (s, 9H), 1.43 — 1.27 (m, 2H), 0.94 (t, J: 7.44 Hz, 3H). MS (M+1): 545.2.
Ste C: +/— 4- 1- 3-meth l 4- trifluorometh l idazol l hen lamino but Ibenzamido ro anoic acid Trifluoroacetic acid (0.4 mL) was added to a solution of (+/—)-z‘ert—butyl 3-(4- (1-(3-methyl(4-(4-(trifluoromethyl)—1H-imidazolyl)phenylamino)butyl) benzamido)propanoate (58 mg, 0.11 mmol) in dichloromethane (0.6 mL). The mixture was stirred at room temperature overnight. The reaction was concentrated and successively evaporated from dichloromethane, ethyl acetate and e, to give (+/—)(4-(1-(3-methyl(4-(trifluoromethyl)-1H-imidazolyl)phenylamino) butyl)benzamido)propanoic acid (10 mg, 16%) as a solid. 1H NMR (400 MHz, CDCI3, 5): 7.77 — 7.72 (m, 1H), 7.72 — 7.68 (m, 2H), 7.40 — 7.35 (m, 2H), 7.30 — 7.25 (m, 1H), 6.90 — 6.84 (m, 2H), 6.40 — 6.36 (m, 1H), 6.33 — 6.28 (m, 1H), 4.41 — 4.32 (m, 1H), 3.82 — 3.67 (m, 2H), 2.75 — 2.66 (m, 2H), 1.97 (s, 3H), 1.89 — 1.73 (m, 2H), 1.49 — 1.31 (m, 2H), 0.94 (t, J: 7.44 Hz, 3H). MS (M+1): 489.2.
Exam le 2: +/— 4- 3-meth l 4- 4- trifluorometh l -1H-imidazol l hen l butox benzamido ro anoic acid Ste A: +/— -meth l 4- 3-meth l 4- 4- orometh l -1H-imidazol yl )Qhenyl )butoxy )benzoate NVN ::: :0 \0‘: Dimethylsulfoxide (1.5 mL) was added to a screw-top reaction vial charged with Intermediate (34) (128 mg, 0.339 mmol), 4-(trifluoromethyl)imidazole (55 mg, 0.406 mmol), copper(|) iodide (13 mg, 0.068 mmol), quinolinol (9.9 mg, 0.068 mmol), and potassium carbonate (92 mg, 0.67 mmol). The vial was evacuated and illed with nitrogen repeatedly then heated with stirring to 100°C overnight.
After 18 hours the on was d with saturated ammonium chloride (20 mL) and ethyl acetate (20 mL). The phases were separated and the organic layer was washed with water (2 x 20 mL) and brine (5 mL). The organics were dried over magnesium sulfate, filtered and concentrated. cation by column chromatography (0 — 50% ethyl acetate in heptanes) gave (+/—)-methyl 4-(3-methyl- 1-(4-(4-(trif|uoromethyl)—1H-imidazoly|)phenyl)butoxy)benzoate (65 mg, 44%) as a clear oil. 1H NMR (400 MHz, CDCI3, 5): 7.94 — 7.89 (m, 2H), 7.84 (s, 1H), 7.58 (s, 1H), 7.53 — 7.48 (m, 2H), 7.40 — 7.36 (m, 2H), 6.89 — 6.84 (m, 2H), 5.31 (dd, J= 9, 4.6 Hz, 1H), 3.86 (s, 3H), 2.04 (m, 1H), 1.96 — 1.83 (m, 1H), 1.67 — 1.59 (m, 1H), 1.04 (d, J: 6.6 Hz, 3H), 0.99 (d, J: 6.6 Hz, 3H). MS (M+1): 433.0.
Ste B: +/— 3-meth l 4- 4- trifluorometh l-1H-imidazol l hen lbutox benzoic acid 0£210“ Zfi/D Methyl 4-(3-methyl(4-(4-(trifluoromethy|)-1H-imidazolyl)phenyl)butoxy) benzoate (65 mg, 0.15 mmol) was dissolved in methanol (1.5 mL) and 1M NaOH (0.75 mL) was added at room temperature. The resulting mixture was stirred overnight. The reaction mixture was diluted with water (10 mL), acidified with 1M HCI (1 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give (+/—)(3-methyl(4-(4-(trifluoromethy|)-1H-imidazoly|)phenyl)butoxy)benzoic acid (65 mg, 100%) as a gum. 1H NMR (400 MHz, CDCI3, 5): 7.98 (d, J: 9Hz, 2H), 7.88 (s, 1H), 7.59 (d, J: 8.5 Hz, 2H), 7.58 (s, 1H), 7.39 (d, J: 8.5 Hz, 2H), 6.89 (d, J: 8.8 Hz, 2H), 5.33 (dd, J: 9, 4.6 Hz, 1H), 2.05 (m, 1H), 1.96-1.83 (m, 1H), 1.67- 1.60 (m, 1H), 1.04 (d, J :66 Hz, 3H), 0.99 (d, J-6.6 Hz, 3H). MS (M+1): 419.0.
Ste C: +/— -meth l 3- 4- 3-meth l 4- 4- trifluorometh l -1H-imidazol | hen Ibutox benzamido ro anoate 4-(3-Methyl(4-(4-(trif|uoromethyl)—1H-imidazoly|)phenyl)butoxy)benzoic acid (65 mg, 0.16 mmol), methyl beta-alanine hydrochloride (31 mg, 0.16 mmol), and triethylamine (0.031 mL) were dissolved in dichloromethane (1 mL). l (3-dimethylaminopropy|)carbodiimide hydrochloride (34 mg, 0.18 mmol) was added.
The solution was stirred at room ature for 15 minutes, and 1-hydroxy azabenzotriazole (34 mg, 0.25 mmol) was then added. The resulting yellow solution was stirred overnight. After 18 hours, the reaction was diluted with ethyl acetate (20 mL) and washed with water (25 mL) and brine (10 mL). The organics were dried over ium sulfate, ed and trated. Purification by column chromatography (0 — 100% ethyl acetate in heptane) gave methy| 3- (4-(3-methyl(4-(4-(trifluoromethyl)—1H-imidazoly|)pheny|)butoxy)benzamido) propanoate (70 mg, 90%). 1H NMR (400 MHz, CDCI3, 5): 7.84 (s, 1H), 7.67 — 7.62 (m, 2H), 7.58 (s, 1H), 7.53 — 7.46 (m, 2H), 7.39 — 7.34 (m 2H), 6.89 — 6.84 (m, 2H), 6.72 (t, J = 5.9 Hz, 1H), 5.29 (dd, J = 8.9, 4.5 Hz, 1H), 3.72 — 3.65 (m, 5H), 2.63 (m, 2H), 2.03 (m, 1H),1.95 — 1.83 (m, 1H), 1.85 — 1.58 (m, 1H), 1.03 (d, J = 6.6 Hz, 3H), 0.99 (d, J: 6.3 Hz, 3H). MS (M+1): 504.0.
Ste D: +/— 4- 3-meth l 4- 4- trifluorometh l idazol l hen l butox ido ro anoic acid Methyl 3-(4-(3-methyl(4-(4-(trifluoromethyl)—1H-imidazolyl)phenyl) butoxy)benzamido)propanoate (70 mg, 0.14 mmol) was dissolved in methanol (2 mL) and 1M lithium hydroxide (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The methanol was d under reduced pressure and the residue was diluted with water (2 mL). Upon stirring a precipitate forms. The solution was further diluted with water (15 mL) and 1M NaOH (3 mL). The solution was extracted with ether (20 mL). The organics were washed with water (10 mL) and the aqueous layers were combined. The aqueous solution was acidified with 1M HCI to give a cloudy solution. The solution was ted with ethyl acetate (2 x mL). The combined cs were dried over sodium sulfate, filtered and concentrated to give (+/—)—3-(4-(3-methyl(4-(4-(trif|uoromethyl)—1 H-imidazol yl)phenyl)butoxy)benzamido)propanoic acid (53.1 mg, 78%) as an off-white solid. 1H NMR (400 MHz, CDCI3, 6): 7.89 (s, 1H), 7.66 — 7.60 (m, 2H), 7.58 (s, 1H), 7.49 (d, J: 8.5 Hz, 2H), 7.36 (d, J: 8.5 Hz, 2H), 6.97 — 6.92 (m, 2H), 6.77 (t, J: 6 Hz, 1H), 5.29 (dd, J: 9, 4.4 Hz, 1H), 3.73 — 3.63 (m, 2H), 2.66 — 2.64 (m, 2H), 2.06 — 2.00 (m, 1H), 1.95 — 1.83 (m, 1H), 1.62 (m, 1H), 1.03 (d, J: 6.6 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H). MS (M+1): 490.2.
Exam le 3: +/— 6- 1- 4- 4- trifluorometh l -1H- razol l henox but I nicotinamido ro anoic acid 0 O \ N/QLOH | H GON’N\ F F WO 07850 Ste A: +/— bromo 1- 4- 4- trifluorometh l-1H- razol l henox but I pyridine 6’9N\ F Intermediate (36) (216 mg, 0.50 mmol), 4-trifluoromethylpyrazole (68 mg, 0.50 mmol), copper(|) iodide (19 mg, 0.10 mmol), transhydroxy—L-proline (26.2 mg, 0.20 mmol) and cesium carbonate (329 mg, 1.00 mmol) were suspended in dimethylsulfoxide and heated to 85°C with stirring for 18 hours. The reaction was diluted with ethyl acetate (25 mL) and washed with water (2 x 25 mL) and brine (20 mL). The organics were dried over magnesium sulfate, filtered and concentrated.
Purification by column tography (0 — 50% ethyl acetate in heptanes) gave 5- bromo(1-(4-(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)pyridine (81 mg, 37%) as a clear oil.1H NMR (400 MHz, CDCI3, 5): 8.63 (d, J = 2.3 Hz, 1H), 8.00 (br. s, 1H), 7.82 (br. s, 1H), 7.75 (dd, J: 8.4, 2.3 Hz, 1H), 7.49 — 7.43 (m, 2H), 7.26 (d, overlaps with CHCI3, 1H), 6.94 — 6.88 (m, 2H), 5.22 (dd, J: 8.0, 4.9 Hz, 1H), 2.03 — 1.86 (m, 2H), 1.62 — 1.38 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).
Ste B: +/— -eth l3- 6- 1- 4- 4- orometh l-1H- razol l henox but I nicotinamido)propanoate F F 0 FWu’N -Bromo(1-(4-(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)pyridine (81 mg, 0.180 mmol), ethyl 3-aminopropanoate hydrochloride (85 mg, 0.55 mmol), molybdenumhexacarbonyl (50 mg, 0.18 mmol), tri-z‘ert—butylphosphonium tetrafluoroborate (8.4 mg, 0.028 mmol), palladium(|l) acetate (2 mg, 9 umol), and azabicycloundecene (150 uL, 1.1 mmol) were placed in a microwave vial and suspended in dry acetonitrile (2 mL). The vial was capped and heated by a Biotage lnitiator microwave to 170°C for 2 minutes. The ing dark amber mixture was filtered through a 1” plug of silica gel, and eluted with ethyl acetate.
The residue was concentrated and purification by column chromatography (0 — 100% ethyl acetate in heptane) gave (+/—)—ethyl 3-(6-(1-(4-(4-(trifluoromethyl)—1H- pyrazoly|)phenoxy)butyl)nicotinamido)propanoate (42 mg, 45%) as a pale amber glass. 1H NMR (400 MHz, CDCI3, 5): 8.63 (dd, J: 2.2, 0.9 Hz, 1H), 8.01 — 7.97 (m, 2H), 7.82 (s, 1H), 7.48 — 7.40 (m, 3H), 6.94 — 6.85 (m, 3H), 5.30 (dd, J: 7.90, 4.8 Hz, 1H), 4.15 (q, J: 7.2 Hz, 2H), 3.74 — 3.68 (m, 2H), 2.65 — 2.60 (m, 2H), 2.05 — 1.87 (m, 2H), 1.63 — 1.39 (m, 2H), 1.28 — 1.23 (m, 3H), 0.96 (t, J: 7.4 Hz, 3H). MS (M+1): 505.4.
Ste C: +/— 6- 1- 4- 4- trifluorometh l-1H- razol l henox but I nicotinamido ro anoic acid (+/—)—Ethyl 3-(6-(1-(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenoxy)butyl) nicotinamido)propanoate (45 mg, 0.089 mmol) was ved in ol (2 mL). 1 M NaOH (2 mL) was added with stirring at room temperature. After stirring for 6 hours, 1M HCI (2 mL) was added. The pH was adjusted to approximately 4, using 1M HCI and 1M NaOH. The resulting cloudy solution was extracted with ethyl acetate (2 x 15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give (+/—)—3-(6-(1-(4-(4-(trifluoromethyl)—1 zol yl)phenoxy)butyl)nicotinamido)propanoic acid (42mg, 100%) as a foamy solid. 1H NMR (400 MHz, CDCI3, 5): 9.23 (d, J: 1.6 Hz, 1H), 8.38 (dd, J: 8.2, 2.1 Hz, 1H), 7.99 (s, 1H), 7.85 — 7.80 (m, 2H), 7.55 (d, 1H), 7.49 — 7.42 (m, 2H), 6.92 — 6.85 (m, 2H), 5.31 (dd, J: 7.7 — 3.76 (m, 2H), 2.75 — 2.69 (m, 2H), 2.09 — , 4.8 Hz, 1H), 3.83 1.85 (m, 2H), 1.60 — 1.39 (m, 2H), 0.96 (t, J: 7.3 Hz, 3H). MS (M+1): 477.3.
Exam le 4: +/— 4- 4-meth l 4- 4- trifluorometh l -1H- razol l hen l entan lbenzamido ro anoic acid F?\/ ,N Ste A: meth l4- 1- 4-bromo hen th l enten l benzoate 4-Bromobenzyltriphenylphosphonium bromide (2.07 g, 4.40 mmol) was suspended in toluene (4.0 mL) and cooled to 0°C. Lithium bis(trimethylsilyl)amide (4.04 mL, 1.0 M in toluene) was added. The ice bath was removed and the reaction was allowed to warm to room temperature and stir for 1 hour. A solution of Intermediate (10) (180 mg, 0.817 mmol) in toluene (0.8 mL) was then added drop-wise, and the reaction was allowed to stir for 18 hours. The reaction was diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted three times with ethyl acetate. The combined organics were washed twice with 1N HCI and once with brine, then dried over magnesium sulfate, ed, and concentrated.
The crude solid was taken up in heptane and the remaining solids (triphenylphospine oxide) were ed off. The filtrate was concentrated and purified by column chromatography (0 — 10% ethyl acetate in heptane) to give methyl 4-(1-(4-bromophenyl)methylpentenyl)benzoate (184.7 mg, 61%) as an approximate 1:1 e of E/Z s. 1H NMR (400 MHz, CDCI3, 6): 8.04 — 8.00 (m, 2H), 7.97 — 7.92 (m, 2H), 7.50 — 7.46 (m, 4H), 7.22 — 7.16 (m, 6H), 6.77 — 6.72 (m, 2H), 6.69 (s, 1H), 6.39 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.58 (d, J: 7.4 Hz, 2H), 2.37 (dd, J: 7212 Hz, 2H), 1.68 — 1.57 (m, 1H), 1.51 (dt, J: 13.5, 6.8 Hz, 1H), 0.88 (d, J: 6.6 Hz, 6H), 0.78 (d, J: 6.6 Hz, 6H).
Ste B: meth l4- 4-meth l4- 4-trifluorometh l-1H- 1- l hen l ent enyl )benzoate WO 07850 An ried and nitrogen-cooled vial was charged with 4-trifluoromethyl pyrazole (77.0 mg, 0.56 mmol), quinolinol (10mg, 0.07 mmol), copper(l) iodide (14 mg, 0.073 mmol), and potassium carbonate (140 mg, 1.0 mmol). A solution of methyl 4-(1-(4-bromophenyl)methylpentenyl)benzoate (182.7 mg, 0.489 mmol) in dimethylsulfoxide (2.5 mL) was then added. The vial was capped and evacuated and back-filled with nitrogen four times. The reaction was then heated to 90°C for 18 hours. The reaction was cooled to room temperature and partitioned between saturated um chloride and ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined organics were dried over magnesium e, filtered, and concentrated. Column chromatography (0 — 10% ethyl acetate in heptane) provided methyl 4-(4-methyl(4-(4-(trifluoromethyl)-1H- pyrazolyl)phenyl)pentenyl)benzoate (19.8 mg, 9.5%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CDCI3, 6): 8.20 (s, 1H), 8.06 (s, 1H), 8.05 — 8.01 (m, 2H), 7.98 — 7.93 (m, 2H), 7.91 (s, 1H), 7.83 (s, 1H), 7.71 — 7.66 (m, 2H), 7.53 — 7.49 (m, 2H), 7.46 — 7.42 (m, 2H), 7.41 — 7.36 (m, 2H), 7.24 — 7.20 (m, 2H), 7.01 — 6.96 (m, 2H), 6.78 (s, 1H), 6.49 (s, 1H), 3.92 (s, 3H), 3.90 (s, 3H), 2.62 (d, J: 7.2 Hz, 2H), 2.41 (dd, J: 7210 Hz, 2H), 1.70 — 1.48 (m, 2H), 0.90 (d, J: 6.6 Hz, 6H), 0.80 (d, J: 6.6 Hz, 6H). MS (M+1): 429.3.
Ste C: 4- 4-meth l 4- 4- trifluorometh l-1H- razol l hen l enten l benzoic acid Methyl 4-(4-methyl(4-(4-(trifluoromethyl)-1H-pyrazolyl)phenyl)pent enyl)benzoate (19.8 mg, 0.0460 mmol) was dissolved in methanol (0.5 mL) and ydrofuran (0.5 mL). 1 N Sodium hydroxide (0.092 mL) was added and the reaction was stirred at room temperature for 60 hours. The reaction was trated. The crude residue was taken up in water and acidified to pH = 2 with 1N HCI. This solution was extracted four times with ethyl acetate, dried over ium sulfate, filtered, and concentrated to provide 4-(4-methyl(4-(4- uoromethyl)—1H-pyrazoly|)pheny|)pentenyl)benzoic acid (18.3 mg, 96%) as an approximate 1:1 mixture of E/Z isomers. 1H NMR (400 MHz, CDgOD, 6): 8.76 (s, 1H), 8.62 (s, 1H), 8.02 (d, J: 8.4 Hz, 2H), 7.98 (s, 1H), 7.97 — 7.93 (m, 2H), 7.90 (s, 1H), 7.85 — 7.79 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.54 — 7.47 (m, 4H), 7.30 — 7.24 (m, 2H), 7.06 — 7.00 (m, 2H), 6.84 (s, 1H), 6.56 (s, 1H), 2.70 (d, J: 7.2 Hz, 2H), 2.46 (dd, J: 7.2, 1.0 Hz, 2H), 1.63 (dt, J: 13.5, 6.7 Hz, 1H), 1.57 — 1.46 (m, 1H), 0.92 (d, J: 6.6 Hz, 6H), 0.80 (d, J: 6.6 Hz, 6H).
Ste D: +/— -meth | 3- 4- 4-meth l 4- 4- trifluorometh | -1H- razol l hen l entan lbenzamido ro anoate To a solution of ethyl(4-(4-(trifluoromethy|)-1 zol yl)phenyl)penteny|)benzoic acid (18.3mg, 0.0440mmol), methyl 3- aminopropanoate hydrochloride (6.70 mg, 0.0480 mmol), 1-hydroxyaza benzotriazole (6.00 mg, 0.0440mmol), and triethylamine (6.6 uL, 0.047 mmol) in dichloromethane (0.5 mL), was added 1-ethyl(3-dimethylaminopropyl) carbodiimide hydrochloride (8.50 mg, 0.0440 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was diluted with dichloromethane and was washed with water and brine. The organic layer was dried over magnesium e, filtered and concentrated.
This crude material was dissolved in methanol (15 mL) and was cycled through a THALES Nano H-cube (10% Pd/C catalyst cartridge, 50°C, full hydrogen g, 1mL/min) for 2 hours. The crude reaction was concentrated. Purification by column chromatography (0 — 40% ethyl acetate in heptane) gave methyl 3-(4-(4- methyl(4-(4-(trifluoromethy|)-1H-pyrazoly|)phenyl)pentanyl)benzamido) propanoate (4.2mg, 19%). 1H NMR (400 MHz, CDCI3, 5): 8.10 (s, 1H), 7.85 (s, 1H), 7.65 — 7.60 (m, 2H), 7.48 — 7.42 (m, 2H), 7.14 — 7.09 (m, 2H), 7.06 — 7.00 (m, 2H), 6.79 — 6.72 (m, 1H), 3.73 — 3.67 (m, 5H), 3.00 — 2.91 (m, 2H), 2.86 — 2.78 (m, 1H), 2.66 — 2.61 (m, 2H), 1.67 (m, 1H), 1.52 — 1.43 (m, 1H), 1.38 — 1.27 (m, 1H), 0.82 (dd, J: 6.5, 2.4 Hz, 6H). MS (M+1): 502.4.
Ste E: +/— 4- 4-meth l4- 4-trifluorometh l-1H- razol l hen l entan- 2- l ido ro anoic acid Methyl 3-(4-(4-methyl(4-(4-(trifluoromethy|)-1H-pyrazolyl)phenyl)pentan zamido)propanoate (4.2 mg, 0.0080 mmol) was dissolved in 1:1 methanol: tetrahydrofuran (0.50 mL). 1N NaOH (0.024 mL) was added and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated to dryness. The crude residue was taken up in water and acidified to pH = 2 with 1N HCl. This solution was extracted three times with ethyl acetate. The combined organics were dried over magnesium sulfate, ed, and concentrated to give (+/— )(4-(4-methyl(4-(4-(trifluoromethy|)-1H-pyrazolyl)phenyl)pentan yl)benzamido)propanoic acid (4.0 mg, 100%), as a white solid. 1H NMR (400 MHz, CDgOD, 5): 8.62 (s, 1H), 7.91 (s, 1H), 7.69 — 7.64 (m, 2H), 7.58 — 7.53 (m, 2H), 7.22 — 7.17 (m, 2H), 7.14 — 7.09 (m, 2H), 3.62 — 3.55 (m, 2H), 3.09 — 2.96 (m, 2H), 2.90 — 2.81 (m, 1H), 2.60 (t, J: 6.9 Hz, 2H), 1.78 — 1.68 (m, 1H), 1.52 (ddd, J: 13.7, 9.2, 4.9 Hz, 1H), 1.39 — 1.25 (m, 1H), 0.83 (dd, J: 6.4, 4.7 Hz, 6H). MS (M+1): 488.4.
Exam le 5: +/— 4- 1- 6- 4- trifluorometh l -1H- razol l ridine lamino but I benzamido ro anoic acid «L:NN‘@NH 2012/050349 The title nd was prepared by a method analogous to that bed for Example 1 using Intermediate (32). 1H NMR (400 MHz, CDCI3, 6): 8.54 (s, 1 H), 7.83 (s, 1 H), 7.81 (d, J: 2.8 Hz, 1 H), 7.69 (d, J: 8.4 Hz, 2 H), 7.62 (d, J: 8.97 Hz, 1 H), 7.38 (d, J: 8.4 Hz, 2 H), 7.06 (t, J: 5.95 Hz, 1 H), 6.98 (dd, J: 8.97, 2.8 Hz, 1 H), 4.37 (t, J: 6.83 Hz, 1 H), 3.71 (m, 2 H), 2.70 (t, J: 5.85 Hz, 2 H), 1.92 — 1.72 (m, 2 H), 1.50 — 1.26 (m, 2 H), 0.93 (t, J: 7.32 Hz, 3 H). MS(M+1): 476.3.
Exam le 6: 3- 4 6- 4- trifluorometh l-1H- razol | ridine lamino but I benzamido ro anoic acid lsomer1 The title compound is obtained by resolving racemic 3-(4-(1-(6-(4- (trifluoromethyl)—1H-pyrazolyl)pyridineylamino)butyl)benzamido)propanoic acid Example 5, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm.
Mobile Phase: 70/30 COZ/methanol. Flow Rate: 2.5 mL/min. Modifier: none.
Retention time: 4.05 minutes.
Exam le 7: 3- 4 6- 4- trifluorometh l-1H- razol | ridine lamino but I benzamido ro anoic acid lsomer2 The title compound is obtained by resolving racemic 3-(4-(1-(6-(4- uoromethyl)—1H-pyrazolyl)pyridineylamino)butyl)benzamido)propanoic acid, the compound of Example 5, by chiral SFC. Column: Chiralpak AD-H.
Dimensions: 4.6mm x 25cm. Mobile Phase: 70/30 COZ/methanol. Flow Rate: 2.5 . Modifier: none. Retention time: 6.40 minutes.
Exam le 8: +/— 4- c clo ent | 6- 4- trifluorometh | -1H-imidazol | ridine- 3- lamino meth l benzamido ro anoic acid N/_\NH Q The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (31) and Intermediate (6). 1H NMR (400 MHz, CDCI3, 5): 8.29 (s, 1 H), 7.81 (s, 1 H), 7.76 (d, J: 2.73 Hz, 1 H), 7.69 (d, J: 8.19 Hz, 2 H), 7.37 (d, J: 8.19 Hz, 2 H), 7.09 — 7.05 (m, 1 H), 6.96 — 6.90 (m, 1 H), 6.85 — 6.80 (m, 1 H), 4.14 (d, J: 8.39 Hz, 1 H), 3.73 — 3.66 (m, 2 H), 2.72 — 2.64 (m, 2 H), 2.24 — 2.14 (m, 1 H), 2.00 — 1.88 (m, 1 H), 1.75 — 1.20 (m, 7 H). MS (M+1): 502.2.
Exam Ie 9: +/— 4- 1- 6- 4- trifluorometh I -1H-imidazol I ridine lamino but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (6). Column: Waters Atlantis dC18 4.6x50mm, 5pm. Modifier: TFA 0.05%. nt: 95%H20 / 5%MeCN linear to 5%H20/ 95%MeCN over 4.0min, HOLD at 5%H20 / N to 5.0min. Flow: 2.0mL/min.
Retention time: 2.83 min. MS (M+1): 476.4.
Exam Ie 10: 3- 4- 1- 6- 4- trifluorometh I -1H-imidazol I lamino but lbenzamido ro anoic acid lsomer1 N/\ / \ The title compound is obtained by resolving racemic 3-(4-(1-(6-(4- (trifluoromethyl)—1H-imidazolyl) yridineylamino)butyl)benzamido)propanoic acid e 9, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 COZ/ethanol. Flow Rate: 2.5 mL/min. Modifier: none. ion time: 4.990 minutes.
Exam le 11: 3- 4- 1- 6- 4- trifluorometh | -1H-imidazol | ridine lamino but lbenzamido ro anoic acid lsomer2 The title compound'Is obtained by resolving racemicH3--(4-(1-(6-(4- (trifluoromethyl)—1H-imidazolyl)pyridineylamino)butyl)benzamido)propanoic acid Example 9, by chiral SFC. : Chiralpak AD-H. Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 hanol. Flow Rate: 2.5 mL/min. Modifier: none.
Retention time: 7.410 minutes.
Exam le 12: +/— 4- 1- 4- 4- trifluorometh | -1H- razol | hen lamino but I benzamido ro anoic acid {EWVQE The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (5) and Intermediate (52). 1H NMR (400 MHz, CDCI3, 5): 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J: 7.6 Hz, 2H), 7.35 (d, J: 6.8 Hz, 2H), 7.27 (d, J = 7.2 Hz, 2H), 7.03 — 6.88 (m, 1H), 6.60 — 6.42 (m, 2H), 4.33 (t, J = 6.3 Hz, 1H), 3.64 (s, 2H), 2.72 — 2.54 (m, 2H), 1.87 — 1.65 (m, 2H), 1.51 — 1.22 (m, 2H), 0.90 (t, J: 7.0 Hz, 3H). MS (M+1): 475.2.
Exam le 13: +/— 4- 1- 3 5-dimeth l 4- trifluorometh | -1H- 1- l hen lamino but lbenzamido ro anoic acid \g/N/N\ NH 0 F \ 3 FF j NH The title compound was prepared by a method analogous to that described for Example 1 using ediate (8). 1H NMR (400 MHz, CDCI3, 6): 7.91 (s, 1 H), 7.72 — 7.61 (m, 3 H), 7.39 (d, J: 8.00 Hz, 2 H), 7.21 — 7.12 (br. t, J: 5.6 Hz, 1 H), 6.49 (s, 2 H), 4.36 (m, 1 H), 3.75 — 3.59 (m, 2 H), 2.71 — 2.57 (m, 2 H), 1.91 — 1.76 (m, 2 H), 1.84 (s, 6 H), 1.40 — 1.16 (m, 2 H), 0.88 (t, J: 7.32 Hz, 3 H). MS (M+1): 503.2.
Exam le 14: 3- 4- 1- 3 5-dimeth l 4- trifluorometh | -1H- razol | hen lamino but Ibenzamido ro anoic acid lsomer1 \g/N/N\ N H o F \ F i o2ng The title compound is obtained by resolving racemic 1-(3,5-dimethyl (4-(trifluoromethyl)-1H-pyrazolyl)phenylamino)butyl)benzamido)propanoic acid Example 13, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm.
Mobile Phase: 75/25 COZ/2-propanol. Flow Rate: 2.5 . Modifier: none.
Retention time: 3.77 minutes.
Exam le 15: 3- 4- 1- 3 5-dimeth l 4- trifluorometh | -1H- razol | hen lamino but Ibenzamido ro anoic acid lsomer2 NH 0 F\g/N \ 3 FF : NH The title compound is obtained by resolving racemic 3-(4-(1-(3,5-dimethyl (4-(trifluoromethyl)-1H-pyrazolyl)phenylamino)butyl)benzamido)propanoic acid Example 13, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6mm x 25cm.
Mobile Phase: 75/25 C02/2-propanol. Flow Rate: 2.5 mL/min. Modifier: none.
Retention time: 4.62 minutes.
Exam le 16: +/— 4- 1- 4- 4- orometh l -1H-imidazol l hen lamino but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (5) and Intermediate (54). 1H NMR (400 MHz, CDCI3, 5): 7.77 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.43 (s, 1H), 7.39 (d, J: 8.4 Hz, 2H), 7.06 (dt, J: 8.8, 3.5 Hz, 2H), 6.83 (t, J: 6.1 Hz, 1H), 6.53 (dt, J: 8.8, 3.3 Hz, 2H), 4.38 (t, J: 6.7 Hz, 1H), 3.73 (q, J: 6.0 Hz, 2H), 2.71 (t, J: 5.8 Hz, 2H), 1.88 — 1.73 (m, 2H), 1.53 — 1.31 (m, 2H), 0.97 (t, J: 7.3 Hz, 3H). MS (M+1): 475.2.
Exam le 17: 3- 4- 1- 4- 4- trifluorometh l -1H-imidazol l hen lamino but I benzamido ro anoic acid lsomer1 The title nd is obtained by resolving racemic 1-(4-(4- (trifluoromethyl)—1H-imidazolyl)phenylamino)butyl)benzamido)propanoic acid Example 16, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10mm x 250mm. Mobile Phase: 70/30 COZ/methanol. Flow Rate: 10.0mL/min. Modifier: none. Retention time: 7.25 minutes.
Exam le 18: 3- 4- 1- 4- 4- trifluorometh l -1H-imidazol l hen lamino but I benzamido ro anoic acid lsomer2 WO 07850 The title compound is obtained by resolving racemic 3-(4-(1-(4-(4- (trifluoromethyl)—1H-imidazolyl)phenylamino)butyl)benzamido)propanoic acid Example 16, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10mm x 250mm. Mobile Phase: 70/30 COZ/methanol. Flow Rate: 10.0mL/min. Modifier: none. Retention time: 8.80 minutes.
Exam le 19: +/— 4- 1- 4- 4- trifluorometh l -1H-imidazol l henox but I benzamido ro anoic acid butyl ate A mixture of Intermediate (27) (130 mg, 0.32 mmol), 4-(trifluoromethyl)-1H- imidazole (50 mg, 0.37 mmol), quinolinol (7.0 mg, 0.048 mmol), copper(l) iodide (9.1 mg, 0.048 mmol), and potassium ate (90.0 mg, 0.65 mmol) in dimethylsulfoxide (1.5 mL) was stirred under nitrogen at 100°C overnight. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and ted ammonium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by column tography gave (+/—)—methy| 4-(1-(4-(4-(trifluoromethyl)—1 H-imidazol yl)phenoxy)butyl)benzoate (95 mg, 71%). 1H NMR (400 MHz, CDCI3, 5): 8.02 — 7.98 (m ,2H), 7.68 (s, 1H), 7.44 — 7.42 (m, 1H), 7.41 — 7.37 (m, 2H), 7.18 — 7.14 (m, 2H), 6.91 — 6.86 (m, 2H), 5.18 — 5.12 (m, 1H), 3.88 (s, 3H), 2.07 — 1.94 (m, 1H), 1.87 — 1.75 (m, 1H), 1.60 — 1.36 (m, 2H), 0.98 — 0.91 (m, 3H).
Ste B: +/— 1- 4- 4- trifluorometh l-1H—imidazol l henox but Ibenzoic Lithium hydroxide (1.0 mL, 1N in water, 1.0 mmol) was added to a room temperature solution of methyl 4-(1-(4-(4-(trifluoromethyl)—1 H-imidazol yl)phenoxy)butyl)benzoate (95 mg, 0.23 mmol) in tetrahydrofuran (2 mL). The solution was stirred at ambient temperature for 18 hours, then at reflux for 2 hours.
The mixture was cooled to room temperature and acidified to pH = 2 with 1N HCI.
The mixture was ted with ethyl acetate. The c layer was dried over magnesium sulfate, filtered and concentrated to give (+/—)(1-(4-(4- (trifluoromethyl)—1H-imidazoly|)phenoxy)butyl)benzoic acid (80 mg, 87%). 1H NMR (400 MHz, CDCI3, 5): 8.09 — 8.04 (m, 2H), 7.71 (s, 1H), 7.46 — 7.41 (m, 3H), 7.20 — 7.14 (m, 2H), 6.92 — 6.87 (m, 2H), 5.20 — 5.14 (m, 1H), 2.08 — 1.95 (m, 1H), 1.88 — 1.76 (m, 1H), 1.62 — 1.36 (m, 2H), 1.01 — 0.92 (m, 3H).
Ste C: +/— -meth l3- 4- 1- 4- 4- trifluorometh l -1H-imidazol l henox but I ido ro anoate 1-Ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) was added to a room temperature on of (+/—)(1-(4-(4-(trifluoromethyl) -1H-imidazoly|)phenoxy)butyl)benzoic acid (80 mg, 0.20 mmol), methyl 3- aminopropanoate hydrochloride (28 mg, 0.20 mmol), 1-hydroxyazabenzotriazole (30 mg, 0.22 mmol), and triethylamine (31 uL, 0.22 mmol) in dichloromethane (2 mL). The solution was d at room temperature overnight. The reaction mixture was diluted with romethane (20 mL) and washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give (+/—)-methyl 1-(4-(4-(trif|uoromethyl)—1H-imidazolyl)phenoxy)butyl) benzamido)propanoate (89 mg, 90%). 1H NMR (400 MHz, CDCI3, 5): 7.74 — 7.70 (m, 2H), 7.69 — 7.66 (s, 1H), 7.44 — 7.41 (m, 1H), 7.40 — 7.36 (m, 2H), 7.18 — 7.13 (m, 2H), 6.91 — 6.86 (m, 2H), 6.83 — 6.75 (m, 1H), 5.16 — 5.12 (m, 1H), 3.72 — 3.66 (m, 5H), 2.66 — 2.60 (m, 2H), 2.06 — 1.93 (m, 1H), 1.86 — 1.74 (m, 1H), 1.55 — 1.35 (m, 2H), 0.99 — 0.91 (m, 3H).
Ste D: +/— 4- 1- 4- 4- trifluorometh l -1H-imidazol l henox but I benzamido ro anoic acid Lithium hydroxide (1.0 mL, 1N in water, 1.0 mmol) was added to a room temperature solution of (+/—)-methyl 3-(4-(1-(4-(4-(trif|uoromethyl)—1 H-imidazol yl)phenoxy)butyl)benzamido)propanoate (89 mg, 0.18 mmol) in tetrahydrofuran (2 mL). The solution was stirred at room temperature 5 hours. The mixture was acidified to pH = 2 with 1N HCl, and ted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and trated to give (+/—)(4-(1- (4-(4-(trifluoromethyl)—1H-imidazolyl)phenoxy)butyl)benzamido)propanoic acid (84 mg, 98%).1H NMR (400 MHz, CDCI3, 5): 7.74 — 7.68 (m, 3H), 7.45 — 7.41 (m, 1H), 7.39 — 7.34 (m, 2H), 7.18 — 7.12 (m, 2H), 6.91 — 6.85 (m, 2H), 6.84 — 6.77 (m, 1H), 5.17 — 5.11 (m, 1H), 3.73 — 3.65 (m, 2H), 2.71 — 2.64 (m, 2H), 2.03 — 1.94 (m, 1H),1.86 — 1.74 (m, 1H), 1.60 — 1.35 (m, 2H), 0.99 — 0.91 (m, 3H). MS (M+1): 475.9.
Exam le 20: +/— 4- 1- 4- 4- meth lthio -1H- razol l henox but I benzamido ro anoic acid Copper iodide (1.31 g, 6.87 mmol), quinolinol (1.00 g, 6.87 mmol), and potassium carbonate (10.5 g, 76.0 mmol) were combined and pulverized. 78 mg of this mixture was added to 4-(methylthio)—1H-pyrazole (0.400 mmol) in a two dram vial. A solution of Intermediate (27) (123 mg, 0.300 mmol) in dimethylsulfoxide (0.500 mL) was added to the vial under a stream of dry nitrogen. The vial was capped and agitated on an l shaker at 120°C for 12 hours. The reaction mixture was concentrated in vacuo.
To the crude residue was added methanol (2.0 mL), tetrahydrofuran (1.0 mL), and s lithium ide (2.0 M, 2.0 mL). The reaction was agitated on an orbital shaker at 60°C for 12 hours. The reaction mixture was trated in vacuo and the remaining crude residue was carefully acidified with 1.0M aqueous hydrochloric acid (5.0 mL). The resulting acidified mixture was concentrated in vacuo.
A mixture of tert—butyl 3-aminopropanoate hydrochloride (12.3 g, 67.7 mmol), 1-hydroxybenzotriazole (6.89 g, 45 mmol) and 1-ethyl(3-dimethylamino propyl)carbodiimide hydrochloride (12.9 g, 67.3 mmol) was suspended in tetrahydrofuran (450 mL). A 3.0 mL aliquot of this solution was transferred to the crude acid from the previous transformation. Triethylamine (0.167 mL, 1.20 mmol) was added and the mixture was agitated on an orbital shaker ght. The reaction mixture was treated with Si-diamine scavenger (ca. 5.0 eq) and was agitated for 12 hours on an orbital shaker. The reaction was filtered through a silica gel plug, washing with tetrahydrofuran (three times). The combined organic filtrate was concentrated in vacuo.
To the crude residue was added dichloromethane (4.0 mL), followed by trifluoroacetic acid (2.0 mL). The reaction was agitated on an l shaker for 12 hours. The reaction mixture was concentrated in vacuo. Purification by reversed- phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—) (4-(4-(methy|thio)-1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid (39.7 mg, 23% over 4 steps). Analytical LCMS: retention time 3.25 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 s; 0.05 % trifluoroacetic acid er; flow rate 2.0 mL/minute); MS (M+1): 454.0.
Exam le 21: +/— 4- 1- 4- 3-2‘ert—but l-1H- razol l henox but I benzamido ro anoic acid /N\Noe The title compound was prepared by a method analogous to that described for Example 20 using 3-tert—butyl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid er) gave (+/—)(4- (1-(4-(3-tert—butyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (50.3 mg, 29% over 4 steps). Analytical LCMS: retention time 3.71 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.0.
Exam le 22: +/— - 3- 4- 1- 4- 4-chlorometh l-1H- razol | henox but I benzamido ro anoic acid LNQO/N\ O The title compound was prepared by a method analogous to that bed for Example 20 using romethyl-1H-pyrazole. Purification by reversed- phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in itrile (0.05% trifluoroacetic acid modifier) gave (+/—)- 3- (4-(1-(4-(4-ch|oromethyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (31 .4mg, 18% over 4 steps). Analytical LCMS: retention time 3.44 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear nt to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 456.0.
Exam le 23: +/— 4- 1- 4- 4-chloro-1H— razol | henox but I benzamido propanoic acid 2012/050349 LNQO/N\ O The title compound was prepared by a method analogous to that described for Example 20 using 4-chloro-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% oroacetic acid modifier) gave 3-(4-(1-(4-(4- chloro-1H-pyrazoly|)phenoxy)buty|)benzamido)propanoic acid (40.1 mg, 24% over 4 steps). Analytical LCMS: retention time 3.31 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid er; flow rate 2.0 mL/minute); MS (M+1): 441.0.
Exam le 24: +/— 4 4- 4-eth lmeth l-1H- 1- | henox but I benzamido ro anoic acid /N\Noe; \ O (o The title compound was prepared by a method analogous to that described for Example 20 using 4-ethylmethyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)—3-(4- (1 -(4-(4-ethylmethyl-1 H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (15.2 mg, 9% over 4 . Analytical LCMS: retention time 3.19 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 450.0.
Exam le 25: +/— 4- 1- 4- 3 5-dieth l-1H- razol | henox but I benzamido ro anoic acid 2012/050349 /N\HQ; \ Q<0 The title compound was prepared by a method analogous to that bed for Example 20 using 3,5-diethyl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(3,5- diethyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (24.4 mg, 14.1 %). Analytical LCMS: retention time 3.31 minutes tis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 s; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.1.
Exam le 26: +/— 4- 1- 4- 4-meth l-1H- 1- | henox but I benzamido propanoic acid LNQO/N\ O \ i 3 NH The title compound was prepared by a method analogous to that described for Example 20 using 4-methyl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(4- methyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (57.5 mg, 36% over 4 steps). Analytical LCMS: retention time 3.10 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 422.0.
Exam le 27: +/— 4 4- 3-iso ro l-1H- razol | henox but I benzamido ro anoic acid Noe o The title compound was prepared by a method ous to that described for Example 20 using 3-isopropyl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% oroacetic acid modifier) gave (+/—)- 3-(4- (1-(4-(3-isopropyl-1H-pyrazolyl)phenoxy)butyl)benzamido)propanoic acid (38.6 mg, 23% over 4 steps). Analytical LCMS: ion time 3.43 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 450.0.
Exam le 28: +/— 4- 1- 4- 4-fluoro-1H- 1- | henox but I benzamido propanoic acid EN/ 0 o The title compound was prepared by a method analogous to that described for Example 20 using 4-fluoro-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(4- fluoro-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (34.4 mg, 23% over 4 . Analytical LCMS: retention time 3.25 minutes (Atlantis C18 4.6 x 50 mm, 5 uM ; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid er; flow rate 2.0mL/minute); MS (M+1): 454.0.
Exam le 29: +/— 4- 1- 4- 3-meth l-1H— razol | henox but I benzamido propanoic acid 2012/050349 g/M30 0 The title compound was prepared by a method analogous to that described for Example 20 using yl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(3- methyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (52 mg, 32% over 4 steps). Analytical LCMS: retention time 3.02 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear nt to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate minute); MS (M+1): 422.0.
Exam le 30: +/— 4- 1- 4- 2H-1 2 3-triazol | henox but I benzamido propanoic acid moo/N\ o The title nd was prepared by a method analogous to that described for Example 20 using ,3-triazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(2H-1,2,3- triazolyl)phenoxy)buty|)benzamido)propanoic acid (18.7 mg, 12% over 4 steps).
Analytical LCMS: retention time 3.07 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 s, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 409.0.
Exam le 31: +/— 4- 1- 4- 3-but l-1H- razol | henox but lbenzamido propanoic acid /\/\Er\:\Noe o The title compound was prepared by a method ous to that described for Example 20 using 3-butyl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(3- butyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (15.3 mg, 9% over 4 steps). Analytical LCMS: retention time 3.4 s (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.0.
Exam le 32: +/— 4 4- x meth l-1H- razol | henox but I benzamido ro anoic acid The title nd was prepared by a method analogous to that described for Example 20 using 5-ethoxymethyl-1H-pyrazole. Purification by reversed- phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid er) gave 3- (4-(1-(4-(5-ethoxymethyl-1H-pyrazolyl)phenoxy)butyl)benzamido)propanoic acid (33.3 mg, 19 % over 4 steps). Analytical LCMS: retention time 3.23 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 466.0.
Exam le 33: +/— 4- 1- 4- 5-methox meth l-1H- razol | henox but I benzamido ro anoic acid )2“\ NQO534o OMe NH The title compound was prepared by a method analogous to that bed for e 20 using 5-methoxymethyl-1H-pyrazole. Purification by reversed- phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—) (4-(1-(4-(5-methoxymethyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (36.3 mg, 21% over 4 . Analytical LCMS: retention time 3.07 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 452.0.
Exam le 34: +/— 4- 1- 4- 4-but l-1H-imidazol | henox but I benzamido propanoic acid The title compound was prepared by a method analogous to that described for Example 20 using 4-butyl-1H—imidazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a nt of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(4- butyl-1H-imidazolyl)phenoxy)butyl)benzamido)propanoic acid (5.9 mg, 3% over 4 steps). Analytical LCMS: retention time 2.45 minutes tis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % acetonitrile over 4.0 minutes, hold at 5 % acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 464.1.
Exam le 35: +/— 4- 1- 4- 2-c ano-34 5-trimeth l-1H- rrol | henox but I benzamido ro anoic acid fi©i///\ Q(o NH The title compound was prepared by a method analogous to that described for Example 20 using 3,4,5-trimethyl-1H-pyrrolecarbonitrile. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column g with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(2—cyano-3,4,5-trimethyl-1H-pyrroly|)phenoxy)butyl) benzamido)propanoic acid (31.9 mg, 18% over 4 steps). Analytical LCMS: retention time 3.6 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 474.0.
Exam le 36: +/— 4- 1- 4- 3-c ano-2 4-dimeth l-1H- rrol | henox but I benzamido ro anoic acid /\NOiQ N O (o The title compound was prepared by a method analogous to that bed for Example 20 using 2,4-dimethyl-1H-pyrrolecarbonitrile. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a nt of water in itrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(3-cyano-2,4-dimethyl-1H-pyrroly|)phenoxy)buty|) benzamido)propanoic acid (19.9 mg, 12% over 4 . Analytical LCMS: retention time 3.4 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 s; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 460.0.
Exam le 37: +/— 4- 1- 4- 2-c meth l-1H- rrol | henox but I b_)_p_p—enzamidoroanoic acid ::043 The title compound was prepared by a method ous to that described for Example 20 using 3-methyl-1H-pyrrolecarbonitrile. Purification by reversed- phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave 3- (4-(2-cyanomethyl-1H-pyrroly|)phenoxy)butyl)benzamido)propanoic acid (37.1 mg, 22% over 4 steps). Analytical LCMS: retention time 3.36 minutes (Atlantis C18 4.6 X 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 s; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 446.0.
Exam le 38: +/— - 3- 6- 1- 4- 3- ro l-1H- razol | henox but I nicotinamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 20 using 3-propyl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)- 3-(6-(1-(4-(3- propyl-1H-pyrazoly|)phenoxy)butyl)nicotinamido)propanoic acid (4.4 mg, 3% over 4 steps). Analytical LCMS: retention time 3.24 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % oroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 450.0.
Exam le 39: +/— 4- 1- 4- eth l-1H- razol | henox but I benzamido ro anoic acid Noe o The title compound was prepared by a method analogous to that bed for Example 20 using 3,4-dimethyl-1H-pyrazole. cation by ed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4- (1-(4-(3,4-dimethyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (22.8 mg, 14% over 4 steps). Analytical LCMS: retention time 3.07 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 436.
Exam le 40: +/— 4- 1- 4- 1H- razol | henox but lbenzamido ro anoic The title compound was prepared by a method analogous to that described for Example 20 using 1H-pyrazole. cation by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column g with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(1H-pyrazol- 1-y|)phenoxy)butyl)benzamido)propanoic acid (46.1 mg, 29% over 4 steps). Analytical LCMS: retention time 2.93 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 408.0.
Exam le 41: +/— 4- 1- 4- 1H-imidazo 1 2-b razol | henox but I benzamido ro anoic acid “JN NH The title compound was ed by a method ous to that described for Example 20 using 1H-imidazo[1,2-b]pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4- (1-(4-(1H-imidazo[1,2-b]pyrazolyl)phenoxy)butyl)benzamido)propanoic acid (29.6 mg, 18 % over 4 steps). Analytical LCMS: retention time 2.74 s (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0mL/minute); MS (M+1): 447.0.
Exam le 42: +/— 4- 1- 4- 3-eth l-1H- razol | henox but I benzamido propanoic acid 8/ ,N—< >70 0 The title compound was prepared by a method analogous to that described for Example 20 using 3-ethyl-1H—pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(3- ethyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (10.0 mg, 6% over 4 steps). Analytical LCMS: retention time 3.07 minutes tis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 436.0.
Exam le 43: +/— - 3- 4- 1- 4- 4-chlorometh l-1H-imidazol | henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 20 using 4-chloromethyl-1H-imidazole. Purification by reversed- phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)- 3- (4-(1-(4-(4-ch|oromethyl-1H-imidazolyl)phenoxy)butyl)benzamido)propanoic acid (5.1 mg, 3% over 4 steps). Analytical LCMS: retention time 2.48 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 456.0.
Exam le 44: +/— 4- 1- 4- 4 5-dieth l-1H-imidazol | henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 20 using 4,5-diethyl-1H-imidazole. Purification by ed-phase HPLC on a Waters e C1819 x 100 mm, 0.005 mm column eluting with a nt of water in itrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4- (1-(4-(4,5-diethyl-1H-imidazolyl)phenoxy)butyl)benzamido)propanoic acid (56.1 mg, 32% over 4 steps). ical LCMS: ion time 2.50 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/ acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.0.
Exam le 45: +/— 4- 1- 4- 3 5-dimeth l-1H- razol | henox but I benzamido ro anoic acid )1/ 0 - loo The title compound was prepared by a method ous to that described for Example 20 using 3,5-dimethyl-1H-pyrazole. Purification by reversed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4- (1-(4-(3,5-dimethyl-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (42.0 mg, 25% over 4 steps). Analytical LCMS: retention time 2.97 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 ute); MS (M+1): 436.0.
Exam le 46: +/— 4- 1- 4- 3-meth l-1H—1 2 4-triazol | henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for e 20 using 3-methyl-1H-1,2,4-triazole. Purification by reversed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4- (3-methyl-1H-1,2,4-triazoly|)phenoxy)butyl)benzamido)propanoic acid (30.3 mg, 19% over 4 . Analytical LCMS: retention time 2.58 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 423.0.
Exam le 47: +/— 4- 1- 4- 1H-1 2 4-triazol | henox but I benzamido propanoic acid 2012/050349 The title compound was prepared by a method ous to that described for Example 20 using 1H-1,2,4-triazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(1H-1,2,4- triazoly|)phenoxy)buty|)benzamido)propanoic acid (44.2 mg, 28% over 4 .
Analytical LCMS: retention time 2.59 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 409.0.
Exam le 48: +/— 4- 1- 4- 2-but l-1H-imidazol | henox but I benzamido propanoic acid The title compound was ed by a method ous to that described for Example 20 using 2-butyl-1H—imidazole. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid er) gave 3-(4-(1-(4-(2- butyl-1H-imidazoly|)phenoxy)buty|)benzamido)propanoic acid (82 mg, 47% over 4 steps). Analytical LCMS: retention time 2.36 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 464.1.
Exam le 49: +/— 4- 1- 4- 4 5-dimeth l-1H-imidazol | henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 20 using 4,5-dimethyl-1H-imidazole. Purification by reversed-phase HPLC on a Waters Sunfire C1819 x 100 mm, 0.005 mm column eluting with a gradient of water in acetonitrile (0.05% oroacetic acid modifier) gave (+/—)—3-(4- (1-(4-(4,5-dimethyl-1H-imidazolyl)phenoxy)butyl)benzamido)propanoic acid (43.1 mg, 26% over 4 steps). Analytical LCMS: retention time 2.19 minutes (Atlantis C18 4.6 x 50 mm, 5 uM column; 95 % water/acetonitrile linear gradient to 5 % water/acetonitrile over 4.0 minutes, hold at 5 % water/acetonitrile to 5.0 minutes; 0.05 % trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 436.0.
Exam le 50: +/— 4- 1- 4- 1- ro l-1H- razol | henox but I benzamido oic acid To 1-propyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)—1H-pyrazole (95.2 mg, 0.400 mmol) and PS-PPhg-Pd (0.170 g, 0.017 mmol) in a microwave vial was added a solution of Intermediate (27) (123 mg, 0.300 mmol) in dimethoxyethane (3.3 mL), followed by an aqueous solution of ium carbonate (2.0M, 1.7 mL). The vial was capped and heated to 100°C for 1 hour. The reaction mixture was filtered, the resin was washed with tetrahydrofuran (2 x 1.0 mL), and the combined organic filtrate was concentrated in vacuo.
To the crude e was added methanol (2.0 mL), tetrahydrofuran (1.0 mL), and aqueous lithium hydroxide (2.0 mL, 2.0M). The reaction was agitated on an orbital shaker at 60°C for 12 hours. The reaction mixture was concentrated in vacuo and the remaining crude residue was carefully acidified with 1.0M aqueous hydrochloric acid (5.0 mL). The ing ied mixture was concentrated in vacuo.
A mixture of tert—butyl 3-aminopropanoate hydrochloride (12.3 g, 67.7 mmol), 1-hydroxybenzotriazole (6.89 g, 45 mmol) and 1-ethyl(3-dimethylamino propyl)carbodiimide hydrochloride (12.9 g, 67.3 mmol) was suspended in tetrahydrofuran (450 mL). A 3.0 mL aliquot of this solution was transferred to the crude acid from the previous transformation. Triethylamine (0.167 mL, 1.20 mmol) was added and the e was agitated on an orbital shaker overnight. The reaction mixture was treated with Si-diamine scavenger (ca. 5.0 eq) and the mixture was agitated for 12 hours on an orbital shaker. The reaction was filtered through a plug of silica gel, g with tetrahydrofuran (3 times). The combined organic filtrate was concentrated in vacuo.
To the crude e was added dichloromethane (4.0 mL), followed by trifluoroacetic acid (2.0 mL). The reaction was agitated on an orbital shaker for 12 hours at ambient temperature. The crude reaction mixture was trated in vacuo. The crude material was purified by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a gradient of water in itrile (0.05% oroacetic acid modifier) to give (+/—)(4-(1-(4-(1-propyl- 1H-pyrazolyl)phenoxy)butyl)benzamido)propanoic acid (56.1 mg, 33% over 4 steps). Analytical LCMS: retention time 3.11 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 450.0.
Exam le 51: +/— 4- 1- 4-1H— razol | henox but Ibenzamido ro anoic The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a gradient of water in itrile (0.05% trifluoroacetic acid modifier) gave the desired product (3.8mg, 2% over 4 steps). Analytical LCMS: retention time 2.65 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% oroacetic acid er; flow rate 2.0 mL/minute); MS (M+1): 408.0.
Exam le 52: +/— 4- 1- 4- 3 5-dimeth |isoxazol l henox but I benzamido propanoic acid I O O The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(3,5-dimethylisoxazol yl)phenoxy)butyl)benzamido)propanoic acid (40.3 mg, 24% over 4 steps). ical LCMS: retention time 3.14 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 437.0.
Exam le 53: +/— 4- 1- 4- 1-meth l orometh l-1H- razol l henox but I benzamido ro anoic acid I \ o O \ NH The title compound was ed by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, m column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(1-methyl(trifluoromethyl)—1 H- pyrazolyl)phenoxy)butyl)benzamido)propanoic acid (53.5 mg, 30% over 4 steps). Analytical LCMS: retention time 3.42 s (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid er; flow rate 2.0 mL/minute); MS (M+1): 490.0.
Exam le 54: +/— 4- 1- 4- 1-meth l-1H— razol l henox but I benzamido oic acid \N \ I >—< >—O O O E The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave 3-(4-(1-(4-(1-methyl-1H-pyrazol yl)phenoxy)butyl)benzamido)propanoic acid (2.5 mg, 2% over 4 steps). Analytical LCMS: retention time 2.85 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 422.0.
Exam le 55: +/— 4- 1- 4- 1 5-dimeth l-1H— razol l henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(1,5-dimethyl-1H-pyrazol yl)phenoxy)butyl)benzamido)propanoic acid (7.0 mg, 4% over 4 steps). Analytical LCMS: retention time 2.86 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 436.0.
Exam le 56: +/— 4 4-1H— razol l henox but I benzamido ro anoic The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)- 3-(4-(1-(4-(1H-pyrazol yl)phenoxy)butyl)benzamido)propanoic acid (1.8 mg, 1% over 4 steps). Analytical LCMS: retention time 2.62 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 408.0.
Exam le 57: +/— 4- 1- 4- 1-meth l-1H- razol l henox but I ido propanoic acid I \ o o The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a nt of water in acetonitrile (0.05% oroacetic acid er) gave (+/—)(4-(1-(4-(1-methyl-1H-pyrazol y|)phenoxy)buty|)benzamido)propanoic acid (8.1 mg, 5% over 4 steps). ical LCMS: retention time 2.85 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 422.0.
Exam le 58: +/— 4- 1- 4- 1 3 5-trimeth l-1H- razol | henox but I benzamido ro anoic acid I \ O O O E The title compound was prepared by a method analogous to that described for Example 50. Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, m column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/—)(4-(1-(4-(1,3,5-trimethyl-1H-pyrazol yl)phenoxy)butyl)benzamido)propanoic acid (21 mg, 12% over 4 steps). Analytical LCMS: retention time 2.81 minutes (Atlantis C18 4.6 x 50mm, 5uM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 s, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 ute); MS (M+1): 450.0.
Exam le 59: +/— 4 4- 4- trifluorometh l-1H- razol | henox but I benzamido ro anoic acid The title compound was ed by a method analogous to that described for Example 19, using 4-(trifluoromethyl)-1H-pyrazole. 1H NMR (400 MHz, CDCI3, ): 8.00 — 7.97 (m, 1H), 7.84 — 7.80 (m, 1H), 7.73 — 7.68 (m, 2H), 7.46 — 7.36 (m, 4H), 6.90 — 6.84 (m, 2H), 6.77 — 6.70 (m, 1H), 5.18 — 5.11 (m, 1H), 3.74 — 3.66 (m, 2H), 2.72 — 2.66 (m, 2H), 2.02 — 1.93 (m, 1H), 1.85 — 1.74 (m, 1H), 1.59 — 1.36 (m, 2H), 0.99 — 0.91 (m, 3H). MS (M-1): 474.0.
Exam le 60: 3- 4- 1- 4- 4- trifluorometh | -1H- razol | henox but I benzamido ro anoic acid lsomer1 F F The title compound is obtained by resolving c 3-(4-(1-(4-(4- (trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid Example 59, by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 10mm x 250mm. Mobile Phase: 80/20 thanol. Flow Rate: 10.0 mL/min. Modifier: none. Retention time: 3.66 minutes.
Exam le 61: 3- 4- 1- 4- 4- trifluorometh l-1H- razol l henox but I benzamido ro anoic acid lsomer2 The title compound is obtained by resolving racemic 1-(4-(4- (trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid Example 59, by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 10mm x 250mm. Mobile Phase: 80/20 COZ/methanol. Flow Rate: 10.0 mL/min. Modifier: none. Retention time: 4.81 minutes.
Exam le 62: +/— 4- 1- 6- 4- hen l-1H- razol l ridine lamino but I benzamido ro anoic acid Ste A: +/— -meth l3- 4 6- 4- hen l-1H- razol l ridine lamino but lbenzamido ro anoate /N\ — N NH \ \N / : f Intermediate (25) (42.1 mg, 0.178 mmol) was dissolved in methanol (0.8 mL).
Intermediate (23) (54.4mg, 0.196mmol) was added, followed by decaborane (13.1 mg, 0.107 mmol). The reaction was stirred at room temperature for 18 hours and was then concentrated. Purification by column chromatography (20 — 100% ethyl acetate in heptane) gave methy| 1-(6-(4-phenyl-1H-pyrazolyl)pyridine- ino)buty|)benzamido)propanoate (81.3 mg, 92%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 8.61 (s, 1H), 7.90 (s, 1H), 7.76 — 7.66 (m, 4H), 7.53 (d, J: 7.2 Hz, 2H), 7.42 — 7.31 (m, 4H), 7.26 — 7.19 (m, 1H), 6.94 (m, 1H), 6.81 — 6.74 (m, 1H), 4.41 — 4.34 (m, 1H), 3.73 — 3.66 (m, 5H), 2.66 — 2.60 (m, 2H), 1.94 — 1.72 (m, 2H), 1.50 — 1.29 (m, 2H), 0.98 — 0.90 (m, 3H). MS (M+1): 498.4.
Ste B: +/— 4 6- 4- hen l-1H- razol l ridine lamino but I benzamido ro anoic acid Methyl 3-(4-(1-(6-(4-phenyl-1H-pyrazoly|)pyridineylamino)butyl) benzamido)propanoate (82.1 mg, 0.165 mmol) was dissolved in methanol (0.5 mL) and tetrahydrofuran (0.5 mL). 1N Sodium hydroxide (0.33 mL) was added and the reaction was stirred at room temperature for 24 hours. The reaction was then concentrated. The crude residue was taken up in water and acidified with 1N hydrochloric acid to pH = 3. A white precipitate formed. The solids were ed off and dried under vacuum to give (+/—)(4-(1-(6-(4-pheny|-1H-pyrazoIy|)pyridine- 3-y|amino)buty|)benzamido)propanoic acid (61.6 mg, 77%) as an off-white solid. 1H NMR (400 MHz, CD30D, 6): 8.57 (d, J: 1.0 Hz, 1H), 7.96 (d, J: 0.8 Hz, 1H), 7.78 — 7.69 (m, 3H), 7.61 — 7.50 (m, 3H), 7.47 (d, J: 8.4 Hz, 2H), 7.38 — 7.31 (m, 2H), 7.24 — 7.16 (m, 1H), 7.05 (dd, J: 8.9, 3.0 Hz, 1H), 4.48 — 4.41 (m, 1H), 3.63 — 3.55 (m, 2H), 2.60 (t, J: 6.9 Hz, 2H), 1.94 — 1.69 (m, 2H), 1.58 — 1.33 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). MS (M+1): 484.4.
Exam le 63: +/— 4- 1- 4- 4-fluoro-1H- razol l hen lamino but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 62 using Intermediate (12). 1HNMR (400 MHz, CDgOD, 6): 7.91 (d, 1H), 7.72 (d, 2H), 7.48 (d, 1H), 7.44 (d, 2H), 7.23 (d, 2H), 6.58 (d, 2H), 4.39 (m, 1H), 3.59 (m, 2H), 2.60 (m, 2H), 1.84 — 1.80 (m, 1H), 1.74 — 1.68 (m, 1H), 1.50 — 1.48 (m, 1H), 1.40 — 1.35 (m, 1H), 0.94 (m, 3H). MS (M+1): 425.3.
Exam le 64: +/— 6- 3-meth l 4- 4- trifluorometh | -1H- razol l hen Ibut lamino nicotinamido ro anoic acid N‘mfg/ O O N N Ste A: +/— 3-meth l4- 4-trifluorometh l-1H- razol | hen | but lamino nicotinic acid N\\mfg/ N N A microwave reaction vial was charged with Intermediate (14) (180 mg, 0.605 mmol) and isopropanol (5 mL). Methyl 6-chloronicotinate (114 mg, 0.665 mmol) and ropylethylamine (313 mg, 2.42 mmol) were added. The ing mixture was heated to 130°C for 15 hours under microwave irradiation. The mixture was trated and the crude residue was purified by column chromatography to give (+/—)—methyl 6-(3-methyl(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenyl) butylamino)nicotinate (30 mg).
To a solution of (+/—)—methyl 6-(3-methyl(4-(4-(trifluoromethyl)—1H- pyrazoly|)phenyl)butylamino)nicotinate (30 mg, 0.069 mmol) in tetrahydrofuran (3 mL) was added lithium hydroxide (0.103 mL, 2N in water, 0.207 mmol). The mixture was stirred at 50°C overnight. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give 6-(3-methyl(4-(4- (trifluoromethyl)—1H-pyrazolyl)phenyl)butylamino)nicotinic acid (25 mg, 87%) as a white solid. MS (M+1): 419.1.
Ste B: +/— -meth l 3- 6- 3-meth l 4- 4- trifluorometh l -1H- razol | hen lbut lamino nicotinamido ro anoate N\\73%/ o o \l H N N To a solution of (+/—)—6-(3-methyl(4-(4-(trifluoromethyl)—1 H-pyrazol nyl)butylamino)nicotinic acid (50 mg, 0.12 mmol) in N,N-dimethylformamide (5 mL) was added O—(7-Azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (67.7 mg, 0.178 mmol). The mixture was stirred for 45 minutes. Methyl 3-aminopropionate hloride (24.6 mg, 0.178 mmol) and diisopropylethylamine (61.5 mg, 0.476 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was d with saturated um chloride. The solution was extracted three times with ethyl acetate. The combined organics were washed with water, dried over sodium sulfate, filtered and trated to give methyl 3-(6-(3-methyl(4-(4-(trifluoromethyl)-1H-pyrazol nyl)butylamino)nicotinamido)propanoate (50 mg, 83%) as a brown oil. MS (M+1): 504.1.
Ste C: +/— 6- 3-meth l 4- 4- trifluorometh l -1H- razol | hen lbut lamino nicotinamido ro anoic acid Methyl 3-(6-(3-methyl(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenyl) butylamino)nicotinamido)propanoate (50 mg, 0.099 mmol) was dissolved in water (5 mL) and tetrahydrofuran (5 mL). m hydroxide (0.387 mL, 2N in water, 0.774 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated.
Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150x30mm, 5um; modifier: formic acid 0.225%; gradient: 10 to 80% acetonitrile in water) gave 3-(6-(3-methyl(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenyl)butylamino) nicotinamido)propanoic acid (25 mg, 52%). 1H NMR (400 MHz, CDgOD, 6): 8.70 (s, 1H), 8.40 (s, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 7.74 (d, 2H), 7.53 (d, 2H), 6.59 (d, 1H), .12 — 5.02 (m, 1H), 3.57 (m, 2H), 2.59 (m, 2H), 1.89 — 1.69 (m, 2H), 1.68 — 1.58 (m, 1H), 1.02 (d, 3H), 0.98 (d, 3H). MS (M+1): 490.5.
Exam le 65: +/— 4- 2-c clo ro l 4- 4- trifluorometh l -1H- razol | henox eth lbenzamido ro anoic acid F F N‘mfg/ O O ”VLOH Ste A: +/— -meth l4- 2-c clo ro l4- 4-trifluorometh l-1H- 1- yl )phenoxy )ethyl )benzoate To a solution of Intermediate (16) (50.0 mg, 0.227 mmol), Intermediate (29) (62.2 mg, 0.272 mmol) and triphenylphosphine (120 mg, 0.454 mmol) in tetrahydrofuran (0.5 mL) was added diethylazodicarboxylate (79.1 mg, 0.454 mmol). The resulting mixture was d at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was ted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave (+/—)-methyl 4-(2-cyclopropyl(4-(4-(trifluoromethyl)—1H- pyrazoly|)phenoxy)ethyl)benzoate (32 mg, 33%). 1HNMR (400MHz, CDCI3, 6): 7.95 — 7.93 (m, 3H), 7.79 (s, 1H), 7.45 — 7.33 (m, 4H), 6.84 (d, 2H), 5.19 (m, 1H), 3.83 (s, 3H), 1.99 — 1.94 (m, 1H), 1.64 — 1.55 (m, 1H), 0.79 — 0.69 (m, 1H), 0.46 — 0.42 (m, 2H), 0.10 — -0.10 (m, 2H).
Ste B: +/— -meth l3- 4- 2-c clo ro l 4- 4- trifluorometh l -1H- 1- l henox eth lbenzamido ro anoate N\\05%/ O 0 ”Aug, To a mixture of (+/—)-methyl 4-(2-cyclopropyl(4-(4-(trifluoromethyl)—1H- pyrazoly|)phenoxy)ethyl)benzoate (104 mg, 0.242 mmol) in methanol (1.2 mL) and water (0.2 L) was added lithium hydroxide drate (50.08 mg, 1.21 mmol) at room temperature. The resulting mixture was stirred overnight. The on mixture was poured into water and acidified to pH = 6 with 1N hydrochloric acid.
The on was extracted with dichloromethane. The organic layer was dried over sodium sulfate, ed, and concentrated. The residue was dissolved in N, N- dimethylformamide (0.84 mL) and O—(7-Azabenzotriazoly|)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (95.8 mg, 0.252 mmol)was added, followed by N-methylmorpholine (50.9 mg, 0.504 mmol). The reaction mixture was stirred for 30 minutes at room temperature. Methyl 3-aminopropionate (23.4 mg, 0.168 mmol) was then added and the on was stirred for 48 hours. The reaction mixture was partitioned between brine and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Purification by column tography gave (+/—)-methyl 3-(4-(2-cyclopropyl(4-(4-(trifluoromethyl)-1H-pyrazol yl)phenoxy)ethyl)benzamido)propanoate (92 mg, 76%). MS (M+Na): 524.1.
WO 07850 Ste C: +/— 4- 2-c clo ro l 4- 4- orometh l -1H- razol | henox eth | benzamido ro anoic acid To a mixture of methyl 3-(4-(2-cyclopropyl(4-(4-(trifluoromethy|)-1H- pyrazoly|)phenoxy)ethy|)benzamido)propanoate (92 mg, 0.18 mmol) in methanol (0.9 mL) and water (0.2 mL) was added lithium hydroxide monohydrate (38.4 mg, 0.92 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into water and acidified with 1N hydrochloric acid to pH = 6. The mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, ed, and concentrated. cation by column chromatography gave (+/—)(4-(2-cyclopropyl(4-(4-(trifluoromethyl)-1H-pyrazol- 1-y|)phenoxy)ethyl)benzamido)propanoic acid (52 mg, 59%). 1HNMR (400 MHz, CDgOD, 6): 8.47 (s, 1H), 7.82 (s, 1H), 7.70 (d, 2H), 7.50 (d, 2H), 7.42 (d, 2H), 6.92 (d, 2H), 5.34 (m, 1H), 3.53 (m, 2H), 2.48 (m, 2H), 1.98 — 1.94 (m, 1H), 1.60 — 1.58 (m, 1H), 0.75 — 0.77 (m, 1H), 0.42 — 0.33 (m, 2H), 0.08 — 0.01 (m, 2H). MS (M+Na): 510.3.
Exam le 66: +/— 4- c clo ent l4- 4- trifluorometh l-1H- razol l henox meth Ibenzamido ro anoic acid 0 O F F The title compound was prepared by a method analogous to that described for Example 65 using Intermediate (37). 1H NMR (400 MHz, CD30D, 6): 8.55 (s, 1H), 7.92 (s, 1H), 7.78 (d, 2H), 7.57 (d, 2H), 7.51 (d, 2H), 6.99 (d, 2H), 5.15 (d, 1H), 3.64-3.60 (m, 2H), 2.65-2.61 (m, 2H), 2.50-2.41 (m, 1H), 1.97-1.90 (m, 1H), 1.80- 1.38 (m, 7H). MS (M+1): 502.3.
Exam le 67: 3- 4- c clo ent l 4- 4- trifluorometh l -1H- razol | henox meth mido ro anoic acid |somer1 WO 07850 F F The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(4-(4- (trifluoromethyl)—1H-pyrazolyl)phenoxy)methyl)benzamido)propanoic acid Example 66, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 x 250mm.
Mobile Phase: 70/30 C02/2-propanol. Flow Rate: 10.0 mL/min. Modifier: none.
Retention time: 4.24 minutes.
Exam le 68: 3- 4- c clo ent l4- 4- trifluorometh l-1H— razol l henox meth lbenzamido ro anoic acid lsomer2 The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(4-(4- (trifluoromethyl)—1H-pyrazolyl)phenoxy)methyl)benzamido)propanoic acid e 66, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 x 250mm.
Mobile Phase: 70/30 C02/2-propanol. Flow Rate: 10.0 mL/min. Modifier: none.
Retention time: 6.00 minutes.
Exam le 69: +/— 4- c clobut l 4- 4- trifluorometh l -1H— razol l henox meth lbenzamido ro anoic acid The title compound was prepared by a method ous to that described for Example 65 using Intermediate (45). 1H NMR (400 MHz, CDgOD, 6): 8.56 (s, 1H), 7.92 (s, 1H), 7.77 (d, 2H), 7.58 (d, 2H), 7.48 (d, 2H), 7.01 (d, 2H), 5.27 — 5.25 (m, 1H), 3.63 — 3.60 (m, 2H), 2.88 — 2.78 (m, 1H), 2.65 — 2.59 (m, 2H), 2.21 — 2.00 (m, 3H), 2.00 — 1.70 (m, 3H). MS (M+1): 488.5.
Exam le 70: +/— - 3- 4- 1- 4- 3- trifluorometh | -1H- razol | henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 19 using 3-(trifluoromethyl)-1H-pyrazole. Analytical LCMS: retention time 3.48 s (Waters Atlantis dC18 4.6 x 50mm, 5pm column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid er; flow rate 2.0 mL/minute); MS (M+1): 475.98.
Exam le 71: +/— 4- 3 3-dimeth l 4- 4- trifluorometh | -1H- razol l henox but I benzamido ro anoic acid The title compound was prepared by a method ous to that described for Example 65 using Intermediate (42). 1H NMR (400 MHz, CDgOD, 6): 8.57 (s, 1H), 7.93 (s, 1H), 7.79 (d, 2H), 7.60 (d, 2H), 7.49 (d, 2H), 6.99 (d, 2H), 5.47 — 5.45 (m, 1H), 3.64 — 3.60 (m, 2H), 2.65 — 2.61 (m, 2H), 2.12 — 2.05 (m, 1H), 1.66 — 1.63 (m, 1H), 1.08 (s, 9H). MS (M+1): 504.4.
Exam le 72: +/— 4- 1- 4- 4-meth l trifluorometh l-1H- razol | henox but I benzamido ro anoic acid filly-QC/N\ O The title nd was prepared by a method analogous to that described for Example 19 using 4-methyl(trifluoromethyl)-1H-pyrazole. Analytical LCMS: retention time 3.63 minutes (Waters Atlantis dC18 4.6 x 50mm, 5pm column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid er; flow rate 2.0 ute); MS (M+1): 489.98.
Exam le 73: +/— 4- 1- 4- 3- trifluorometh | -1H-1 2 4-triazol | henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 19 using 3-(trifluoromethyl)-1H-1,2,4-triazole. 1H NMR (400 MHz, CD30D, 5): 8.99 (s, 1H), 7.76 (d, J: 8.2 Hz, 2H), 7.57 — 7.63 (m, 2H), 7.46 (d, J: 8.4 Hz, 2H), 6.99 — 7.05 (m, 2H), 5.35 (dd, J: 7.8, 5.1 Hz, 1H), 3.55 — 3.62 (m, 2H), 2.59 (t, J: 6.9 Hz, 2H), 1.94 — 2.05 (m, 1H), 1.76 — 1.87 (m, 1H), 1.36 — 1.61 (m, 2H), 0.96 (t, 3H). MS (M+1): 477.1.
Exam le 74: +/— 4- 1- 4- 3-meth l trifluorometh | -1H- razol | henox but I benzamido ro anoic acid F /M30 The title compound was prepared by a method analogous to that described for Example 19 using 3-methyl(trifluoromethyl)-1H-pyrazole. Analytical LCMS: retention time 3.57 minutes (Waters Atlantis dC18 4.6 x 50mm, 5pm column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at % water/acetonitrile to 5.0 minutes; 0.05% oroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): .
Exam le 75: +/— 4- 1- 4- 2-meth l orometh | -1H-imidazol l henox but I benzamido ro anoic acid 0 o N \N F F The title compound was prepared by a method analogous to that described for Example 19 using 2-methyl(trifluoromethyl)-1H-imidazole. 1H NMR (400 MHz, CDCI3, 6): 7.75 — 7.70 (m, 2H), 7.40 — 7.35 (m, 2H), 7.23 (s, 1H), 7.11 — 7.05 (m, 2H), 6.93 — 6.85 (m, 3H), 5.16 — 5.11 (m, 1H), 3.73 — 3.67 (m, 2H), 2.71 — 2.65 (m, 2H), 2.31 (s, 3H), 2.03 — 1.94 (m, 1H), 1.84 — 1.74 (m, 1H), 1.58 — 1.48 (m, 1H), 1.47 — 1.37 (m, 1H), 0.98 — 0.92 (m, 3H). MS (M+1): 490.3.
Exam le 76: +/— 4- c clo ro | 4- 4- trifluorometh | -1H- razol l henox meth lbenzamido ro anoic acid © 0 u) The title compound was prepared by a method analogous to that described for Example 65 using Intermediate (19). 1H NMR (400 MHz, CDCI3, 6): 8.00 (s, 1H), 7.83 (s, 1H), 7.73 (m, 2H), 7.44 — 7.42 (m, 4H), 6.89 — 6.87 (m, 2H), 6.77 — 6.76 (m, 1H), 4.69 — 4.67 (m, 1H), 3.74 — 3.70 (m, 2H), 2.71 — 2.69 (m, 2H), 1.38 — 1.34 (m, 1H), 0.73 — 0.68 (m, 1H), 0.63 — 0.46 (m, 3H). MS (M+1): 474.4, MS (M+23): 496.3.
Exam le 77: +/— 4- 2-meth l 4- 4- trifluorometh | -1H- razol l henox ro Ibenzamido ro cid Ste A: +/— -z‘en‘-but | 3- N-tert—but l 2-meth l 4- 4- trifluorometh | -1H- razol l henox ro l benzamido ro anoate O O DON’N\ F F To a 0 oC solution of Intermediate (17) (120 mg, 0.32 mmol) and Intermediate (29) (103 mg, 0.48 mmol) in toluene (2 mL) was added tributylphosphine (129 mg, 0.64 mmol) followed by 1,1’-(azodicarbonyl)dipiperidine (134 mg, 0.64 mmol). The reaction was warmed to ambient temperature and stirred overnight. Brine (20 mL) was added and the mixture was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography gave tert—butyl 3-(N-tert— butyl(2-methyl(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenoxy)propyl) benzamido)propanoate (60 mg, 32%). 1H NMR (400 MHz, CDCI3, 5): 7.93 (s, 1H), 7.75 (s, 1H), 7.37 — 7.32 (m, 2H), 7.30 — 7.20 (m, 4H), 6.81 — 6.79 (m, 2H), 4.78 (d, 1H), 3.47 — 3.43 (m, 2H), 2.31 — 2.27 (m, 2H), 2.10 — 2.05 (m, 1H), 1.44 (s, 9H), 1.21 (s, 9H), 0.97 (d, 3H), 0.85 (d, 3H).
Ste B: +/— 4- 2-meth l 4- 4- trifluorometh l-1H- razol l henox ro l benzamido ro anoic acid To a room temperature solution of tert—butyl ert—butyl(2-methyl(4- (4-(trifluoromethyl)-1H-pyrazoly|)phenoxy)propyl)benzamido)propanoate (60 mg, 0.10 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.0 mL). The e was stirred at room temperature for 3 hours. The reaction mixture was concentrated and purification by HPLC gave 3-(4-(2-methyl(4-(4- (trifluoromethyl)—1H-pyrazoly|)phenoxy)propyl)benzamido)propanoic acid (11.4 mg, 24%). 1H NMR (400 MHz, CDgOD, 6): 8.53 (s, 1H), 7.89 (s, 1H), 7.76 (d, 2H), 7.55 (d, 2H), 7.45 (d, 2H), 6.97 (d, 2H), 5.06 (d, 1H), 3.61 — 3.58 (m, 2H), 2.62 — 2.59 (m, 2H), 2.21 — 2.11 (m, 1H), 1.08 (d, 3H), 0.93 (d, 3H). MS (M+1): 476.4.
Exam le 78: +/— 4 4- 4- trifluorometh l-1H- razol l henox ro l benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 77 using Intermediate (46). 1H NMR (400 MHz, SO, 6): 8.97 (s, 1H), 8.49 — 8.47 (m, 1H), 8.11 (s, 1H), 7.80 — 7.78 (d, 2H), 7.69 — 7.65 (m, 2H), 7.49 — 7.47 (m, 2H), 7.05 — 7.01 (m, 2H), 5.40 — 5.37 (m, 1H), 3.51 — 3.40 (m, 2H), 2.50 — 2.46 (m, 2H), 2.00 — 1.81 (m, 2H), 0.96 — 0.92 (m, 3H). MS (M+1): 462.5.
Exam le 79: +/— 4- 3-meth l 4- 4- trifluorometh l -1H-imidazol l hen lbutox benzamido ro anoic acid The title nd was prepared by a method analogous to that bed for Example 19 using Intermediate (41). 1H NMR (400MHz, CD30D, 6): 7.78 — 7.77 (m, 3H), 7.50 — 7.44 (m,4H), 7.39 (s, 1 H), 6.96 — 6.92 (m, 2H), 5.33 — 5.31 (m,1H), 3.75 (s, 3 H), 3.67 — 3.59 (m, 2H), 2.64 — 2.60 (m, 2H), 2.05 — 1.95 (m, 1H), 1.87 — 1.61 (m, 1H), 1.61 — 1.41 (m, 2H), 0.98 — 0.94 (m, 3H). MS (M+1): 438.1.
Exam le 80: +/— 4- 3-meth l 4- 4- trifluorometh | -1H- razol | henox but I benzamido ro anoic acid F F The title compound was prepared by a method analogous to that described for Example 77 using Intermediate (15). 1H NMR (400 MHz, CDgOD, 6): 8.52 (s, 1H), 7.89 (s, 1H), 7.76 (d, 2H), 7.57 (d, 2H), 7.47 (d, 2H), 6.97 (d, 2H), 5.39 — 5.36 (m, 1H), 3.61 — 3.57 (m, 2H), 2.62 — 2.58 (m, 2H), 2.00 — 1.92 (m, 1H), 1.89 — 1.82 (m, 1H), 1.63 — 1.57 (m, 1H), 1.02 — 0.97 (m, 6H). MS (M+1): 490.5.
Exam le 81: 3- 4- 3-meth l 4- 4- trifluorometh | -1H- razol | henox but I benzamido ro anoic acid lsomer2 F F The title compound is obtained by resolving racemic 3-(4-(3-methyl(4-(4- (trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 80, by chiral SFC. Column: pak AD-H. ions: 10 X 250mm. Mobile Phase: 70/30 C02/2-propanol. Flow Rate: 10.0 mL/min. Modifier: none. Retention time: 3.39 minutes (second peak eluted).
Exam le 82: +/— 4- 1- 3 5-dimeth l 4- orometh l -1H- razol l henox but I benzamido ro anoic acid 0 O NAAOH N \ F N\ F Ste A: +/— -eth l4- 1- 3 5-dimeth l 4- trifluorometh l -1H- razol yl )phenoxy )butyl )benzoate Diisopropyl azodicarboxylate (0.14 mL, 0.67 mmol) was added dropwise to a solution of Intermediate (26) (119.9 mg, 0.47 mmol), ethyl 4-(1-hydroxybutyl) benzoate (98.0 mg, 0.44 mmol), and triphenylphosphine (178 mg, 0.67 mmol) in tetrahydrofuran (4.4 mL). After 18 hours, the reaction was concentrated and purification by column chromatography (0 — 40% ethyl acetate in heptanes) gave (+/—)-ethy| 4-(1-(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazoly|)phenoxy)buty|) benzoate (140 mg, 69%) as an oil. 1H NMR (400 MHz, CDCI3, 6): 8.02 (d, J = 8.8 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.40 (d, J: 8.2 Hz, 2H), 6.57 (s, 2H), 5.16 (dd, J = 7.9, 5.0 Hz, 1H), 4.37 (q, J: 7.0 Hz, 2H), 2.06 — 1.91 (m, 1H), 1.88 (s, 6H), 1.86 — 1.74 (m, 1H), 1.54 - 1.41 (m, 2H), 1.38 (t, J: 7.1 Hz, 3H), 0.96 (t, J: 7.3 Hz, 3H).
MS (M+1): 461.
Ste B: +/— 1- 3 5-dimeth l 4- trifluorometh | -1H- razol l henox but I benzoic acid To a vial containing ethyl 4-(1-(3,5-dimethyl(4-(trifluoromethyl)-1H- pyrazoly|)phenoxy)butyl)benzoate (135 mg, 0.29 mmol) was added water (0.59 mL), tetrahydrofuran (0.591 mL), and ol (0.59 mL). Lithium hydroxide monohydrate (615.0 mg, 14.6 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. The e was acidified to pH = 3 with citric acid (5%). The mixture was extracted three times with ethyl e. The organics were dried over sodium sulfate, filtered and concentrated to give (+/—)(1-(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol- 1-y|)phenoxy)butyl)benzoic acid (120 mg, 95%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 8.07 (d, J: 8.4 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.45 (d, J: 8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J: 8.0, 4.9 Hz, 1H), 2.04 — 1.92 (m, 1H), 1.89 (s, 6H), 1.87 - 1.75 (m, 1H), 1.61 - 1.36 (m, 2H), 0.97 (t, J: 7.4 Hz, 3H). MS (M+1): 433.
Ste C: +/— -eth | 3- 4- 1- 3 th l 4- trifluorometh | -1H- razol l henox but I benzamido ro anoate O O NVKOA N,N-dimethylformamide (1.88 mL) was added to a vial containing 4-(1-(3,5- dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzoic acid (122.0 mg, 0.28 mmol), ethyl 3-aminopropanoate hydrochloride (86.6 mg, 0.56 mmol) and O—(7-azabenzotriazoly|)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (214.0 mg, 0.56 mmol). Diisopropylethylamine (0.25 mL, 1.41 mmol) was then added. After stirring for 4 hours, the reaction was d with saturated ammonium chloride and extracted three times with l ether. The combined organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 — 25% ethyl acetate in heptane) afforded (+/—)-ethy| 3-(4-(1- (3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzamido) propanoate (117 mg, 78% yield). 1H NMR (400 MHz, CDCI3, 6): 7.87 (s, 1H), 7.73 (d, J: 8.0 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J: 8.2 Hz, 2H), 6.84 (d, J: 5.9 Hz, 1H), 6.57 (s, 2H), 5.15 (dd, J: 7.8, 5.1 Hz, 1H), 4.17 (q, J: 7.1 Hz, 2H), 3.71 (q, J: 6.0 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.04 - 1.91 (m, 1H), 1.88 (s, 6H), 1.86 - 1.71 (m, 1H), 1.58 - 1.33 (m, 2H), 1.26 (t, J: 7.0 Hz, 3H), 0.96 (t, J: 7.4 Hz, 3H). MS (M+1): 532.
Ste D: +/— 4- 1- 3 th l 4- trifluorometh l -1H- 1- | henox but I benzamido ro anoic acid To a flask containing ethyl 3-(4-(1-(3,5-dimethyl(4-(trifluoromethy|)-1H- pyrazoly|)phenoxy)butyl)benzamido)propanoate (117 mg, 0.22 mmol) was added water (0.55 mL), tetrahydrofuran (0.55 mL), and methanol (0.55 mL). Lithium hydroxide monohydrate (508 mg, 12.1 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was concentrated and acidified to pH = 3 with citric acid (10%). A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (+/—)(4-(1-(3,5- dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid (90 mg, 81%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 7.88 (s, 1H), 7.73 (d, J: 8.2 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J: 8.4 Hz, 2H), 6.80 (t, J: 5.9 Hz, 1H), 6.56 (s, 2H), 5.16 (dd, J: 7.8, 5.1 Hz, 1H), 3.71 (q, J: 5.9 Hz, 2H), 2.69 (t, J: 5.8 Hz, 2H), 2.04 — 1.91 (m, 1H), 1.88 (s, 6H), 1.86 - 1.67 (m, 1H), 1.63 - 1.31 (m, 2H), 0.96 (t, J: 7.3 Hz, 3H). MS (M+1): 504.
Example 83: S 4- 1- 3 5-dimeth l 4- trifluorometh | -1H- 1- | henox but I benzamido ro anoic acid 0 O WNWH pewN\ F The title nd is obtained by ing racemic 3-(4-(1-(3,5-dimethyl (4-(trifluoromethyl)-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 82, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 X 250mm. Mobile Phase: 80/20 C02/2-propanol. Flow Rate: 10.0 mL/min. Modifier: 0.2% isopropylamine. Retention time: 3.23 minutes.
Alternatively (S)(4-(1-(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol yl)phenoxy)butyl)benzamido)propanoic acid, the compound of Example 83 can be prepared by chiral synthesis as follows.
Ste A: S-eth l4- 1- 3 5-dimeth l 4- trifluorometh l-1H- 1- yl )phenoxy )butyl )benzoate To a solution of Intermediate (56) (4.51 g, 20.3 mmol) and Intermediate (26) (5.2 g, 20.0 mmol) in tetrahydrofuran (100 mL) was added diisopropyl azodicarboxylate (13.1 mL, 30.4 mmol). Tributylphosphine (7.86 mL, 31.5 mmol) was added dropwise at room temperature, maintaining the internal temperature below 30 oC. The e was d at room temperature for 2 hours. The reaction was then concentrated. The resulting solid was diluted with dichloromethane and hydrochloric acid (1 N). The mixture was extracted twice with dichloromethane. The combined c layers were dried over sodium sulfate, filtered, and concentrated.
Purification by column chromatography (0-8% ethyl e in heptanes) afforded (S)-ethyl 4-(1-(3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazolyl)phenoxy)butyl) benzoate (6.9 g, 74%) as an oil: 1H NMR (400 MHz, CDCI3, 6): 8.02 (d, J = 8.8 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.40 (d, J: 8.2 Hz, 2H), 6.57 (s, 2H), 5.16 (dd, J: 7.9, 5.0 Hz, 1H), 4.37 (q, J: 7.0 Hz, 2H), 2.06 — 1.91 (m, 1H), 1.88 (s, 6H), 1.86 — 1.74 (m, 1H), 1.54 - 1.41 (m, 2H), 1.38 (t, J: 7.1 Hz, 3H), 0.96 (t, J: 7.3 Hz, 3H).
MS (M+1): 461.
Ste B: S 1- 3 th l 4- trifluorometh l -1H- razol | henox but I benzoic acid To a flask containing (S)-ethyl 4-(1-(3,5-dimethyl(4-(trifluoromethyl)—1H- pyrazoly|)phenoxy)butyl)benzoate (11.8 g, 25.6 mmol) was added water (32.0 mL), tetrahydrofuran (32.0 mL), and methanol (32.0 mL). Lithium hydroxide monohydrate (2.15 g, 51.2 mmol) was then added. The suspension was stirred at room temperature. After 1.5h, another (1.07 g, 25.6 mmol) of lithium hydroxide monohydrate was added. After 2h, the reaction was concentrated. The crude residue was dissolved in water and the solution was acidified to pH = 3 with 1N hydrochloric acid. A white precipitate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)(1-(3,5-dimethyl(4-(trifluoromethyl)- 1H-pyrazoly|)phenoxy)butyl)benzoic acid (11.1 g, 100%) as a white gum. 1H NMR (400 MHZ, CDCI3, 6): 8.07 (d, J: 8.4 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.45 (d, J = 8.2 Hz, 2H), 6.58 (s, 2H), 5.18 (dd, J = 8.0, 4.9 Hz, 1H), 2.04 — 1.92 (m, 1H), 1.89 (s, 6H), 1.87 - 1.75 (m, 1H), 1.61 - 1.36 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). MS (M+1): 433.
Ste C: S -eth l 3- 4- 1- 3 5-dimeth l 4- trifluorometh l -1H- razol | henox but I benzamido ro anoate O 0 N’N\ N,N-dimethylformamide (17.6 mL) was added to a vial containing (S)(1- (3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzoic acid (6.1 g, 14.1 mmol), ethyl 3-aminopropanoate hydrochloride (4.33 g, 28.2 mmol) and O- (7-azabenzotriazoly|)-N,N,N’,N’-tetramethyluronium uorophosphate (10.7 g, 28.2 mmol). Diisopropylethylamine (12.3 mL, 70.5 mmol) was then added. The on was stirred for 1h, and was then concentrated. cation by column tography (0 — 30% ethyl acetate in heptane) afforded (S)-ethy| 3-(4-(1-(3,5- dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)butyl)benzamido) propanoate (7.07 g, 94% yield) as a colorless gum. 1H NMR (400 MHz, CDCI3, 5): 7.87 (s, 1H), 7.73 (d, J: 8.0 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J: 8.2 Hz, 2H), 6.84 (d, J: 5.9 Hz, 1H), 6.57 (s, 2H), 5.15 (dd, J: 7.8, 5.1 Hz, 1H), 4.17 (q, J: 7.1 Hz, 2H), 3.71 (q, J: 6.0 Hz, 2H), 2.63 (t, J: 5.7 Hz, 2H), 2.04 - 1.91 (m, 1H), 1.88 (s, 6H), 1.86 - 1.71 (m, 1H), 1.58 - 1.33 (m, 2H), 1.26 (t, J: 7.0 Hz, 3H), 0.96 (t, J: 7.4 Hz, 3H). MS (M+1): 532.
Ste D: S 4- 1- 3 5-dimeth l 4- trifluorometh l -1H- razol | henox but I benzamido ro anoic acid To a flask containing ethyl (S)-ethyl 3-(4-(1-(3,5-dimethyl(4- (trifluoromethyl) razoIy|)phenoxy)buty|)benzamido)propanoate (6.95 g, 13.1 mmol) was added water (33.0 mL), tetrahydrofuran (33.0 mL), and methanol (33.0 mL). Lithium hydroxide monohydrate (1.1 g, 26.1 mmol) was then added. The suspension was stirred at room temperature for 13 hours. The reaction was concentrated. The crude residue was dissolved in water, and the solution was acidified to pH = 4 with 1N hydrochloric acid. A white itate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)(4-(1-(3,5- dimethyl(4-(trifluoromethyl)—1H-pyrazoly|)phenoxy)buty|)benzamido)propanoic acid (5.7g, 87%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 7.88 (s, 1H), 7.73 (d, J: 8.2 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J: 8.4 Hz, 2H), 6.80 (t, J: 5.9 Hz, 1H), 6.56 (s, 2H), 5.16 (dd, J: 7.8, 5.1 Hz, 1H), 3.71 (q, J: 5.9 Hz, 2H), 2.69 (t, J: 5.8 Hz, 2H), 2.04 — 1.91 (m, 1H), 1.88 (s, 6H), 1.86 - 1.67 (m, 1H), 1.63 - 1.31 (m, 2H), 0.96 (t, J: 7.3 Hz, 3H). MS (M+1): 504.
Another alternative sis of (S)(4-(1-(3,5-dimethyl(4- (trifluoromethy|)-1H-pyrazoIy|)phenoxy)buty|)benzamido)propanoic acid, the compound of Example 83 is provided by chiral synthesis as follows.
Ste A: R 1-h drox but I benzoic acid To a solution of ediate (56) (3.25 g, 14.6 mmol), was added water (25.0 mL), tetrahydrofuran (25.0 mL), and methanol (25.0 mL). Lithium hydroxide monohydrate (1.23 g, 29.2 mmol) was then added. The suspension was stirred at room temperature. After 2.5h, the reaction was concentrated. The crude residue was dissolved in ethyl acetate and the solution was acidified to pH = 3 with 1N hloric acid. The mixture was ted three times with ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated to give (R)—4-(1-hydroxybutyl)benzoic acid (2.63 g, 93%) as a white solid. 1H NMR (400 MHz, CDCI3, 5): 8.09 (d, J: 8.2 Hz, 2H), 7.46 (d, J: 8.2 Hz, 2H), 4.79 (dd, J: 7.6, .5 Hz,1H),1.86 - 1.76 (m, 1H), 1.76 - 1.64 (m, 1H), 1.54 - 1.40 (m, 1H), 1.40 - 1.27 (m, 1H), 0.95 (t, J: 7.3 Hz, 3H). MS (M-1): 193.
Ste B: R-eth |3- 4- 1-h drox but Ibenzamido ro anoate O O WQKHVLOA N,N-dimethylformamide (16.9 mL) was added to a vial containing (R)—4-(1- hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-aminopropanoate hloride (4.16 g, 27.1 mmol) and O—(7-azabenzotriazoly|)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (10.3 g, 27.1 mmol).
Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The reaction was stirred for 1h, and was then concentrated. Purification by column chromatography (0 — 50% ethyl acetate in heptane) afforded (R)—ethyl 3-(4-(1- hydroxybuty|)benzamido)propanoate (3.97 g, 100% yield) as an OH. 1H NMR (400 MHz, CDCI3, 5): 7.75 (d, J: 8.2 Hz, 2H), 7.40 (d, J: 8.0 Hz, 2H), 6.83 (br. s., 1H), 4.74 (t, J: 8.2 Hz, 1H), 4.18 (q, J: 7.1 Hz, 2H), 3.73 (q, J: 5.9 Hz, 2H), 2.64 (t, J = 6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84 - 1.62 (m, 2H), 1.49 - 1.30 (m, 2H), 1.28 (t, J: 7.1 Hz, 3H), 0.93 (t, J: 7.3 Hz, 3H). MS (M+1): 294.
Ste C: S -eth l 3- 4- 1- 3 5-dimeth l 4- trifluorometh l -1H- razol | henox but I benzamido ro anoate To a solution of azeotropically dried (R)—ethyl 3-(4-(1-hydroxybutyl) benzamido)propanoate (2.6 g, 8.9 mmol) and azodicarboxylic acid dipiperidine (3.8 g, 15.1 mmol) (with toluene) in tetrahydrofuran (49.2 mL) was added tributylphosphine (3.9 mL, 16.0 mmol) dropwise at room temperature. Intermediate (26) (2.3 g, 8.9 mmol) was then added portionwise. The mixture was stirred at room temperature for 16 hours. The reaction was d with ethyl acetate and then extracted twice with sodium hydroxide (1 N), once with water, once with hydrochloric acid (1 N), and finally once with brine. The organic layer was dried over sodium e, ed, and concentrated. Purification by column chromatography (0-30% ethyl acetate in heptanes) afforded (S)-ethy| 4-(1-(3,5-dimethy|—4-(4- uoromethy|)-1H-pyrazoIy|)phenoxy)buty|) te (3.53 g, 75%) as colorless gum: 1H NMR (400 MHz, CDCI3, 6): 7.87 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J: 8.2 Hz, 2H), 6.84 (d, J: 5.9 Hz, 1H), 6.57 (s, 2H), 5.15 (dd, J: 7.8, 5.1 Hz, 1H), 4.17 (q, J: 7.1 Hz, 2H), 3.71 (q, J: 6.0 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.04 - 1.91 (m, 1H), 1.88 (s, 6H), 1.86 - 1.71 (m, 1H), 1.58 - 1.33 (m, WO 07850 2H), 1.26 (t, J: 7.0 Hz, 3H), 0.96 (t, J: 7.4 Hz, 3H). MS (M+1): 532. Chiral SFC.
Column: Chiralpak AD-H. Dimensions: 4.6 x 250mm. Mobile Phase: 80/20 COZ/ethanol. Flow Rate: 2.5 mL/min. Modifier: None. Retention time: 3.05 minutes.
Ste D: S 4- 1- 3 th l 4- trifluorometh l-1H- razol l henox but I ido ro anoic acid To a flask containing ethyl (S)-ethyl 3-(4-(1-(3,5-dimethyl(4- uoromethyl) -1H-pyrazolyl)phenoxy)butyl)benzamido)propanoate (3.5 g, 6.6 mmol) was added tetrahydrofuran (16.5 mL), methanol (16.5 mL), and sodium hydroxide (1N) (16.5 mL, 16.5 mmol). The suspension was stirred at room temperature for 18 hours. The reaction was concentrated. The crude residue was dissolved in water, and the solution was acidified to pH = 3 with 1N hydrochloric acid. A white itate formed. The solid was filtered, rinsed with water, and dried under vacuum to give (S)(4-(1-(3,5-dimethyl(4-(trifluoromethyl)—1 H-pyrazol yl)phenoxy)butyl)benzamido)propanoic acid (2.87 g, 87%) as a white solid.
Recrystallization was performed using methyl utyl ether to provide a crystalline compound. The crystalline compound can be characterized by powder X-ray diffraction to provide the spectrum substantially as shown in Figure 1. 1H NMR (400 MHz, CDCI3, 5): 7.88 (s, 1H), 7.73 (d, J: 8.2 Hz, 2H), 7.65 (s, 1H), 7.39 (d, J: 8.4 Hz, 2H), 6.80 (t, J: 5.9 Hz, 1H), 6.56 (s, 2H), 5.16 (dd, J: 7.8, 5.1 Hz, 1H), 3.71 (q, J: 5.9 Hz, 2H), 2.69 (t, J: 5.8 Hz, 2H), 2.04 — 1.91 (m, 1H), 1.88 (s, 6H), 1.86 - 1.67 (m, 1H), 1.63 - 1.31 (m, 2H), 0.96 (t, J: 7.3 Hz, 3H). MS (M+1): 504. Mp 157- 159 °C. [d]D = -43.8 (c=1; CHCI3).
A further synthesis of the compound of Example 83 is provided below.
OMe OMe Ste 1 : R-meth l4- 1-h drox but lbenzoate To a solution of borane diethylaniline complex (20.6 g, 25.2 mL, 126 mmol) in tetrahydrofuran (130 mL) at 20 °C was added (s)—methyl oxazaborilidine (6.3 mL, 6.3 mmol). A solution of ketone (26.0 g, 126 mmol) in tetrahydrofuran (130 mL) was added over 2.5 h. The reaction was stirred 10 min before quenching with WO 07850 2012/050349 methanol (15.3 mL). To the ed solution was added 1 M HCI (125 mL) and the product was extracted with heptane (2 x 130 mL). The combined organic solution was washed with 1 M HCI (125 mL) and concentrated to a final volume of 250 mL. The solution was cooled to -10 °C the product filtered and washed with cold heptanes to give (R)—methyl 4-(1-hydroxybutyl)benzoate as a white solid (23.3 g, 89% yield). 1H NMR (400 MHz, CDCI3) 8: 7.99 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 4.73 (dd, J = 7.4, 5.9 Hz, 1H), 3.89 (s, 3H), 1.81-1.61 (m, 2H), 1.47- 1.26 (m, 2H), 0.92 (t, J: 7.4 Hz, 3H).
Br OH NCZ NCZ Ste 1s :3 5-dimeth l 4- trifluorometh l-1H- razol l henol To a solution of the aryl bromide (intermediate 7) (15.3 g, 49 mmol) and potassium hydroxide (9.50 g, 144 mmol) in N-methylpyrrolidone (38 mL) and water (38 mL) was added tris(dibenzylidineacetone)dipalladium (0.44 g, 0.48 mmol) and t- butyl X-Phos (0.41 g, 0.96 mmol). The solution was heated to 90 °C. After 30 min the reaction was cooled to room temperature and ethyl acetate (75 mL) was added.
The solution was acidified with conc. HCI (9 mL). The aq. phase was split and the organic layer washed with a 0.5 M potassium phosphate, tribasic solution (75 mL).
The solvent was removed and e (75 mL) added. The toluene solution was cooled to 0 °C and filtered to give 3,5-dimethyl(4-(trifluoromethyl)—1 zol yl)phenol (9.21 g, 75% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 8: 9.71 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 6.57 (s, 1H), 1.82 (s, 6H).
Ste 2 3.4 : S 1- 3 5-dimeth l 4- trifluorometh l -1H- razol l henox but I benzoic acid tromethamine salt. 0 NH2 N'N KL\/OH \\ /Z OH OH Step (2): (R)—methyl methylsulfonyloxy)butyl)benzoate: To a on of (R)—methyl 4-(1-hydroxybutyl)benzoate, intermediate (26) (10 g, 48 mmol) in methyl t—butyl ether (80 mL) containing triethylamine (6.32 g, 62 mmol) was added methanesulfonyl chloride (6.05 g, 53 mmol) slowly at 20 °C. The solution was filtered to remove triethylamine salts and the solution used in the next step without isolation.
Ste 3 : S-meth l4- 1- 3 5-dimeth l 4- trifluorometh l -1H- razol yl)phenoxy)butyl)benzoate: To a solution of 3,5-dimethyl(4-(trifluoromethyl)—1H-pyrazolyl)phenol (intermediate 26) (12.6 g, 49 mmol) in 2-methyltetrahydrofuran (70 mL) was added cesium carbonate (23.5 g, 72 mmol) and the solution of mesylate from step 2. The reaction was heated to 65 °C for 5 h. The reaction was then cooled to room temperature and water (80 mL) was added. The aq. layer was split and the organic solution was used in the next step without isolation.
Ste 4 : S 1- 3 5-dimeth l 4- trifluorometh l -1H- razol l henox but I benzoic acid tromethamine salt: To the on from step 3 was added 5 M sodium hydroxide on (29 mL, 145 mmol) and methanol (30 mL). The solution was heated to 35 °C for 6 h.
After cooling to room temperature, the solution was acidified with conc. HCI (12.4 mL). The on was washed with water (30 mL). The organic solution was concentrated and the residue taken up in acetonitrile (100 mL). A on of tris(hydroxymethyl)aminomethane (5.82 g in water (5 mL) was added , 48 mmol) slowly. The resulting slurry was cooled to 0 °C. The product was filtered and washed with acetonitrile to give the desired salt as a white solid (20.5 g, 77% yield) 1H NMR (400 MHz, DMSO-d6) 8: 8.53 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.74 (s, 2H), 5.38 (dd, J = 7.4, 5.1 Hz, 1H), 3.37 (s, 6H), 1.94-1.85 (m, 1H), 1.79 (s, 6H), 1.76-1.68 (m, 1H), 1.45-1.29 (m, 2H), 0.89 (t, J = 7.5 Hz, 3H).
Ste 5-6 : S 4- 1- 3 5-dimeth l 4- trifluorometh l -1H- razol | henox but I benzamido ro anoic acid: Q H N\/\n/CH O O Ste 5 : S-meth l 3- 4- 1- 3 5-dimeth l 4- orometh l -1H- razol | henox but I benzamido ro anoate To a solution of the tromethamine salt (20 g, 36 mmol) in 2- methyltetrahydrofuran (200 mL) was added B-alanine ethyl ester (7.08 g, 45 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (8.25 g, 47 mmol) and N-methylmorpholine (7.31 g, 72 mmol). The reaction was stirred at 20 °C for 2 h. The reaction was washed with water (2x72 ml) and the organic solution used in the next step without isolation.
Ste 6 : S 4- 1- 3 th l 4- trifluorometh l -1H- razol | henox but I benzamido ro anoic acid: To the solution from step 5 was added ol (40 mL), water (54 mL) and sodium hydroxide (4.34 g, 108 mmol). The reaction was stirred 1 h at 30 °C. The solution was acidified with conc. HCI (9.33 mL) and the aq. phase split. The c solution was washed with 1 N HCI (40 mL). The organic phase was concentrated and the residue taken up in acetonitrile (300 mL). The solution was cooled to 0 °C and stirred 5 h. The solid product was filtered and washed with cold acetonitrile, giving the d compound as a white solid (14.6 g, 80% yield). 1H NMR (400 MHz, CDCI3) 8: 7.88 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.38 (d, J: 8.3 Hz, 2H), 6.89 (t, J = 6.2 Hz, 1H), 6.55 (s, 2H), 5.15 (dd, J = 7.8, 4.6 Hz, 1H), 3.68 (q, J = 6.2 Hz, 2H), 2.65 (t, J = 6.2 Hz, 2H), 1.95 (m, 1H), 1.86 (s, 6H), 1.78 (m, 1H), 1.55-1.38 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). The final compound was recrystallized from acetonitrile (5 vol). The compound was heated to 80 °C and then cooled to 0 °C to provide a purity of 99.01%.
Exam le 84: R 4- 1- 3 5-dimeth l 4- trifluorometh l -1H- razol | henox but I benzamido ro anoic acid O O \/\/©)\H/\)J\OH Nfi’fiN\ F The title compound is obtained by resolving racemic 3-(4-(1-(3,5-dimethyl (4-(trifluoromethyl)-1H-pyrazoly|)phenoxy)butyl)benzamido)propanoic acid, the nd of Example 82, by chiral SFC. Column: Chiralpak AD-H. Dimensions: 10 X 250mm. Mobile Phase: 80/20 C02/2-propanol. Flow Rate: 10.0 mL/min. Modifier: 0.2% isopropylamine. Retention time: 3.65 minutes.
Exam le 85: +/— 4- 1- 5- 4- trifluorometh l -1H- razol l ridine lox but I benzamido ro anoic acid F?\/ ,N \ o | o /N NdOH The title compound was prepared by a method analogous to that bed for Example 19 using Intermediate (49) and 4-(trifluoromethyl)-1H-pyrazole. 1H NMR (400 MHz, CDgOD, 6): 8.62 (s, 1H), 8.42 (d, J: 2.3 Hz, 1H), 8.03 (dd, J: 9.0, 2.9 Hz, 1H), 7.94 (s, 1H), 7.76 — 7.72 (m, 2H), 7.49 — 7.44 (m, 2H), 6.99 — 6.93 (m, 1H), 6.09 (dd, J: 7.9, 5.6 Hz, 1H), 3.63 — 3.55 (m, 2H), 2.60 (t, J: 6.9 Hz, 2H), 2.08 — 1.96 (m, 1H), 1.90 — 1.78 (m, 1H), 1.54 — 1.33 (m, 2H), 0.98 — 0.92 (m, 3H).
MS (M+1): 477.3.
Exam le 86: +/— 4- 1- 6- 4- orometh l -1H- razol l ridine lox but I benzamido ro anoic acid -1H- razoll yloxy )butyl )benzoate / N,N\ To a 0 °C mixture of Intermediate (20) (150 mg, 0.72 mmol) and Intermediate (38) (110 mg, 0.48 mmol) in tetrahydrofuran (5.0 mL) was added triphenylphosphine (252 mg, 0.96 mmol) ed by lazodicarboxylate (167 mg, 0.96 mmol). The mixture was stirred at 40°C overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate, ed and concentrated. Purification by column chromatography gave (+/—)-methy| 4-(1-(6-(4-(trifluoromethy|)-1H-pyrazolyl)pyridine yloxy)butyl)benzoate (170 mg, 84%). 1H NMR (400 MHz, CDCI3, 5): 8.60 (s, 1H), 7.97 — 7.93 (m, 3H), 7.75 (s, 1H), 7.72 (d, 1H), 7.34 (d, 2H), 7.20 — 7.17 (m, 1H), .13 — 5.10 (m ,1H), 3.83 (s, 3H), 2.01 — 1.95 (m, 1H) — 1.78 (m, 1H), 1.48 — , 1.81 1.47 (m, 1H), 1.38 — 1.36 (m, 1H), 0.92 — 0.89 (m, 3H).
Ste B: +/— 4- 1- 6- 4- trifluorometh | -1H- razol | ridine lox but I benzamido ro anoic acid To a 0 °C solution of methyl 4-(1-(6-(4-(trifluoromethy|)-1H-pyrazol yl)pyridineyloxy)butyl)benzoate (170.0 mg, 0.405 mmol) in tetrahydrofuran (3 mL) was added 2N lithium hydroxide (610 uL, 1.22 mmol). The mixture was stirred at 50 °C overnight. The reaction was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated, to give 164 mg of a ess solid. To a solution of 100 mg of the crude residue in N,N-dimethylformamide (5 mL) was added O—(7- azabenzotriazoly|)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (141 mg, 0.37 mmol). The mixture was stirred for 45 minutes and then methyl 3- aminopropionate hydrochloride (51.1 mg, 0.37 mmol) and diisopropylethylamine (128 mg, 0.988 mmol) were added. The resulting e was stirred at room temperature for 2 hours. The mixture was diluted with saturated ammonium chloride, and the layers were separated. The organic layer was washed with water, dried over sodium e, filtered and trated. The crude residue was dissolved in water (5 mL) and ydrofuran (5 mL). 2N lithium hydroxide (330 uL, 0.66 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl e. The organic layer was dried over sodium sulfate, ed and concentrated. Purification by HPLC (column: Boston Analytics Symmetrix ODS-H 150x30mm, 5pm; modifier: formic acid 0.225%; gradient: 47 to 67% acetonitrile in water) gave (+/—)(4-(1-(6-(4-(trifluoromethy|)-1 H-pyrazoly|)pyridine yloxy)buty|)benzamido)propanoic acid (90 mg) as a colorless solid. 1H NMR (400 MHz, CDgOD, 5): 8.71 (s, 1H), 7.98 (m, 1H), 7.84 (s, 1H), 7.71 — 7.69 (m, 3H), 7.42 — 7.35 (m, 3H), 5.33 — 5.30 (m, 1H), 3.53 — 3.50 (m, 2H), 2.54 — 2.51 (m, 2H), 1.97 — 1.92 (m, 1H), 1.79 — 1.73 (m, 1H), 1.49— 1.38 (m, 1H), 1.37— 1.34 (m, 1H), 0.90 (t, 3H). MS (M+1): 477.5.
Exam le 87: +/— 4- 1- 6- 4- trifluorometh | -1H-imidazol | ridine lox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 86 using Intermediate (50). 1H NMR (400 MHz, CDgOD, 5): 8.43 (s, 1H), 8.22 (s, 1H), 8.14 (d, 1H), 7.80 — 7.78 (m, 2H), 7.57 — 7.55 (m, 1H), 7.47 — 7.44 (m, 3H), 5.44 — 5.41 (m, 1H), 3.61 — 3.57 (m, 2H), 2.62 — 2.58 (m, 2H), 2.06 — 2.03 (m, 1H), 1.89 — 1.85 (m, 1H), 1.57 —1.55(m,1H), 1.47 — 1.43 (m, 1H), 1.00 — 0.96 (m, 3H). MS (M+1): 477.2.
Exam le 88: +/— 4- 1- 4- 4-c ano-1H- razol l henox but Ibenzamido Ste A: 1- 4-methox hen l -1H— razole 05).)/ / A mixture of (4-methoxyphenyl)hydrazine hydrochloride (8.0 g, 0.046 mol) and 1,1,3,3-tetramethoxypropane (8.3 g, 0.05 mol) in ethanol (120 mL) was heated to reflux for 1 hour. The reaction was then cooled to room temperature and trated. The residue was diluted with ted sodium bicarbonate (50 mL) and ethyl acetate (100 mL). The phases were separated and the aqueous was extracted with ethyl acetate (2 x 20 mL). The combined organics were washed with brine (50 mL), dried over sodium e, filtered and concentrated. Purification by column tography gave 1-(4-methoxyphenyl)—1H-pyrazole (7.7 g, 97%) as a yellow oi|.1H NMR (400 MHz, CDCI3, 5): 7.82 (m, 1H), 7.69 (m, 1H), 7.59 (d, J: 9.2 Hz, 2H), 6.97 (d, J: 9.2 Hz, 2H), 6.43 (m, 1H), 3.83 (s, 3H).
Ste B: 4-bromo 4-methox hen l -1H— razole To a solution of 1-(4-methoxyphenyl)—1H-pyrazole (7.2 g, 0.042 mol) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (7.3 g, 0.042 mol). The reaction was stirred at room temperature for 3 hours. The reaction was concentrated and purification by column chromatography gave 4-bromo—1-(4- methoxyphenyl)—1H-pyrazole (8.9 g, 84%) as a white solid. 1H NMR (400MHz, CDCI3, 5): 7.83 (s, 1H), 7.63 (s, 1H), 7.52 (d, J: 8.8 Hz, 2H), 6.97 (d, J: 8.8 Hz, 2H), 3.84 (s, 3H).
Ste C: 1- 4-methox hen | -1H— razolecarbaldeh de \ ,N O To a -78°C solution of 4-bromo—1-(4-methoxyphenyl)—1 H-pyrazole (506mg, 2.0mmol) in anhydrous tetrahydrofuran (20mL) was added n-butyllithium in hexane (0.95mL, 2.4mmol). The reaction was stirred for 2h at -78°C. N,N- dimethylformamide , 4mmol) was added and the reaction continued to stir at -78°C for 1h, then at room temperature for 2h. The reaction was quenched with saturated ammonium chloride (20mL) and extracted with ethyl acetate (3 x 30mL).
The combined organics were washed with brine (30mL), dried over sodium sulfate, ed and trated. Purification by column chromatography gave 1-(4- methoxyphenyl)—1H-pyrazolecarbaldehyde (80mg, 20%) as a yellow oil. 1H NMR (400 MHz, CDCI3, 6): 9.95 (s, 1H), 8.33 (s, 1H), 8.13 (s, 1H), 7.62 (d, J: 9.2 Hz, 2H), 7.01 (d, J: 9.2 Hz, 2H), 3.86 (s, 3H).
Ste D: thox hen l-1H- razolecarbonitrile To a mixture of 1-(4-methoxypheny|)-1H-pyrazoIecarbaldehyde (80 mg, 0.54 mmol) in tetrahydrofuran (3 mL) and ammonium hydroxide (3 mL) was added iodine (138 mg, 0.54 mmol). The reaction was stirred at room ature for 5 hours. The reaction was d with saturated sodium thiosulphate (5 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to give 1-(4- methoxyphenyl)—1H-pyrazolecarbonitrile (78 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CDCI3, 5): 8.19 (s, 1H), 7.96 (s, 1H), 7.56 (d, J: 9.2 Hz, 2H), 7.01 (d, J: 9.2 Hz, 2H), 3.86 (s, 3H).
Ste E: 1- 4-h drox hen l-1H- razole—4-carbonitrile To a solution of 1-(4-methoxyphenyl)—1H-pyrazolecarbonitrile (115 mg, 0.575 mmol) in dichloromethane (5 mL) was added boron tribromide (431 mg, 1.73 mmol) at -10°C. The reaction was then warmed to room temperature and stirred for 16 hours. The reaction was quenched with methanol (0.5 mL) and water (5 mL), and extracted with ethyl acetate (3 x 15 mL). The combined organics were washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated to give 1-(4- hydroxyphenyl)—1H-pyrazolecarbonitrile (46 mg, 43%) as a yellow solid. 1H NMR (400 MHz, CDCI3, 5): 9.89 (s, 1H), 9.12 (s, 1H), 8.27 (s, 1H), 7.62 (d, J: 9.2 Hz, 2H), 6.90 (d, J: 9.2 Hz, 2H).
Ste F: +/— 4- 1- 4- 4-c ano-1H— razol l henox but I benzamido propanoic acid The title compound was prepared by a method analogous to that described for Example 77 using Intermediate (48), 1-(4-hydroxyphenyl)—1H-pyrazole carbonitrile, triphenylphosphine, and diethylazodicarboxylate. ical LCMS: retention time 1.310 minutes (Atlantis C18 4.6 x 50mm, 5pM column; 95% acetonitrile linear gradient to 5% water/acetonitrile over 4.0 s, hold at % water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 433.2.
Exam le 89: +/— 4- 1- 4- 4 5 6 7-tetrah dro-2H—indazol l henox but I benzamido ro anoic acid /N\woo Ste A: +/— -meth l4 4- 4 5 6 7-tetrah —indazol l henox but I Intermediate (27) (111 mg, 0.271 mmol) was combined with 4,567- tetrahydro-2H-indazole (39.4 mg, 0.323 mmol), copper(|) iodide (2.7 mg, 0.014 mmol), potassium carbonate (78.6 mg, 0.569 mmol), trans-dimethylcyclohexane- 1,2-diamine (9.0 uL, 0.054 mmol), and e (2 mL). The reaction was refluxed for 16 hours, then cooled to room temperature, and partitioned between ethyl acetate and water/ammonium ide. The organic layer was washed with 0.5N HCI and brine, dried over magnesium sulfate, filtered and concentrated.
Purification by column chromatography (0 — 30% ethyl acetate in heptane) gave (+/—)-methy| 4-(1-(4-(4,5,6,7-tetrahydro-2H-indazolyl)phenoxy)butyl)benzoate (0.056g, 51%) as a clear oil. 1H NMR (400 MHz, CDCI3, 5): 8.01 (d, J: 8.2 Hz, 2H), 7.35 — 7.48 (m, 5H), 6.84 (d, J: 9.0 Hz, 2H), 5.15 (dd, J: 7.6, 5.1 Hz,1H), 3.91 (s, 3 H), 2.74 (t, J: 6.2 Hz, 2H), 2.58 (t, J: 6.1 Hz, 2H), 1.94 — 2.04 (m, 1H), 1.70 — 1.90 (m, 5H), 1.37 — 1.56 (m, 2H), 0.96 (t, 3H). MS (M+1): 405.2.
Ste B: +/— 4- 1- 4- 4 5 6 7-tetrah dro-2H—indazol | henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 20 using methyl 4-(1-(4-(4,5,6,7-tetrahydro-2H—indazoly|)phenoxy) butyl)benzoate. Column: Waters is C18 4.6 x 50mm, 5pm; er: TFA 0.05%; nt: 95% H20 / 5% acetonitrile linear to 5% H20 / 95% acetonitrile over 4.0 min, hold at 5% H20 / 95% acetonitrile to 5.0min. Flow: 2.0 mL/ min.; Retention time: 3.39 minutes. MS (M+1): 462.2.
Exam le 90: +/— 4- 1- 4- 5 6-dih droc clo enta c razol-2 4 - l henox but I benzamido ro anoic acid Ste A: +/— -meth l4- 1- 4- 5 6-dih droc clo enta c razol-2 4H - yl)phenoxy)butyl)benzoate WO 07850 The title compound was prepared by a method analogous to that described for Example 89, Step A, using 1,4,5,6-tetrahydro-cyclopenta[c]pyrazole hydrochloride. The product obtained was a 4:1 mixture of regioisomers. 1H NMR (500 MHz, CDCI3, 5): 8.01 (d, J = 8.1 Hz, 2H), 7.46 — 7.29 (m, 5H), 6.88 — 6.79 (m, 2H), 5.19 — 5.11 (m, 1H), 3.91 (s, 3H), 2.93 — 2.36 (m, 6H), 2.04 — 1.94 (m, 1H), 1.87 — 1.75 (m, 1H), 1.56 — 1.38 (m, 2H), 0.97 (t, 3H). MS (M+1): 391.3.
Ste B: +/— 4- 1- 4- 5 6-dih droc clo enta c razol-2 4 - l henox but I ido ro anoic acid The title compound was prepared by a method analogous to that described for Example 20 using methyl 4-(1-(4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)- yl)phenoxy)buty|)benzoate. 1H NMR (400 MHz, CDCI3, 6): 7.72 (d, J = 8.2 Hz, 2H), 7.45 — 7.30 (m, 5H), 6.90 — 6.76 (m, 3H), 5.13 (dd, J: 7.5, 5.4 Hz, 1H), 3.76 — 3.64 (m, 2H), 2.94 — 2.73 (m, 2H), 2.73 — 2.35 (m, 6H), 2.10 — 1.93 (m, 1H), 1.88 — 1.74 (m, 1H), 1.64 — 1.36 (m, 2H), 0.96 (t, 3H). MS (M+1): 448.4.
Exam le 91: +/— 4- 1- 4- 2H-indazol l henox but I benzamido ro anoic The title compound was ed by a method analogous to that described for Intermediate (27), using Intermediate (55). 1H NMR (400 MHz, CDCI3, 6): 8.26 (s, 1H), 8.03 (d, J: 8.4 Hz, 2H), 7.75 (d, J: 9.0 Hz, 1H), 7.72 — 7.64 (m, 3H), 7.44 (d, J: 8.2 Hz, 2H), 7.31 (d, J: 7.4 Hz, 1H), 7.14 — 7.05 (m, 1H), 6.95 (d, J: 9.0 Hz, 2H), 5.21 (dd, J: 7.6, 5.3 Hz, 1H), 3.91 (s, 3H), 2.11 — 1.97 (m, 1H), 1.91 — 1.77 (m, 1H), 1.65 — 1.37 (m, 2H), 0.98 (t, J: 7.3 Hz, 3H). MS (M+1): 211.2.
Ste B: +/— 4- 1- 4- 2H—indazol l henox but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for e 20 using methyl 4-(1-(4-(2H-indazolyl)phenoxy)butyl)benzoate.
Column: Waters Atlantis C18 4.6 x 50mm, 5pm; Modifier: TFA 0.05%; Gradient: 95% H20 / 5% acetonitrile linear to 5% H20 / 95% acetonitrile over 4.0min, hold at % H20 / 95% acetonitrile to 5.0min. Flow: 2.0 mL/ min.; Retention time: 3.23 minutes. MS (M+1): 458.2.
Exam le 92: +/— 4- 1- 4- 4-meth l-1H-1 2 3-triazol | hen lamino but I benzamido ro anoic acid The title nd was prepared by a method analogous to that described for Example 62 using Intermediate (47) and Intermediate (23). 1HNMR (400 MHz, CDgOD, 6): 8.0 (s, 1H), 7.76 (d, 2H), 7.48 (d, 2H), 7.37 (d, 2H), 6.65 (d, 2H), 4.47 (m, 1H), 3.62 (m, 2H), 2.63 (m, 2H), 2.36 (s, 3H), 1.89 — 1.84 (m, 1H), 1.79 — 1.72 (m, 1H), 1.57 — 1.45 (m, 1H), 1.44 — 1.38 (m, 1H), 1.00 (m, 3H). MS (M+1): 422.4.
Exam le 93: +/— 2- 3-meth l 4- 4- trifluorometh | -1H- razol l hen lbut lamino rimidinecarboxamido ro anoic acid O O NJ\\N Ste A: +/— -eth l2- 3-meth l 4- 4- trifluorometh | -1H- razol l hen lbut lamino rimidinecarbox late 2012/050349 N/ o/\ A vial was charged with Intermediate (14) (180 mg, 0.605 mmol), ethanol (5 mL), ethyl 2-chloropyrimidinecarboxylate (115 mg, 0.665 mmol), and diisopropylamine (156 mg, 1.21 mmol). The resulting mixture was heated under microwave irradiation at 100 °C for 20 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and trated. Purification by column chromatography gave (+/—)-ethy| 2-(3-methyl(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenyl) butylamino)pyrimidinecarboxylate (120 mg, 44%). 1H NMR (400 MHz, CDCI3, 5): 8.80 (s, 2H), 8.13 (s, 1H), 7.88 (s, 1H), 7.62 (d, 2H), 7.46 (d, 2H), 5.97 — 5.95 (m, 1H), 5.29 — 5.22 (m, 1H), 4.34 — 4.29 (m, 2H), 1.82 — 1.78 (m, 1H), 1.70 — 1.66 (m, 2H), 1.35 — 1.32 (m, 3H), 0.99 — 0.95 (m, 6H).
Ste B: +/— 2- 3-meth l 4- 4- trifluorometh l-1H- razol l hen l but lamino rimidinecarboxamido ro anoic acid To a solution of ethyl 2-(3-methyl(4-(4-(trifluoromethyl)—1 H-pyrazol yl)phenyl)butylamino)pyrimidinecarboxylate (120 mg, 0.268 mmol) in anhydrous ydrofuran (3 mL) was added 1N lithium hydroxide (0.83 mL, 0.83 mmol). The mixture was stirred at 50 °C ght. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL). O—(7-Azabenzotriazoly|)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (149 mg, 0.393 mmol) was added. The mixture was stirred for 45 s at room ature. Methyl 3-aminopropionate hloride (54.3 mg, 0.393 mmol) and diisopropylethylamine (136 mg, 1.05 mmol) were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with aqueous ammonium chloride and ethyl acetate.
The layers were separated and the organic layer was washed with water, dried over sodium sulfate, filtered and concentrated.
The residue was ved in water (5 mL) and tetrahydrofuran (5 mL). 1N Lithium hydroxide (0.774 mL, 0.774 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Kromasil EternityC18 150 x 30mm, 5pm; er: formic acid 0.225%; gradient: 36 to 56% acetonitrile in water) gave 3-(2-(3-methyl(4-(4-(trif|uoromethyl)—1 H- pyrazolyl)phenyl)butylamino)pyrimidine—5-carboxamido)propanoic acid (50 mg). 1H NMR (400 MHz, CD30D, 6): 8.70 (s, 1H), 8.64 (s, 2H), 7.96 (s, 1H), 7.73 (d, 2H), 7.53 (d, 2H), 5.27 — 5.21 (m, 1H), 3.62 — 3.53 (m, 2H), 2.68 — 2.53 (m, 2H), 1.94 — 1.82 (m, 1H), 1.79 — 1.68 (m, 1H), 1.68 — 1.58 (m, 1H), 1.06 — 0.91 (m, 6H). MS (M+1): 491.4.
Exam le 94: +/— 4- c clo ent l6- 4- trifluorometh l-1H- razol l ridine- 3- lamino meth l benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (31) and Intermediate (32). 1H NMR (400 MHz, CDCI3, 6): 8.54 (s, 1 H), 7.82 (s, 1 H), 7.77 (d, J: 2.73 Hz, 1 H), 7.69 (d, J: 8.19 Hz, 2 H), 7.60 (d, J: 8.97 Hz, 1 H), 7.40 (d, J: 8.19 Hz, 2 H), 7.01 — 6.95 (m, 1 H), 6.93 (dd, J: 8.88, 2.83 Hz, 1 H), 4.15 (d, J: 8.58 Hz, 1 H), 3.77 — 3.66 (m, 2 H), 2.76 — 2.65 (m, 2 H), 2.25 — 2.12 (m, 1 H), 2.00 — 1.87 (m, 1 H), 1.73 — 1.16 (m, 7 H). MS (M+1): 502.2.
Exam le 95: 3- 4- c clo ent l6- 4- trifluorometh l-1H- razol l lamino meth lbenzamido ro anoic acid lsomer1 N/_\NH Q The title compound'Is obtained by resolving racemicH3--(4-(cyclopentyl(6-(4- uoromethyl)—1H-pyrazoly|)pyridineylamino)methyl)benzamido)propanoic acid, the nd of Example 94, by chiral SFC. Column: Chiralpak AD-H.
Dimensions: 4.6mm x 25cm. Mobile Phase: 80/20 COZ/methanol. Flow Rate: 2.5 mL/min. Modifier: 0.2% isopropylamine. Retention time: 3.49 minutes.
Exam le 96: 3- 4- c clo ent l6- 4- trifluorometh l-1H— 1- l ridine lamino meth lbenzamido ro anoic acid lsomer2 The title compound is obtained by resolving racemIc 3-(4-(cyclopentyl(6-(4- (trifluoromethyl)—1H-pyrazoly|)pyridineylamino)methyl)benzamido)propanoic acid, the nd of Example 94, by chiral SFC. Column: Chiralpak AD-H.
Dimensions: 4.6mm x 25cm. Mobile Phase: 80/20 COZ/methanol. Flow Rate: 2.5 mL/min. Modifier: 0.2% isopropylamine. Retention time: 4.38 s.
Exam le 97: 3- 4- c clo ent l6- 4- trifluorometh l-1H—imidazol l ridin lamino meth lbenzamido ro anoic acid lsomer1 FfiwN-QNHN/\ / \ The title compound is obtained by resolving racemic 3-(4-(cyclopentyl(6-(4- (trifluoromethyl)—1H-imidazolyl)pyridinylamino)methyl)benzamido)propanoic acid, the compound of Example 8, by chiral SFC. Column: Chiralpak AD-H.
Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 COZ/2-propanol. Flow Rate: 2.5 mL/min. Modifier: none. Retention time: 3.92 minutes.
Exam le 98: 3- 4- c clo ent l 6- 4- trifluorometh l-1H—imidazol l ridin lamino meth Ibenzamido ro anoic acid Isomer2 The title compound is obtained by resolving c 3-(4-(cyclopenty|(6-(4- (trifluoromethyl)-1H-imidazolyl)pyridinylamino)methyl)benzamido)propanoic acid, the compound of Example 8, by chiral SFC. Column: Chiralpak AD-H.
Dimensions: 4.6mm x 25cm. Mobile Phase: 65/35 COZ/2-propanol. Flow Rate: 2.5 mL/min. Modifier: none. Retention time: 4.91 minutes.
Exam le 99: +/— 2— c clohex l 6- 4- trifluorometh l -1H—imidazol l ridine- 3- | meth lamino nicotinamido ro anoic acid N _ o F \ F HNWN NH Ste A: +/— -meth l6- c clohex l4- 4- orometh l-1H— razol l hen l amino)nicotinate FYLN/N\ HN F W0\ / N o F / A round bottom flask equipped with a condenser was charged with Intermediate (2) (230 mg, 0.958 mmol) and 2-methylpropane-sulfinamide (120 mg, 0.958 mmol) in dichloromethane (5 mL). Titanium(|V) ethoxide (437 mg, 1.92 mmol) was added in one n and the mixture was stirred at reflux for 2 hours.
Then methanol (1.5 mL) and ted sodium bicarbonate (1.5 mL) were added to the reaction. A itate formed. The mixture was diluted with ethyl acetate and the slurry was ed through celite, rinsing with ethyl acetate. The organics were dried over sodium sulfate, filtered and concentrated to give (E)-N-(4-(4- (trifluoromethyl)—1H-pyrazoly|)benzylidene)—2-methylpropanesulfinamide (290 mg, 0.845 mmol).
This crude e was diluted in tetrahydrofuran (3 mL) and cooled to —78 °C. Cyclohexyl magnesium chloride (1.27 mL, 2M in diethyl ether, 2.54 mmol) was then added dropwise. The reaction mixture was warmed to room temperature and stirred for 3 hours. The mixture was quenched with ted s ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was dissolved in methanol (4.2 mL). Hydrogen chloride (4M in dioxane) was added. The mixture was stirred at room temperature for 3 hours. The reaction was then concentrated. To this crude e was added N,N- dimethylformamide (1 mL), methyl 6-fluoronicotinate (155 mg, 1.0 mmol) and potassium carbonate (207 mg, 1.5 mmol). The reaction was heated to 120°C for 2 hours. The mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0 — 45% ethyl acetate in heptane) gave (+/—)-methyl 6-(cyclohexyl(4-(4-(trifluoromethyl)-1H- lyl)phenyl)methylamino)nicotinate. 1H NMR (400 MHz, CDCI3, 6): 8.69 (d, J: 1.56 Hz, 1 H), 8.13 (s, 1 H), 7.93 — 7.82 (m, 2 H), 7.67 — 7.53 (m, 2 H), 7.45 — 7.33 (m, 2 H), 6.16 (d, J: 8.78 Hz, 1 H), 5.67 — 5.51 (m, 1 H), 4.61 — 4.41 (m, 1 H), 3.81 (s, 3 H), 1.94 — 0.98 (m, 11 H). MS (M+1): 459.1.
Ste B: +/— -z‘en‘-but l3- 2- c clohex l 4- 4- trifluorometh l -1H- razol l hen lmeth lamino nicotinamido ro anoate N _ o F \ HN \ F / N NH Lithium hydroxide (800 mg) was added to a solution of methyl 6- (cyclohexyl(4-(4-(trifluoromethyl)—1H-pyrazolyl)phenyl)methylamino)nicotinate (129 mg, 0.281 mmol) in methanol (1.67 mL), tetrahydrofuran (1.67 mL), and water (1 .67 mL). The mixture was d at room temperature for 4 hours. The mixture was acidified with 4N hydrochloric acid and extracted with three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated.
To the crude acid was added N,N-dimethylformamide (2 mL), tert—butyl 3- aminopropanoate hydrochloride (94.1 mg, 0.518 mmol), O—(7-azabenzotriazoly|)- N,N,N’,N’-tetramethyluronium hexafluorophosphate) (197 mg, 0.518 mmol), and ropylethylamine (251 uL, 1.44 mmol). The mixture was stirred at room ature overnight and was then trated. cation by column chromatography (0 — 45% ethyl acetate in heptane), gave (+/—)-z‘en‘-butyl 3-(2- (cyclohexyl(4-(4-(trifluoromethyl)—1H-pyrazoly|)phenyl)methylamino)nicotinamido) propanoate. 1H NMR (400 MHz, CDCI3, 6): 8.49 — 8.40 (m, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.75 — 7.66 (m, 1H), 7.59 (d, J: 8.41 Hz, 2H), 7.36 (d, J: 8.41 Hz, 2H), 6.73 — 6.58 (m, 1H), 6.24 — 6.10 (m, 1H), 5.58 — 5.41 (m, 1H), 4.57 — 4.38 (m, 1H), 3.66 — 3.50 (m, 2H), 2.53 — 2.40 (m, 2H), 2.08 — 0.95 (m, 11H), 1.41 (s, 9H). MS (M+1): 572.3.
Ste C: +/— 2- c clohex l 4- 4- trifluorometh l -1H- razol l hen l meth lamino nicotinamido ro anoic acid Trifluoroacetic acid (0.30 mL) was added to a solution of tert—butyl 3-(2- (cyclohexyl(6-(4-(trifluoromethyl)—1H-pyrazolyl)pyridine yl)methylamino)nicotinamido)propanoate (30 mg, 0.052 mmol) in dichloromethane (0.4mL). The mixture was stirred at room temperature for 2 hours. The reaction was concentrated and the residue was co-evaporated with dichloromethane, ethyl acetate and toluene l times, to give (+/—)(2-(cyclohexyl(4-(4- (trifluoromethyl)—1H-pyrazolyl)phenyl)methylamino)nicotinamido)propanoic acid, as a solid. 1H NMR (400 MHz, CDCI3, 5): 9.81 (br. s, 1H), 8.94 (br. s, 1H), 8.31 — 8.21 (m, 1H), 8.15 (s, 1H), 7.87 (s, 1H), 7.66 (d, J: 8.58 Hz, 2H), 7.61 — 7.51 (m, 1H), 7.39 (d, J = 8.39 Hz, 2H), 6.70 — 6.58 (m, 1H), 4.29 — 4.17 (m, 1H), 3.69 — 3.53 (m, 2H), 2.76 — 2.65 (m, 2H), 2.00 — 0.91 (m, 11H). MS (M+1): 516.2.
Exam le 100: +/— 4- 3 3-dimeth l 6- 4- trifluorometh l -1H-imidazol l ridine—3- lamino but Ibenzamido ro anoic acid F F NI \ o o / MACH l ridine lamino but I benzoate To a solution of Intermediate (43) (220 mg, 0.939 mmol) and Intermediate (6) (214 mg, 0.939 mmol) in methanol (48 mL) was added decaborane (57.3 mg, 0.469 mmol). The mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated and purification by preparative TLC gave methyl 4-(3,3-dimethyl(6-(4-(trifluoromethyl)—1H-imidazoly|)pyridineylamino)butyl) benzoate (50 mg, 12%). 1H NMR (400 MHz, CDCI3, 5): 8.03 (s, 1H), 7.94 (d, 2H), 7.71 (m, 2H), 7.32 (d, 2H), 7.01 (d, 1H), 6.78 — 6.75 (m, 1H), 4.41 — 4.34 (m, 1H), 3.83 (s, 3H), 1.71 — 1.68 (m, 2H), 0.95 (s, 9H).
Ste B: +/— 4- 3 3-dimeth l 6- 4- orometh l -1H-imidazol l lamino but I benzamido ro anoic acid To a solution of methyl 4-(3,3-dimethyl(6-(4-(trifluoromethyl)-1H-imidazol- 1-yl)pyridineylamino)butyl)benzoate (50 mg, 0.11 mmol) in tetrahydrofuran (5 mL) was added 2N lithium hydroxide (5 mL, 10 mmol). The reaction mixture was heated to 70°C for 12 hours. The mixture was adjusted to pH = 2 by addition of 1N aqueous hydrochloric acid and the resulting solution extracted with ethyl acetate.
The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in N,N-dimethylformamide (5 mL). zabenzotriazol y|)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (70.0 mg, 0.184 mmol) was added and the solution stirred at room temperature for 30 minutes. Methyl 3- aminopropionate hydrochloride (19.3 mg, 0.138 mmol) was added followed by ropylamine (47.6 mg, 0.37 mmol). The ing mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (4 mL) and 2N Lithium hydroxide (4 mL, 8 mmol) was added. The mixture was stirred at room temperature for 1 hour. 1N Aqueous hydrochloric acid was added to adjust the pH = 2 and the solution was extracted with ethyl e. The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by HPLC (column: Boston ics Symmetrix ODS-H 150 x 30mm, 5pm; modifier: formic acid 0.225%; nt: 39 to 59% acetonitrile in water) gave 3-(4-(3,3-dimethyl (6-(4-(trifluoromethyl)—1H-imidazolyl)pyridineylamino)butyl)benzamido) propanoic acid (22.7 mg, 41%). 1H NMR (400 MHz, CDgOD, 5): 8.21 (s, 1H), 8.01 (s, 1H), 7.72 (s, 1H), 7.65 (d, 2H), 7.36 (d, 2H), 7.26 (d, 1H), 6.94 (m, 1H), 4.48 — 4.45 (m, 1H), 3.51 — 3.48 (m, 2H), 2.53 — 2.49 (m, 2H), 1.81 — 1.75 (m, 1H), 1.58 — 1.53 (m, 1H), 0.94 (s, 9H). MS (M+1): 504.3.
Exam le 101: +/— 4- c clohex l 6- 4- trifluorometh l -1H- razol l ridine- 3- lamino meth | benzamido ro anoic acid F F NI \ 0 o / NVLOH The title compound was prepared by a method analogous to that described for e 100 using Intermediate (44) and Intermediate (32). 1HNMR (400 MHz, 2012/050349 CDgOD, 5): 8.64 (s, 1H), 7.86 (s, 1H), 7.74 — 7.72 (m, 3H), 7.55 (d, 1H), 7.42 (d, 2H), 7.04 (m, 1H), 4.19 (m, 1H), 3.59 (m, 2H), 2.60 (m, 2H), 2.07 — 2.04 (m, 1H), 1.79 — 1.66 (m, 4H), 1.43 — 1.40 (m, 1H), 1.30 — 1.04 (m, 5H). MS (M+1): 516.2.
Exam le 102: +/— 6- 3-meth l 5-meth l 4- trifluorometh | -1H- razol l ridin lamino but I nicotinamido ro anoic acid 0 o Ste A: 5-meth l 4- trifluorometh l-1H- razol | ridinamine The title compound was prepared by a method analogous to that described for Intermediate (6) using luoromethyl-1H-pyrazole and ro—3-methyl nitro-pyridine.1H NMR (400 MHz, CDCI3, 5): 8.21 (s, 1H), 7.85 (s, 1H), 7.75 (d, J: 2.4 Hz, 1H), 6.93 (d, J: 2.4 Hz, 1H), 3.85 (s, 2H), 2.32 (s, 3H).
Ste B: meth | 6- 5-meth l 4- trifluorometh | -1H- razol | ridin ylimino)methyl)nicotinate A mixture of methyl 6-formylnicotinate (251.3 mg, 1.52 mmol) and 5-methyl- 6-(4-(trifluoromethyl)—1H-pyrazolyl)pyridinamine (369 mg, 1.52 mmol) in toluene (8mL) was heated at reflux under nitrogen overnight. The reaction mixture was concentrated to give methyl 6-((5-methyl(4-(trifluoromethyl)-1H-pyrazol yl)pyridinylimino)methyl)nicotinate (592 mg, 100%). 1H NMR (400 MHz, (CD3)ZSO, 6): 9.09 (d, 1H), 8.83 (s, 1H), 8.72 (s, 1H), 8.35 — 8.30 (m, 2H), 8.20 — 8.17 (m, 1H), 8.11 (s, 1H), 7.90 (d, 1H), 3.79 (s, 3H), 2.32 (s, 3H).
Ste C: +/— -meth | 6- 3-meth l 5-meth l 4- trifluorometh | -1H- razol | ridin lamino but I nicotinate To a 0°C solution of methyl 6-((5-methyl-|6-(4-(trifluoromethyl)—1 H-pyrazol yl)pyridinylimino)methyl)nicotinate (592 mg, 1.52 mmol) in anhydrous tetrahydrofuran (8 mL) was added isobutylmagnesium bromide (1.0 mL, 2.0M in THF, 2.0 mmol). The reaction mixture was allowed to warm to room temperature and stir for 3 hours. Saturated aqueous ammonium chloride (10 mL) was added and the e extracted with ethyl e. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by preparative TLC gave methyl 6-(3-methyl(5-methyl(4-(trif|uoromethyl)—1H- pyrazoly|)pyridinylamino)buty|)nicotinate (250 mg). 1H NMR (400 MHz, CDCI3, ): 9.18 — 9.17 (m, 1H), 8.26 — 8.23 (m, 1H), 8.16 (s, 1H), 7.81 (s, 1H), 7.69 — 7.68 (m, 1H), 7.40 — 7.38 (m, 1H), 6.79 — 6.78 (m, 1H), 4.65 — 4.58 (m, 1H), 4.00 (s, 3H), 2.27 (s, 3H), 1.78 — 1.66 (m, 3H), 1.02 (d, 3H), 0.96 (d, 3H).
Ste D: +/— 6- 3-meth l 5-meth l 4- trifluorometh l -1H- razol l ridin lamino but I nicotinamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 100 step B using methyl 6-(3-methyl(5-methyl(4-(trifluoromethyl)— 1H-pyrazolyl)pyridinylamino)butyl)nicotinate. 1H NMR (400 MHz, CDgOD, 5): 8.91 (d, 1H), 8.32 (s, 1H), 8.14 — 8.11 (m, 1H), 7.91 (s, 1H), 7.65 — 7.64 (d, 1H), 7.55 — 7.53 (m, 1H), 6.90 — 6.89 (m, 1H), 4.63 — 4.60 (m, 1H), 3.62 — 3.59 (m, 2H), 2.63 — 2.59 (m, 2H), 2.08 (s, 3H), 1.81 — 1.78 (m, 2H), 1.70 — 1.65 (m, 1H), 1.01 (d, 3H), 0.97 (d, 3H). MS (M+1): 505.3.
Exam le 103: 3- 4 4- 4- orometh l-1H- 1- l hen lamino but I benzamido ro anoic acid |somer1 Fé/NQNH/N\ 3 O FF : NH Ste A: 4- 1- 4- 4- trifluorometh | -1H- 1- | hen lamino but I c acid The title compound was prepared by a method analogous to that described for Example 1 using Intermediate (5) and Intermediate (52). MS (M-1): 402.0.
Ste B: eth l3- 4- 1- 4- 4- orometh | -1H- razol | hen lamino but I benzamido ro anoate lsomers1 and 2 \ NQNH To a mixture of ethyl 3-aminopropanoate hydrochloride (418 mg, 2.72 mmol), 4-(1-(4-(4-(trif|uoromethyl)-1H-pyrazoly|)pheny|amino)buty|) benzoic acid (732 mg, 1.82 mmol), 1-hydroxybenzotriazole hydrate (292 mg, 1.91 mmol), and N,N-diisopropylethylamine (1.20 mL, 7.26 mmol) in tetrahydrofuran (18.2 mL) was added 1-ethyl(3-dimethylaminopropyl) carbodiimide (557 mg, 2.90 mmol). The mixture was stirred for 48 hours at ambient temperature. The on mixture was concentrated and the crude material was purified by column chromatography (0 — 100% ethyl acetate in heptane) to afford racemic ethyl 3-(4-(1-(4-(4-(trifluoromethyl) -1H-pyrazolyl)phenylamino)butyl)benzamido)propanoate (684 mg, 85%) as a solid. The racemate was further purified via chiral SFC to afford 300 mg of lsomer 1 and 300 mg of lsomer 2, which were used in conversion to the final enatiopure products. 1H NMR (400 MHz, CDCI3,5 ): 7.94 (q, J: 0.8 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J: 8.2 Hz, 2H), 7.39 (d, J: 8.2 Hz, 2H), 7.32 (d, J: 9.0 Hz, 2H), 6.84 (t, J: 5.8 Hz, 1H), 6.53 (d, J: 8.8 Hz, 2H), 4.42 — 4.34 (m, 1H), 4.31 (d, J: 4.7 Hz, 1H), 4.16 (q, J: 7.2 Hz, 2H), 3.71 (q, J: 6.1 Hz, 2H), 2.63 (t, J: 5.9 Hz, 2H), 1.88 — 1.71 (m, 2H), 1.53 — 1.31 (m, 2H), 1.27 (t, J: 7.0 Hz, 3H), 0.95 (t, J: 7.3 Hz, 3H). Chiral SFC: Chiralpak AD-H, 10 x 250mm; Mobile Phase 65:35 COZ/methanol, 65mL/min, Retention time: 3.95min (lsomer1), 6.81min (lsomer 2).
Ste C: 3- 4- 1- 4- 4- orometh l -1H- razol l hen lamino but I benzamido ro anoic acid Isomer 1 lsomer 1 of ethyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-pyrazolyl) phenylamino)butyl)benzamido)propanoate (0.300 g, 0.597 mmol) was dissolved in methanol (8.0 mL) and ydrofuran (4.2 mL) and treated with 2N aqueous lithium hydroxide (4.2 mL, 8.4 mmol). The mixture was stirred at ambient temperature for 4 hours. The crude reaction mixture was concentrated and the residual solid was dissolved in water and acidified to pH = 4 with 1.0M aqueous hydrochloric acid. A brown precipitate . The precipitate was collected by filtration, washed with water, and dried in vacuo to afford 3-(4-(1-(4-(4- (trifluoromethyl)—1H-pyrazolyl)phenylamino)butyl)benzamido)propanoic acid, lsomer1 (0.220 g, 78%) as a solid. 1H NMR (400 MHz, CDCI3, 6): 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J: 7.6 Hz, 2H), 7.35 (d, J: 6.8 Hz, 2H), 7.27 (d, J: 7.2 Hz, 2H), 7.03 — 6.88 (m, 1H), 6.60 — 6.42 (m, 2H), 4.33 (t, J: 6.3 Hz, 1H), 3.64 (s, 2H), 2.72 — 2.54 (m, 2H), 1.87 — 1.65 (m, 2H), 1.51 — 1.22 (m, 2H), 0.90 (t, J: 7.0 Hz, 3H).
MS (M+1): 475.2.
Exam le 104: 3- 4 4- 4- orometh l-1H- razol l hen lamino but I benzamido ro anoic acid lsomer2 goo?/N\ F \ O )0 F NH F 0:? The title compound was prepared by a method analogous to that described for Example 103 using lsomer 2 of ethyl 3-(4-(1-(4-(4-(trif|uoromethyl)—1 zol yl)phenylamino)butyl)benzamido)propanoate. 1H NMR (400 MHz, CDCI3, 6): 7.91 (s, 1H), 7.78 (s, 1H), 7.67 (d, J: 7.6 Hz, 2H), 7.35 (d, J: 6.8 Hz, 2H), 7.27 (d, J: 7.2 Hz, 2H), 7.03 — 6.88 (m, 1H), 6.60 — 6.42 (m, 2H), 4.33 (t, J: 6.3 Hz, 1H), 3.64 (s, 2H), 2.72 — 2.54 (m, 2H), 1.87 — 1.65 (m, 2H), 1.51 — 1.22 (m, 2H), 0.90 (t, J: 7.0 Hz, 3H). MS (M+1): 475.2.
Exam le 105 : +/— 4- 3-meth I 5-meth I 4- trifluorometh I -1H- razol I ridin lamino but mido ro anoic acid The title compound was prepared by a method analogous to that described for Example 62, using Intermediate (58) and 5-methyl(4-(trifluoromethyl)-1H-pyrazol y|)pyridinamine (Step A of Example 102). 1H NMR (400 MHz, CD30D, 6): 8.32 (s, 1 H), 7.92 (s, 1 H), 7.77 (dd, J: 2.4, 8.4 Hz, 2 H), 7.65 (d, J: 2.4 Hz, 1 H), 7.48 (dd, J: 2.0, 8.4 Hz, 2 H), 6.91 (s, 1 H), 4.54 — 4.58 (m, 1 H), 3.61 (t, J: 4.8 Hz, 2 H), 2.60 — 2.64 (m, 2 H), 2.08 (d, J: 2.0 Hz, 3 H), 1.72 — 1.86 (m, 2 H), 1.53 — 1.61 (m, 1 H), 0.97 — 1.04 (m, 6 H).
MS (M+1): 504.3.
Exam le 106 : +/— 4- c clobut I 6- 4- trifluorometh I -1H- razol I ridin lamino meth I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for e 100, using Intermediate (59) and Intermediate (32). 1H NMR (400 MHz, CDCI3, 6): 8.66 (s, 1 H), 7.88 (s, 1 H), 7.76 (d, J: 1.6 Hz, 1 H), 7.75 (s, 2 H), 7.58 (d, J: 8.8 Hz, 1 H), 7.48 (d, J: 1.6 Hz, 1 H), 7.47 (s, 1 H), 7.05 (dd, J: 2.8, 8.8 Hz, 1 H), 4.36 (d, J: 8.4 Hz,1 H), 3.60 (t, J: 6.0 Hz, 2 H), 2.59 — 2.68 (m, 3 H), 2.24 (s, 1 H), 1.75 — 2.00 (m, 5 H). MS (M+1): 510.2.
Exam le 107: +/— 4- 2-c clo ro I 6- 4- trifluorometh I-1H- razol I ridin lamino eth I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 100, using Intermediate (60) and Intermediate (32). 1H NMR (400 MHz, CD30D, 6): 8.61 (s, 1 H), 7.83 (s, 1 H), 7.70 — 7.72 (m, 3 H), 7.54 (d, J: 6.4 Hz, 1 H), 7.46 (d, J: 6.4 Hz, 2 H), 7.01 (d, J: 6.4 Hz, 1 H), 4.48 — 4.52 (m, 1 H), 3.55 (t, J: 6.8 Hz, 2 H), 2.56 (t, J: 6.8 Hz, 2 H), 1.78— 1.89 (m, 1 H), 1.52 — 1.61 (m, 1 H), 0.67 — 0.79 (m, 1 H), 0.31 — 0.49 (m, 2 H), 0.00 — 0.14 (m, 2 H). MS (M+1) 488.4.
Exam le 108: +/— 4- 1- 3-meth I 4- trifluorometh I -1H- razol I henox but Ibenzamido ro anoic acid The title nd was ed by a method analogous to that described for Example 86, using Intermediate (61). 1H NMR (400 MHz, CD3OD, 6): 8.23 (s, 1 H), 7.95 (s, 1 H), 7.79 (d, J: 8.0 Hz, 2 H), 7.49 (d, J: 8.0 Hz, 2 H), 7.16 (d, J: 8.8 Hz, 1 H), 7.90 (s,1 H), 6.82 (d, J: 8.8 Hz, 1 H), 5.36 — 5.39 (m, 1 H), 3.61 — 3.64 (m, 2 H), 2.62 — 2.65 (m, 2 H), 2.06 (s, 3 H), 1.98—2.05 (m, 1 H), 1.81 — 1.86 (m, 1 H) 1.54— 1.58 (m, 1 H), 1.45— 1.51 (m, 1 H), 0.97 — 1.01 (m, 3 H). MS (M+1) 490.4.
Exam le 109: 3- 3-fluoro 1- 6- 4- trifluorometh I -1H- razol I ridin lamino but I benzamido ro anoic acid Isomer1 O O F NVkOH / N’N\ F F Ste A: +/— -meth l3-fluoro 1- 6- 4- trifluorometh l-1H- razol l ridin N’N\ Decaborane (65.4 mg, 0.535 mmol) was added to a solution of Intermediate (32) (244 mg, 1.07 mmol) and Intermediate (62) (240 mg, 1.07 mmol) in methanol (8 mL). The reaction was heated to 60 °C for 24 hours. The reaction was cooled to 35 °C and stirred for r 24 hours. The reaction was concentrated and ed by flash column chromatography to give (+/—)-methy| 3-fluoro(1-(6-(4-(trifluoromethyl)-1H-pyrazol yl)pyridinylamino)butyl)benzoate (400 mg, 86%) as a yellow oil. 1H NMR (400 MHz, CDCI3, 6): 8.55 (s, 1 H), 7.60 — 7.90 (m, 5 H), 7.29 — 7.33 (m, 1 H), 6.86 (dd, J: 8.8, 2.8 Hz, 1 H), 4.64 — 4.69 (m, 1 H), 4.16 (d, J: 6.8 Hz, 1 H), 3.83 (s, 3 H), 1.75 — 1.98 (m, 2 H), 1.21 — 1.45 (m, 2 H), 0.90 (t, J: 7.2 Hz, 3 H).
Ste B: meth l3- 3-fluoro 1- 6- 4- trifluorometh l-1H- razol l ridin lamino but I benzamido ro anoate lsomers 1 and 2 / N,N\ F F 2012/050349 2 N Aqueous lithium hydroxide (15 mL, 30 mmol) was added to (+/—)-methy| 3- (1-(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridinylamino)butyl)benzoate (400 mg, 0.9 mmol) in tetrahydrofuran (15 mL). The reaction was heated to 80 °C for 12 hours. The reaction was cooled to room temperature and acidified to pH ~ 2 with 1 N aqueous hloric acid. The mixture was extracted with ethyl acetate (3 x 10 mL) and the ed organics were dried over sodium sulfate, ed, and concentrated to give a yellow solid (380 mg). The solid was taken up in N,N-dimethylformamide (30 mL) and O-(7- azabenzotriazoly|)-N,N,N,N-tetramethyluronium hexafluorophosphate (1.86 g, 4.88 mmol) was added. The mixture was stirred at room temperature for 30 minutes. Methyl 3- aminopropanoate hydrochloride (511 mg, 3.66 mmol) and diisopropylethylamine (1.26 g, 9.76 mmol) were added, and the reaction was stirred for 1 hour. The reaction was diluted with saturated aqueous ammonium chloride and extracted with ethyl e (3 x 30 mL).
The combined organics were dried over sodium e, filtered, and concentrated.
Purification by flash column chromatography gave racemic methyl 3-(3-fluoro(1-(6-(4- (trifluoromethyl)-1H-pyrazolyl)pyridinylamino)buty|)benzamido)propanoate (450 mg, 96%) as a yellow solid. The racemate was further purified via chiral SFC to afford 180 mg of lsomer 1 and 150 mg of lsomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Gradient: 95% C02 / 5% l linear to 60% C02 / 40% ethanol over 3.0 minutes. Flow: 4mL/min. ion time: 1.44 minutes (lsomer 1), 1.75 minutes (lsomer 2).
Ste C: 3- 3-fluoro 1- 6- 4- trifluorometh l -1H- razol l ridin lamino but I benzamido ro anoic acid lsomer1 To a solution of lsomer 1 of methyl 3-(3-fluoro(1-(6-(4-(trif|uoromethy|)-1H- pyrazolyl)pyridinylamino)butyl)benzamido)propanoate (180 mg, 0.36 mmol) in tetrahydrofuran (8 mL) was added 2 N s lithium hydroxide (8 mL, 16 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was acidified to pH ~ 2 with 1 N aqueous hydrochloric acid and extracted with ethyl acetate (3 x 5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give 3-(3- (1-(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridinylamino)buty|)benzamido) propanoic acid, lsomer 1 (104 mg, 59%) as a white solid. 1H NMR (400 MHz, CD30D, 6): 8.57 (s, 1 H), 7.77 (s, 1 H), 7.63 (s, 1 H), 7.50 (d, J: 8.8 Hz, 1 H), 7.43 — 7.46 (m, 2 H), 7.34 — 7.38 (m, 1 H), 6.93 (d, J: 8.8 Hz, 1 H), 4.66 (t, J: 6.8 Hz, 1 H), 3.48 (t, J: 6.8 Hz, 2 H), 2.50 (t, J: 6.8 Hz, 2 H), 1.65— 1.82 (m, 2 H), 1.17 — 1.49 (m, 2 H), 0.89 (t, J: 6.8 Hz, 3 H).
MS (M+1) 494.2. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA.
Gradient: 95% C02 / 5% ethanol linear to 60% C02 / 40% ethanol over 3.0 minutes. Flow: 4mL/min. Retention time: 1.74 minutes, 100% ee(lsomer1).
WO 07850 Exam le 110 : 3- 3-fluoro 1- 6- 4- trifluorometh l -1H- razol l ridin lamino but I benzamido ro anoic acid lsomer2 O O F NVLOH / N’N\ F F The title compound was prepared by a method analogous to that described for Example 109, using Isomer 2 of methyl 3-(3-fluoro(1-(6-(4-(trifluoromethyl)-1H-pyrazol yl)pyridinylamino)butyl)benzamido)propanoate in Step C. 1H NMR (400 MHz, CD30D, 6): 8.57 (s, 1 H), 7.77 (s, 1 H), 7.63 (s, 1 H), 7.50 (d, J: 8.4 Hz, 1 H), 7.43 — 7.46 (m, 2 H), 7.34 — 7.38 (m, 1 H), 6.94 (d, J: 8.4 Hz, 1 H), 4.66 (t, J: 7.2 Hz, 1 H), 3.48 (t, J: 7.2 Hz, 2 H), 2.50 (t, J: 6.8 Hz, 2 H), 1.67 — 1.82 (m, 2 H), 1.29 — 1.48 (m, 2 H), 0.89 (t, J: 7.6 Hz, 3 H).
MS (M+1) 494.2. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA.
Gradient: 95% C02 / 5% ethanol linear to 60% C02 / 40% ethanol over 3.0 minutes. Flow: 4mL/min. Retention time: 1.42 minutes, 99% ee (Isomer 2).
Exam le 111: 3- 3-meth l 1- 6- 4- trifluorometh l-1H- 1- l ridin lamino but I benzamido ro anoic acid 1 Ste A: meth l3- 3-meth l1- 6- 4- trifluorometh l-1H- razol l ridin lamino but I benzamido ro anoate lsomers 1 and 2 The title compounds were prepared by a method analogous to that described in Steps A — B of Example 109, using Intermediate (63). Purification of racemic methyl 3-(3-methyl(1-(6- (4-(trifluoromethyl)-1H-pyrazolyl)pyridinylamino)butyl)benzamido) propanoate via chiral SFC afforded 140 mg of lsomer 1 and 140 mg of lsomer 2, which were used in conversion to the final enantiopure ts. 1H NMR (400 MHz, CDCI3, 6): 8.60 (s, 1 H), 7.79 (s, 1 H), 7.59 — 7.66 (m, 3 H), 7.49 (d, J: 8.0 Hz, 1 H), 7.36 (d, J: 8.4 Hz, 1 H), 6.75 — 6.82 (m, 2 H), 4.56 — 4.61 (m, 1 H), 4.26 (d, J: 4.8 Hz, 1 H), 3.66 — 3.72 (m, 5 H), 2.64 (t, J: 5.8 Hz, 2 H), 2.50 (s, 3 H), 1.73 — 1.78 (m, 2 H), 1.40 — 1.57 (m, 2 H), 0.99 (t, J: 7.2 Hz, 3 H). Chiral SFC: Chiralpak AD-2, 30 x 50mm, 3pm. Modifier: none. Mobile Phase: 60/40 COZIethanol.
Flow rate: 80 mL/min. Retention time: 1.46 minutes (lsomer 1)and 2.13 minutes r 2).
Ste B: 3- 3-meth l 1- 6- 4- trifluorometh l-1H- razol l 3- lamino but I benzamido ro anoic acid lsomer1 The title compound was prepared by a method analogous to that described in Step C of Example 109, using lsomer 1 of methyl 3-(3-methyl(1-(6-(4-(trifluoromethyl)-1H- pyrazolyl)pyridinylamino)butyl)benzamido)propanoate. 1H NMR (400 MHz, CD30D, 6): 8.65 (s, 1 H), 7.86 (s, 1 H), 7.63 (d, J: 2.8 Hz, 2 H), 7.53 — 7.58 (m, 2 H), 7.40 (d, J: 8.0 Hz, 1 H), 6.92 (dd, J: 8.8, 2.8 Hz, 1 H), 4.60 —4.64 (m, 1 H), 3.58 (t, J: 6.4 Hz, 2 H), 2.59 (t, J: 7.0 Hz, 2 H), 2.52 (s, 3 H), 1.70 — 1.79 (m, 2 H), 1.61 — 1.67 (m, 1 H), 1.46 — 1.51 (m, 1 H), 0.99 (t, J: 7.2 Hz, 3 H). MS (M+1) 490.1. Chiral SFC: Chiralpak AD-H, 4.6 x 250mm, 5pm. Modifier: 0.05% DEA. Mobile Phase: 75/25 COZIethanol. Flow rate: 35 mL/min.
Retention time: 3.92 minutes, 99.9% ee(lsomer1).
Exam le 112: 3- 3-meth l 1- 6- 4- trifluorometh l-1H- 1- l 3- lamino but I benzamido ro anoic acid lsomer2 The title compound was prepared by a method analogous to that described for Example 111, using lsomer 2 of methyl ethyl(1-(6-(4-(trifluoromethyl)—1H-pyrazol- 1-yl)pyridinylamino)butyl)benzamido)propanoate. 1H NMR (400 MHz, CD3OD, 6): 8.65 (s, 1 H), 7.86 (s, 1 H), 7.63 (d, J: 2.8 Hz, 2 H), 7.53 — 7.58 (m, 2 H), 7.40 (d, J: 8.0 Hz,1 H), 6.92 (dd, J: 8.8, 2.8 Hz, 1 H), 4.60 — 4.64 (m, 1 H), 3.58 (t, J: 6.4 Hz, 2 H), 2.59 (t, J: 7.0 Hz, 2 H), 2.52 (s, 3 H), 1.70 — 1.79 (m, 2 H), 1.61 — 1.67 (m, 1 H), 1.46 — 1.51 (m, 1 H), 0.99 (t, J: 7.2 Hz, 3 H). MS (M+1) 490.1. Chiral SFC: pak AD-H, 4.6 x 250mm, 5pm.
Modifier: 0.05% DEA. Mobile Phase: 75/25 COZIethanol. Flow rate: 35 mL/min. Retention time: 5.38 minutes, 99.7% ee (Isomer 2).
Exam le 113: 3- 4- 1- 2- 4- trifluorometh l -1H- razol l rimidin lamino but I benzamido ro anoic acid lsomer1 Ste A: meth l3- 4- 1- 2- 4- trifluorometh l-1H- razol l rimidin lamino but I benzamido ro anoate lsomer 1 and 2 O O N O N N’N\ The title compound was prepared by a method analogous to that described in Step A of Example 62, using Intermediate (64). Purification of racemic methyl 3-(4-(1-(2-(4- uoromethyl)—1H-pyrazolyl)pyrimidinylamino)butyl)benzamido)propanoate via chiral SFC afforded 400 mg of lsomer 1 and 420 mg of lsomer 2, which were used in conversion to the final enantiopure products. 1H NMR (400 MHz, CD30D, 6): 8.84 (s, 1 H), 8.08 (s, 2 H), 7.99 (s, 1 H), 7.79 (d, J: 8.4 Hz, 2 H), 7.50 (d, J: 8.4 Hz, 2 H), 4.52 (t, J: 7.0 Hz, 1 H), 3.69 (s, 3 H), 3.63 (t, J: 6.8 Hz, 2 H), 2.66 (t, J: 6.8 Hz, 2 H), 1.75 — 1.99 (m, 2 H), 1.39 — 1.60 (m, 2 H), 1.00 (t, J: 7.2 Hz, 3 H). Chiral SFC: Chiralpak AD, 50 x 250mm, 10pm.
Modifier: 0.05% DEA. Mobile Phase: 70/30 Gog/methanol. Flow rate: 200 mL/min. Retention time: 8.65 minutes (lsomer 1) and 10.5 minutes (lsomer 2).
Ste B: 3- 4- 1- 2- 4- trifluorometh l-1H- razol l rimidin lamino but lbenzamido propanoic acid, lsomer 1 The title nd was prepared by a method ous to that described in Step C of Example 109, using lsomer 2 of methyl 1-(2-(4-(trifluoromethyl)-1H-pyrazol yl)pyrimidinylamino)butyl)benzamido)propanoate. 1H NMR (400 MHz, CD30D, 6): 8.73 (s, 1 H), 7.97 (s, 2 H), 7.89 (s, 1 H), 7.68 (d, J: 8.4 Hz, 2 H), 7.38 (d, J: 8.4 Hz, 2 H), 4.40 (t, J: 6.8 Hz, 1 H), 3.50 (t, J: 6.8 Hz, 2 H), 2.52 (t, J: 6.4 Hz, 2 H), 1.67 — 1.82 (m, 2 H), 1.20 — 1.50 (m, 2 H), 0.87 (t, J: 7.2 Hz, 3 H). MS (M+1)477.2. Chiral SFC: Chiralpak AD-3, 4.6 x 150mm, 3pm. Modifier: 0.05% DEA. Gradient: 95% C02 / 5% methanol linear to 60% C02 / 40% methanol over 16.0 minutes. Flow rate: 2.5 mL/min. Retention time: 7.69 minutes, 99.8% ee r 1).
Exam le 114: 3- 4- 3 th lc clobut l 6- 4-trifluorometh l-1H- razol l ridin lamino meth l benzamido ro anoic acid lsomer1 Ste A: +/— -eth l4- 33-dimeth lc clobut l 6- 4- trifluorometh l-1H- razol l ridin- 3-ylamino )methyl )benzoate \ N’N\ kgfiF The title compound was prepared by a method ous to that described in Step A of Example 1, using Intermediate (65) and Intermediate (32). 1H NMR (400 MHz, CDCI3, 6): 8.54 (s, 1 H), 7.93 (d, J: 8.00 Hz, 2 H), 7.72 (s, 1 H), 7.55 — 7.60 (m, 2 H), 7.31 (d, J: 8.00 Hz, 2 H), 6.79 (d, J: 8.80 Hz, 1 H), 4.26 — 4.31 (m, 2 H), 4.14 (d, J: 8.80 Hz, 1 H), 2.38 —2.43 (m, 1 H), 1.92 — 1.98 (m, 1 H), 1.50 — 1.67 (m, 3 H), 1.30 (t, J: 7.20 Hz, 3 H), 1.06 (s, 3 H), 1.01 (s, 3 H). MS (M+1) 473.2.
Ste B: 3- 4- 3 3-dimeth lc clobut l 6- 4- trifluorometh l -1H- razol l ridin lamino meth l benzamido ro anoic acid lsomer1 The title compound was prepared by a method analogous to that described in Steps B — C of Example 99, using (+/—)-ethyl 4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H- pyrazolyl)pyridinylamino)methyl)benzoate. Purification of c (3,3- dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-pyrazolyl)pyridin ylamino)methyl)benzamido)propanoic acid via chiral SFC afforded the single enantiomer product. 1H NMR (400 MHz, CDCI3, 6): 8.53 (s, 1 H), 7.84 (s, 1 H), 7.80 (d, J: 2.7 Hz, 1 H), 7.68 (d, J: 8.4 Hz, 2 H), 7.61 (d, J: 9.0 Hz, 1 H), 7.38 (d, J: 8.2 Hz, 2 H), 6.98 - 7.05 (m, 1 H), 6.95 (dd, J: 8.9, 2.8 Hz, 1 H), 4.21 (d, J: 9.4 Hz, 1 H), 3.72 (q, J: 5.9 Hz, 2 H), 2.72 (t, J: 5.9 Hz, 2 H), 2.42 - 2.56 (m, 1 H), 1.99 (m, 1 H), 1.53 - 1.73 (m, 3 H), 1.11 (s, 3 H), 1.07 (s, 3 H). MS (M+1) 516.1. Chiral SFC: MiniGram-2, 20 x 250mm. Modifier: None.
Mobile Phase: 60/40 COZIethanol. Flow rate: 10.0 mL/min. Retention time: 2.37 minutes (lsomer 1).
Exam le 115: 3- 4- 3 3-dimeth lc clobut l 6- 4- trifluorometh l -1H- razol l ridin lamino meth mido ro anoic acid lsomer2 2012/050349 The title compound was prepared by a method analogous to that bed in Steps B — C of e 99, using (+/—)-ethy| 4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethy|)-1H- pyrazolyl)pyridinylamino)methyl)benzoate. Purification of c (3,3- dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-pyrazolyl)pyridinylamino)methyl) benzamido)propanoic acid via chiral SFC afforded the single enantiomer product. 1H NMR (400 MHz, CDCI3, 6): 8.53 (s, 1 H), 7.84 (s, 1 H), 7.80 (d, J: 2.7 Hz, 1 H), 7.68 (d, J: 8.4 Hz, 2 H), 7.61 (d, J: 9.0 Hz, 1 H), 7.38 (d, J: 8.2 Hz, 2 H), 6.98 - 7.05 (m, 1 H), 6.95 (dd, J = 8.9, 2.8 Hz, 1 H), 4.21 (d, J: 9.4 Hz, 1 H), 3.72 (q, J: 5.9 Hz, 2 H), 2.72 (t, J: 5.9 Hz, 2 H), 2.42 - 2.56 (m, 1 H), 1.99 (m, 1 H), 1.53 - 1.73 (m, 3 H), 1.11 (s, 3 H), 1.07 (s, 3 H). MS (M+1) 516.1. Chiral SFC: MiniGram-2, 20 x 250mm. Modifier: None. Mobile Phase: 60/40 Cog/ethanol. Flow rate: 10.0 mL/min. Retention time: 4.12 minutes (lsomer 2).
Exam le 116: 3- 4 4- 2H-indazol lmeth l henox but lbenzamido ro anoic acid lsomer 2 Ste A: meth l3- 44-2H-indazol lmeth l henox but lbenzamido ro anoate lsomers 1 and 2 IZ O The title compound was prepared by a method analogous to that described in Steps A — C of Example 82, using Intermediate (66) in Step A and methyl 3-aminopropanoate hydrochloride in Step C. Racemic methyl 3-(4-(1-(4-(2H-indazolyl) methylphenoxy)butyl)benzamido)propanoate was purified via chiral SFC to afford lsomer 1 and lsomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Berger MultiGram SFC, Mettler Toledo Co Ltd., OD 30 x 250mm, 5pm. Modifier: none.
Mobile Phase: 60/40 C02/methanol. Flow rate: 50 mL/min. Retention time: 8.89 minutes (lsomer 1) and 9.42 minutes (lsomer 2).
Ste B: 3- 4 4- 2H-indazol lmeth l henox but Ibenzamido ro anoic acid lsomer 2 The title compound was prepared by a method analogous to that described in Step D of Example 82, using lsomer 2 of methyl 3-(4-(1-(4-(2H-indazolyl) phenoxy)butyl)benzamido) propanoate. 1H NMR (400 MHz, CD30D, 6): 8.25 (s, 1 H), 7.78 (d, J: 8.4 Hz, 2 H), 7.74 (d, J: 8.4 Hz, 1 H), 7.62 (d, J: 8.8 Hz, 1 H), 7.49 (d, J: 8.4 Hz, 2 H), 7.30 — 7.35 (m, 1 H), 7.23 (d, J: 8.4 Hz, 1 H), 7.09 — 7.13 (m, 1 H), 6.92 (d, J: 2.4 Hz, 1 H), 6.83 (dd, J: 8.4, 2.8 Hz, 1 H), 5.37 — 5.40 (m, 1 H), 3.60 (t, J: 6.4 Hz, 2 H), 2.61 (t, J: 6.8 Hz, 2 H), 1.96 — 2.02 (m, 4 H), 1.80 — 1.86 (m, 1 H), 1.44 — 1.57 (m, 2 H), 1.00 (t, J: 6.4 Hz, 3 H). MS (M+1) 472.3. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm.
Modifier: 0.05% DEA. Gradient: 95% C02 / 5% methanol linear to 60% C02 / 40% ol over 3 minutes. Flow rate: 4 mL/min. Retention time: 1.94 minutes, 96.1% ee r 2).
Exam le 117: 3- 6- c clohex l2-meth l 4- trifluorometh l -1H- razol l hen lmeth lamino nicotinamido ro anoic acid lsomer1 o o / HA/lkOH HN N Ste A: +/— -c clohex l2-meth l 4- trifluorometh l-1H- razol l hen namine To a solution of Intermediate (67) (300.0 mg, 1.19 mmol) in tetrahydrofuran (3 mL) was added cyclohexylmagnesium bromide (1.79 mL, 3.58 mmol, 2 M in THF). The reaction vessel was sealed and heated to 120 °C in a microwave for 20 minutes. The reaction was cooled to 0 °C and methanol (1 mL) was added, followed by sodium borohydride (90.4 mg, 2.39 mmol). The reaction was stirred at 0 °C for 10 minutes. The reaction was quenched with water and extracted with ethyl acetate (3 x 10 mL). The combined cs were dried over sodium e, filtered, and concentrated. Purification by flash column chromatography gave (+/—)-cyclohexyl(2-methyl(4-(trifluoromethy|)-1H-pyrazolyl)phenyl)methanamine (80 mg, 20%) as a brown solid. 1H NMR (400 MHz, CDCI3, 6): 8.09 (s, 1 H), 7.82 (s, 1 H), 7.41 — 7.45 (m, 3 H), 3.87 (d, J: 8.00 Hz, 1 H), 2.34 (s, 3 H), 1.94 — 1.98 (m, 1 H), 0.98 — 1.85 (m, 10 H).
Ste B: +/— -meth |6- c clohex |2-meth l 4- trifluorometh l-1H- razol yl )phenyl )methylamino )nicotinate / o/ HN N mN,N\ To a solution of (+/—)-cyclohexyl(2-methyl(4-(trifluoromethy|)-1 H-pyrazol y|)pheny|)methanamine (80.0 mg, 0.237 mmol) in N,N—dimethylformamide (3 mL) was added methyl 6-fluoronicotinate (55.2 mg, 0.356 mmol) and potassium carbonate (98.4 mg, 0.712 mmol). The reaction was heated to 110 °C and d overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3 x 5 mL).
The combined organics were dried over sodium sulfate, filtered, and concentrated. cation by flash column chromatography gave (+/—)-methy| lohexyl(2-methyl(4- (trifluoromethyl)-1H-pyrazolyl)phenyl)methylamino)nicotinate (20 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCI3, 6): 8.63 (s, 1 H), 8.06 (s, 1 H), 7.79 — 7.82 (m, 2 H), 7.43 (s, 1 H), 7.33 — 7.36 (m, 1 H), 7.25 (d, J: 8.4 Hz, 1 H), 6.03 (d, J: 8.8 Hz, 1 H), 5.39 (d, J: 6.8 Hz, 1 H), 4.74 (m, 1 H), 3.75 (s, 3 H), 2.49 (s, 3 H), 1.85 — 1.88 (m, 1 H), 1.58— 1.72 (m, H), 1.05— 1.19 (m, 5 H).
Ste C: meth l3- 6- c clohex |2-meth l 4- trifluorometh l-1H- razol l hen lmeth lamino nicotinamido ro anoate lsomers1and2 O O l H HN N The title compound was prepared by a method ous to that described in Steps B — C of e 82, using (+/—)-methy| 6-(cyclohexyl(2-methyl(4-(trifluoromethy|)-1H- pyrazolyl)phenyl)methylamino)nicotinate in Step B and methyl 3-aminopropanoate hydrochloride in Step C. Racemic methyl 3-(6-(cyclohexyl(2-methyl(4-(trifluoromethy|)- 1H-pyrazolyl)phenyl)methylamino)nicotinamido)propanoate was purified by chiral SFC to afford lsomer 1 and lsomer 2, which were used in conversion to the final enantiopure products. Chiral SFC: Chiralpak AD-H, 4.6 x 250 mm, 5 pm. Modifier: 0.05% DEA. Mobile Phase: 60/40 Cog/ethanol. Flow: 2.35 mL/min. ion time: 5.19 minutes (Isomer 1) and 7.83 minutes (Isomer 2).
Step D: 3-(6-(cyclohexyll2-methyl(4-(trifluoromethyl )—1 H-pyrazol l hen l meth lamino nicotinamido ro anoic acid lsomer 1 The title compound was prepared by a method analogous to that described in Step D of Example 82, using lsomer 1 of methyl 3-(6-(cyclohexyl(2-methyl(4-(trifluoromethy|)- azolyl)phenyl)methylamino)nicotinamido)propanoate. 1H NMR (400 MHz, CD30D, 6): 8.68 (s, 1 H), 8.41 (d, 1 H), 7.95 (s, 1 H), 7.72 — 7.75 (m, 1 H), 7.54 — 7.57 (m, 2 H), 7.45 (d, 1 H), 6.49 (d, 1 H), 5.08 (d, 1 H), 3.55 (t, 2 H), 2.56 — 2.60 (m, 5 H), 2.08 (m, 1 H), 1.68— 1.79 (m, 4 H), 1.40 — 1.50 (m, 1 H), 1.00 — 1.35 (m, 5 H). MS (M+1) 530.1. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Mobile Phase: 60/40 002/2- propanol. Flow: 4 mL/min. Retention time: 0.78 s, 99.7% ee(lsomer1).
Exam le 118: 3- 6- c clohex l2-meth l 4- trifluorometh l -1H- razol l hen lmeth lamino namido ro anoic acid lsomer2 O O HN N The title compound was prepared by a method analogous to that described in Step D of e 82, using lsomer 2 of methyl 3-(6-(cyclohexyl(2-methyl(4-(trifluoromethy|)- 1H-pyrazolyl)phenyl)methylamino)nicotinamido)propanoate. 1H NMR (400 MHz, CD30D, 6): 8.68 (s, 1 H), 8.41 (d, 1 H), 7.95 (s, 1 H), 7.72 — 7.75 (m, 1 H), 7.54 — 7.57 (m, 2 H), 7.45 (d, 1 H), 6.49 (d, 1 H), 5.08 (d, 1 H), 3.55 (t, 2 H), 2.56 — 2.60 (m, 5 H), 2.08 (m, 1 H), 1.68— 1.79 (m, 4 H), 1.40 — 1.50 (m, 1 H), 1.00 — 1.35 (m, 5 H). MS (M+1) 530.1. Chiral SFC: Chiralpak AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Mobile Phase: 60/40 002/2- propanol. Flow: 4 mL/min. Retention time: 1.46 minutes, 100% ee (Isomer 2).
Exam le 119: +/— 4- 4- 2H-indazol l henox c clo ent lmeth l benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 86, using Intermediate (55) and Intermediate (68), and heating the reaction in toluene to 110 °C for 18 hours in Step A. 1H NMR (400 MHz, CD30D, 6): 8.64 (s, 1 H), 7.84 (d, J: 8.4 Hz, 2 H), 7.79 (dd, J: 9.2, 2.8 Hz, 3 H), 7.70 (d, J: 8.8 Hz, 1 H), 7.59 (d, J: 8.0 Hz, 2 H), 7.38 (t, J: 7.2 Hz, 1 H), 7.16 (t, J: 8.0 Hz, 1 H), 7.10 (d, 2 H), 5.24 (d, J: 7.6 Hz, 1 H), 3.67 (t, J: 6.8 Hz, 2 H), 2.68 (t, J: 6.8 Hz, 2 H), 1.99 — 2.10 (m, 1 H), 1.62 — 1.80 (m, 6 H), 1.49 — 1.56 (m, 2 H). MS (M+1) 484.4.
Exam le 120: 3- 4- 6- ro-1H-imidazol I ridin lamino c clo ent I meth I benzamido ro anoic acid |somer1 benzoate HN|\N / NAN \\<C| The title nd was prepared by a method analogous to that described in Step A of Example 1, using Intermediate (31) and Intermediate (69). 1H NMR (400 MHz, CD30D, 6): 8.11 (d, J: 1.6 Hz, 1 H), 7.97 (d, J: 8.4 Hz, 2 H), 7.80 (d, J: 2.8 Hz, 1 H), 7.59 (d, J: 1.6 Hz, 1 H), 7.52 (d, J: 8.0 Hz, 2 H), 7.26 (d, J: 8.8 Hz, 1 H), 7.04 (dd, J: 8.8, 2.8 Hz,1 H), 4.35 (q, J: 7.2 Hz, 2 H), 4.22 (d, J: 8.8 Hz, 1 H), 2.21 —2.32 (m, 1 H), 2.03 — 2.11 (m, 1 H), 1.68— 1.78 (m, 3 H), 1.48 — 1.66 (m, 2 H), 1.25— 1.45 (m, 5 H).
Ste B: 3- 4- 6- 4-chloro-1H-imidazol l ridin lamino c clo ent lmeth l benzamido ro anoic acid lsomer 1 The title compound was prepared by a method analogous to that described in Example 65, Steps B — C, using ethyl 4-((6-(4-chloro-1H-imidazolyl)pyridin ylamino)(cyclopentyl) methyl)benzoate. Racemic 3-(4-((6-(4-chloro-1H-imidazolyl)pyridin- 3-ylamino)(cyclopentyl) methyl)benzamido)propanoic acid was resolved by chiral SFC to afford the single enantiomer ct. 1H NMR (400 MHz, CD3OD, 6): 7.99 (d, J: 1.2 Hz, 1 H), 7.68 (d, J: 2.8 Hz, 1 H), 7.65 (d, J: 8.4 Hz, 2 H), 7.47 (d, J: 1.6 Hz, 1 H), 7.38 (d, J: 8.4 Hz, 2 H), 7.14 (d, J: 8.8 Hz, 1 H), 6.92 (dd, J: 8.8, 2.8 Hz, 1 H), 4.09 (d, J: 9.2 Hz,1 H), 3.50 (t, J: 6.8 Hz, 2 H), 2.50 (t, J: 6.8 Hz, 2 H), 2.11 — 2.18 (m, 1 H), 1.91 — 1.97 (m, 1 H), 1.51 — 1.63 (m, 3 H), 1.37 — 1.43 (m, 2 H), 1.17 — 1.28 (m, 2 H). MS (M+1) 468.1. Chiral SFC: Chiralcel AD-3, 4.6 x 50mm, 3pm. Modifier: 0.05% DEA. Mobile Phase: 40/60 COZImethanol. Flow rate: 3 mL/min. Retention time: 0.81 minutes, 100% ee(lsomer1).
Exam le 121 : +/— 4- 2 2 luoro 6- 4- trifluorometh l -1H-imidazol l 3- lamino eth l benzamido ro anoic acid l ridinamine A on of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (253 mg, 1.00 mmol) in dichloromethane (10 mL) was cooled to 0 °C. Added Intermediate (6) (228 mg, 1.00 mmol), titanium(lV) isopropoxide (1.1 g, 4.0 mmol), and ropylethylamine (0.7 mL, 4 mmol).
The reaction was warmed to 30 °C and stirred for 18 hours. The reaction was cooled to 0 °C and sodium borohydride (80 mg, 2 mmol) was added. The reaction was allowed to warm to °C and stir for 2 hours. The reaction was concentrated and purification by flash column chromatography gave (+/—)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)(4-(trif|uoromethy|)- 1H-imidazolyl)pyridinamine (100 mg, 21%) as an oil. 1H NMR (400 MHz, CDCI3, 6): 8.09 (s, 1 H), 7.84 (d, J: 2.8 Hz, 1 H), 7.77 (s, 1 H), 7.51 (d, J: 8.4 Hz, 2 H), 7.28 (d, J: 8.4 Hz, 2 H), 7.11 (d, J: 9.2 Hz, 1 H), 6.97 (dd, J: 6.0, 8.8 Hz, 1 H), 4.82 (m, 1 H).
Ste B: +/— 4- 2 2 2-trifluoro 6- 4- trifluorometh l idazol l ridin lamino eth l benzamido ro anoic acid A mixture of (+/—)-N-(1-(4-bromophenyl)-2,2,2-trifluoroethyl)(4-(trif|uoromethy|)- dazolyl)pyridinamine (100 mg, 0.2 mmol), ethyl 3-aminopropanoate hydrochloride (90 mg, 0.6 mmol), molybdenum hexacarbonyl (57 mg, 0.21 mmol), 1,8- diazabicyclo[5.4.0]undecene (165 mg, 1.07 mmol), palladium(|l) acetate (2.4 mg, 0.01 mmol), and tri-tert-butylphosphine tetrafluoroborate (9.4 mg, 0.03 mmol) in acetonitrile (2 mL) was heated to 170 °C for 5 minutes in a microwave. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The ed organics were dried over sodium sulfate, ed, and trated. The residue (40 mg) was taken up in tetrahydrofuran (2 mL) and cooled to 0°C. 2 N Aqueous lithium hydroxide (0.4 mL, 0.8 mmol) was added and the mixture was allowed to warm to room temperature and stir for 1 hour. The pH was ed to 4 with 1 N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2 x 20 mL). The combined organics were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated.
Purification by reversed-phase HPLC gave 3-(4-(2,2,2-trifluoro(6-(4- (trifluoromethyl)-1H-imidazolyl)pyridinylamino)ethy|)benzamido)propanoic acid (12 mg, 31%) as a white solid. 1H NMR (400 MHz, CD3OD, 6): 8.29 (s, 1 H), 8.08 (s, 1 H), 7.94 (d, J = 2.8 Hz, 1 H), 7.75 (d, J: 8.4 Hz, 2 H), 7.58 (d, J: 8.0 Hz, 2 H), 7.38 (d, J: 9.2 Hz, 1 H), 7.23 (dd, J: 2.8, 8.8 Hz, 1 H), 5.40 (m, 1 H), 3.51 (t, J: 6.8 Hz, 2 H), 2.53 (t, J: 6.8 Hz, 2 H). MS (M+1) 502.0.
Exam le 122: 3- 4- 6- 4-tert-but l-1H-imidazol l ridin lamino c clo ent l meth lbenzamido ro anoic acid To a 0 °C solution of Intermediate (68) (5 g, 20 mmol) in anhydrous romethane (30 mL) was added triethylamine (6 g, 60 mmol) and methanesulfonyl chloride (2.54 g, 22 mmol). The solution was stirred at 20 °C for 4 h. The mixture was diluted with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were dried over anhydrous NaZSO4, filtered, and concentrated under reduced pressure to afford crude ethyl 4-(cyclopentyl(methylsulfonyloxy)methy|)benzoate (6 g) as a yellow oil.
To a solution of crude ethyl lopentyl(methylsulfonyloxy)methyl)benzoate (1 .43g, 4.58 mmol) and Intermediate (73) (900 mg, 3.92 mmol) in acetonitrile (15 mL) was added potassium carbonate (1.15 g, 8.33 mmol). The mixture was stirred at 80 °C for 12 h. The reaction was diluted with water and extracted with ethyl e (10 mL x 3). The organic layer was dried over anhydrous NaZSO4 and concentrated under reduced pressure.
Purification by silica gel chromatography gave impure ethyl (4-tert-butyl-1H-imidazol yl)pyridinylamino)(cyclopenty|)methyl)benzoate (250 mg) as a colorless solid, which was dissolved in THF (8 mL). 8 mL 2N aqueous lithium hydroxide was added. The mixture was refluxed for 2 h. The mixture was adjusted to pH 1-2 by on of 1N aqueous HCI and extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over NaZSO4 and concentrated under reduced pressure to give a yellow solid which was dissolved in DMF (5 mL). HATU (425.7 mg, 1.12 mmol) was added. After 30 min methyl 3- aminopropanoate hydrochloride (116.13 mg, 0.84 mmol) was added followed by addition of diisopropylethelamine (361.78 mg, 2.8 mmol). The resulting mixture was stirred at room temperature for 2 h. The on mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate (30 mL x 3). The combined c layers were dried over NaZSO4 and concentrated under reduced pressure to give a yellow solid which was dissolved in THF (5 mL). 5 mL 2N aqueous lithium hydroxide was added. The mixture was stirred at 25 °C for 2 h. The e was adjusted to pH 1-2 by addition of 1N aqueous HCI and extracted with ethyl acetate (5 mL x 3). The combined organic layers were dried over NaZSO4 and concentrated under reduced pressure. HPLC purification using a il EternityC18 150 x 30 mm x 5pm column eluting with 23 to 43% acetonitrile in water (0.225% formic acid modifier) gave (+/-)(4-((6-(4-tert-butyl-1H-imidazoly|)pyridin ylamino)(cyclopentyl)methyl)benzamido)propanoic acid (34 mg) as a colorless solid. 1H NMR (400 MHz, CD3OD) 6 8.96 (s, 1H), 8.46-8.50 (m, 1H), 7.84 (d, J=2.8 Hz, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.66 (d, J=1.2 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.39 (d, J=9.2 Hz, 1H), 7.07 (dd, J=8.8, 3.2 Hz, 1H), 4.22 (d, J=9.2 Hz, 1H), 3.59-3.63 (m, 2H), 2.60-2.64 (m, 2H), 2.30- 2.24 (m, 1H), 2.08-2.04 (m, 1H), .65 (m, 3H), 1.55-1.51 (m, 2H), 1.29-1.49 (m, 11 H).
MS (M+1) =490.2 Exam le 123: 3- 4- c clo ent l6- 4-iso ro l-1H-imidazol l ridin lamino meth l benzamido ro anoic acid The title compound was prepared using a method analogous to that describe in Example 122, starting from Intermediate (76) and Intermediate (68). Colorless solid. 1H NMR (400 MHz, CD30D) 6 9.23 (d, J: 1.6 Hz, 1H), 7.88 (d, J: 2.8Hz, 1H), 7.82 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.09 (dd, J=8.8 Hz, J=3.2 Hz, 1H), 4.24 (d, J=9.2 Hz, 1H), 3.60-3.64 (m, 2H), 3.12-3.02 (m, 1H), 2.61-2.65 (m, 2H), .25 (m, 1H), 2.13-2.02 (m, 1H), 1.81-1.62 (m, 3H), 1.59-1.49 (m, 2H), 1.48-1.30 (m, 1H), 1.36 (d, J=6.8 Hz, 6H). MS (M+1) =476.3.
Exam le 124: 3- 4- 1- 4- 2-indazol I henox but I benzamido ro anoic acid lsomer1 Ste A: +/- 4- 1- 4- 2-indazol I henox but lbenzamido ro anoic acid c 3-(4-(1-(4-(2-indazolyl)phenoxy)butyl)benzamido)propanoic acid was prepared using a method analogous to that described for Example 86 using Intermediate 55 and ethyl 4-(1-hydroxybutyl)benzoate (prepared as described in preparation of Intermediate 5). 1H NMR (400 MHz, CD30D) 6 8.57 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.73-7.70 (m, 3H), 7.63 (d, J: 8.8 Hz, 1H), 7.50 (d, J: 8.4 Hz, 2H), 7.32-7.28 (m, 1H), 7.10-7.01 (m, 3H), 5.39-5.36 (m, 1H), 3.59 (m, 2H), 2.60 (m, 2H), 2.02-1.99 (m, 1H), .83 (m, 1H),1.58-1.45 (m, 2H), 0.98 (t, J: 7.2 Hz MS (M+1) =458.2 , 3H).
Ste B: 3- 4- 1- 4- 2-indazol I henox but I ido ro anoic acid lsomer1 Racemic 3-(4-(1-(4-(2-indazolyl)phenoxy)butyl)benzamido)propanoic acid was resolved by SFC (Column: OJ 300 x 50 mm x 10 um; Eluent: 60:40 C02:methanol; Flow rate: 200 mL/min; Modifier: none) to provide 3-(4-(1-(4-(2-indazol yl)phenoxy)butyl)benzamido)propanoic acid, lsomer 1 tion time: 1.38 min) and 3-(4-(1- (4-(2-indazoIyl)phenoxy)butyl)benzamido)propanoic acid, lsomer 2 (retention time 0.75 min) as colorless . Spectral data for isomer 1: 1H NMR (400 MHz, CD30D) 6 8.57 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.73-7.70 (m, 3H), 7.63 (d, J: 8.8 Hz, 1H), 7.50 (d, J: 8.4 Hz, 2H), .28 (m, 1H), 7.10-7.01 (m, 3H), 5.39-5.36 (m, 1H), 3.59 (m, 2H), 2.60 (m, 2H), 2.02-1.99 (m, 1H), 1.86-1.83 (m, 1H),1.58-1.45 (m, 2H), 0.98 (t, J: 7.2 Hz MS (M+1) , 3H). =458.2 Exam le 125: 3- 4- 1- 4- 7-meth I-2H-indazol I henox but lbenzamido ro anoic acid O O NVKOH CON’N\ A suspension of Intermediate (77) (300 mg, 0.795 mmol), 7-methylindazole (126 mg, 0.954 mmol), copper(|) iodide (7.5 mg, 0.0397 mmol), K3PO4 (354 mg, 1.67 mmol) and N,N- dimethylcyclohexane-1,2-diamine (22.7 mg 0.159 mmol) in toluene (3 mL) was stirred at 48h at 110 °C under a nitrogen here. The mixture was concentrated and the residue purified by preparative TLC to give 110 mg impure ethyl 4-(1-(4-(7-methyl-2H-indazol yl)phenoxy)butyl)benzoate as an oil. This material was dissolved in THF (5 mL). 5 mL aqueous 2N sodium hydroxide was added. The resulting e was stirred at 30 °C overnight. The mixture was acidified to pH 3 by addition of 1N s HCI. The mixture was extracted with ethyl acetate (3 x 5 mL). The combined c layers were dried over anhydrous NaZSO4 and concentrated under d pressure. The residue was dissolved in DMF (2 mL). HATU (128.3 mg, 1.95 mmol) was added. The mixture was stirred for 20 min.
Methyl 3-aminopropanoate hydrochloride (46.8 mg, 0.338 mmol), and diisopropylethylamine (145.4 mg, 1.125 mmol) were added. The resulting mixture was stirred at room temperature for 30 min. The mixture was poured into water (10 mL) and ted with ethyl acetate (2 x mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaZSO4 and concentrated under reduced pressure. The residue was dissolved in THF (5 mL). 5 mL 2N aqueous lithium hydroxide was added. The resulting mixture was stirred at room temperature for 1h. The mixture was adjusted to pH 5 by addition of 1N aqueous HCI. The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were dried over ous NaZSO4 and concentrated under reduced pressure. ative HPLC purification using a il EternityC18 150 x 30mm x 5 pm column eluting with 52 to 68% acetonitrile in water (0.225% formic acid modifier) gave 3-(4- (1-(4-(7-methyl-2H-indazolyl)phenoxy)buty|)benzamido)propanoic acid_(19.1 mg) as a colorless solid. 1H NMR (400MHz, CD3OD) 6 8.46 (s, 1H), 7.76 (d, J=8.4Hz, 2H), 7.68 (d, J=8.8Hz, 2H), 7.45-7.51 (m, 3H), 7.04-6.94 (m, 4H), 5.32-5.35 (m, 1H), .61 (m, 2H), 2.58-2.62 (m, 2H), 2.55 (s, 3H), 2.01-1.97 (m, 1H), 1.84-1.80 (m, 1H), 1.56-1.53 (m, 1H), 1.46-1.42 (m, 1H), 0.96 (t, J=7.2Hz, 3H). MS (M+1) = 472.1.
Exam le 126: 3- 4- 1- 4- 6-meth l-2H-indazol l henox but lbenzamido ro anoic acid WO 07850 The title compound was prepared using a method analogous to that bed for Example 125 using Intermediate (77) and ylindazole. Colorless solid. 1H NMR (400MHz, CD3OD) 6 8.47 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4Hz, 2H), 7.67 (d, J=8.8Hz, 2H), 7.58 (d, J=8.8Hz, 1H), 7.47 (d, J=8.4Hz, 2H), 7.37 (s, 1H), 7.01 (d, J=8.8Hz, 2H), 6.93 (dd, J=8.8, 1.2Hz, 1H), 5.33-5.36 (m, 1H), .59 (m, 2H), 2.50-2.54 (m, 2H), 2.41 (s, 3H), 2.04-1.96 (m, 1H), 1.85-1.79 (m, 1H), 1.60-1.52 (m, 1H), 1.50-1.42 (m, 1H), 0.97 (t, J=7.2 Hz, 3H). MS (M+1) = 472.4.
Exam le 127: 3- 4- 1- 4- 4-meth l-2H-indazol l henox but lbenzamido ro anoic acid The title compound was prepared using a method analogous to that described for Example 126 using Intermediate (77) and 4-methylindazole. Colorless solid. 1H NMR (400MHz CD3OD) 6 8.63 (s, 1H), 7.77 (d, J=8.4Hz, 2H), 7.72 (d, J=8.8Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.43 (d, J=8.8Hz, 1H), 7.20 (dd, J=8.8, 6.8Hz, 1H), 7.03 (d, J=8.8Hz, 2H), 6.84 (d, J=6.8Hz, 1H), 5.35-5.38 (m, 1H), .61 (m, 2H), 2.59-2.62 (m, 2H), 2.54 (s, 3H), 2.02-1.98 (m, 1H), 1.85-1.82 (m, 1H), 1.56-1.55 (m, 1H), 1.48-1.44 (m, 1H), 0.98 (t, J=7.2Hz, 3H). MS (M+1)=472.1.
Exam le 128: 3- 4- 1- 4- 5-meth l-2H-indazol l henox but lbenzamido ro anoic acid O O NAAOH CON’N\ The title compound was prepared using a method analogous to that described in Example 126 using Intermediate (77) and 5-methylindazole. Colorless solid. 1H NMR (400MHz, CD3OD) 6 8.42 (s, 1H), 7.77 (d, J=8.4Hz, 2H), 7.67 (d, J=8.8Hz, 2H), 7.44-7.52 (m, 4H), 7.15 (dd, J=8.8, 1.2Hz, 1H), 7.00 (d, J=8.8Hz, 2H), 5.33-5.36 (m, 1H), 3.57-3.60 (m, 2H), 2.53-2.56 (m, 2H), 2.38 (s, 3H), 2.04-1.96 (m, 1H), 1.85-1.78 (m, 1H), 1.61-1.52 (m, 1H), .40 (m, 1H), 0.97 (t, J=7.2Hz, 3H). MS (M+1)= 472.1.
Exam le 129: 3- 4- 1- 6- 4- hen I-1H-imidazol I ridin lamino but I benzamido ro anoic acid lsomer1 To a solution of Intermediate (78) (3.9 g, 27.1 mmol) 5-nitrochloropyridine (5.15 g, 32.5 mmol) in acetonitrile (30 mL) was added potassium carbonate (7.47 g, 54.2 mmol). The ing mixture was stirred at 85 °C overnight. The reaction mixture was washed with water (200 ml), and extracted with ethyl acetate (150 mL x 4). The ed organic extracts were dried over NaZSO4, filtered, and concentrated under reduced re. The residue was dissolved in MeOH (20 mL). 10% Pd/C (800 mg) was added. The mixture was stirred overnight at 35 °C under a 40 psi atmosphere of hydrogen. The reaction mixture was filtered and concentrated under reduced pressure to give a yellow solid. The solid was dissolved in methanol (15 mL). ediate (23) (3.52 g, 12.71 mmol) was added followed by decaborane (776.6 mg, 6.35 mmol). The resulting mixture was d at 35 °C for 72 h.
The reaction was trated and purified by silica gel chromatography to give methyl 3- (6-(4-phenyI-1H-imidazoIyl)pyridinylamino)butyl)benzamido)propanoate (1.1 g) as a yellow solid. The solid was dissolved in THF (8 mL). 8 mL 2N aqueous lithium hydroxide was added. The mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 4 with 1 N aqueous HCI, and extracted with ethyl acetate (4 x 100 mL). The WO 07850 combined organic layers were dried over NaZSO4 and concentrated. Purification by silica gel chromatography gave racemic 3-(4-(1-(6-(4-phenyl-1H-imidazoly|)pyridinylamino)butyl) benzamido)propanoic acid as a colorless solid. Resolution of this al by SFC (Column: Chiralcel AD 250 x 30 mm x 20 um, mobile phase: 45:55 C02:methanol, flow rate: 80 ) gave 3-(4-(1-(6-(4-phenyl-1H-imidazolyl)pyridinylamino)butyl)benzamido) oic acid, lsomer 1 (retention time: 2.63 min) and 3-(4-(1-(6-(4-phenyl-1H-imidazol idinylamino)butyl)benzamido)propanoic acid, lsomer 2 (retention time 0.85 min). al data for isomer 1: 1H NMR (400MHz, CD30D) 6 8.29 (s, 1H), 7.99 (s, 1H), 7.81 (d, J: 2.4 Hz, 1H), 7.78 (d, J: 5.6 Hz, 4H), 7.49 (d, J: 8.0 Hz, 2H), 7.40-7.35 (m, 3H), 7.26 (t, J: 7.0 Hz, 1H), 7.06 (dd, J: 8.8, 2.0 Hz, 1H), 4.47 (t, J: 7.0 Hz, 1H), 3.61 (t, J: 7.0 Hz, 2H), 2.62 (t, J: 6.8 Hz, 2H), 1.95-1.86 (m, 1H), 1.83-1.76 (m, 1H), 1.59-1.56 (m, 1H), 1.46- 1.39 (m, 1H), 0.99 (t, J: 7.4 Hz, 3H).MS (M+1)=484.2.
Exam le 130 : +\- 4- 1- 4- 4-chloro-1H- razol l -3 5-dimeth l henox but I benzamido ro anoic acid 0 o NVLOH N’N\ (+\-)(4-(1-(4-(4-ch|oro-1H-pyrazoly|)-3,5-dimethylphenoxy)buty|)benzamido)propanoic acid was prepared using a method analogous to that described in Example 86 starting from Intermediate (81) and ethyl 4-(1-hydroxybutyl)benzoate (prepared as described in preparation of Intermediate 5). Colorless solid. 1H NMR (400 MHz, Methanol-d4) 6 8.50-8.60 (m, 1H), 7.77-7.81 (m, 3H) 7.68 (s, 1H), 7.48 (d, J=8.0Hz, 2H), 6.70 (s, 2H), 5.35-5.38 (m, 1H), 3.61-3.64 (m, 2H), 2.62-2.68 (m, 2H), 2.00-1.96 (m, 1H), 1.89 (s, 6H), 1.87-1.79 (m, 1H), 1.57-1.44 (m, 2H), 0.99 (t, J=7.2Hz, 3H). MS (M+23) =492.2.
Exam le 131: +\- 4- c clo ent l 3 5-dimeth l 4- trifluorometh l -1H-imidazol l henox meth lbenzamido ro anoic acid (+\-)(4-(cyclopentyl(3,5-dimethyl(4-(trifluoromethyl)-1H-imidazoIyl)phenoxy)methyl) benzamido)propanoic acid was prepared using a method analogous to that described in e 86 starting from Intermediate (83) and Intermediate (68). Colorless solid. 1H NMR (400 MHz, CD30D) 6 .78 (m, 3H), 7.62 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 6.73 (s, 2H), .15 (d, J=7.6 Hz, 1H), 3.60-3.63 (m, 2H), 2.60-2.64 (m, 2H), 2.42-2.38 (m, 1 H), 1.92 (s, 6H), 1.89-1.87(m, 1H), 1.67-1.54 (m, 5H), 1.47-1.40 (m, 2H). MS (M+1) =530.2.
Exam le 132: +\- 6- 1- 6- 4- hen I-1H- razol I ridin lamino but I nicotinamido ro anoic acid 0 O WN¢OH/ H N N/ N’N\ 3-(6-(1-(6-(4-phenyI-1H-pyrazoIyl)pyridinylamino)butyl)nicotinamido)propanoic acid was prepared using a method ous to that described for Example 102 ng from Intermediate 25 and methyl 6-formylnicotinate using n—propylmagnesium chloride in Step C. Colorless solid. 1H NMR (400 MHz, CD30D) 6 8.88 (d, J=1.2 Hz, 1H), 8.54 (s, 1H), 8.23 (d, J=7.6 Hz, 1H), 7.92 (s, 1H), 7.67-7.63 (m, 2H), 7.55-7.50 (m, 3H), 7.28-7.25 (m 2H), 7.15-7.11 (m 1H), 7.03-7.06 (m, 1H), 4.54-4.58 (m, 1H), 3.52-3.55 (m, 1H), 2.52-2.55 (m, 1H), 1.84-1.80 (m, 2H), 1.52-1.37 (m, 2H), 0.90 (t, J=6.8 Hz, 3H). MS (M+1)=485.3.
Exam le 133: +\- 6 6- 4- hen I-1H- razol I ridin on but Ibenzamido ro anoic acid 0 0 WW“H N/ N’N\ (+\-)(6-(1-(6-(4-phenyI-1H-pyrazoIyl)pyridinyloxy)butyl)benzamido)propanoic acid was prepared using a method analogous to that described in Example 86, starting from Intermediate (20) and ediate (84). Colorless solid. 1H NMR (400 MHz, CD30D) 6 8.71 (s, 1H), 8.04 (d, J=2.8 Hz, 1H), 8.02 (s, 1H), 7.73-7.79 (m, 3H), 7.60 (d, J=7.6Hz, 2H), 7.49 (d, J=8.4Hz, 2H), 7.43-7.46 (m, 1H), 7.35 (t, J=7.6Hz, 2H), 7.22 (t, J=7.6Hz, 1H). 5.37-5.40 (m, 1H), 3.57-3.61 (m, 2H), 2.58-2.62 (m, 2H), .02 (m, 1H), 1.87-1.84 (m, 1H), 1.57- 1.55 (m, 1H), 1.47-1.43 (m, 1H), 0.98 (t, J=7.2Hz, 3H). MS (M+1) =485.2.
Exam le 134: 3- 4- 3 th lc clobut l 6- 4- trifluorometh l-1H-imidazol l ridin lamino meth l ido ro anoic acid |somer1 and Exam le 135: 3- 4- 3 3-dimeth lc clobut l 6- 4- trifluorometh l-1H-imidazol l ridin lamino meth Ibenzamido ro anoic acid |somer2 HN HN \ \ I I / / N N/\ A \N N N 1F XF F F F F Ste A: meth l3- 4- 3 3-dimeth lc clobut l 6- 4- trifluorometh l-1H-imidazol l ridin- 3- lamino meth l ido ro anoate Isomer 1 and Isomer 2. o o O 0 HM HN \ \ I I / / N N/\ /\\ \N N N 1F 1FN F F F F (+\-)—methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1 H-imidazoly|)pyridin o)methyl)benzamido)propanoate was prepared using a method analogous to that described in Example 1, using appropriately substituted Intermediates such as Intermediate 6 in Step A and methyl 3-aminopropanoate hloride in Step B. Yellow solid. (+\-)- methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazolyl)pyridin ylamino)methyl)benzamido)propanoate was resolved by SFC (column: Chiralpak AS-H 250 x 4.6 mm x 5pm; mobile phase: 5% to 40% methanol in C02; modifier: 0.05% diethylamine; flow rate: 2.35 mL/min) to give methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)- 1H-imidazoly|)pyridinylamino)methyl)benzamido)propanoate, Isomer 1(retention time: 8.26 min) and methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazol yl)pyridinylamino)methyl)benzamido)propanoate, Isomer 2 (retention time: 7.43 min).
Ste B: 3- 4- 3 3-dimeth lc clobut l 6- 4- trifluorometh l-1H-imidazol l ridin lamino meth l benzamido ro anoic acid |somer1 To a solution of methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethy|)-1H-imidazol yl)pyridinylamino)methyl)benzamido)propanoate, lsomer 1 (550 mg, 1.10 mmol) in THF (5 mL) was added 2N aqueous lithium hydroxide (5.00 mL, 10 mmol). The reaction mixture was stirred for 1h at room temperature. The mixture was acidified to pH 3 by addition of 1N aqueous HCI. The mixture was extracted with ethyl acetate (10 mL x 3) The combined organic layers were washed with water, brine, dried over NaZSO4 and concentrated to s. The crude residue was purified by silica gel chromatography to give 3-(4-((3,3- dimethylcyclobutyl)(6-(4-(trifluoromethy|)-1H-imidazolyl)pyridinylamino)methyl) benzamido)propanoic acid, lsomer 1 (255.8 mg) as an off-white solid. 1H NMR (400 MHz, Methanol-d4) 6 8.33 (s, 1H), 8.12 (s, 1H), 7.82-7.76 (m, 3H), 7.48 (d, J=8.40 Hz, 2H), 7.35 (d, J=8.80 Hz, 1H), 7.04 (d, J=8.80 Hz, 1H), 4.31 (d, J=8.80 Hz, 1H), 3.62 (t, J=6.80 Hz, 2H), 2.64-2.55 (m, 3H), 2.11-2.03 (m, 1H), 1.77-1.68 (m, 2H), 1.59-1.50 (m, 1H), 1.16 (s, 3H), 1.11 (s, 3H). MS (M+1)=516.1.
Ste C: 3- 4- 3 th lc clobut l 6- 4- trifluorometh midazol l ridin lamino meth l benzamido ro anoic acid lsomer2 To a solution of methyl 3-(4-((3,3-dimethylcyclobutyl)(6-(4-(trifluoromethy|)-1H-imidazol yl)pyridinylamino)methyl)benzamido)propanoate, lsomer 2 (550 mg, 1.10mmol) in THF (5 mL) was added 2N aqueous lithium hydroxide (5.00 mL, 10 mmol). The reaction mixture was stirred for 1h at room ature. The mixture was acidified to pH 3 by addition of 1N aqueous HCI. The mixture was extracted with ethyl acetate (10 mL x 3) The combined organic layers were washed with water, brine, dried over NaZSO4 and concentrated to dryness. The crude residue was purified by silica gel chromatography to give 3-(4-((3,3- dimethylcyclobutyl)(6-(4-(trifluoromethy|)-1H-imidazolyl)pyridinylamino)methyl) benzamido)propanoic acid, lsomer 2 (255.8 mg) as an ite solid. 1H NMR (400 MHz, Methanol-d4) 6 8.33 (s, 1H), 8.12 (s, 1H), 7.82-7.76 (m, 3H), 7.48 (d, J=8.40 Hz, 2H), 7.35 (d, J=8.80 Hz, 1H), 7.04 (d, J=8.80 Hz, 1H), 4.31 (d, J=8.80 Hz, 1H), 3.62 (t, J=6.80 Hz, 2H), 2.64-2.55 (m, 3H), 2.11-2.03 (m, 1H), 1.77-1.68 (m, 2H), 1.59-1.50 (m, 1H), 1.16 (s, 11(s,3H).MS(M+1)=516.1.
Exam le 136: 3- 4- 1- 6- -but l-1H- razol l ridin lamino but I ido ro anoic acid lsomer 1 and Exam le 137: 3- 4- 1- 6- 4-tert-but l-1H- razol- 1- l ridin lamino but lbenzamido ro anoic acid lsomer2 O O o o NVKOH NVkOH H H V0,, HN HN \ \ / I IN / [N Ste A: meth l3- 4- 1- 6- 4-tert-but l-1H- razol l ridin lamino but I benzamido ro anoate lsomer 1 and meth l3- 4- 1- 6- 4-tert-but l-1H- razol l ridin lamino but Ibenzamido ro anoate lsomer2 O O NAAO/ N N,N\ To a solution of intermediate (87) (1.2 g, 5.5 mmol) and Intermediate (23) (1.54 g, 5.55 mmol) in anhydrous methanol (15 mL) was added decaborane (340 mg, 2.78 mmol). The solution as stirred at 30 °C overnight. The solution was concentrated under reduced pressure. The e was purified by silica gel chromatography to give (+\-)-methy| 3-(4-(1- (6-(4-tert-butyl-1H-pyrazolyl)pyridinylamino)buty|)benzamido)propanoate (1.6 g) as a colorless solid. 1H NMR (400 MHz, CD3OD) 6 8.06 (d, J=0.8 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H),7.68 (d, J=2.8 Hz, 1H), 7.48 (s, 1H), 7.44-7.47 (m, 3H), 7.01-7.04 (m, 1H), 4.43 (t, 1H), 3.67 (s, 3H), 3.59-3.62 (m, 2H), .65 (m, 2H), 1.95-1.70 (m, 2H), 1.60-1.35 (m, 2H), 1.29 (s, 9H), 0.97 (t, J=7.2 Hz, 3H). (+\-)-methy| 3-(4-(1-(6-(4-tert-butyl-1H-pyrazol yl)pyridinylamino)butyl)benzamido)propanoate was resolved by SFC (Column: Chiralpak OJ-H 250 x 4.6 mm x 5 pm; mobile phase: 5 to 40% methanol in C02; modifier: 0.05% lamine; flow rate: 2.35 mL/min) to give methyl 3-(4-(1-(6-(4-tert-butyl-1H-pyrazol yl)pyridinylamino)butyl)benzamido)propanoate, lsomer 1 (retention time 6.43 min) and methyl 3-(4-(1-(6-(4-tert-butyl-1H-pyrazolyl)pyridinylamino)butyl)benzamido) propanoate, lsomer 2 (retention time, 7.37 min).
Ste B: 3- 4- 1- 6- 4-tert-but l-1H- 1- l ridin lamino but Ibenzamido ro anoic acid, lsomer 1 To a solution of methyl 3-(4-(1-(6-(4-tert-butyl-1H-pyrazolyl)pyridin ylamino)butyl)benzamido)propanoate, lsomer 1 (500 mg, 1.05 mmol) in THF (5 mL) was added 2M aqueous lithium hydroxude (5 mL, 10 mmol). The e was stirred at room ature for 1h. The mixture was neutralized with 1N aqueous HCI and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over NaZSO4 and concentrated to dryness. The crude residue was purified by silica gel chromatography to give 3-(4-(1-(6-(4-tert-butyl-1H-pyrazolyl)pyridinylamino)butyl)benzamido)propanoic acid, lsomer1 (261.5 mg) as a colorless solid. 1H NMR (400 MHz, MeOD): 68.06 (s, 1H), 7.74 (d, J=8.4 Hz, 1H),7.68 (d, J=2.8 Hz, 1H), 7.48 (s, 1H), 7.46 (m, 3H), 7.03 (dd, J=8.8 Hz, 1H), 4.43 (t, 1H), 3.61 (t, J=6.8 Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), .70 (m, 2H), 1.60-1.35 (m, 2H), 1.29 (s, 9H), 0.97 (t, J=7.2 Hz, 3H). MS (M+1)=464.2 Ste C: 3- 4 6- 4-tert-but l-1H- razol l ridin lamino but Ibenzamido ro anoic acid lsomer 2 To a solution of methyl 3-(4-(1-(6-(4-tert-butyl-1H-pyrazoly|)pyridin ylamino)butyl)benzamido)propanoate, lsomer 2 (500 mg, 1.05 mmol) in THF (5 mL) was added 2M aqueous lithium hydroxude (5 mL, 10 mmol). The e was stirred at room temperature for 1h. The mixture was neutralized with 1N aqueous HCI and extracted with ethyl acetate (10 mL x 3). The combined organic layer was dried over NaZSO4 and concentrated to dryness. The crude residue was purified by silica gel chromatography to give 3-(4-(1-(6-(4-tert-butyl-1H-pyrazolyl)pyridinylamino)butyl)benzamido)propanoic acid, lsomer 2 (271.3 mg) as a colorless solid. 1H NMR (400 MHz, MeOD): 68.06 (s, 1H), 7.74 (d, J=8.4 Hz, 1H),7.68 (d, J=2.8 Hz, 1H), 7.48 (s, 1H), 7.46 (m, 3H), 7.03 (dd, J=8.8 Hz, 1H), 4.43 (t, 1H), 3.61 (t, J=6.8 Hz, 2H), 2.64 (t, J=6.8 Hz, 2H), 1.95-1.70 (m, 2H), 1.60-1.35 (m, 2H), 1.29 (s, 9H), 0.97 (t, J=7.2 Hz, 3H). MS (M+1)=464.2 Exam le 138: 3- 4- c clobut l 3 5-dimeth l 4- orometh l -1H- razol l henox meth Ibenzamido ro anoic acid 1 Ste A: meth l3- 4- c clobut l 3 th l 4- trifluorometh l -1H- razol l henox meth Ibenzamido ro anoate lsomer1 F F (+/-)-methy| 3-(4-(cyclobutyl(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol noxy)methyl)benzamido)propanoate was prepared using a method analogous to that described in Example 65, Steps A—B, starting from Intermediate (26) and Intermediate (45).
Resolution of the c material by SFC (column: Chiralpak AD-3 50 x 4.6 mm x 3 pm; mobile phase: gradient 5 to 40% methanol in C02; modifier: 0.05% diethylamine; flow rate: 2.5 mL/min) gave methyl 3-(4-(cyclobutyl(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol yl)phenoxy)methyl)benzamido)propanoate, lsomer 1 (retention time: 5.14 min) and methyl 3-(4-(cyclobutyl(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazolyl)phenoxy)methyl) benzamido)propanoate, lsomer 2 (retention time: 5.74 min) as colorless solids._Spectral data for Isomer 1: 1H NMR (400 MHz, CDCI3) 6 7.80 (s, 1H), 7.65 (d, J: 8.4 Hz, 2H), 7.58 (s, 1H), 7.30 (d, J: 8.0 Hz, 2H), 6.73 (t, J: 6.0 Hz, 1H), 6.51 (s, 2H), 4.97 (d, J: 7.2 Hz, 1H), 3.67-3.63 (m, 5H), 2.71-2.65 (m, 1H), 2.58-2.60 (m, 2H), 2.02-1.91 (m, 3H), 1.91-1.76 (m, 9 H).
Ste B: 3- 4- c clobut l 3 5-dimeth l 4- trifluorometh l -1H- 1- l henox meth l benzamido ro anoic acid lsomer 1 To a solution of methyl 3-(4-(cyclobutyl(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol yl)phenoxy)methyl)benzamido)propanoate, lsomer 1 (450 mg, 0.85 mmol) in THF (4 mL) was added 2N aqueous lithium hydroxide (4mL, 8.0 mmol). The resulting mixture was stirred at 20 °C for 1h. THF was removed under reduced pressure. The residue was acidified by addition of 1N s HCI to pH 3-4 and extracted with dichloromethane (20mL*2). The organic layer was trated to give 3-(4-(cyclobutyl(3,5-dimethyl(4- (trifluoromethyl)—1H-pyrazolyl)phenoxy)methyl)benzamido)propanoic acid, lsomer 1 (330 mg) as a colorless solid. 1H NMR (400 MHz, Methanol-d4) 6 8.08 (s, 1H), 7.88 (s, 1H), 7.65 (d, J: 8.0 Hz, 2H), 7.35 (d, J: 8.0 Hz, 2H), 6.61 (s, 2H), 5.15 (d, J = 7.2 Hz, 1H), 3.50 (t, J = 6.8 Hz, 2H), 2.70-2.67 (m, 1H), 2.52 (t, J: 6.8 Hz, 2H), 2.04-1.94 (m, 3H), .72 (m, 9H). MS (M+1) = 516.1.
Exam le 139: +\- 4- 1- 4- 7-chloro-2H-indazol l henox but I benzamido propanoic acid (+\-)(4-(1-(4-(7-chloro-2H-indazolyl)phenoxy)butyl)benzamido)propanoic acid was prepared using a method analogous to that described in e 125, starting from Intermediate (77) and 7-chloroindazole. Colorless solid. 1HNMR (400MHz Methanol-d4) 6 8.67 (s, 1H), 7.74-7.78 (m, 4H) 7.66 (d, J=8.4Hz, 1H), 7.49 (d, J=8.4Hz, 2H), 7.33 (d, J=7.2Hz, 1H), 7.01-7.05 (m, 3H), 5.36-5.39 (m, 1H), 3.59 (t, J=6.8Hz, 2H), 2.60 (t, z, 2H), 2.02-1.98 (m, 1H), 1.87-1.81 (m, 1H), 1.58-1.53 (m, 1H), 1.50-1.44 (m, 1H), 0.98 (t, J=7.2Hz, 3H). MS (M+1) = 492.2.
Exam le 140: +\- 4 4- 5-chloro-2H-indazol l henox but I benzamido ro anoic acid O O NVKOH CON’N\ 3-(4-(1-(4-(5-chloro-2H-indazolyl)phenoxy)butyl)benzamido)propanoic acid was prepared using a method analogous to that described in Example 82, starting from Intermediate (88) and ethyl 4-(1-hydroxybutyl)benzoate (prepared as described in preparation of ediate 5). Colorless solid. 1H NMR (400MHz, Methanol-d4) 6 8.56 (s, 1H), 7.77 (d, J=8.4Hz, 2H), 7.70-7.72 (m, 3H), 7.62 (d, J=8.4Hz, 1H), 7.48 (d, z, 2H), 7.24 (dd, J=9.2, 2.0Hz, 1H), 7.03 (d, J=9.2Hz, 2H), 5.35-5.38 (m, 1H), 3.59 (t, J=6.8Hz, 2H), 2.59 (t, J=6.8Hz, 2H), 2.02-1.98 (m, 1H), 1.86-1.82 (m, 1H), 1.57-1.54 (m, 1H), 1.48-1.44 (m, 1H), 0.97 (t, J=7.2Hz, 3H). MS (M+1) = 492.2.
Exam le 141: +\- 4- 1- 3 5-dimeth I 4- trifluorometh I -1H-imidazol I henox but mido ro anoic acid 0 O N/\\N K35F (+\-)(4-(1-(3,5-dimethyl(4-(trifluoromethyl)-1H-imidazoIyl)phenoxy)butyl)benzamido) propanoic acid was prepared using a method analogous to that described in Example 86 starting from Intermediate (83) and ethyl ydroxybutyl)benzoate (prepared as described in ation of Intermediate 5). Colorless solid. 1H NMR (400 MHz, CD30D) 6 7.78-7.80 (m, 3H), 7.65 (s, 1H), 7.49 (d, J=8.4 Hz, 2 H), 6.76 (s, 2H), 5.36-5.39 (m, 1H), 3.64 (t, J=6.8 Hz, 1H), 2.65 (t, J=6.8 Hz, 2H), 2.03-1.97 (m, 1H), 1.94 (s, 6H), 1.87-1.79 (m, 1H), 1.58-1.43 (m, 2H), 0.99 (t, J=7.2 Hz, 3H). MS (M+1) = 504.2.
Exam le 142: 3- 6- 3-meth I 6- 4- trifluorometh I -1H- razol I ridin yl)butylamino)nicotinamido)propanoic acid, Isomer 1 and Example 143: 3-(6-(3-methyl(6- 4- trifluorometh I-1H- razol I ridin Ibut lamino nicotinamido ro anoic acid Isomer 2 I2 I2 / ,N / N \ N’N\ F F F F Ste A: +\- -meth |6- tert-butox carbon l 3-meth l 6- 4- trifluorometh l -1H- razol l ridin l but lamino nicotinate A '/ /N’N\ To a 0 °C solution of Intermediate (89) (1.40 mg, 4.67 mmol), ediate (90) (1.18 mg, 4.67 mmol), and triphenylphosphine (2.05 mg, 7.81 mmol) in THF (20 mL) was added di-iso- propyl azodicarboxylate (1.58 g, 7.8 mmol). The reaction was allowed to warm to 25 °C and stirred overnight. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30mL x 2). The combined organic layers were dried over anhydrous NaZSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give methyl 6-(tert-butoxycarbonyl(3-methyl(6-(4-(trifluoromethyl) -1H-pyrazolyl)pyridinyl)butyl)amino)nicotinate (1 .10g) as an oil. 1H NMR (400 MHz, CDCI3) 6 8.95 (d, J=1.6 Hz, 1H), 8.78 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.15 (dd, J=2.0, 8.4 Hz, 1H), 7.95 (dd, J=2.4, 8.8 Hz, 1H), 7.86-7.82 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), .92 , 3.87 (s, 3H), 2.27-2.20 (m, 1H), 1.91-1.84 (m,1H), 1.57-1.54 (m, 1H), 1.19 (s, 9H), 0.88 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.8 Hz, 3H).
Ste B: +\- -meth |6- 3-meth l 6- 4- trifluorometh l-1H- razol l ridin yl)butylamino)nicotinate To a 0 °C solution of (+\-)-methy| 6-(tert-butoxycarbonyl(3-methyl(6-(4-(trifluoromethyl)- 1H-pyrazolyl)pyridinyl)butyl)amino)nicotinate (110 mg, 4.7 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL). The solution was stirred at 20 °C for 2 h.
The solvent was removed under d pressure. The residue was dissolved in romethane (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous NaZSO4, filtered, and concentrated to give (+\-)-methyl 6-(3-methyl(6-(4- (trifluoromethyl)-1H-pyrazolyl)pyridinyl)butylamino)nicotinate (800 mg) as a colorless solid. 1H NMR (400 MHz,CDCI3)611.11 (d, J=4.0 Hz, 1H ), 8.76 (s, 1H), 8.45 (d, J=1.6 Hz, 1H), 8.36 (d, J=1.6 Hz, 1H), 8.17 (d, J=9.2 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.86-7.82 (m, 2H), 6.59 (d, J=9.6 Hz, 1H), 4.54-4.49 (m, 1H), 3.83 (s, 3H), 2.06-1.97 (m, 1H), 1.72-1.58 (m, 2H), 0.96 (d, J=6.4 Hz, 3H), 0.89 (d, J=6.4 Hz, 3H).
Ste C: meth l 3- 6- 3-meth l 6- 4- trifluorometh l -1H- razol l ridin l but lamino nicotinamido ro anoate lsomer 1 and methyl 3-methyl(6-(4- trifluorometh l-1H- razol l ridin lbut lamino nicotinamido ro anoate lsomer2 O O O O \ NVJxO/ \ N O/ l/ H H HN N “N N / N’N\ / ,N N \ F F F F To a solution of (+\-)-methy| 6-(3-methyl(6-(4-(trifluoromethy|)-1H-pyrazolyl)pyridin ylamino)nicotinate (800 mg, 1.85 mmol) in methanol (5 mL) was added 2N aqueous sodium hydroxide (9.2 mL, 18.4 mmol). The resulting e was stirred at 20 °C for 2 h.
Methanol was removed under reduced pressure and the residue was acidified by addition of 1N aqueous HCI to pH 3-4 and extracted with dichloromethane (30mL x 2). The combined organic layers were concentrated under reduced pressure. The resiude was dissolved in DMF (10 mL). HATU (1.36 mg, 3.58 mmol) and N,N-di-iso-propylethylamine (1.15 mg, 8.95 mmol) were added. Methyl 3-aminopropanoate hydrochloride (370 mg, 2.68 mmol) was added. The resulting mixture was stirred at 30 °C for 1 h. The mixture was poured into brine (30 mL) and ted with ethyl acetate (30mL x 2). The combined organic layers were washed with 1N s HCI (30 mL), dried over anhydrous NaZSO4 and concentrated to dryness. The crude residue was purified silica gel tography to give (+\-)-methy| 3-(6- (3-methyl(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridin yl)butylamino)nicotinamido)propanoate (850mg) as an oil. 1H NMR (400 MHz, CDCI3) 6 8.75 (s, 1H), 8.37 (d, J=12.0 Hz, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.76-7.70 (m, 2H), 6.52 (s, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.07 (d, J=4.0 Hz, 1H), 4.86 (d, J=9.2 Hz, 1H), 3.62- 3.58 (m, 5H), 2.54 (t, J=5.6 Hz, 2H), 1.77-1.59 (m, 3H), 1.75-1.63 (m, 2H), 0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.0 Hz, 3H). (+\-)-methy| 3-methyl(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridin y|)buty|amino)nicotinamido)propanoate was resolved by SFC (column: Chiralpak AD-3, 50 x 4.6 mm x 3 pm; mobile phase: 40% methanol in C02; modifier: 0.05% diethylamine; flow rate: 4 mL/min) to give methyl 3-(6-(3-methyl(6-(4-(trifluoromethyl)-1H-pyrazol y|)pyridinyl)butylamino)nicotinamido)propanoate, lsomer 1 (450 mg, retention time: 0.62 min) and methyl 3-methyl(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridin y|)buty|amino)nicotinamido)propanoate, isomer 2 (400 mg, retention time: 1.30 min).
Ste D: 3- 6- 3-meth l 6- 4- trifluorometh l -1H- 1- l ridin l but lamino nicotinamido ro anoic acid lsomer1 To a solution of methyl 3-(6-(3-methyl(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridin y|)buty|amino)nicotinamido)propanoate, lsomer 1 (450 mg, 0.89 mmol) in THF (4 mL) was added 2N s lithium hydroxide (4.5 mL, 9.0 mmol). The resulting mixture was stirred at 20 °C for 1hour. Methanol was d under reduced pressure. The residue was acidified by addition of 1N aqueous HCI to pH 3-4 and extracted with dichloromethane 2). The organic layer was concentrated to give 3-(6-(3-methyl(6-(4- (trifluoromethyl)-1H-pyrazolyl)pyridinyl)butylamino)nicotinamido)propanoic acid, lsomer 1 (400 mg) as a colorless solid. 1H NMR (400 MHz, Methanol-d4) 6 8.87 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=1.2 Hz, 1H), 8.10 (dd, J=2.0, 9.2 Hz, 1H), 7.94-7.90 (m, 3H), 7.01 (d, J=9.6 Hz, 1H), 5.00-4.97 (m, 1H), 3.47 (t, J=6.8 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 2H), 0.90-0.95 (m, 6H). MS (M+1)= 491.1.
Ste E: 3- 6- 3-meth l 6- 4- trifluorometh l -1H- razol l ridin l but lamino nicotinamido ro anoic acid lsomer2 To a solution of methyl 3-(6-(3-methyl(6-(4-(trif|uoromethy|)-1H-pyrazolyl)pyridin y|)buty|amino)nicotinamido)propanoate, lsomer 2 (400 mg, 0.79 mmol) in THF (4 mL) was added 2N aqueous m hydroxide (4mL, 8.0 mmol). The resulting mixture was stirred at °C for 1h. Methanol was removed under reduced pressure. The residue was acidified by addition of 1N s HCI to pH 3-4 and extracted with dichloromethane (20mL x 2). The organic layer was concentrated to give 3-(6-(3-methyl(6-(4-(trifluoromethyl)-1H-pyrazol idinyl)butylamino)nicotinamido)propanoic acid, lsomer 2 (330 mg) as a colorless solid. 1H NMR (400 MHz, Methanol-d4) 6 8.87 (s, 1H), 8.45 (s, 1H), 8.22 (d, J=1.2 Hz, 1H), 8.10 (dd, J=2.0, 9.2 Hz, 1H), 7.94-7.90 (m, 3H), 7.01 (d, J=9.6 Hz, 1H), 5.00-4.97 (m, 1H), 3.47 (t, J=6.8 Hz, 2H), 2.49 (t, J=6.8 Hz, 2H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 2H), 0.90- 0.95 (m,, 6H). MS (M+1)=491.1.
WO 07850 dimeth l henox but Ibenzamido ro anoic acid WE?” 3-(4-(1-(4-(4-cyc|opropyl-1H-pyrazoly|)-3,5-dimethylphenoxy)buty|)benzamido) propanoic acid was prepared using a method analogous to that describe for Example 82, starting from Intermediate (93) and ethyl 4-(1-hydroxybutyl) benzoate. Colorless solid. 1H NMR (400 MHz, CD30D) 6 7.75 (d, J=8.0 Hz 7.44 (s, J=8.0 Hz, 2H), 7.36 (s, 1H), , 2H), 6.64 (s, 2H), 5.33-5.30 (m, 1H), 3.59 (t, J=6.8 Hz, 2H), 2.63 (t, J=6.8 Hz 1.98—1.92 (m, , 2H), 1H), 1.81 (s, 6H), 1.81-1.72 (m, 2H), 159-1.35 (m, 2H), 096 (t, J=7.6 Hz, 3H), 0.88-0.84 (m, 2H), 0.56-0.52 (m, 2H). MS (M+1)=476.3.
Exam le 145: 3- 4- 1- 4- ro-1H- razol l -3 5-dimeth l henox but I benzamido propanoic acid, lsomer 1 o o NVKOH N’N\ (+\-)-methyl 3-(4-(1-(4-(4-chloro-1H-pyrazoly|)-3,5-dimethylphenoxy)butyl)benzamido) propanoate was prepared using a method analogous to that described in Example 82, Steps A—C, using Intermediate (81) in Step A and methyl 3-aminopropanoate hydrochloride in Step C. (+\-)-methy| 3-(4-(1-(4-(4-chloro-1H-pyrazoly|)-3,5-dimethylphenoxy)butyl) benzamido)propanoate was resolved by SFC (column: Chiralpak AD-3 50 x 4.6 mm, 3 pm; mobile phase: nt elution 5% to 40% methanol in C02; modifier: 0.05% diethylamine; flow rate: 4 mL/min) to give methyl 3-(4-(1-(4-(4-chloro-1H-pyrazolyl)—3,5- dimethylphenoxy)butyl)benzamido)propanoate, lsomer1 (retention time: 1.32 min) and methyl 3-(4-(1-(4-(4-chloro-1H-pyrazoly|)-3,5-dimethylphenoxy)butyl)benzamido) propanoate, lsomer 2 (retention time: 1.49 min). methyl 1-(4-(4-chloro-1H-pyrazol y|)-3,5-dimethylphenoxy)butyl) benzamido)propanoate, lsomer 1 (70.0 mg, 0.145 mmol) was ved in THF (1.5 mL). 1N aqueous lithium hydroxide (1.50 mL, 1.50) was added. The reaction mixture was stirred for 1 h at room temperature. The mixture was acidified to pH 3 by addition of 1N aqueous HCI. The mixture was ted with ethyl acetate (10 mL x 3).
The combined organic layers were washed with water, brine, dried over NaZSO4 and concentrated under d pressure. The residue was purified by silica gel chromatography to give 3-(4-(1-(4-(4-chloro-1H-pyrazoly|)-3,5-dimethylphenoxy)butyl) benzamido)propanoic acid, lsomer 1 (23.9 mg) as an ite solid. 1H NMR (400 MHz, Methanol-d4) 6 7.77-7.81 (m, 3H) 7.68 (s, 1H), 7.48 (d, J=8.0Hz, 2H), 6.70 (s, 2H), 5.35- .38 (m, 1H), 3.61-3.64 (m, 2H), 2.62-2.68 (m, 2H), 2.00-1.96 (m, 1H), 1.89 (s, 6H), 1.87- 1.79 (m, 1H), 1.57-1.44 (m, 2H), 0.99 (t, J=7.2Hz, 3H). MS (M+23) =492.2.
Exam le 146: 3- 4- c clohex l 6- 4- trifluorometh l -1H- razol l ridine lamino meth l benzamido ro anoic acid lsomer1 and Exam le 147: 3- 4- c clohex l6- 4- orometh l-1H- razol l ridine lamino meth lbenzamido ro anoic acid lsomer2 F F F F / \ /_§4F/ \ N, N, N N \ o 0 o o I Ni \ / NVkOH / H MdOH HN HN (+\-)(4-(cyclohexyl(6-(4-(trifluoromethy|)-1H-pyrazolyl)pyridineylamino)methyl) ido)propanoic acid (Example 101) was resolved by SFC (Column: Chiralpak AD-H x 4.6 mm; mobile phase: 25% ethanol in COZ; modifier: 0.2% isopropylamine; flow rate: 2.5 mL/min) to provide 3-(4-(cyclohexyl(6-(4-(trifluoromethy|)-1H-pyrazolyl)pyridine ylamino)methyl)benzamido)propanoic acid, lsomer 1 (retention time: 6.93 min) and 3-(4- (cyclohexyl(6-(4-(trifluoromethy|)-1H-pyrazolyl)pyridineylamino)methyl)benzamido) propanoic acid, lsomer 2 tion time: 9.58 min) as their isopropylammonium salts. The salts were dissolved in water and the pH adjusted to 3.5 by on of 1N aqueous HCI.
The mixtures were extracted with dichloromethane. The organic layers were dried over MgSO4 and concentrated to provide 3-(4-(cyclohexyl(6-(4-(trifluoromethy|)-1H-pyrazol yl)pyridineylamino)methyl)benzamido)propanoic acid, lsomer 1 and 3-(4-(cyclohexyl(6-(4- (trifluoromethyl)—1H-pyrazolyl)pyridineylamino)methyl)benzamido)propanoic acid, lsomer 2. Spectral data for lsomer 1: 1H NMR (400 MHz, CDCI3) 6 8.58 (s, 1H), 7.77 (s, 1H), 7.65-7.72 (m, 3H), 7.60 (d, J=8.8Hz), 7.32 (d, J=8.2Hz, 2H), 6.82-6.88 (m, 1H), 6.71-6.78 (m, 1H), 4.15 (d, J=6.2Hz, 1H), 3.65-3.73 (m, 2H), 2.63-2.73 (m, 2H), 1.83-1.93 (m, 1H), 1.59-1.82 (m, 4H), 1.46-1.56 (m, 1H), 0.94-1.28 (m, 6H). MS (M+H)=516.2.
Exam le 148: +\- 4- 1- 3 5-dimeth I 4- orometh I -1H-1 2 3-triazol I henox but mido ro anoic acid (+\-)(4-(1-(3,5-dimethyl(4-(trifluoromethyl)-1H-1,2,3-triazolyl)phenoxy)butyl) benzamido)propanoic acid was prepared using a method analogous to that described in Example 82, starting from Intermediate (95). Colorless solid. 1H NMR (400 MHz, CDCI3) 6 7.84 (s, 1H), 7.72 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 6.82-6.91 (m, 1H), 6.59 (s, 1H), .12-5.20 (m, 1H), 3.64-3.74 (m, 2H), 2.63-2.72 (m, 2H), 1.90-2.01 (m, 1H), 1.84 (s, 6H), 1.71-1.82(m, 1H), .57 (m, 2H), 0.94 (t, J=7.2 Hz, 3H). MS (M+H)=505.0.
Exam le 149: +/- 4- 1- 2- 4- trifluorometh I -1H- razol I rimidin on but mido ro anoic acid h H N OH \ W NfN O O The title compound was ed by a method analogous to that described for Example 82- Steps A and D using Intermediate (105) and Intermediate (96). cation by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column eluting with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)(4-(1-(2- (4-(trifluoromethyl)-1H-pyrazoIyl)pyrimidinyloxy)butyl) benzamido)propanoic acid.
Analytical LCMS: retention time 2.95 minutes (Atlantis C18 4.6 x 50mm, 5pM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 478.2.
Exam le 150: +/- 4- 1- 5-meth I 4- trifluorometh I -1H- razol I ridin on but Ibenzamido ro anoic acid N\’N/t; The title compound was prepared by a method ous to that described for Example 82- Steps A and D using Intermediate (97) and Intermediate (96). Purification by reversed-phase HPLC on a Waters Sunfire C18 19 x 100mm, 0.005mm column e|uting with a gradient of water in itrile (0.05% trifluoroacetic acid modifier) gave (+/-) (4-(1-(5- methyl(4-(trifluoromethy|)-1H-pyrazoIy|)pyridinyloxy)butyl) benzamido)propanoic acid. Analytical LCMS: retention time 3.27 minutes (Atlantis C18 4.6 x 50mm, 5pM column; 95% water/acetonitrile linear gradient to 5% water/acetonitrile over 4.0 minutes, hold at 5% acetonitrile to 5.0 minutes; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 491.2.
Exam le 151: +/- 4- c clobut I 3 5-dimeth I 4- trifluorometh I -1H- razol I henox meth lbenzamido ro anoic acid N\/\n/OH O O The title compound was prepared by a method analogous to that described for Example 82-Steps A and D using Intermediate (98) and Intermediate (26). Purification by reversed-phase HPLC on a Waters e C18 19 x 100mm, 0.005mm column g with a gradient of water in acetonitrile (0.05% trifluoroacetic acid modifier) gave (+/-)(4- (cyclobutyl(3,5-dimethyl(4-(trifluoromethyl)-1H-pyrazol yl)phenoxy)methyl)benzamido)propanoic acid. Analytical LCMS: retention time 3.46 minutes (Atlantis C18 4.6 x 50mm, 5pM column; 95% water/acetonitrile linear gradient to 5% acetonitrile over 4.0 minutes, hold at 5% water/acetonitrile to 5.0 s; 0.05% trifluoroacetic acid modifier; flow rate 2.0 mL/minute); MS (M+1): 516.2.
Exam le 152: +/- 4- 3 5-dimeth l 4- trifluorometh l-1H- razol l henox 3 3- dimeth lc clobut lmeth Ibenzamido ro anoic acid N\/\n/OH o o Ste A : eth l4- 3 5-dimeth l 4- trifluorometh l-1H- razol l henox 3 3- Diisopropyl azodicarboxylate (0.310 mL, 0.730 mmol) was added dropwise to a solution of Intermediate 26 (120 mg, 0.490 mmol), Intermediate (100) (128 mg, 0.490 mmol), and tributylphosphine (0.190 mL, 0.760 mmol) in tetrahydrofuran (2.20 mL). After 18 hours, r 0.5 equiv. of both diisopropyl azodicarboxylate and tributylphosphine were added. After an onal 3 h, the reaction was concentrated. The mixture was diluted with methylene chloride and ied with 1 N hydrochloric acid. The mixture was then extracted twice with methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 1.00 g of crude material. The crude material was purified by column chromatography (0 — 8% ethyl acetate in es) gave ethyl 4-((3,5-dimethyl- 4-(4-(trifluoromethyl)-1H-pyrazolyl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoate (134 mg, 54%) as an OH. 1H NMR (400 MHz, CDCI3) 6 8.00 (d, J: 8.2 Hz, 2H), 7.87 (s, 1H), 7.64 (s, 1H), 7.37 (d, J: 8.2 Hz, 2H), 6.57 (s, 2H), 5.01 (d, J: 6.8 Hz, 1H), 4.36 (q, J: 7.0 Hz, 2H), 2.67 (d, J: 7.0 Hz, 1H), 1.88 (s, 6H), 1.87-1.74 (m, 3H), 1.69-1.59 (m, 1H), 1.38 (t, J: 7.4 Hz, 3H), 1.14 (s, 3H), 1.10 (s, 3H). MS (M+1): 501.4.
Ste B :4- 3 th l 4- trifluorometh l-1H- razol l henox 3 3- dimeth lc clobut lmeth l benzoic acid To a flask containing ethyl 4-((3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol noxy)(3,3-dimethylcyclobutyl)methyl)benzoate (135 mg, 0.270 mmol) was added anhydrous tetrahydrofuran (0.680 mL), methanol (0.680 mL), water (0.680 mL) and sodium hydroxide (55.7 mg, 1.35 mmol). After 8 h, the reaction was concentrated and dissolved in ethyl acetate and water. 1 N hydrochloric acid was added to pH 3 and the mixture was extracted three times with ethyl acetate. The combined c layers were dried over sodium sulfate, ed, and concentrated to give 4-((3,5-dimethyl(4-(trifluoromethy|)-1H- lyl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoic acid (110 mg, 86% yield) as an OH. 1H NMR (400 MHz, CDCI3) 6 8.06 (d, J: 8.2 Hz, 2H), 7.88 (s, 1H), 7.65 (s, 1H), 7.41 (d, J: 8.4 Hz, 2H), 6.58 (s, 2H), 5.03 (d, J: 6.8 Hz, 1H), 2.80-2.55 (m, 1H), 2.07-1.72 (m, 9H), 1.67 (dd, J: 8.2, 3.5 Hz, 1H), 1.14 (s, 3H), 1.10 (s, 3H). MS (M+1): 473.5.
Ste C : eth l3- 4- 3 5-dimeth l 4- trifluorometh l -1H- razol l henox 3 3- dimeth lc clobut lmeth lbenzamido ro anoate Tetrahydrofuran (1.2 mL) was added to a vial containing 4-((3,5-dimethyl(4- (trifluoromethyl)-1H-pyrazolyl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzoic acid (115 mg, 0.240 mmol), ethyl 3-aminopropanoate hydrochloride (74.7 mg, 0.490 mmol) and O-(7- azabenzotriazoly|)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (185 mg, 0.490 mmol). Diisopropylethylamine (0.210 mL, 1.22 mmol) was then added. The reaction was stirred for 1h, and was then concentrated. Purification by column chromatography (0 — 50% ethyl acetate in heptane) afforded ethyl 3-(4-((3,5-dimethyl(4-(trifluoromethyl)-1H-pyrazol- 1-yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoate (110 mg, 39% yield) as an OH. 1H NMR (400 MHz, CDCI3) 6 7.87 (s, 1H), 7.71 (d, J: 8.6 Hz, 2H), 7.64 (s, 1H), 7.36 (d, J: 8.2 Hz, 2H), 6.81 (t, J: 4.8 Hz, 1H), 6.57 (s, 2H), 5.00 (d, J: 6.8 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.71 (q, J: 6.1 Hz, 2H), 2.57 - 2.74 (m, 3H), 1.87 - 1.92 (m, 7H), 1.80 -1.87 WO 07850 (m, 1H), 1.72 - 1.80 (m, 1H), 1.59 - 1.68 (m, 1H), 1.21 - 1.35 (m, 3H), 1.13 (s, 3H), 1.10 (s, 3H). MS (M+1): 572.3.
Ste D: +/- 4- 3 th l 4- trifluorometh l-1H- razol l henox 3 3- dimeth lc clobut lmeth Ibenzamido ro anoic acid To a flask containing ethyl 3-(4-((3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol yl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoate (100 mg, 0.180 mmol) was added water (0.437 mL), tetrahydrofuran (0.437 mL), and methanol (0.437 mL). Sodium hydroxide (36.1 mg, 0.880 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl e. The combined organic layers were dried over sodium sulfate, ed, and concentrated to give 108 mg of crude material. The crude material was azeotrophed three times with toluene and three times with methylene chloride and then dried in vacuo for 18 h to provide (+/-)(4-((3,5-dimethyl(4-(trifluoromethyl)-1H- pyrazolyl)phenoxy)(3,3-dimethylcyclobutyl)methyl)benzamido)propanoic acid (99.0 mg, 100%) as a solid. 1H NMR (400 MHz, CDCI3) 6 7.88 (s, 1H), 7.71 (d, J: 8.2 Hz, 2H), 7.65 (s, 1H), 7.36 (d, J: 8.4 Hz, 2H), 6.76 (t, J: 6.2 Hz, 1H), 6.56 (s, 2H), 5.01 (d, J: 7.0 Hz, 1H), 3.72 (q, J: 5.9 Hz, 2H), 2.74 - 2.59 (m, 3H), 1.88 (s, 6H), 1.87 - 1.68 (m, 3H), 1.68 - 1.58 (m, 1H), 1.13 (s, 3H), 1.10 (s, 3H). MS (M+1): 544.3.
Exam le 153: +/- 4- 1- 3-methox meth l 4- trifluorometh l -1H- razol l henox but Ibenzamido ro anoic acid l henox but Ibenzamido ro anoate Tetrahydrofuran (0.450 mL) was added to azodicarboxylic acid dipiperidine (34.2 mg, 0.130 mmol), Intermediate (96) (26.0 mg, 0.0900 mmol) and Intermediate (103) (24.2 mg, 0.0900 mmol). Tributylphosphine (0.035 mL, 0.142 mmol) was added dropwise at room temperature. Another 0.450 mL of tetrahydrofuran was added. The e was stirred at room temperature for 16 hours. The on was diluted with ethyl acetate and then extracted twice with sodium hydroxide (1N), once with water, once with hydrochloric acid (1N), and finally once with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. cation by column chromatography (0-30% ethyl acetate in heptanes) afforded ethyl 3-(4-(1-(3-methoxymethyl(4-(trif|uoromethy|)-1H-pyrazol yl)phenoxy)buty|)benzamido)propanoate (39.5 g, 81%) as an oil: 1H NMR (400 MHz, CDCI3) 6 7.86 (s, 1H), 7.74 (d, J: 8.2 Hz, 2H), 7.66 (s, 1H), 7.40 (d, J: 8.4 Hz, 2H), 6.84 (t, J: 6.0 Hz, 1H), 6.35 (d, J: 2.5 Hz, 1H), 6.26 (d, J: 2.5 Hz, 1H), 5.16 (dd, J: 7.7, 5.2 Hz,1H), 4.17 (q, J: 7.2 Hz, 2H), 3.77 - 3.67 (m, 2H), 3.64 (s, 3H), 2.70 - 2.54 (m, 2H), 2.08 — 1.93 (m, 1H), 1.91 (s, 3H), 1.87 - 1.72 (m, 1H), 1.60 - 1.36 (m, 2H), 1.36 - 1.18 (m, 3H), 0.97 (t, J = 7.4 Hz, 3H). MS (M+1): 548.4.
Ste B : +/- 4- 1- 3-methox meth l 4- trifluorometh l -1H- razol l henox but lbenzamido ro anoic acid To a flask ning ethyl 3-(4-(1-(3-methoxymethyl(4-(trif|uoromethyl)-1H- lyl)phenoxy)butyl)benzamido)propanoate (37.0 mg, 0.0700 mmol) was added tetrahydrofuran (0.170 mL), methanol (0.170 mL), and 1 N sodium ide (0.170 mL, 0.170 mmol) was then added. The suspension was stirred at room temperature for 18 hours. The reaction was quenched with 1 N hydrochloric acid to pH 2 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to provide (+/-)(4-(1-(3- methoxymethyl(4-(trifluoromethy|)-1H-pyrazoly|)phenoxy)butyl)benzamido) propanoic acid (26.0 mg, 74%) as a solid. 1H NMR (400 MHz, CDCI3) 6 7.87 (s, 1H), 7.73 (d, J: 8.4 Hz, 2H), 7.66 (s, 1H), 7.39 (d, J: 8.2 Hz, 2H), 6.88 (t, J: 6.0 Hz, 1H), 6.41 - 6.21 (m, 2H), 5.17 (dd, J: 7.7, 5.2 Hz, 1H), 3.75 - 3.65 (m, 2H), 3.63 (s, 3H), 2.66 (t, J: 5.9 Hz, 2H), 2.04 — 1.93 (m, 1H), 1.89 (s, 3H), 1.86 - 1.74 (m, 1H), 1.62 - 1.35 (m, 2H), 0.96 (t, J: 7.4 Hz, 3H). MS (M+1): 520.4.
Exam le 154: +/- 4- 3 3-difluoroc clobut l 6- 4- trifluorometh midazol l ridin lamino meth lbenzamido ro anoic acid F F I \/\n/ /N O O Ste A : eth l4- 3 3-difluoroc clobut l 6- 4- trifluorometh l-1H-imidazol l ridin To a solution of impure Intermediate (104) (72.0 mg, approximately 0.214 mmol pure) and intermediate 6 (61.2 mg, 0.270 mmol) in methanol (0.670 ml) was added decaborane (19.7 mg, 0.160 mmol). The reaction was stirred for 16 hours at ambient temperature. The reaction mixture was quenched with aqueous 1.0M hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, ed, and concentrated. cation by silica gel flash chromatography (0 — 50% ethyl acetate in heptane) ed impure ethyl 3-difluorocyclobutyl)(6-(4- (trifluoromethyl)-1H-imidazolyl)pyridinylamino)methyl)benzoate (30.0 mg, imately 0.050 mmol pure) as a solid. MS (M+1): 481.1.
Ste B :4- 3 3-difluoroc clobut l 6- 4- trifluorometh l-1H-imidazol l ridin lamino meth l benzoic acid To a flask containing impure ethyl 4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)- 1H-imidazolyl)pyridinylamino)methyl)benzoate (35.0 mg, 0.073 mmol) was added tetrahydrofuran (0.180 mL), methanol (0.180 mL), and 1 N sodium hydroxide (0.180 mL, 0.180 mmol) was then added. After 2 h, another 5 equiv. of aqueous sodium hydroxide was added. The suspension was stirred at room temperature for 18 hours. Another 5 equiv. of WO 07850 2012/050349 aqueous sodium hydroxide was added and the reaction was heated to 50 °C. After 2 h, the reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give crude material. The crude material was azeotrophed three times with methylene chloride and then dried in vacuo for 18 h to e crude 4-((3,3- difluorocyclobuty|)(6-(4-(trifluoromethy|)-1H-imidazolyl)pyridinylamino)methyl)benzoic acid (24.0 mg). MS (M+1): 453.2.
Ste C : eth l3- 4- 3 3-difluoroc clobut l 6- 4- trifluorometh l-1H-imidazol l ridin lamino meth lbenzamido ro anoate F F H o \ \/ I \/\n/ /N O O Dimethylformamide (0.270 mL) was added to a vial containing crude 4-((3,3- difluorocyclobuty|)(6-(4-(trifluoromethy|)-1H-imidazolyl)pyridinylamino)methyl)benzoic acid (24.0 mg, approximately 0.120 mmol pure), ethyl 3-aminopropanoate hydrochloride (16.3 mg, 0.110 mmol) and O—(7-azabenzotriazoly|)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (40.3 mg, 0.110 mmol). Diisopropylethylamine (0.046 mL, 0.270 mmol) was then added. The reaction was d for 16h, and was then concentrated. Purification by column chromatography (0 — 60% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethy|)-1H-imidazolyl)pyridin ylamino)methyl)benzamido)propanoate (7.00 mg) as an oil. MS (M+1): 552.3.
Ste D : +/- 4- 3 3-difluoroc clobut l 6- 4- trifluorometh l-1H-imidazol l 3- lamino meth l benzamido ro anoic acid To a flask ning 3-(4-((3,3-difluorocyclobutyl)(6-(4-(trifluoromethyl)-1H- imidazoly|)pyridinylamino)methyl)benzamido)propanoate (7.00 mg, 0.0100 mmol) was added water (0.0650 mL), tetrahydrofuran (0.0650 mL), and methanol (0.0650 mL). Lithium hydroxide monohydrate (27.3 mg, 0.650 mmol) was then added. The suspension was stirred at room temperature for 2 hours. The reaction was quenched with 1 N hydrochloric acid to pH 3 and extracted three times with ethyl e. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give (+/-)(4-((3,3- rocyclobutyl)(6-(4-(trifluoromethyl)-1H-imidazolyl)pyridinylamino)methyl) benzamido)propanoic acid (4.5 mg, 70%) ofa glass-like material. 1H NMR (400 MHz, CDCI3) 6 8.36 - 8.34 (m, 1H), 8.16 - 8.12 (m, 1H), 7.86 (d, J: 2.9 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.58 - 7.51 (m, 2H), 7.39 (dd, J: 8.8, 0.6 Hz, 1H), 7.10 (dd, J: 8.8, 2.9 Hz, 1H), 4.48 (d, J: 8.8 Hz, 1H), 3.63 (t, J: 6.9 Hz, 2H), 2.94 - 2.73 (m, 1H), 2.64 (t, J: 6.9 Hz, 2H), 2.61 - 2.49 (m, 2H), 2.49 - 2.33 (m, 2H). MS (M+1): 524.3.
Exam le 155: 3- 4- 33-dimeth lc clobut l 2- 4- trifluorometh l-1H- 1- l rimidin- - lox meth Ibenzamido ro anoic acid lsomer 1 and Example 156: 3- 4- 3 3-dimeth lc clobut l 2- 4- trifluorometh l -1H- rimidin- - lox meth Ibenzamido ro anoic acid lsomer1 CH”; Ste A : eth |3- 4- 3 3-dimeth lc clobut l 2- 4- trifluorometh l-1H- razol l rimidin- - lox meth Ibenzamido ro anoate lsomer1 and lsomer2 PAC“ \NJ\N’N\ Azodicarboxylic acid ridine (814 mg, 3.19 mmol) and Intermediate (102) (781 mg, 2.34 mmol) were azeotrophed twice with toluene. To this e was added anhydrous tetrahydrofuran (10.6 mL). Tributylphosphine (0.840 mL, 3.41 mmol) was then added dropwise. Intermediate (105) (490 mg, 2.13 mmol) was then added as a solid in one portion. After 18 hours, the reaction was not complete so another 0.5 equiv. of Azodicarboxylic acid ridine and tributylphosphine were added. After another 4 h, the reaction was diluted with ethyl acetate to fully dissolve the solid. The mixture was washed twice with 1.0 M sodium hydroxide, water, 1.0 M hydrochloric acid, and brine. The organic layer was dried over magnesium sulfate, filtered, and trated to a viscous oil.
Purification by silica gel flash chromatography (0 — 30% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethy|)-1H-pyrazolyl)pyrimidin yloxy)methyl)benzamido)propanoate (520 mg, 45% yield) as a white solid. lsomer 1 is obtained by resolving (+/-)-ethy| 3-(4-((3,3-dimethylcyclobutyl)(2-(4- (trifluoromethyl)-1H-pyrazolyl)pyrimidinyloxy)methyl)benzamido)propanoate by chiral SFC. Column: Chiralcel OJ-H. Dimensions: 21mm x 25cm. Mobile Phase: 70/30 C02/methanol. Flow Rate: 65.0 mL/min. Modifier: none. Retention time: 2.05 minutes, isomer 1, 2.71 minutes, isomer 2. lsomer 1: 1H NMR (400 MHz, CDCI3) 6 8.71 (s, 1H), 8.29 (s, 2H), 7.92 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 6.81 (t, J = 6.2 Hz, 1H), 5.08 (d, J = 7.4 Hz, 1H), 4.27 - 4.02 (m, 2H), 3.70 (q, J: 6.0 Hz, 2H), 2.85 - 2.66 (m, 1H), 2.62 (t, J: 5.9 Hz, 2H), 1.96 - 1.82 (m, 2H), 1.79 - 1.69 (m, 1H), 1.69 - 1.59 (m, 1H), 1.30 - 1.21 (m, 3H), 1.15 (s, 3H), 1.11 (s, 3H). MS (M+1): 546.4. Isomer 2:) 1H NMR (400 MHz, CDCI3) 6 8.72 (s, 1H), 8.29 (s, 2H), 7.92 (s, 1H), 7.74 (d, J: 8.2 Hz, 2H), 7.35 (d, J: 8.2 Hz, 2H), 6.81 (t, J: 6.1 Hz, 1H), 5.08 (d, J: 7.4 Hz, 1H), 4.23 - 4.03 (m, 2H), 3.71 (q, J = 6.0 Hz, 2H), 2.84 - 2.67 (m, 1H), 2.62 (t, J: 5.8 Hz, 2H), 1.97 - 1.84 (m, 2H), 1.78 -1.69 (m, 1H), 1.69 - 1.58 (m, 1H), 1.31 - 1.22 (m, 3H), 1.15 (s, 3H), 1.11 (s, 3H). MS (M+1): 546.4.
Ste B : 3- 4- 3 3-dimeth lc clobut l 2- 4- trifluorometh l-1H- razol l rimidin lox meth Ibenzamido ro anoic acid 1 The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-dimethylcyclobutyl)(2- (4-(trifluoromethyl)-1H-pyrazolyl)pyrimidinyloxy)methyl)benzamido)propanoate, isomer 1 using the conditions in Example 152, Step D. 1H NMR (400 MHz, CDCI3) 6 8.71 (s, 1H), 8.29 (s, 2H), 7.92 (s, 1H), 7.80 - 7.68 (m, 2H), 7.42 - 7.31 (m, 2H), 6.74 (t, J: 6.1 Hz, 1H), .08 (d, J = 7.2 Hz, 1H), 3.72 (q, J = 6.0 Hz, 2H), 2.82 - 2.74 (m, 1H), 2.71 (t, J = 6.0 Hz, 2H), 1.97 - 1.82 (m, 2H), 1.80 - 1.68 (m, 1H), 1.68 - 1.58 (m, 1H), 1.15 (s, 3H), 1.11 (s, 3H).
MS (M+1): 518.2. Chiral SFC. Column: Chiralpak AD-H. Dimensions: 4.6 x 250mm. Mobile Phase: 60/40 Cog/methanol. Flow Rate: 2.5 mL/min. Modifier: None. Retention time: 3.80 Ste B : 3- 4- 3 3-dimeth lc clobut l 2- 4- orometh l-1H- razol l rimidin lox meth Ibenzamido ro anoic acid lsomer2 The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-dimethylcyclobutyl)(2- (4-(trifluoromethyl)-1H-pyrazolyl)pyrimidinyloxy)methyl)benzamido)propanoate, isomer 2 using the ions in Example 152, Step D. 1H NMR (400 MHz, CDCI3) 6 8.71 (s, 1H), 8.29 (s, 2H), 7.92 (s, 1H), 7.77 - 7.67 (m, 2H), 7.42 - 7.32 (m, 2H), 6.75 (t, J: 6.3 Hz, 1H), .08 (d, J: 7.4 Hz, 1H), 3.72 (q, J: 6.2 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.71 (t, J: 6.0 Hz, 2H),1.96 - 1.83 (m, 2H), 1.80 - 1.69 (m, 1H), 1.69 -1.58(m,1H),1.15(s,3H),1.11(s,3H).
MS (M+1): 518.2. Chiral SFC. : Chiralpak AD-H. Dimensions: 4.6 x 250mm. Mobile Phase: 60/40 Cog/methanol. Flow Rate: 2.5 mL/min. Modifier: None. Retention time: 5.93 minutes.
Exam le 157: 3- 4- 33-dimeth lc clobut I 2- 4- trifluorometh I-1H- razol I rimidin- - lamino meth Ibenzamido ro anoic acid Isomer1 and Exam le 158: 3- 4- 33-dimeth lc clobut I 2- 4- trifluorometh I-1H- razol I rimidin- - lamino meth Ibenzamido ro anoic acid Isomer2 Ste A : eth I3- 4- 3 3-dimeth lc clobut I 2- 4- trifluorometh I-1H- razol I rimidin- - lamino meth Ibenzamido ro anoate O 0 HN(L N N’N\ To a solution of Intermediate (101) (1.19 g, 3.60 mmol) and Intermediate (106) (750 mg, 3.27 mmol) in methanol (10.9 ml) was added decaborane (240 mg, 1.96 mmol). The reaction was stirred for 12 hours at ambient temperature. The reaction mixture was quenched with aqueous 1.0M hydrochloric acid and extracted three times with ethyl acetate.
The ed organic layers were dried over sodium sulfate, filtered, and concentrated. cation by silica gel flash tography (0 — 70% ethyl acetate in heptane) afforded ethyl 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethy|)-1H-pyrazoIyl)pyrimidin ylamino)methyl)benzamido)propanoate (842 mg, 47% yield) as a yellow solid. (+/-)-ethy| 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1H-pyrazol yl)pyrimidinylamino)methyl)benzamido)propanoate was ed by chiral SFC n: Chiralpak IA. ions: 10mm x 25cm. Mobile Phase: 65/35 COZ/methanol. Flow Rate: .0 mL/min. Modifier: none) to give ethyl 3-(4-((3,3-dimethylcyclobutyl)(2-(4- (trifluoromethyl)-1H-pyrazoIy|)pyrimidinylamino)methyl)benzamido)propanoate Isomer 1 (retention time: 3.42 min) and ethyl 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trif|uoromethy|)- 1H-pyrazoIyl)pyrimidinylamino)methyl)benzamido)propanoate, Isomer 2 (retention WO 07850 2012/050349 time: 4.55 min). Isomer 1: 1H NMR (400 MHz, CDCI3) 6 8.64 (s, 1H), 7.97 (s, 2H), 7.88 (s, 1H), 7.79 - 7.64 (m, 2H), 7.41 - 7.31 (m, 2H), 6.82 (t, J: 5.9 Hz, 1H), 4.22 (d, J: 9.4 Hz, 1H), 4.16 (q, J: 7.0 Hz, 2H), 3.80 - 3.64 (m, 2H), 2.61 (t, J: 5.9 Hz, 2H), 2.58 - 2.45 (m, 1H), 2.05-1.97 (m 1.75 - 1.63 (m, 2H), 1.63 - 1.55 (m, 1H), 1.26 , 1H), (t, J: 7.2 Hz, 3H), 1.13 (s, 3H), 1.09 (s, 3H). MS (M+1): 545.4. Isomer 2: 1H NMR (400 MHz, CDCI3) 6 8.64 (s, 1H), 7.97 (s, 2H), 7.88 (s, 1H), 7.80 - 7.67 (m, 2H), 7.43 - 7.30 (m, 2H), 6.82 (t, J: 6.0 Hz, 1H), 4.22 (d, J: 9.4 Hz, 1H), 4.16 (q, J: 7.2 Hz, 2H), 3.77 - 3.64 (m, 2H), 2.63 (t, J = 5.7 Hz, 2H), 2.58 - 2.40 (m, 1H), 2.05-1.97 (m, 1H), 1.76 - 1.64 (m, 2H), 1.64 - 1.52 (m, 1H), 1.26 (t, J: 7.1 Hz, 3H), 1.13 (s, 3H), 1.09 (s, 3H). MS (M+1): 545.4.
Ste B : 3- 4- 3 3-dimeth lc clobut l 2- 4- trifluorometh l-1H- razol l rimidin lamino meth l benzamido ro anoic acid lsomer1 The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-dimethylcyclobutyl)(2- (4-(trifluoromethyl)-1H-pyrazolyl)pyrimidinylamino)methyl)benzamido)propanoate, isomer 1 using the conditions in Example 152, Step D. 1H NMR (400 MHz, CDCI3) 6 8.80 - 8.53 (m, 1H), 8.01 (br. s., 2H), 7.89 (br. s., 1H), 7.78 - 7.67 (m, 2H), 7.41 - 7.30 (m, 2H), 6.84 (s, 1H), 4.22 (d, J: 9.4 Hz, 1H), 3.71 (q, J: 4.7 Hz, 2H), 2.70 (t, J: 5.7 Hz, 2H), 2.64 - 2.40 (m, 1H), 2.12 — 1.90 (m, 1H), 1.77 - 1.47 (m, 3H), 1.12 (s, 3H), 1.08 (s, 3H). MS (M+1): 517.3.
Ste C : 3- 4- 3 th lc clobut l 2- 4- trifluorometh l-1H- razol l rimidin lamino meth lbenzamido ro anoic acid lsomer2 The title compound is obtained by hydrolyzing ethyl 3-(4-((3,3-dimethylcyclobutyl)(2- (4-(trifluoromethyl)-1H-pyrazolyl)pyrimidinylamino)methyl)benzamido)propanoate, isomer 2 using the conditions in Example 152, Step D. 1H NMR (400 MHz, CDCI3) 6 8.72 - 8.58 (m, 1H), 8.00 (br. s., 2H), 7.89 (br. s., 1H), 7.76 - 7.65 (m, 2H), 7.40 - 7.29 (m, 2H), 6.87 (br. s, 1H), 4.22 (d, J: 9.4 Hz, 1H), 3.78 - 3.66 (m, 2H), 2.70 (t, J: 5.5 Hz, 2H), 2.62 - 2.42 (m, 1H), 2.08 — 1.93 (m, 1H), 1.77 - 1.51 (m, 3H), 1.12 (s, 3H), 1.08 (s, 3H). MS (M+1): 517.3.
Exam le 159: 3- 4- 1- 2-meth l 4- trifluorometh l-1H- razol l henox but I benzamido ro anoic acid Ste A: 1- benz lox iodometh lbenzene A mixture of 4-iodomethylphenol (700 mg, 3.0 mmol), benzyl bromide (563 mg, 3.3 mmol), ium carbonate (620 mg, 4.5 mmol), and acetonitrile (15 ml) was stirred at the ambient temperature for three days. The on was concentrated in vacuum and theresidue was partitioned between water and ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, and loaded on silica gel.
Chromatography on a silica gel column, eluting with a gradient from 5% to 30% of ethyl acetate in heptane gave the target product as a colorless solid (950 mg, 98%). 1H NMR (500 MHz,CDCI3) 6 7.48 (d, 1H), 7.38 - 7.45 (m, 5H), 7.33 - 7.37 (m, 1H), 6.66 (d, J: 8.54 Hz, 1H), 5.07 (s, 2H), 2.25 (s, 3H).
Ste B: 1- 4- benz lox meth l hen l orometh l-1H- razole 6%N\ F A e of 1-(benzyloxy)iodomethylbenzene (850 mg, 2.6 mmol), 4-(trifluoromethyl)- 1H-pyrazole (535 mg, 3.9 mmol), copper iodide (100 mg, 0.52 mmol), dimethylglycine (54 mg, 0.52 mmol), potassium carbonate (906 mg, 6.6 mmol), and DMSO (10 ml) was stirred at +120o for 20 hours. The reaction was cooled to the ambient temperature, diluted with 10 ml of 5% aqueous ammonia and 10 ml of ethyl e and vigorously stirred for 20 min.
The e was extracted with ethyl acetate (2x20 ml). The combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, and loaded on silica gel.
Chromatography on a silica gel column, eluting with a gradient from 5% to 30% of ethyl acetate in heptane gave the target product as an oil, which crystallized upon standing to a colorless solid (670 mg, 77%). MS (M+1): 333.1.
Ste C: 2-meth l 4- trifluorometh l -1H- razol l henol (WN\ F A mixture of 1-(4-(benzyloxy)methylphenyl)(trifluoromethyl)-1H-pyrazole (670 mg, 2.0 mmol), 20% palladium hydroxide on activated carbon (50 mg), ethanol (20 ml), and THF (20 ml) was shaken under 40 psi of hydrogen gas at the ambient temperature for 3 days and at +500 for 1 day, to drive reaction to tion. The reaction was filtered through a pad of Celite and the mother liquor was concentrated to obtain the target product as a ess solid (420 mg, 86%). MS (M+1): 243.0.
Ste D: eth l4- 1- 2-meth l 4- trifluorometh l-1H- razol l henox but I benzoate O1113*: 2-Methyl(4-(trifluoromethyl)-1H-pyrazolyl)phenol (200 mg, 0.83 mmol) was combined with ethyl 4-(1-hydroxybuty|)benzoate (see Intermediate 5) (19 mg, 0.87 mmol) and dissolved in anhydrous tetrahydrofuran (5 mL). Triphenylphosphine (347 mg, 1.3 mmol) was added at 00 under stirring followed by 0.83 ml of 1.5 M on of diazoethyl azodicarboxylate (1.24 mmol). The reaction was stirred at room temperature as a yellow solution. At 17 hours, the on was concentrated and 10 ml of ethyl acetate and 5 ml of heptanes were added. Solid was filtered off and the mother liquor was loaded on silica gel.
Chromatography on a silica gel column (gradient from 5% to 40% of ethyl acetate in heptane) gave the target product as a colorless glass (90 mg, 24%). MS (M+1): 447.2.
Ste E: 4- 1- 2-meth l 4- trifluorometh l -1H- razol l henox but I benzoic acid OLl3*: A mixture of ethyl 4-(1-(2-methyl(4-(trifluoromethyl)-1H-pyrazolyl)phenoxy)butyl) benzoate (90 mg, 0.2 mmol), lithium hdroxide drate (24 mg, 1.0 mmol), methanol (2 ml), THF (3 ml), and water (1 ml) was stirred at +450 for 18 hours. The mixture was concentrated, d with 8 ml of water and 2 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate-heptane (1:1), extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the target product as a white solid (84 mg, 99%). MS (M+1): 419.2.
Ste F: eth l3- 4- 1- 2-meth l 4- orometh l-1H- razol l henox but I- benzamido ro anoate O O o’eN\ F To a mixture of ethyl 3-aminopropanoate hydrochloride (46 mg, 0.3 mmol), 4-(1-(2-methyl ifluoromethyl)-1H-pyrazolyl)phenoxy)butyl)benzoic acid (84 mg, 0.2 mmol), HOBt e (34 mg, 0.22 mmol), and DIPEA (0.133 ml, 0.8 mmol), and THF (3 ml) was added EDCI hydrochloride (62 mg, 0.32 mmol) in one portion at the ambient temperature and the reaction was stirred at the same temperature for three days. The mixture was diluted with 3 ml of ethyl aceate, 3 ml of es, and washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and loaded on silica gel. Chromatography on a silica gel column, eluting with a nt from 10% to 50% of ethyl acetate in heptane gave the target product as a colorless gum (55 mg, 53%). 1H NMR (500 MHz, CDCI3) 6 8.01 (s, 1H), 7.84 (s, 1H), 7.75 (d, J: 8.29 Hz, 2H), 7.45 (d, J = 2.68 Hz, 1H), 7.40 (d, J: 8.05 Hz, 2H), 7.20 (dd, J: 2.68, 8.78 Hz, 1H), 6.81 - 6.87 (m, 1H), 6.61 (d, J: 8.78 Hz, 1H), 5.21 (dd, J: 5.12, 7.56 Hz, 1H), 4.18 (q, J= 7.16 Hz, 2H), 3.73 (q, J= 6.02 Hz, 2H), 2.64 (t, J: 5.85 Hz, 2H), 2.40 (s, 3H), 2.00 - 2.10 (m, 1H), 1.81 - 1.90 (m, 1H), 1.52 - 1.61 (m, 1H), 1.44 - 1.51 (m, 1H), 1.28 (t, J: 7.20 Hz, 3H), 0.98 (t, J: 7.44 Hz, 3H). MS (M+1): 518.2.
Ste G: 3- 4- 1- 2-meth l 4- trifluorometh l -1H- razol l henox but I ido - propanoic acid ; 31%: A mixture of ethyl ethyl 3-(4-(1-(2-methyl(4-(trifluoromethyl)-1H-pyrazol yl)phenoxy)butyl)-benzamido)propanoate (55 mg, 0.11 mmol), lithium hdroxide monohydrate (7.2 mg, 0.3 mmol), methanol (2 ml), THF (2 ml), and water (0.3 ml) was stirred at 220 for 3 days. The mixture was concentrated, diluted with 8 ml of water and 0.35 ml of 1 M potassium hydrogen sulfate. The mixture was extracted with ethyl acetate, the extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain 3-(4-(1-(2-methyl(4-(trifluoromethy|)-1H-pyrazoly|)phenoxy)butyl)benzamido)— propanoic acid as a white solid (50 mg, 96%). 1H NMR (500 MHz, CDCI3) 6 8.00 (s, 1H), 7.84 (s, 1H), 7.73 (d, J: 8.29 Hz, 2H), 7.43 (d, J: 2.68 Hz, 1H), 7.39 (d, J: 8.29 Hz, 2H), 7.18 (dd, J: 2.68, 8.78 Hz, 1H), 6.84 - 6.90 (m, 1H), 6.59 (d, J: 8.78 Hz, 1H), 5.20 (dd, J: .12, 7.56 Hz, 1H), 3.71 (q, J: 5.94 Hz, 2H), 2.69 (t, J: 5.85 Hz, 2H), 2.39 (s, 3H), 1.99 - 2.09 (m, 1H), 1.80 - 1.89 (m, 1H), 1.51 - 1.61 (m, 1H), 1.42 - 1.50 (m, 1H), 0.98 (t, J: 7.32 Hz, 3H). MS (M+1): 490.2.
Exam le 160: 3- 4 6- 4- hen l-1H- razol l ridine lamino but I benzamido ro anoic acid lsomer1 The title compound is obtained by resolving racemic 3-(4-(1-(6-(4-phenyl-1H- pyrazolyl)pyridineylamino)butyl)benzamido)propanoic acid Example 62, by chiral SFC.
: Chiralcel AS—H. Dimensions: 4.6mm x 250mm. Mobile Phase: 60/40 COZIisopropanol. Flow Rate: 2.5 mL/min. Modifier: 0.2% isopropylamine. Retention time: .33 minutes.
Exam le 161: 3- 4 6- 4- hen l-1H- razol l ridine lamino but I benzamido ro anoic acid lsomer2 O O NVkOH / N,N\ The title nd is obtained by resolving racemic 3-(4-(1-(6-(4-phenyl-1H- pyrazolyl)pyridineylamino)butyl)benzamido)propanoic acid Example 62, by chiral SFC.
Column: cel AS—H. Dimensions: 4.6mm x 250mm. Mobile Phase: 60/40 COZIisopropanol. Flow Rate: 2.5 mL/min. er: 0.2% isopropylamine. Retention time: 6.25 minutes.
Exam le 162: +/— 4- 1- 6- 4- hen l-1H-imidazol l ridin lamino but I benzamido ro anoic acid o o N/QKOH N/\\N The title compound was prepared by a method analogous to that described for Example 62, using 6-(4-phenyl-1H-imidazolyl)pyridinamine. : Waters Atlantis dC18 4.6 x 50mm, 5pm. Modifier: TFA 0.05%. nt: 95%H20 / 5%MeCN linear to %H20 / 95%MeCN over 4.0min, Hold at 5%H20 / 95%MeCN to 5.0min. Flow: 2.0mL/min.
Retention time: 2.38 min. MS (M+1): 484.0.
Exam le 163: +/— 4- 6- 4-chlorometh l-1H- razol l ridin lamino c clo ent lmeth lbenzamido ro anoic acid 0 O /\)J\OH Ste A: +/— -eth l4- 6- 4-chlorometh l-1H- razol l ridin lamino The title compound was prepared by a method analogous to that bed in Step A of Example 1, using Intermediate (31) and Intermediate (108). 1H NMR (400 MHz, CDCI3, 6): 8.18 (s, 1 H), 7.96 — 8.00 (m, 2 H), 7.62 (d, J: 2.7 Hz, 1 H), 7.52 (d, J: 8.8 Hz, 1 H), 7.36 — 7.40 (m, 2 H), 6.85 (dd, J: 8.9, 2.8 Hz, 1 H), 4.34 (q, J: 7.0 Hz, 2 H), 4.13 (d, J: 8.4 Hz, 1 H), 2.26 (s, 3 H), 2.13 — 2.22 (m, 1 H), 1.87 — 1.96 (m, 1 H), 1.38 — 1.72 (m, 6 H), 1.33 — 1.38 (m, 3 H), 1.22 — 1.32 (m, 2 H). MS (M+1) 439.3.
Ste B: +/— 6- 4-chlorometh l-1H- razol l ridin lamino c clo ent l methyl)benzoic acid To a solution of (+/—)-ethy| 4-((6-(4-chloromethyl-1H-pyrazolyl)pyridin ylamino)(cyclopentyl)methyl)benzoate (78.6 mg, 0.179 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL) was added 1 N aqueous sodium hydroxide (0.36 mL, 0.36 mmol).
The on was heated to 50 °C for 10 minutes. The heat was removed and the reaction was allowed to stir at room temperature for 1 hour. The reaction was concentrated. The residue was taken up in water and acidified to pH = 4 with 1 N aqueous hydrochloric acid.
The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (68.3 mg, 93%) as a white solid. 1H NMR (400 MHz, CD3OD, 6): 8.19 (s, 1 H), 7.92 — 7.96 (m, 2 H), 7.66 — 7.69 (m, 1 H), 7.48 (d, J: 8.4 Hz, 2 H), 7.42 — 7.45 (m, 1 H), 7.03 (dd, J: 8.9, 2.8 Hz, 1 H), 4.18 (d, J: 9.2 Hz, 1 H), 2.22 (s, 3 H), 1.98 —2.07 (m, 1 H), 1.43 — 1.74 (m, 6 H), 1.23 — 1.38 (m, 2 H). MS (M+1) 411.3.
Ste C: +/— -meth l3- 4- 6- 4-chlorometh l-1H- razol l ridin lamino c clo ent lmeth mido ro anoate / N,N\ The title compound was ed by a method analogous to that described in Step C of Example 2, using (+/—)((6-(4-chloromethyl-1H-pyrazolyl)pyridin ylamino)(cyclopentyl)methyl)benzoic acid. 1H NMR (400 MHz, CDCI3, 6): 8.18 (s, 1 H), 7.66 — 7.72 (m, 2 H), 7.61 (d, J: 2.7 Hz, 1 H), 7.49 — 7.54 (m, 1 H), 7.37 (d, J: 8.4 Hz, 2 H), 6.85 (dd, J: 8.8, 2.9 Hz, 1 H), 6.78 (t, J: 6.0 Hz, 1 H), 4.09 —4.14 (m, 1 H), 3.65 — 3.73 (m, H), 2.59 — 2.65 (m, 2 H), 2.25 (s, 3 H), 1.86 — 1.96 (m, 1 H), 1.35— 1.73 (m, 6 H), 1.19 — 1.32 (m, 2 H). MS (M+1) 496.4.
Ste D: +/— 4- 6- 4-chlorometh l-1H- 1- l ridin lamino c clo ent lmeth lbenzamido ro anoic acid The title compound was prepared by a method analogous to that described in Step E of Example 4, using (+/—)-methy| 3-(4-((6-(4-chloromethyl-1H-pyrazolyl)pyridin ylamino)(cyclopentyl)methyl)benzamido)propanoate. 1H NMR (400 MHz, CD3OD, 6): 8.19 (s, 1 H), 7.70 — 7.75 (m, 2 H), 7.66 (d, J: 2.5 Hz, 1 H), 7.41 — 7.49 (m, 3 H), 7.05 (dd, J: 9.0, 2.9 Hz, 1 H), 4.17 (d, J: 9.2 Hz, 1 H), 3.58 (t, J: 6.9 Hz, 2 H), 2.59 (t, J: 6.9 Hz, 2 H), 2.22 (s, 3 H), 1.97 —2.08 (m, 1 H), 1.42 — 1.75 (m, 5 H), 1.23 — 1.39 (m, 3 H). MS (M+1) 482.4.
Exam le 164: +/— 4- 1- 6- 4- ridin l-1H- razol l ridin lamino but I benzamido ro anoic acid NVKOH / N’N\ / N\ Ste A: +/— -eth |4- 1- 6- 4- ridin l-1H- razol l ridin lamino but Ibenzoate To a solution of Intermediate (109) (42.3 mg, 0.178 mmol) in methanol (1.8 mL) was added glacial acetic acid (20 uL, 0.4 mmol) and Intermediate (5) (43.0 mg, 0.195 mmol). , added decaborane (13 mg, 0.11 mmol) and let reaction stir at room temperature for 65 hours. The on was concentrated. The crude residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate (3 x) and brine, dried over magnesium e, filtered, and concentrated. Purification by flash column chromatography (10-70% ethyl acetate / heptanes) gave ethyl 4-(1-(6-(4-(pyridinyl)-1H-pyrazolyl)pyridin ylamino)buty|)benzoate (19.6 mg, 25%). 1H NMR (400 MHz, CDCI3, 6): 8.82 (s, 1 H), 8.56 (dd, J: 4.9, 1.0 Hz, 1 H), 8.16 (s, 1 H), 8.00 (d, J: 8.2 Hz, 2 H), 7.61 — 7.72 (m, 3 H), 7.50 (d, J: 8.0 Hz, 1 H), 7.39 (d, J: 8.2 Hz, 2 H), 7.10 (ddd, J: 7.5, 5.0, 1.0 Hz, 1 H), 6.88 (dd, J: 8.9, 2.8 Hz, 1 H), 4.34 (q, J: 7.2 Hz, 2 H), 4.23 (d, J: 5.5 Hz, 1 H), 1.71 — 1.90 (m, 2 H), 1.31 — 1.54 (m, 5 H), 0.94 (t, J: 7.3 Hz, 3 H). MS (M+1) 442.4. 2012/050349 Ste B: +/— 4- 1- 6- 4- 2- l-1H- 1- l ridin lamino but I benzamido ro anoic acid The title compound was prepared by a method analogous to that described for Example 163, Steps B — D, using (+/—)-ethyl 4-(1-(6-(4-(pyridinyl)-1H-pyrazolyl)pyridin- 3-ylamino)butyl)benzoate. : Waters Atlantis dC18 4.6 x 50mm, 5pm. Modifier: TFA 0.05%. Gradient: 95%H20 / 5%MeCN linear to 5%H20 / 95%MeCN over 4.0min, Hold at %H20 / 95%MeCN to 5.0min. Flow: 2.0mL/min. Retention time: 2.20 min. MS (M+1): 485.0.
Exam le 165: +/— N-meth l 1- 6- 4- hen l-1H- razol l ridin lamino but I benzamido ro anoic acid Ste A: +/— -eth l4 6- 4- hen l-1H- razol l ridin lamino but lbenzoate The title compound was prepared by a method analogous to that described in Step A of Example 62, using Intermediate (5). 1H NMR (400 MHz, CDCI3, 6): 8.59 (s, 1 H), 7.98 — 8.03 (m, 2 H), 7.90 (s, 1 H), 7.65 — 7.71 (m, 2 H), 7.51 — 7.56 (m, 2 H), 7.32 — 7.43 (m, 4 H), 7.20 — 7.25 (m, 1 H), 6.90 (dd, J: 8.8, 2.9 Hz, 1 H), 4.31 —4.41 (m, 3 H), 1.73 — 1.90 (m, 2 H), 1.32 — 1.51 (m, 5 H), 0.92 — 0.98 (m, 3 H). MS (M+1) 441.4.
Ste B: +/— -tert-but l3- N-meth l1- 6- 4- hen l-1H- razol l ridin lamino but I benzamido ro anoate The title compound was prepared by a method analogous to that described in Steps B and C of Example 2, using ethyl 4-(1-(6-(4-phenyl-1H-pyrazoly|)pyridin y|amino)buty|)benzoate and tert-butyl 3-(methylamino)propanoate. MS (M+1) 554.5.
Ste C: +/— N-meth l1- 6- 4- hen l-1H- razol l ridin lamino but I ido ro anoic acid The title compound was prepared by a method analogous to that described in Step C of Example 1, using (+/—)-tert-buty| 3-(N-methyl(1-(6-(4-phenyl-1H-pyrazolyl)pyridin- 3-ylamino)butyl)benzamido)propanoate. Column: Waters Atlantis dC18 4.6 x 50mm, 5pm.
Modifier: TFA 0.05%. Gradient: 95%H20 / 5%MeCN linear to 5%H20 / 95%MeCN over 4.0min, Hold at 5%H20 / 95%MeCN to 5.0min. Flow: 2.0mL/min. ion time: 3.27 min.
MS (M+1): 498.1.
Exam le 166: 3- 4- 1- 6- 4-eth lmeth l-1H- razol l ridin lamino but I benzamido ro anoic acid 1 and Exam le 167: 3- 4 6- 4-eth lmeth l-1H- 1- l ridin lamino but I benzamido ro anoic acid lsomer2 Racemic 3-(4-(1-(6-(4-ethylmethyl-1H-pyrazolyl)pyridin y|amino)buty|)benzamido)propanoic acid was prepared by a method analogous to that described for Example 62, using Intermediate (110). 1H NMR (400 MHz, CD3OD, 6): 7.95 (s, 1 H), 7.72 — 7.76 (m, 2 H), 7.61 (d, J: 2.5 Hz, 1 H), 7.40 — 7.47 (m, 3 H), 7.08 (dd, J: 8.9, 2.8 Hz, 1 H), 4.41 (t, J: 6.9 Hz, 1 H), 3.58 (t, J: 6.9 Hz, 2 H), 2.60 (t, J: 6.9 Hz, 2 H), 2.44 (q, J: 7.5 Hz, 2 H), 2.20 (s, 3 H), 1.67 — 1.92 (m, 2 H), 1.31 — 1.56 (m, 2 H), 1.18 (t, J = 7.5 Hz, 3 H), 0.95 (t, J: 7.4 Hz, 3 H). MS (M+1) 450.4.
Racemic 3-(4-(1-(6-(4-ethylmethyl-1H-pyrazolyl)pyridin y|amino)buty|)benzamido)propanoic acid was resolved by chiral SFC to afford the two single enantiomers. Chiral SFC: Chiralcel OJ-H, 10 x 250 mm; Mobile Phase 65:35 COZImethanol, 10mL/min, Retention time: 3.03 minutes (Isomer 1), 5.47 s (Isomer 2).
Exam le 168: R 6- 1- 3 th l 4- trifluorometh l -1H- razol | hen Imeth Ibut lamino nicotinamido ro anoic acid 0 O / N/\)J\OH I H HN N “l \ CF3 To a solution of Intermediate (118) (218 mg, 0.400 mmol) in tetrahydrofuran (2.00 mL) and methanol (2.00 mL) was added 1 N aq sodium hydroxide (2.00 mL, 2.00 mmol).
After 10 minutes, the solution was trated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 4. The mixture was diluted with sat. aq sodium chloride (20 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organics were dried (NaZSO4) and filtered, and the filtrate was concentrated under reduced re to provide (R)(6-((1-(3,5-dimethyl(4- (trifluoromethyl)—1H-pyrazoly|)phenyl)methylbutyl)amino)nicotinamido)propanoic acid. 1H NMR (400 MHz, CDCI3, 6): 9.25 - 9.15 (m, 1 H), 8.25 (s, 1 H), 8.18 (d, J: 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.78 - 7.68 (m, 2 H), 7.11 (s, 2 H), 6.46 (d, J: 9.2 Hz, 1 H), 4.48 - 4.39 (m, 1 H), 3.85 - 3.65 (m, 2 H), 2.64 (t, J: 5.6 Hz, 2 H), 2.10 (s, 1 H), 2.00 (s, 6 H), 1.96 - 1.86 (m, 1 H), 1.81 - 1.70 (m, 1 H), 1.70 - 1.59 (m, 1 H), 1.02 (d, J: 6.4 Hz, 3 H), 0.96 (d, J: 6.4 Hz, 3 H). MS (M+1): 518.7.
Exam le 169: S 6- 1- 3 th l 4- trifluorometh l -1H- razol | hen Imeth Ibut lamino nicotinamido ro anoic acid O O KYLNAAOH\ H H'E N mychN\ The title compound was prepared by a method analogous to that described for Example 168 using Intermediate (119). 1H NMR (400 MHz, CDCI3, 6): 9.25 - 9.15 (m, 1 H), 8.25 (s, 1 H), 8.18 (d, J: 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.78 - 7.68 (m, 2 H), 7.11 (s, 2 H), 6.46 (d, J: 9.2 Hz, 1 H), 4.48 - 4.39 (m, 1 H), 3.85 - 3.65 (m, 2 H), 2.64 (t, J: 5.6 Hz, 2 H), 2.10 (s, 1 H), 2.00 (s, 6 H), 1.96 - 1.86 (m, 1 H), 1.81 - 1.70 (m, 1 H), 1.70 - 1.59 (m, 1 H), 1.02 (d, J: 6.4 Hz, 3 H), 0.96 (d, J: 6.4 Hz, 3 H). MS (M+1): 518.7.
Exam le 170: 3- 6- c clo ent l3 5-dimeth l 4- trifluorometh l-1H- 1- | hen Imeth lamino nicotinamido ro anoic acid Isomer1 O O N/QKOH /| H HN N N \ CFs Ste A: +/— -N- c clo ent l3 5-dimeth l 4- orometh l-1H- razol l hen lmeth lmeth l ro anesulfinamide t—Bu’S\NH S {Ry}.N\ Cyclopentylmagnesium bromide (2 M in diethyl ether, 3.46 mL, 6.92 mmol) and dimethylzinc (2 M in toluene, 3.89 mL, 7.78 mmol) were allowed to stirfor 15 minutes. This solution was then added se to a solution of Intermediate (1003) (1.28 g, 3.46 mmol) in tetrahydrofuran (34.6 mL) at -78 °C. After 5 hours, an additional portion of cyclopentylmagnesium bromide (2 M in diethyl ether, 0.86 mL, 1.72 mmol) and dimethylzinc (2 M in toluene, 0.95 mL, 1.90 mmol) that had been allowed to mix for 15 minutes was added dropwise to the reaction mixture at -78 °C.
After 1 hour, the solution was quenched at -78 °C by addition of sat. aq ammonium chloride (10 mL). The resulting slurry was allowed to warm to room temperature.
The mixture was d with 120 mL sat. aq ammonium chloride and enough water to dissolve precipitated solids. This solution was then extracted with ethyl acetate (3 x 120 mL). The combined organics were dried (NaZSO4) and filtered, and the te was concentrated under reduced pressure. Purification by column chromatography (ethyl acetate / heptane) gave N-(cyclopentyl(3,5-dimethyl (4-(trifluoromethyl)—1H-pyrazolyl)pheny|)methyl)methy|propanesulfinamide. 1H NMR (400 MHz, CDCI3, 6): 7.94 (s, 1 H), 7.75 (s, 1 H), 7.09 (s, 2 H), 4.03 (d, J: 9.2 Hz, 1 H), 2.41 - 2.27 (m, 1 H), 2.02 (s, 6 H), 1.99 - 1.87 (m, 1 H), 1.72 - 1.35 (m, 7 H), 1.23 (s, 9 H), 1.16 - 1.04 (m, 1 H). MS (M+1): 442.5.
Ste B: +/— -c clo ent l3 5-dimeth l 4- trifluorometh l-1H- razol yl)phenyl)methanamine hydrochloride HCI NH2 3 gem To a solution of (+/—)—N-(cyclopentyl(3,5-dimethyl(4-(trifluoromethyl)—1 H- pyrazoly|)phenyl)methyl)methy|propanesulfinamide (1.184 g, 2.680 mmol) in methanol (13.4 mL) was added en de (4 M in dioxane, 3.35 mL, 13.4 mmol) se. The reaction was concentrated under reduced pressure to provide (+/—)—cyclopentyl(3,5-dimethyl(4-(trifluoromethyl)—1 H-pyrazol yl)phenyl)methanamine hydrochloride. 1H NMR (400 MHz, CDgOD, 6): 8.33 (s, 1 H), 8.07 (s, 1 H), 7.31 (s, 2 H), 4.05 (d, J: 10.6 Hz, 1 H), 2.35 - 2.51 (m, 1 H), 2.10 - 1.98 (m, 7 H), 1.89 - 1.39 (m, 6 H), 1.20 - 1.14 (m, 1 H).
Ste C: meth l +/— c clo ent l3 5-dimeth l 4- trifluorometh l-1H- razol yl )phenyl )methyl )amino )nicotinate 2012/050349 To a mixture of cyclopentyl(3,5-dimethyl(4-(trifluoromethyl)—1 H- pyrazolyl)phenyl)methanamine hydrochloride (1.002 g, 2.680 mmol) and potassium carbonate (1.51 g, 10.7 mmol) in N,N-dimethylformamide (5.36 mL) was added methyl 6-fluoronicotinate (472 mg, 2.95 mmol). The reaction was heated to 85 °C. After 15 h, the reaction was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organics were dried (NaZSO4) and filtered, and the filtrate was concentrated under reduced pressure. Purification by column tography (ethyl acetate / heptane) gave methyl (+/—)((cyclopentyl(3,5-dimethyl(4-(trifluoromethyl)—1 H-pyrazol yl)phenyl)methyl)amino)nicotinate. 1H NMR (400 MHz, CDCI3, 6): 8.67 (d, J = 1.6 Hz, 1 H), 7.99 (dd, J: 9.0, 2.0 Hz, 1 H), 7.93 (s, 1 H), 7.75 (s, 1 H), 7.12 (s, 2 H), 6.28 (d, J: 9.0 Hz, 1 H), 4.43 - 4.33 (m, 1 H), 3.87 (s, 3 H), 2.36 - 2.23 (m, 1 H), 2.04 - 1.97 (m, 7 H), 1.77 - 1.41 (m, 6 H), 1.37 - 1.28 (m, 1 H). MS (M+1): 473.2.
Ste D: +/— c clo ent l3 5-dimeth l 4- trifluorometh l-1H- razol l hen l meth l amino nicotinic acid HN N WeN\ To a solution of methyl (+/—)((cyc|openty|(3,5-dimethyI(4- (trifluoromethyl)—1H-pyrazoly|)phenyl)methyl)amino)nicotinate (753 mg, 1.59 mmol) in ydrofuran (7.97 mL) and methanol (7.97 mL) was added 1 N aq sodium hydroxide (7.97 mL, 7.97 mmol). After 16 h, the solution was concentrated under reduced pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 4. The mixture was diluted with sat. aq sodium de (30 mL) and extracted with ethyl acetate (3 x 50 mL).
The combined organics were dried (NaZSO4) and filtered, and the te was concentrated under reduced pressure to provide (+/—)—6-((cyc|openty|(3,5-dimethyl- 4-(4-(trifluoromethyl)—1H-pyrazolyl)phenyl)methyl)amino)nicotinic acid. 1H NMR (400 MHz, CDCI3, 5): 8.68 (s, 1 H), 8.14 (d, J: 9.2 Hz, 1 H), 7.94 (s, 1 H), 7.75 (s, 1 H), 7.15 (s, 2 H), 5.39 (d, J: 9.2 Hz, 1 H), 4.28 - 4.18 (m, 1 H), 2.44 - 2.31 (m, 1 H), 2.12 - 2.05 (m, 1 H), 2.01 (s, 5 H), 1.78 - 1.40 (m, 5 H), 1.35 - 1.28 (m, 1 H). MS (M+1): 459.5.
Ste E: eth l3- 6- c clo ent l3 5-dimeth l 4- trifluorometh l-1H- razol l hen l meth lamino nicotinamido ro anoate lsomer1 and eth l3- 6- c clo ent l3 th |- 4- 4- trifluorometh l-1H- razol l hen lmeth lamino nicotinamido ro anoate lsomer 2 O O KYLNVKOIH\ H HN N o @905 To a mixture of 6-((cyclopentyl(3,5-dimethyl(4-(trifluoromethy|)-1 H-pyrazol y|)pheny|)methy|)amino)nicotinic acid (731 mg, 1.59 mmol), B-alanine ethyl ester hydrochloride (516 mg, 3.19 mmol), and 1-hydroxyazabenzotriazole (336 mg, 2.39 mmol) in dichloromethane (15.9 mL) was added triethylamine (0.782 mL, 5.58 mmol) followed by N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (465 mg, 2.39 mmol). After 70 hours, the mixture was d with dichloromethane (50 mL) and washed with water (3 x 50 mL) and sat. aq sodium chloride (50 mL). The organic layer was dried 4) and filtered, and the filtrate was concentrated under reduced re. Purification by column chromatography (ethyl acetate / heptane) followed by chiral SFC (Cellulose-2 column, 21 mm x 250 mm, 35% methanol / carbon dioxide eluent) gave ethyl 3-(6-((cyclopentyl(3,5- dimethyl(4-(trifluoromethyl)-1H-pyrazol y|)pheny|)methy|)amino)nicotinamido)propanoate, lsomer 1 (SFC retention time 2.71 min) and ethyl 3-(6-((cyclopentyl(3,5-dimethyl(4-(trifluoromethy|)-1H-pyrazol y|)pheny|)methy|)amino)nicotinamido)propanoate, lsomer 2 (SFC retention time 3.43 min). 1H NMR (400 MHz, CDCI3, 6): 8.45 (d, J: 2.0 Hz, 1 H), 7.91 (s, 1 H), 7.81 - 7.72 (m, 2 H), 7.09 (s, 2 H), 6.84 (t, J: 5.7 Hz, 1 H), 6.41 - 6.27 (m, 1 H), 6.26 (d, J: 9.0 Hz, 1 H), 4.33 (t, J: 7.6 Hz, 1 H), 4.14 (q, J: 7.1 Hz, 2 H), 3.65 (q, J: 6.0 Hz, 2 H), 2.59 (t, J: 6.0 Hz, 2 H), 2.33 - 2.19 (m, 1 H), 1.98 (s, 6 H), 1.96 - 1.85 (m, 1 H), 1.74 - 1.37 (m, 6 H), 1.34 - 1.21 (m, 4 H). MS (M+1): 558.5.
Ste F: 3- 6- c clo ent l3 5-dimeth l 4- trifluorometh l-1H- razol l hen lmeth lamino nicotinamido ro anoic acid lsomer1 Exam le 170 O O mkNVkOH\ H HN N 3 @WW To a solution of ethyl 3-(6-((cyclopentyl(3,5-dimethyl(4-(trifluoromethy|)-1H- lyl)phenyl)methyl)amino)nicotinamido)propanoate, lsomer 1 (255 mg, 0.457 mmol) in ydrofuran (2.29 mL) and methanol (2.28 mL) was added 1 N aq sodium hydroxide (2.28 mL, 2.28 mmol). After 10 minutes, the solution was concentrated under d pressure to remove tetrahydrofuran and methanol. 1 N aq hydrochloric acid was added until the mixture was at pH 3. The mixture was diluted with sat. aq sodium chloride (15 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organics were dried 4) and filtered, and the filtrate was concentrated under reduced pressure to provide 3-(6- ((cyclopentyl(3,5-dimethyl(4-(trifluoromethyl)-1H-pyrazol yl)phenyl)methyl)amino)nicotinamido)propanoic acid, lsomer 1. 1H NMR (400 MHz, CDCI3, 6): 9.54 - 9.42 (m, 1 H), 8.58 - 8.48 (m, 1 H), 8.22 (d, J: 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 - 7.72 (m, 2 H), 7.12 (s, 2 H), 6.54 (d, J: 9.4 Hz, 1 H), 4.20 - 4.08 (m, 1 H), 3.81 - 3.64 (m, 2 H), 2.67 (t, J: 5.5 Hz, 2 H), 2.44 - 2.33 (m, 1 H), 2.18 - 2.06 (m, 1 H), 2.01 (s, 6 H), 1.75 - 1.36 (m, 6 H), 1.33 - 1.19 (m, 1 H). MS (M+1): 530.4.
Exam le 171: 3- 6- c clo ent l 3 5-dimeth l 4- trifluorometh l-1H- razol l hen lmeth lamino nicotinamido ro anoic acid lsomer2 O O mLN/QkOH\ H HN N 3 Qty...N\ The title compound was prepared by a method analogous to that bed for Example 170, Step F, using ethyl 3-(6-((cyclopentyl(3,5-dimethyl(4-(trifluoromethy|)-1H- pyrazolyl)phenyl)methyl)amino)nicotinamido)propanoate, lsomer 2. 1H NMR (400 MHz, CDCI3, 6): 9.54 - 9.42 (m, 1 H), 8.58 - 8.48 (m, 1 H), 8.22 (d, J: 9.2 Hz, 1 H), 7.93 (s, 1 H), 7.82 - 7.72 (m, 2 H), 7.12 (s, 2 H), 6.54 (d, J: 9.4 Hz, 1 H), 4.20 - 4.08 (m, 1 H), 3.81 - 3.64 (m, 2 H), 2.67 (t, J: 5.5 Hz, 2 H), 2.44 - 2.33 (m, 1 H), 2.18 - 2.06 (m, 1 H), 2.01 (s, 6 H), 1.75 - 1.36 (m, 6 H), 1.33 - 1.19 (m, 1 H). MS (M+1): 530.4.
Exam le 172: N- 4- 4 4 4-trifluoro 6- 4- trifluorometh l -1H- razol l ridin l amino but I benzo l -beta-alanine lsomer 1 and Exam le 173: N- 4- 4 4 luoro 6- 4- trifluorometh l -1H- 1- l ridin l amino but I benzo l -beta-alanine lsomer 2 O NWOH H O N\/\fl/OH | \ F | E /N F /N F \ 7“ \ / F F Ste A: +/— -eth |4- 4 4 4-trifluoroh drox but I benzoate Ho 0 F 0_\ To a on of the ethyl 4-iodobenzoate (1.21 ml, 7.24 mmol) in tetrahydrofuran (12 ml) at - 40 °C was added isopropylmagnesium chloride lithium chloride complex (6.13 ml, 7.97 mmol, 1.3M in tetrahydrofuran) dropwise. The mixture was stirred for approximately 1 hour whereupon the 4,4,4-trifluorobutanal (0.761 ml, 0.724 mmol) was added dropwise. The e was stirred at -40 °C for 15 minutes and slowly warmed to ambient temperature over 12 hours. The reaction was quenched with aqueous 1.0M hydrochloric acid and the aqueous layer was extracted with ethyl acetate (3x). The combined organic layers were dried over magnesium e, filtered, and concentrated in vacuo. The alcohol was used without further purification.
Step B: ethyl 4-(4,4,4-trifluorobutanoyl)benzoate O O A mixture of (+/—)-ethy| 4-(4,4,4-trif|uorohydroxybutyl)benzoate (2.10 g, 7.60 mmol) in romethane (28 ml), dimethyl sulfoxide (22 ml), and ylamine (5.29 ml, 38.0 mmol) was cooled to 0 °C. Sulfur trioxide pyridine complex (3.63 g, 22.8 mmol) was added in portions and the mixture stirred at 0 °C for 1 hour, then slowly raised to ambient temperature over 12 h. The reaction was quenched with water and diluted with diethylether.
The aqueous layer was extracted with lether and the combined organic layers were washed with brine. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to affording the crude product as a solid that was used without further purification.
Ste C: +/— -eth |4trifluoro 6- 4- trifluorometh l-1H- razol l ridin yl {amino )butyl |benzoate To a solution of crude ethyl 4-(4,4,4-trifluorobutanoyl)benzoate (0.060 g, 0.22 mmol) and 6- ifluoromethyl)-1H-pyrazolyl]pyridinamine (0.050 g, 0.22 mmol) in methanol (2.2 ml) was added decaborane (8.0 mg, 0.066 mmol). The reaction was stirred for 12 hours at ambient temperature. The reaction mixture was quenched with s 1.0M hydrochloric acid and concentrated in vacuo. The crude al was purified via ISCO MPLC (SiOZ, 0- 100% ethyl acetate in heptane) to yield the product (47g, 42%) as an oil. 1H NMR (400 MHz, CDCI3): 6 8.63 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.38 - 7.45 (m, 2H), 6.96 (dd, J = 8.8, 2.7 Hz, 1H), 4.50 (t, J = 6.2 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 2.07 - 2.32 (m, 4H), 1.39 (t, J = 7.2 Hz, 3H). MS (M+1): 487.3.
Ste D: +/— 4 4 4-trifluoro 6- 4- trifluorometh l -1H- razol l ridin l amino but I benzoic acid F — /N \ NH o \N N F F A mixture of (+/—)-ethy| 4-[4,4,4-trifluoro({6-[4-(trifluoromethyl)-1H-pyrazolyl]pyridin yl}amino)butyl]benzoate (46 mg, 0.095 mmol) in methanol (0.19 ml) and tetrahydrofuran(0.095 ml) was d with aqueous lithium hydroxide (0.095 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient temperature for 12 hours. The reaction was concentrated in vacuo, then diluted with water and acidified with aqueous 1.0M hydrochloric acid. The mixture was then concentrated in vacuo a second time, and the crude residue was used directly for further transformations.
Ste E: +/— -eth l N- 4- 4 4 4-trifluoro 6- 4- trifluorometh l -1H- razol l ridin l amino but I benzo l -beta-alaninate To a mixture of ethyl 3-aminopropionate hydrochloride (23 mg, 0.19 mmol), (+/—)[4,4,4- trifluoro({6-[4-(trifluoromethyl)-1H-pyrazolyl]pyridinyl}amino)butyl]benzoic acid (44 mg, 0.096 mmol), hydroxybenzotriazole hydrate (15 mg, 0.096 mmol), and triethylamine (55 ul, 0.39 mmol) in dichloromethane (0.96 ml)was added 1-ethyl(3- dimethylaminopropyl)carbodiimide hydrochloride (21 mg, 0.11 mmol). The mixture was d for 2 hours at ambient ature. The reaction was diluted with water and the organic layer was separated. The aq. layer was extracted with dichloromethane (2x) and the ed organic layers were dried over sodium e, filtered, and concentrated in vacuo. The crude material was used without further cation .
Ste F: + & — -N- 4-4 44-trifluoro 6- 4- trifluorometh l-1H- razol l ridin yltamino)butyl|benzoyl§-beta-alanine A mixture of crude (+/—)-ethyl N-{4-[4,4,4-trifluoro({6-[4-(trifluoromethyl)-1H-pyrazol idinyl}amino)butyl]benzoyl}-beta-alaninate (52 mg, 0.093 mmol) was dissolved in methanol (0.20 ml) and tetrahydrofuran (0.10 ml) and treated with aqueous lithium hydroxide (0.093 ml, 0.19 mmol, 2.0M). The mixture was stirred at ambient temperature for 1 hour. The crude reaction mixture was concentrated in vacuo and the residual solid was dissolved in water (0.50 ml) and treated with aqueous 1.0M hydrochloric acid until approximately pH 6 was reached, ing in the precipitation of c N-{4-[4,4,4- trifluoro({6-[4-(trifluoromethy|)-1H-pyrazolyl]pyridiny|}amino)butyl]benzoyl}-beta- alanine as a white gummy solid. The two enantiomeric ts were separated by chiral SFC Column: Chiralpak AD-H. Dimensions: 21 x 250mm. Mobile Phase: 70/30 thanol, (peak 1, 0.30 g, 22% and peak 2, 0.30 g, 22%). Flow Rate: 65mL/min.
Modifier: none. Analytical SFC: Chiralpak AD-H, 4.6 mm x 25 cm; SFC Mobile Phase 70:30 CO2/Methanol, 2.5 mL/min, analytical retention time: 2.97 min (lsomer 1) and 5.15 (lsomer 2). 1H NMR (400 MHz, CDCI3): 6 8.64 (s, 1H), 7.73 - 7.84 (m, 4H), 7.70 (d, J = 8.8 Hz, 1H), 7.37 - 7.43 (m, 2H), 6.98 (br. dd, J = 8.6, 2.0 Hz, 1H), 6.73 - 6.86 (m, 1H), 4.48 (br. t, J = 6.3 Hz, 1H), 3.73 (br. q, J = 5.9 Hz, 2H), 2.72 (br. t, J = 5.8 Hz, 2H), 2.06 - 2.34 (m, 4H). MS (M+1): 530.3.
Exam le 174: N- 4- 6- 4-c clo ro l-1H- razol l 3- lamino 33- dimeth lc clobut lmeth lbenzo l-beta-alanine lsomer 1 and Exam le 175: N- 4- 6- 4-c clo ro l-1H- razol l ridin lamino 33- dimeth lc clobut l meth lbenzo l-beta-alanine lsomer2
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