20-HETE FORMATION INHIBITORS

BACKGROUND

The current disclosure pertains to a new series of drug-like 20-HETE formation (CYP4) inhibitors.

Cytochrome P450 (CYP) enzymes produce mono-oxygenated metabolites of arachidonic acid (AA) that are highly vasoactive and are critical regulators of microvascular tone. Specifically, the terminal hydroxylation of AA to form 20-hydroxyeicosatetraenoic acid (20-HETE) is catalyzed by the CYP4 family of enzymes. In vivo and in vitro studies have demonstrated that 20-HETE is a potent vasoconstrictive eicosanoid and is involved in brain microvascular autoregulation (Edson et al., Current Topics in Medicinal Chemistry 2013, 13, 1429 and references therein; Elshenaway et al., Pharmaceutics, 2017, 9, 9 and references therein) Studies have shown that 20-HETE synthesis is increased after ischemic events and inhibitors of 20-HETE synthesis protect neurons and prevent cerebral blood flow impairment, brain edema, and blood-brain barrier (BBB) dysfunction after injury. For instance, inhibition of 20-HETE formation is neuroprotective in animal models of temporary focal ischemia (TFI), cardiac arrest (CA), stroke and subarachnoid hemorrhage (SAH) (see Edson et al. (2013); Elshenaway et al. (2017). Clinical studies have also demonstrated that 20-HETE is found in human cerebrospinal fluid (CSF) and that high 20-HETE CSF levels are associated with higher mortality and poor outcomes in aneurysmal subarachnoid hemorrhage (aSAH) patients (see Crago et al., Stroke, 2011, 42, 1872; Donelly et al., J Cereb Blood Flow Metab., 2015, 35, 1515). 20-HETE formation is also implicated in proliferation of renal epithelial cells and has potential in treating polycystic kidney disease (PKD). 20-HETE formation is involved in the increased proliferation of renal epithelial cells in polycystic kidney disease (PKD) and inhibition of 20-HETE formation led to reduction of cyst formation and improvement in markers of kidney function in animal models of PKD (Elshenaway et al. (2017)). There is a need for small molecule 20-HETE formation (CYP4) inhibitors with good stability and appropriate blood brain barrier penetration ability and other physicochemical properties for treating post-injury hypoperfusion and secondary neuronal injury after CA or other ischemic events or for the treatment of PKD. An object of this disclosure is to provide such compounds, their compositions and methods of use.

SUMMARY

This disclosure provides novel compounds that are able to potently inhibit CYP4 and 20-HETE formation. Data on selected compounds from this series show that the series can provide compounds with excellent physicochemical properties, potency, solubility, high microsomal stability and/or high BBB penetration potential.

In one aspect, the present disclosure includes a compound of formula I:

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or a pharmaceutically acceptable salt or solvate thereof, wherein: X is optionally substituted aryl or optionally substituted heteroaryl; Y is a bond, O, S, S═O, SO₂, or an optionally substituted methylene; Z is N or CH; and R¹is an optionally substituted pyrazolyl.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, R¹is optionally substituted pyrazol-5-yl, optionally substituted pyrazol-4-yl, or optionally substituted pyrazol-3-yl.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, R¹is optionally methyl substituted pyrazol-5-yl, optionally methyl substituted pyrazol-4-yl, or optionally methyl substituted pyrazol-3-yl.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, Y is a bond.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, X is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, X is:

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wherein:

each R²is independently selected from a group consisting of H, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocyclyl, C₁-C₆alkoxy, halo, —SR³, —S(O)R³, —CH₂OR³, —(CH₂)nS(O)R³, —(CH₂)nS(O)₂R³, —SO₂R³, —CO₂R³, —SO₂NHR⁴, —(CH₂)n-OR⁴, —OR⁴, —CO₂R⁴, —NR⁵R⁶, —NR⁵C(O)R⁶, —(CH₂)n-NR⁵C(O)R⁶, —CH(CH₃)—NR⁵C(O)R⁶, —CONR⁵R⁶, —N(R⁵)S(O)₂R⁶, —N(R⁵)(CH₂)nS(O)R⁶, —N(R⁵)(CH₂)nS(O)₂R⁶, —SO₂NR⁵R⁶, and —NR⁴C(O)R³;

R³is an optionally substituted C₁-C₆alkyl or an optionally substituted C₃-C₆cycloalkyl or an optionally substituted alkylene forming a 4, 5 or 6-member ring with the aromatic carbon atom adjacent to the location of the R²substituent;

R⁴is H, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted tetrahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

R⁵and R⁶are each independently H, optionally substituted C₁-C₆alkyl, or optionally substituted C₃-C₆cycloalkyl; or R⁵and R⁶and the atoms to which they are attached, together form an optionally substituted 4 to 6 membered ring;

A, B and C are —(C(R^2′)₂)_1-2— where in R^2′ is H or F and one of A, B and C is O or SO₂;

Y is a bond;

Z is CH; and

n and p are each independently 1, 2, or 3.

In another aspect, for the compound of the prior paragraph, or a pharmaceutically acceptable salt or solvate thereof, R¹is

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wherein

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH; and

M is H or CH₃.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

X is

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and R¹is

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and wherein:

each R²is independently selected from a group consisting of H, F, Cl, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocyclyl, —SR³, —S(O)R³, —SO₂R³, —SO₂NHR⁴, —OR⁴, —(CH₂)n-OR⁴, —CO₂R⁴, —NR⁵R⁶, —NR⁵C(O)R⁶, —CONR⁵R⁶, —N(R⁵)SO₂R⁶, and —SO₂NR⁵R⁶;

R³is optionally substituted C₁-C₆alkyl or optionally substituted C₃-C₆cycloalkyl;

R⁴is H, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted tertahydrofuranyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted azetidinyl, or optionally substituted oxetanyl;

Y is O;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

X is

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and R¹is

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and wherein:

Y is S, S═O, or SO₂;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

X is

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and R¹is

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and wherein:

Y is CH₂;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

X is

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and R¹is

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and wherein:

R²is selected from a group consisting of H, F, Cl, optionally substituted C₁-C₆alkyl, optionally substituted C₃-C₆cycloalkyl, optionally substituted heterocyclyl, —OR⁴, —(CH₂)n-OR⁴, —CO₂R⁴, —NR⁵R⁶, —NR⁵C(O)R⁶, —CONR⁵R⁶, and —N(R⁵)SO₂R⁶;

Y is a bond or CH₂;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

X is

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and R¹is

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and wherein:

Y is a bond or CH₂;

Z is N;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

X is

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and R¹is

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and wherein:

Y is a bond or CH₂;

Z is CH or N;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently is 1, 2, or 3.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof,

X is

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and R¹is

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and wherein:

Y is S;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In another aspect, for the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, Z is CH.

In another aspect of the disclosure, the compound is selected from the compounds listed in Table 1 below, or a pharmaceutically acceptable salt or solvate thereof:

TABLE 1

In another aspect, the present disclosure includes a method of inhibiting the biosynthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any embodiment herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present disclosure includes a method of inhibiting CYP4, the method comprising contacting CYP4 with a compound of any embodiment herein, or a pharmaceutically acceptable salt or solvate thereof. In another aspect, the contacting is in vitro. In yet another aspect, the contacting is in vivo in a subject in need.

In another aspect, the present disclosure provides a method of preventing cerebral blood flow impairment in a subject experiencing or having experienced an ischemic event, the method comprising administering to the subject a therapeutically effective amount of a compound of any embodiment herein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present disclosure provides a method of producing neuroprotection and decreased brain damage by preventing cerebral microvascular blood flow impairment and anti-oxidant mechanisms in a subject experiencing or having experienced an ischemic event, comprising administering to the subject a therapeutically effective amount of o a compound of any embodiment herein, or a pharmaceutically acceptable salt or solvate thereof. Further, in yet another aspect, the ischemic event can comprise trauma, focal ischemia (TFI), subarachnoid hemorrhage (SAH), vasoconstriction, thrombosis, embolism, cardiac arrest, stroke, aneurysm, hypertension, sickle cell disease, application of g-forces, arteriovenous malformation, peripheral artery occlusive disease, central nervous system (CNS) depressant overdose, or a combination thereof.

In another aspect, the present disclosure provides a method of reducing the size or stop the growth of kidney cysts in polycystic kidney disease (PKD) by preventing 20-HETE formation and 20-HETE driven renal epithelial cell proliferation in a subject suffering from PKD comprising administering a therapeutically and/or pharmacologically effective amount of the compound of any of the embodiments herein, or pharmaceutically acceptable salt thereof. In another aspect, PKD is of the autosomal dominant or recessive type. In a further aspect, the subject is a human.

Both the foregoing summary and the following detailed description are exemplary and explanatory. They are intended to provide further details, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description.

DETAILED DESCRIPTION
I. Compounds

In one aspect, the present disclosure includes a compound of formula I:

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or a pharmaceutically acceptable salt or solvate thereof, wherein:

X is optionally substituted aryl or optionally substituted heteroaryl or optionally substituted hetercycle;

Y is a bond, O, S, S═O, SO₂, or an optionally substituted methylene;

Z is N or CH; and

R¹is an optionally substituted pyrazolyl.

In one embodiment, R¹is optionally substituted pyrazol-5-yl, optionally substituted pyrazol-4-yl, or optionally substituted pyrazol-3-yl. In one embodiment, R¹is optionally methyl substituted pyrazol-5-yl, optionally methyl substituted pyrazol-4-yl, or optionally methyl substituted pyrazol-3-yl.

In one embodiment, Y is a bond. In one embodiment, Y is a O. In one embodiment, Y is a S. In one embodiment, Y is a SO₂. In one embodiment Y is S═O. In one embodiment, Y is an optionally substituted methylene. In one embodiment, Y is a methylene. In one embodiment, Y is a methylene substituted with an alkyl, such as methyl. In one embodiment, Y is a methylene substituted with an alkyl, and the alkyl is (R) or (S).

In one embodiment, X is optionally substituted phenyl, optionally substituted pyridinyl, or optionally substituted pyrimidinyl. In one embodiment, X is optionally substituted phenyl. In one embodiment, X is optionally substituted pyridinyl. In one embodiment, X is optionally substituted pyrimidinyl. In one embodiment, X is phenyl, pyridinyl, or pyrimidinyl. In one embodiment, X is phenyl. In one embodiment, X is pyridinyl. In one embodiment, X is pyrimidinyl.

In one embodiment, Z is N. In one embodiment, Z is CH.

In one embodiment, X is:

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wherein:

Y is a bond;

Z is CH; and

n and p are each independently 1, 2, or 3.

In some embodiments, X is:

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such as

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such as

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wherein A, B and C are —(C(R^2′)₂)_1-2— where in R^2′ is H or F and one of A, B and C is O or SO₂. In some embodiments, B is O or SO₂. In some embodiments, B is O or SO₂and A and C are each CH₂. In some embodiments, R²is selected from H, halo, and optionally substituted C₁-C₆alkyl.

In some embodiments, X is:

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wherein

R^2xis:

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where R′ is H, F, or alkyl and Y′ is a bond or an optionally substituted alkylene. In one embodiment, Y′ is a methylene. In one embodiment, Y′ is a methylene substituted with an alkyl, such as methyl. In one embodiment, Y′ is a methylene substituted with an alkyl, and the alkyl is (R) or (S). In some embodiments, X is:

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In one embodiment, R¹is

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wherein:

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH; and

M is H or CH₃.

In one embodiment, X is

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and R¹is

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and wherein:

R³is optionally substituted C₁-C₆alkyl or optionally substituted C₃-C₆cycloalkyl;

Y is O;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In one embodiment, X is

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and R¹is

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and wherein:

Y is S, S═O, or SO₂;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH3 when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In one embodiment, X is

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and R¹is

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and wherein:

R³is an optionally substituted C₁-C₆alkyl or an optionally substituted C₃-C₆cycloalkyl;

Y is CH₂;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In one embodiment, X is

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and R¹is

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and wherein:

Y is a bond or CH₂;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In one embodiment, X is

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and R¹is

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and wherein:

Y is a bond or CH₂;

Z is N;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In one embodiment, X is

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and R¹is

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and wherein:

Y is a bond or CH₂;

Z is CH or N;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In one embodiment X is

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and R¹is

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and wherein:

Y is S;

Z is CH;

Q is N or CH;

L is N, CH or CCH₃, provided that L is not N when Q is N, and L is not CH or CCH₃when Q is CH;

M is H or CH₃; and

n and p are each independently 1, 2, or 3.

In some embodiments, R²is optionally substituted heterocyclyl, for example, optionally substituted heterocyclyl selected from morpholino, thiomorpholine oxide, and thiomopholine dioxide.

In one aspect, the present disclosure includes a compound, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from a group consisting of:

TABLE 2

In some embodiments, the compound is not

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or a pharmaceutically acceptable salt or solvate thereof.

II. Methods

In another aspect, the present disclosure includes a method of inhibiting CYP4, the method comprising contacting CYP4 with a compound of any embodiment herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo in a subject in need.

In another aspect, the present disclosure provides a method of treating polycystic kidney disease (PKD) in a subject suffering from autosomal dominant polysistic kidney disease (ADPKD) or autosomal recessive polysistic disease (ARPKD), the method comprising of administering to the subject a therapeutically effective amount of a compound of any embodiment herein, or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, the ischemic event comprises, trauma, focal ischemia (TFI), subarachnoid hemorrhage (SAH), vasoconstriction, thrombosis, embolism, cardiac arrest, stroke, aneurysm, hypertension, sickle cell disease, application of g-forces, arteriovenous malformation, peripheral artery occlusive disease, central nervous system (CNS) depressant overdose, or a combination thereof.

One aspect provides for use of the compound or a pharmaceutically acceptable salt or solvate thereof of any embodiment herein, or the pharmaceutical composition herein, for use in the manufacture of a medicament for inhibiting the biosynthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) in a subject in need thereof.

In some embodiments, the subject is a human. In some embodiments, the subject is a human, canine, feline, primate, aves, reptile, or murine.

III. Routes of Administration

Administration may be accomplished through various modes of delivery, and encompass any pharmaceutically acceptable method of administration. Preferred methods of delivery include systemic and localized delivery. Such routes of administration include but are not limited to, oral, intra-arterial, intrathecal, intraspinal, intramuscular, intraperitoneal, intranasal, and inhalation routes.

More particularly, compounds of the present disclosure may be administered for therapy by any suitable route, including without limitation, oral, rectal, nasal, topical (including transdermal, aerosol, buccal and sublingual), vaginal, parenteral (including subcutaneous, intravenous, intramuscular, and intradermal), intrathecal, and pulmonary. In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered orally. In some embodiments, the compound, or a pharmaceutically acceptable salt or solvate thereof, is administered through an injection. The preferred route will, of course, vary with the condition and age of the recipient, the particular syndrome being treated, and the specific combination of drugs employed.

IV. Dosage

“Therapeutically effective amount” can be empirically determined and will vary with the particular condition being treated, the subject, and the efficacy and toxicity of each of the active agents contained in the composition. The actual dose to be administered will vary depending upon the age, weight, and general condition of the subject as well as the severity of the condition being treated and the judgment of the health care professional.

Therapeutically effective amounts can be determined by those skilled in the art and will be adjusted to the requirements of each particular case. Generally, a therapeutically effective amount of the compound, or pharmaceutically acceptable salt or solvate thereof, will range from a total daily dosage of about 0.1 mg/day-about 4,000 mg/day, about 0.1 mg/day to about 720 mg/day, about 60-about 600 mg/day, or about 100-about 480 mg/day, or more preferably, in an amount between about 1-about 240 mg/day, about 30-about 240 mg/day, about 30-about 200 mg/day, about 30-about 120 mg/day, about 1-about 120 mg/day, about 50-about 150 mg/day, about 60-about 150 mg/day, about 60-about 120 mg/day, or about 60-about 100 mg/day, administered as either a single dosage or as multiple dosages. In some embodiments, the therapeutically effective amount of the compound, or pharmaceutically acceptable salt or solvate thereof, is from about 30-200 mg/day, administered as either a single dosage or as multiple dosages. In some embodiments, multiple dosages include two, three, or four doses per day. In some embodiments, multiple dosages include two or three doses per day.

In some embodiments, the dosage amounts of the compound, or pharmaceutically acceptable salt or solvate thereof, includes dosages greater than about 20 mg BID or TID. In some embodiments, the dosage amount of the compound, or pharmaceutically acceptable salt or solvate thereof, is greater than about 0.1 mg/day, about 1 mg/day, about 5 mg/day, about 10 mg/day, about 30 mg/day, about 60 mg/day, about 80 mg/day, about 90 mg/day, about 120 mg/day, about 150 mg/day, about 180 mg/day, about 210 mg/day, about 240 mg/day, about 270 mg/day, about 300 mg/day, about 360 mg/day, about 400 mg/day, about 440 mg/day, about 480 mg/day, about 520 mg/day, about 580 mg/day, about 600 mg/day, about 620 mg/day, about 640 mg/day, about 680 mg/day, and about 720 mg/day or more.

In some embodiments, the therapeutically effective amount of the compound, or pharmaceutically acceptable salt or solvate thereof, is at least about 30 mg/day, at least about 40 mg/day, at least about 50 mg/day, at least about 60 mg/day, at least about 70 mg/day, at least about 80 mg/day, at least about 90 mg/day, at least about 100 mg/day, at least about 110 mg/day, at least about 120 mg/day, at least about 130 mg/day, at least about 140 mg/day, at least about 150 mg/day, at least about 160 mg/day, at least about 170 mg/day, at least about 180 mg/day, at least about 190 mg/day, at least about 200 mg/day, at least about 225 mg/day, at least about 250 mg/day, at least about 275 mg/day, at least about 300 mg/day, at least about 325 mg/day, at least about 350 mg/day, at least about 375 mg/day, at least about 400 mg/day, at least about 425 mg/day, at least about 450 mg/day, at least about 475 mg/day, at least about 500 mg/day, at least about 525 mg/day, at least about 550 mg/day, at least about 575 mg/day, at least about 600 mg/day, at least about 625 mg/day, at least about 650 mg/day, at least about 675 mg/day, at least about 700 mg/day, or at least about 720 mg/day. In some embodiments, the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt of solvate thereof is at least about 30 mg/day, at least about 60 mg/day, at least about 80 mg/day, or at least about 100 mg/day.

In some embodiments, the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt of solvate thereof is about 30 mg/day, about 40 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 90 mg/day, about 100 mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, about 170 mg/day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day, about 275 mg/day, about 300 mg/day, about 325 mg/day, about 350 mg/day, about 375 mg/day, about 400 mg/day, about 425 mg/day, about 450 mg/day, about 475 mg/day, about 500 mg/day, about 525 mg/day, about 550 mg/day, about 575 mg/day, about 600 mg/day, about 625 mg/day, about 650 mg/day, about 675 mg/day, about 700 mg/day, or about 720 mg/day. In some embodiments, the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt of solvate thereof is about 30 mg/day, about 60 mg/day, about 80 mg/day, or about 100 mg/day.

Depending upon the dosage amount and precise condition to be treated, administration can be one, two, three, or four times daily for a time course of one day to several days, weeks, months, and even years, and may even be for the life of the subject. Illustrative dosing regimens will last a period of at least about a week, from about 1-4 weeks, from about 1-8 weeks, from 1-12 weeks, from 1-16 weeks, from 1-20 weeks, from 1-24 weeks, from 1-36 weeks, from 1-48 weeks, from 1-52 weeks, from 1-60 weeks, from 1-72 weeks, from 1-84 weeks, from 1-96 weeks, from 1 week to 1 year, from 1 week to 2 years, from 1 week to 3 years, from 1 week to 4 years, from 1 week to 5 years, or longer. In some embodiments, a dosing regimen is for a period of at least about 12, 24, 36, 48, 60, 72, 84, or 96 weeks. In some embodiments, a dosing regimen is for a period of about 12, 24, 36, 48, 60, 72, 84, or 96 weeks. In some embodiments, a dosing regimen is for a period of at least about 1 year, 2 years, 3 years, 4 years, or 5 years. In some embodiments, a dosing regimen is for a period of about 1 year, 2 years, 3 years, 4 years, or 5 years, or longer.

Practically speaking, a unit dose of any given composition of the disclosure or active agent can be administered in a variety of dosing schedules, depending on the judgment of the clinician, needs of the patient, and so forth. The specific dosing schedule will be known by those of ordinary skill in the art or can be determined experimentally using routine methods. Exemplary dosing schedules include, without limitation, administration five times a day, four times a day, three times a day, twice daily, once daily, every other day, three times weekly, twice weekly, once weekly, twice monthly, once monthly, and so forth.

V. Formulations

In another aspect, the present disclosure includes a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of solvate thereof, according to any embodiment herein and a pharmaceutically acceptable excipient. In one embodiment the composition comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt of solvate thereof. Pharmaceutical compositions of the disclosure may be formulated as described below.

The active agents described herein, such as the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, may be administered in a formulation which may optionally contain one or more additional components as described below.

In one aspect provided herein is a composition comprising, consisting essentially of, or consisting of a therapeutically effective amount of the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient and/or carrier. In some embodiments, the composition further comprises a neuroprotectant drug and/or a drug used to treat temporary focal ischemia (TFI), cardiac arrest (CA) and/or subarachnoid hemorrhage (SAH).

A. Excipients/Carriers

The compositions of the disclosure may further comprise one or more pharmaceutically acceptable excipients or carriers. Exemplary excipients include, without limitation, polyethylene glycol (PEG), PEG 400, (2-Hydroxypropyl)-β-cyclodextrin, hydrogenated castor oil (HCO), cremophors, carbohydrates, starches (e.g., corn starch), inorganic salts, antimicrobial agents, antioxidants, binders/fillers, surfactants, lubricants (e.g., calcium or magnesium stearate), glidants such as talc, disintegrants, diluents, buffers, acids, bases, film coats, combinations thereof, and the like.

A composition of the disclosure may include one or more carbohydrates such as a sugar, a derivatized sugar such as an alditol, aldonic acid, an esterified sugar, and/or a sugar polymer. Specific carbohydrate excipients include, for example: monosaccharides, such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

Also suitable for use in the compositions of the disclosure are potato and corn-based starches such as sodium starch glycolate and directly compressible modified starch.

Further representative excipients include inorganic salt or buffers such as citric acid, sodium chloride, potassium chloride, sodium sulfate, potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic, and combinations thereof.

A composition of the disclosure may also contain one or more antioxidants. Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the drug(s) or other components of the preparation. Suitable antioxidants for use in the present disclosure include, for example, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, and combinations thereof.

Additional exemplary excipients include surfactants such as polysorbates, e.g., “Tween 20” and “Tween 80,” and pluronics such as F68 and F88 (both of which are available from BASF, Mount Olive, N.J.), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, and phosphatidylethanolamines), fatty acids and fatty esters, steroids such as cholesterol, and chelating agents, such as EDTA, zinc and other such suitable cations.

Further, a composition of the disclosure may optionally include one or more acids or bases. Non-limiting examples of acids that can be used include those acids selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, citric acid, malic acid, lactic acid, formic acid, trichloroacetic acid, nitric acid, perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, and combinations thereof. Non-limiting examples of suitable bases include, without limitation, bases selected from the group consisting of sodium hydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide, ammonium acetate, potassium acetate, sodium phosphate, potassium phosphate, sodium citrate, sodium formate, sodium sulfate, potassium sulfate, potassium fumarate, and combinations thereof.

The amount of any individual excipient in the composition will vary depending on the role of the excipient, the dosage requirements of the active agent components, and particular needs of the composition. Typically, the optimal amount of any individual excipient is determined through routine experimentation, i.e., by preparing compositions containing varying amounts of the excipient (ranging from low to high), examining the stability and other parameters, and then determining the range at which optimal performance is attained with no significant adverse effects.

Generally, however, the excipient will be present in the composition in an amount of about 1% to about 99% by weight, preferably from about 5% to about 98% by weight, more preferably from about 15% to about 95% by weight of the excipient. In general, the amount of excipient present in the composition of the disclosure is selected from the following: at least about 2%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 95% by weight.

These foregoing pharmaceutical excipients along with other excipients are described in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), the “Physician's Desk Reference”, 52.sup.nd ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H., Handbook of Pharmaceutical Excipients, 3.sup.rd Edition, American Pharmaceutical Association, Washington, D.C., 2000.

B. Other Actives

A formulation (or kit) in accordance with the disclosure may contain, in addition to the compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof, optionally, one or more additional active agents. In some embodiments, the one or more active agents possesses a mechanism of action different from that of the compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof. Such active ingredients can be found listed in the FDA's Orange Book, Goodman & Gilman The Pharmacological Basis of Therapeutics, J. Griffith Hardman, L. L. Limbird, A. Gilman, 11th Ed., 2005, The Merck Manual, 18th edition, 2007, and The Merck Manual of Medical Information 2003.

C. Sustained Delivery Formulations

In some embodiments, the compositions of the disclosure are formulated in order to improve stability and extend the half-life of the compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof. For example, the compound, or a pharmaceutically acceptable salt of solvate thereof may be delivered in a controlled or extended-release formulation. Controlled or extended-release formulations are prepared by incorporating the compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof, into a carrier or vehicle such as liposomes, nonresorbable impermeable polymers such as ethylenevinyl acetate copolymers and Hytrel® copolymers, swellable polymers such as hydrogels, or resorbable polymers such as collagen and certain polyacids or polyesters such as those used to make resorbable sutures. Additionally, the compound, or a pharmaceutically acceptable salt of solvate thereof can be encapsulated, adsorbed to, or associated with, particulate carriers. Examples of particulate carriers include those derived from polymethyl methacrylate polymers, as well as microparticles derived from poly(lactides) and poly(lactide-co-glycolides), known as PLG. See, e.g., Jeffery et al., Pharm. Res. (1993) 10:362-368; and McGee et al., J. Microencap. (1996).

Extended release polymers suitable for this purpose are known in the art and include hydrophobic polymers such as cellulose ethers. Non-limiting examples of suitable cellulose ethers include ethyl cellulose, cellulose acetate and the like; polyvinyl esters such as polyvinyl acetate, polyacrylic acid esters, methacrylic and acrylate polymers (pH-independent types); high molecular weight polyvinyl alcohols and waxes such as fatty acids and glycerides, methacrylic acid ester neutral polymers, polyvinyl alcohol-maleic anhydride copolymers and the like; ethylacrylate-methylmethacrylate copolymers; aminoalkyl methacrylate copolymers; and mixtures thereof.

D. Delivery Forms

The compositions described herein encompass all types of formulations, and in particular, those that are suited for systemic or intrathecal administration. Oral dosage forms include tablets, lozenges, capsules, syrups, oral suspensions, emulsions, granules, microbeads, and pellets. In some embodiments, the oral dosage form is a tablet, capsule, granule, or microbead dosage form. In some embodiments, the oral dosage form is a tablet. In some embodiments, the tablet is an extended release tablet. In some embodiments, the oral dosage form is a capsule. In some embodiments, the capsule is an extended release capsule. In some embodiments, the oral dosage form is in a liquid dosage form. In some embodiments, the oral dosage form is an extended release formulation.

Alternative formulations include aerosols, transdermal patches, gels, creams, ointments, suppositories, powders or lyophilates that can be reconstituted, as well as liquids. Examples of suitable diluents for reconstituting solid compositions, e.g., prior to injection, include bacteriostatic water for injection, dextrose 5% in water, phosphate-buffered saline, Ringer's solution, saline, sterile water, deionized water, and combinations thereof. With respect to liquid pharmaceutical compositions, solutions and suspensions are envisioned. Preferably, the compound, or a pharmaceutically acceptable salt of solvate thereof, or the composition of the disclosure is one suited for oral administration.

For oral delivery formulations, tablets can be made by compression or molding, optionally with one or more accessory ingredients or additives. Compressed tablets are prepared, for example, by compressing in a suitable tableting machine, the active ingredients in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) and/or surface-active or dispersing agent.

Molded tablets are made, for example, by molding in a suitable tableting machine, a mixture of powdered compounds moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredients, using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, such as a thin film, sugar coating, or an enteric coating to provide release in parts of the gut other than the stomach. Processes, equipment, and toll manufacturers for tablet and capsule making are well-known in the art.

Formulations for topical administration in the mouth include lozenges comprising the active ingredients, generally in a flavored base such as sucrose and acacia or tragacanth and pastilles comprising the active ingredients in an inert base such as gelatin and glycerin or sucrose and acacia.

A pharmaceutical composition for topical administration may also be formulated as an ointment, cream, suspension, lotion, powder, solution, paste, gel, spray, aerosol or oil.

Alternatively, the formulation may be in the form of a patch (e.g., a transdermal patch) or a dressing such as a bandage or adhesive plaster impregnated with active ingredients and optionally one or more excipients or diluents. Topical formulations may additionally include a compound that enhances absorption or penetration of the ingredients through the skin or other affected areas, such as dimethylsulfoxidem bisabolol, oleic acid, isopropyl myristate, and D-limonene, to name a few.

For emulsions, the oily phase is constituted from known ingredients in a known manner. While this phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat and/or an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of cream formulations. Illustrative emulgents and emulsion stabilizers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

Formulations for rectal administration are typically in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for vaginal administration generally take the form of a suppository, tampon, cream, gel, paste, foam or spray.

Formulations suitable for nasal administration, wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns. Such a formulation is typically administered by rapid inhalation through the nasal passage, e.g., from a container of the powder held in proximity to the nose. Alternatively, a formulation for nasal delivery may be in the form of a liquid, e.g., a nasal spray or nasal drops.

Aerosolizable formulations for inhalation may be in dry powder form (e.g., suitable for administration by a dry powder inhaler), or, alternatively, may be in liquid form, e.g., for use in a nebulizer. Nebulizers for delivering an aerosolized solution include the AERx® (Aradigm), the Ultravent® (Mallinkrodt), and the Acorn II® (Marquest Medical Products). A composition of the disclosure may also be delivered using a pressurized, metered dose inhaler (MDI), e.g., the Ventolin® metered dose inhaler, containing a solution or suspension of a combination of drugs as described herein in a pharmaceutically inert liquid propellant, e.g., a chlorofluorocarbon or fluorocarbon.

Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile solutions suitable for injection, as well as aqueous and non-aqueous sterile suspensions.

Parenteral formulations of the disclosure are optionally contained in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the types previously described.

A formulation of the disclosure may also be an extended release formulation, such that each of the drug components is released or absorbed slowly over time, when compared to a non-sustained release formulation. Sustained release formulations may employ pro-drug forms of the active agent, delayed-release drug delivery systems such as liposomes or polymer matrices, hydrogels, or covalent attachment of a polymer such as polyethylene glycol to the active agent.

In addition to the ingredients particularly mentioned above, the formulations of the disclosure may optionally include other agents conventional in the pharmaceutical arts and particular type of formulation being employed, for example, for oral administration forms, the composition for oral administration may also include additional agents as sweeteners, thickeners or flavoring agents.

E. Kits

Also provided herein is a kit containing at least one composition of the disclosure, compound (or pharmaceutically acceptable salt or solvate thereof) of the disclosure, accompanied by instructions for use.

For example, in instances in which each of the drugs themselves are administered as individual or separate dosage forms, the kit comprises the compound, or a pharmaceutically acceptable salt of solvate thereof along with instructions for use. The compound, or a pharmaceutically acceptable salt of solvate thereof may be packaged in any manner suitable for administration, so long as the packaging, when considered along with the instructions for administration, clearly indicates the manner in which drug component is to be administered.

For example, in an illustrative kit comprising the compound, or a pharmaceutically acceptable salt of solvate thereof the kit may be organized by any appropriate time period, such as by day. As an example, for Day 1, a representative kit may comprise unit dosages of each of the compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof. If the drug is to be administered twice daily, then the kit may contain, corresponding to Day 1, two rows of unit dosage forms of the compound, or a pharmaceutically acceptable salt of solvate thereof along with instructions for the timing of administration. Various embodiments according to the above may be readily envisioned, and would of course depend upon the corresponding dosage form, recommended dosage, intended subject population, and the like. The packaging may be in any form commonly employed for the packaging of pharmaceuticals, and may utilize any of a number of features such as different colors, wrapping, tamper-resistant packaging, blister packs, dessicants, and the like.

It is to be understood that while the disclosure has been described in conjunction with preferred specific embodiments, the foregoing description as well as the examples that follow are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

All references mentioned in this application, including any patents, published patent applications, books, handbooks, journal publications, or the FDA Orange Book are hereby incorporated by reference herein, in their entirety.

The following examples are given for the purpose of illustrating various embodiments of the disclosure and are not meant to limit the present disclosure in any fashion. One skilled in the art will appreciate readily that the present disclosure is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. The present examples, along with the methods described herein are presently representative of embodiments and are exemplary, and are not intended as limitations on the scope of the disclosure. Changes therein and other uses which are encompassed within the spirit of the disclosure as defined by the scope of the claims will occur to those skilled in the art.

VI. Definitions

The terms “pharmacologically effective amount” or “therapeutically effective amount” of a composition or agent, as provided herein, refer to a nontoxic but sufficient amount of the composition or agent to provide the desired response. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, mode of administration, and the like. An appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation, based upon the information provided herein.

As used in the specification and claims, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof.

As used herein, the term “comprising” is intended to mean that the compounds, compositions and methods include the recited elements, but not exclude others. “Consisting essentially of” when used to define compounds, compositions and methods, shall mean excluding other elements of any essential significance to the combination. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants, e.g., from the isolation and purification method and pharmaceutically acceptable carriers, preservatives, and the like. “Consisting of” shall mean excluding more than trace elements of other ingredients. Embodiments defined by each of these transition terms are within the scope of this technology.

All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (−) by increments of 1, 5, or 10%. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term “about.” It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

The term “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term. For example, in some embodiments, it will mean plus or minus 5% of the particular term. Certain ranges are presented herein with numerical values being preceded by the term “about.” The term “about” is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number, which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number.

“Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

“Pharmaceutically acceptable excipient or carrier” refers to an excipient that may optionally be included in the compositions of the disclosure and that causes no significant adverse toxicological effects to the patient.

“Substantially” or “essentially” means nearly totally or completely, for instance, 95% or greater of some given quantity. In some embodiments, “substantially” or “essentially” means 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.9%.

“20-HETE” or “20-Hydroxyeicosatetraenoic acid” is a compound represented by the formula:

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“Optionally substituted” refers to a group selected from that group and a substituted form of that group. A “substituted” group, refers to that group substituted with any substituent described or defined below. In one embodiment, substituents are selected from, for example, CF₃, OCF₃, halo, haloaryl, alkoxy, aryloxy, haloalkoxy, dihydroxy, aminohydroxy, carboxy, amido, sulfoxy, sulfonyl, haloaryloxy, aryl, benzyl, benzyloxy, heteroaryl, nitrile, C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₃-C₆cycloalkyl, C₁-C₆haloalkyl, C₁-C₆haloalkenyl, C₁-C₆haloalkynyl, C₃-C₆halocycloalkyl, C₆-C₁₀aryl, C₃-C₈cycloalkyl, C₂-C₁₀heterocyclyl, C₁-C₁₀heteroaryl, —N₃, nitro, —CO₂H or a C₁-C₆alkyl ester thereof, any of the functional groups described or defined below, or combinations thereof.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—), isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—), sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl (CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—). A Cx-Cy alkyl will be understood to have from x to y carbons.

“Alkenyl” refers to monovalent straight or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (>C═C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-1-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.

“Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (—C≡C—) unsaturation. Examples of such alkynyl groups include acetylenyl (—C≡CH), and propargyl (—CH₂C≡CH).

“Substituted alkyl” refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein and with the proviso that any hydroxyl or thiol substitution is not attached to an acetylenic carbon atom.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groups preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched. This term is exemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene (—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)— or —CH(CH₃)CH₂—), butylene (—CH₂CH₂CH₂CH₂—), isobutylene (—CH₂CH(CH₃)CH₂—), sec-butylene (—CH₂CH₂(CH₃)CH—), and the like. Similarly, “alkenylene” and “alkynylene” refer to an alkylene moiety containing respective 1 or 2 carbon-carbon double bonds or a carbon-carbon triple bond.

“Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and oxo wherein said substituents are defined herein. In some embodiments, the alkylene has 1 to 2 of the aforementioned groups, or having from 1-3 carbon atoms replaced with —O—, —S—, or —NR^Q— moieties where R^Qis H or C₁-C₆alkyl. It is to be noted that when the alkylene is substituted by an oxo group, 2 hydrogens attached to the same carbon of the alkylene group are replaced by “═O”. “Substituted alkenylene” and “substituted alkynylene” refer to alkenylene and substituted alkynylene moieties substituted with substituents as described for substituted alkylene.

A “protecting group” or “P²” (wherein z is an integer) intends any protecting group suitable for alcohol(s) and amine(s) and which are well known in the art. Non-limiting examples include 2,2,2-trichloroethyl carbonate (Troc), 2-methoxyethoxymethyl ether (MEM), 2-naphthylmethyl ether (Nap), 4-methoxybenzyl ether (PMB), acetate (Ac), benzoate (Bz), benzyl ether (Bn), benzyloxymethyl acetal (BOM), benzyloxymethyl acetal (BOM), methoxymethyl acetal (MOM), methoxypropyl acetal (MOP), methyl ether, tetrahydropyranyl acetal (THP), triethylsilyl ether (TES), triisopropylsilyl ether (TIPS), trimethylsilyl ether (TMS), tert-Butyldimethylsilyl ether (TBS, TBDMS), or tert-butyldiphenylsilyl ether (TBDPS). In the case of a 1,2 diol or 1,2 aminoalcohols suitable protecting groups include acetonide, benzaldehyde acetal or carbonate and others. These protecting groups and others are well known to the skilled artisan, as evidenced by Green et al: Greene's Protective Groups in Organic Synthesis, Fourth Edition Author(s): Peter G. M. Wuts and Theodora W. Greene First published: 10 Apr. 2006, Copyright © 2007 John Wiley & Sons, Inc, the disclosure of which is incorporated by reference.

“Deprotection,” “deprotecting,” and the like, intend removal of the protecting group by any conventional means known to the skilled artisan or present in Green et al. It will be readily apparent that the conditions for deprotecting depend upon which protecting group is used.

“Alkoxy” refers to the group —O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

“Substituted alkoxy” refers to the group —O-(substituted alkyl) wherein substituted alkyl is defined herein.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—, cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the “acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR⁴⁶C(O)R⁴⁷wherein R⁴⁶and R⁴⁷are each independently, hydrogen, alkyl, substituted alkyl, alkylene, substituted alkylene, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, and wherein R⁴⁶and R⁴⁷are optionally joined, together to form a heterocyclic or substituted heterocyclic group, provided that R⁴⁶and R⁴⁷are both not hydrogen, and wherein alkyl, substituted alkyl, alkylene, substituted alkylene, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substituted alkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, cycloalkenyl-C(O)O—, substituted cycloalkenyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O— wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR⁴⁸R⁴⁹where R⁴⁸and R⁴⁹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂— alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂— cycloalkenyl, —SO₂-substituted cylcoalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂— heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substituted heterocyclic and wherein R⁴⁸and R⁴⁹are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R⁴⁸and R⁴⁹are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R⁴⁸is hydrogen and R⁴⁹is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R⁴⁸and R⁴⁹are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R⁴⁸or R⁴⁹is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R⁴⁸nor R⁴⁹are hydrogen.

“Aminocarbonyl” refers to the group —C(O)NR⁵⁰R⁵¹where R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminothiocarbonyl” refers to the group —C(S)NR⁵⁰R⁵¹where R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR⁴⁷C(O)NR⁵⁰R⁵¹where R⁴⁷is hydrogen or alkyl and R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR⁴⁷C(S)NR⁵⁰R⁵¹where R⁴⁷is hydrogen or alkyl and R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the group —O—C(O)NR⁵⁰R⁵¹where R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminosulfonyl” refers to the group —SO₂NR⁵⁰R⁵¹where R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR⁵⁰R⁵¹where R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminosulfonylamino” refers to the group —NR⁴⁷SO₂NR⁵⁰R⁵¹where R⁴⁷is hydrogen or alkyl and R⁵⁰and R⁵¹are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Amidino” refers to the group —C(═NR⁵²)NR⁵⁰R⁵¹where R⁵⁰, R⁵¹, and R⁵²are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁵⁰and R⁵¹are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

“Substituted aryl” refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

“Aryloxy” refers to the group —O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

“Substituted aryloxy” refers to the group —O-(substituted aryl) where substituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, where aryl is as defined herein.

“Substituted arylthio” refers to the group —S-(substituted aryl), where substituted aryl is as defined herein.

“Azide” refers to the group —N═N⊕=N⊖.

“Carbonyl” refers to the divalent group —C(O)— which is equivalent to —C(═O)—.

“Carboxyl” or “carboxy” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl, —C(O)O— substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl, —C(O)O— substituted alkynyl, —C(O)O-aryl, —C(O)O-substituted aryl, —C(O)O-cycloalkyl, —C(O)O— substituted cycloalkyl, —C(O)O-cycloalkenyl, —C(O)O-substituted cycloalkenyl, —C(O)O— heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic, and —C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“(Carboxyl ester)amino” refers to the group —NR⁴⁷C(O)O-alkyl, —NR⁴⁷C(O)O— substituted alkyl, —NR⁴⁷C(O)O-alkenyl, —NR⁴⁷C(O)O-substituted alkenyl, —NR⁴⁷C(O)O— alkynyl, —NR⁴⁷C(O)O-substituted alkynyl, —NR⁴⁷C(O)O-aryl, —NR⁴⁷C(O)O-substituted aryl, —NR⁴⁷C(O)O-cycloalkyl, —NR⁴⁷C(O)O-substituted cycloalkyl, —NR⁴⁷C(O)O-cycloalkenyl, —NR⁴⁷C(O)O-substituted cycloalkenyl, —NR⁴⁷C(O)O-heteroaryl, —NR⁴⁷C(O)O-substituted heteroaryl, —NR⁴⁷C(O)O-heterocyclic, and —NR⁴⁷C(O)O-substituted heterocyclic wherein R⁴⁷is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“(Carboxyl ester)oxy” refers to the group —O—C(O)O-alkyl, —O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substituted alkenyl, —O—C(O)O-alkynyl, —O—C(O)O— substituted alkynyl, —O—C(O)O-aryl, —O—C(O)O-substituted aryl, —O—C(O)O-cycloalkyl, —O—C(O)O-substituted cycloalkyl, —O—C(O)O-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl, —O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl, —O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

An animal, subject or patient for diagnosis, treatment, or administration of the compounds if the disclosure thereto, refers to an animal such as a mammal, or a human, ovine, bovine, feline, canine, equine, simian, etc. Non-human animals subject to diagnosis, treatment, or administration thereto of compounds of the disclosure include, for example, simians, murine, such as, rat, mice, canine, leporid, livestock, sport animals, and pets.

A “composition” “pharmaceutical composition” as used herein, intends an active agent, such as a compound as disclosed herein and a carrier, inert or active. The carrier can be, without limitation, solid such as a bead or resin, or liquid, such as phosphate buffered saline.

Administration or treatment in “combination” refers to administering two agents such that their pharmacological effects are manifest at the same time. Combination does not require administration at the same time or substantially the same time, although combination can include such administrations.

“Cyano” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. The fused ring can be an aryl ring provided that the non-aryl part is joined to the rest of the molecule. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one >C═C<ring unsaturation and preferably from 1 to 2 sites of >C═C<ring unsaturation.

“Substituted cycloalkyl” and “substituted cycloalkenyl” refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

“Cycloalkyloxy” refers to —O-cycloalkyl.

“Substituted cycloalkyloxy” refers to —O-(substituted cycloalkyl).

“Cycloalkylthio” refers to —S-cycloalkyl.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl).

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkenyloxy” refers to —O-(substituted cycloalkenyl).

“Cycloalkenylthio” refers to —S-cycloalkenyl.

“Substituted cycloalkenylthio” refers to —S-(substituted cycloalkenyl).

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to —NR⁵³C(═NR⁵³)N(R⁵³)₂where each R⁵³is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, heterocyclic, and substituted heterocyclic and two R⁵³groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R⁵³is not hydrogen, and wherein said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. Certain non-limiting examples include pyridinyl, pyrrolyl, indolyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinyl and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy” refers to the group —O-(substituted heteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl.

“Substituted heteroarylthio” refers to the group —S-(substituted heteroaryl).

“Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, or sulfonyl moieties.

“Substituted heterocyclic” or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substituted heterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl.

“Substituted heterocyclylthio” refers to the group —S-(substituted heterocycyl).

Examples of heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, furan, thiophene, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

“Nitro” refers to the group —NO₂.

“Oxo” refers to the atom (═O).

Phenylene refers to a divalent aryl ring, where the ring contains 6 carbon atoms.

Substituted phenylene refers to phenylenes which are substituted with 1 to 4, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are as defined herein.

“Spirocycloalkyl” and “spiro ring systems” refers to divalent cyclic groups from 3 to 10 carbon atoms having a cycloalkyl or heterocycloalkyl ring with a spiro union (the union formed by a single atom which is the only common member of the rings) as exemplified by the following structure:

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“Sulfonyl” refers to the divalent group —S(O)2-.

“Substituted sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substituted alkyl, —SO₂— alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl, —SO₂-substituted cycloalkyl, —SO₂— cycloalkenyl, —SO₂-substituted cylcoalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂— heteroaryl, —SO₂-substituted heteroaryl, —SO₂-heterocyclic, —SO₂-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-SO₂—, phenyl-SO₂—, and 4-methylphenyl-SO₂—.

“Substituted sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl, —OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl, —OSO₂-substituted cycloalkyl, —OSO₂-cycloalkenyl, —OSO₂-substituted cylcoalkenyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl, —OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, —OSO₂-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substituted alkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—, substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substituted cycloalkyl-C(S)—, cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—, aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substituted heteroaryl-C(S)—, heterocyclic-C(S)—, and substituted heterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thiocarbonyl” refers to the divalent group —C(S)— which is equivalent to —C(═S)—.

“Thioxo” refers to the atom (═S).

“Alkylthio” refers to the group —S-alkyl wherein alkyl is as defined herein.

“Substituted alkylthio” refers to the group —S-(substituted alkyl) wherein substituted alkyl is as defined herein.

“Pharmaceutically acceptable salt” refers to salts of a compound, which salts are suitable for pharmaceutical use and are derived from a variety of organic and inorganic counter ions well known in the art and include, when the compound contains an acidic functionality, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate (see Stahl and Wermuth, eds., “Handbook of Pharmaceutically Acceptable Salts,” (2002), Verlag Helvetica Chimica Acta, Zürich, Switzerland), for a discussion of pharmaceutical salts, their selection, preparation, and use.

“Active molecule” or “active agent” as described herein includes any agent, drug, compound, composition of matter or mixture which provides some pharmacologic, often beneficial, effect that can be demonstrated in vivo or in vitro. This includes foods, food supplements, nutrients, nutraceuticals, drugs, vaccines, antibodies, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. In specific embodiments, the active molecule or active agent includes the compound of formula I, or a pharmaceutically acceptable salt or solvate thereof.

Generally, pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for in vivo administration. Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, etc.), glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also include salts formed when an acidic proton present in the parent compound is either replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or by an ammonium ion (e.g., an ammonium ion derived from an organic base, such as, ethanolamine, diethanolamine, triethanolamine, morpholine, piperidine, dimethylamine, diethylamine, triethylamine, and ammonia).

A solvate of a compound is a solid-form of a compound that crystallizes with less than one, one or more than one molecules of a solvent inside in the crystal lattice. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but are not limited to, water, C1-C6 alcohols (such as methanol, ethanol, isopropanol, butanol, and can be optionally substituted) in general, tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art. Additionally, various organic and inorganic acids and bases can be added to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate. In some embodiments, one molecule of a compound can form a solvate with from 0.1 to 5 molecules of a solvent, such as 0.5 molecules of a solvent (hemisolvate, such as hemihydrate), one molecule of a solvent (monosolvate, such as monohydrate) and 2 molecules of a solvent (disolvate, such as dihydrate).

An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications or dosages and is determined by the system in which the drug or compound is delivered, e.g., an effective amount for in vitro purposes is not the same as an effective amount for in vivo purposes. For in vivo purposes, the delivery and “effective amount” is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents disclosed herein for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal and its body weight, general health, sex, the diet of the animal, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vivo. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.

As used herein, “treating” or “treatment” of a disease in a patient refers to (1) preventing the symptoms or disease from occurring in an animal that is predisposed or does not yet display symptoms of the disease; (2) inhibiting the disease or arresting its development; or (3) ameliorating or causing regression of the disease or the symptoms of the disease. As understood in the art, “treatment” is an approach for obtaining beneficial or desired results, including clinical results. For the purposes of this technology, beneficial or desired results can include one or more, but are not limited to, alleviation or amelioration of one or more symptoms, diminishment of extent of a condition (including a disease), stabilized (i.e., not worsening) state of a condition (including disease), delay or slowing of condition (including disease), progression, amelioration or palliation of the condition (including disease), states and remission (whether partial or total), whether detectable or undetectable.

As used herein, the term “contacting” intends bringing the reagents into close proximity with each other so that a chemical or biochemical reaction can occur among the reagents. In one aspect, the term intends admixing the components, either in a reaction vessel or on a plate or dish. In another aspect, it intends in vivo administration to a subject.

The term “binding” or “binds” as used herein are meant to include interactions between molecules that may be covalent or non-covalent which, in one embodiment, can be detected using, for example, a hybridization assay. The terms are also meant to include “binding” interactions between molecules. Interactions may be, for example, protein-protein, antibody-protein, protein-nucleic acid, protein-small molecule or small molecule-nucleic acid in nature. This binding can result in the formation of a “complex” comprising the interacting molecules. A “complex” refers to the binding of two or more molecules held together by covalent or non-covalent bonds, interactions or forces.

VII. Examples
Example 1: Synthesis of Compounds

Abbreviations as used herein: (1) THF is tetrahydrofuran; (2) DMF is N,N-dimethylformamide; (3) DMA is N,N-dimethylacetamide; (4) NMP is N-methylpyrolidone DMSO is dimethylsulfoxide; (5) DCM is dichloromethane; (6) DME is dimethoxyethane, MeOH is methanol; (7) EtOH is ethanol; (8) TFA is 1,1,1-trifluoroacetatic acid; (9) HOBT is 1-hydroxybenzotriazole, (10) PyBroP is bromotripyrrolidinophosphonium hexafluorophosphate; (11) EDCI is 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride; (12) HATU is 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; (13) DCC is N,N′-dicyclohexylcarbodiimide; (14) Boc is tert-butyloxy carbonyl; (15) Cbz is carboxybenzyl; (16) DIPEA is diisopropylethylamine; (17) Boc is tert-butyloxycarbonyl; (18) NBS is N-bromosuccinimde; (19) NIS is N-iodosuccinimide; (20) NCS is N-chlorosuccinimide; (21) DMAP is N,N-dimethylamino-pyridine; (22) DEAD is diethyl azodicarboxylate; (23) Brine is saturated aqueous sodium chloride solution; (24) TLC is thin layer chromatography; (25) HR-MS is high resolution mass spectrometry; (26) NMR is nuclear magnetic resonance spectroscopy; (27) LC-MS is liquid chromatographic mass spectrometry,

RT is room or ambient temperature; (28) ESI is electron spray ionization mass spectrometry; (29) HLM is Human Liver Microsomes; (30) 20-HETE is 20-hydroxyeicosatetraenoic acid; (31) AA is arachidonic acid; (32) 8,9-EET is 8, 9-epoxyeicosatrienoic acid; (33) 11,12-EET is 11,12-epoxyeicosatrienoic acid; (34) 14,15-EET is 14,15-epoxyeicosatrienoic acid; (35) 5,6-DiHET is 5,6-dihydroxyeicosatrienoic acid; (36) 8,9-DiHET is 8,9-dihydroxyeicosatrienoic acid; (37) 11,12-DiHET is 11,12-dihydroxyeicosatrienoic acid; (38) 14,15-DiHET is 14,15-dihydroxyeicosatrienoic acid; (39) THP is tetrahydropyranyl; (40)Trityl is triphenylmethyl DHP is 3,4 dihydro-2H-pyran; and (41) SEM is 2-(Trimethylsilyl)ethoxymethyl.

Compounds disclosed herein may be prepared by commercially available starting materials and via synthetic techniques and procedures known to those skilled in the art. Outlined below in scheme 1 is a general reaction scheme suitable for preparing the compounds of the general structure IV that are disclosed in the present disclosure. Further exemplification for the synthesis of disclosed compounds may be found in the specific examples listed below.

In general, the compounds of the general structure IV (see scheme 1), can be prepared via the coupling of a suitable N-protected iodopyrazole, or a suitable N-protected bromopyrazole, of the structure II (scheme 1) with a desired 4-substituted piperidine of the general structure Ia or Ib or a piperazine of the general structure Ic under appropriate Ullman or Buckwald/Hardwick coupling conditions to afford the intermediate coupling product III. This coupling, depending on the pyrazole halogen substituent and functionality present in Ia, Ib or Ic may be effected via appropriate transition metal catalyst/ligand systems in a suitable solvent and in the presence of a base under conditions available in the literature and known to the persons skilled in the art.

For example, the coupling could be effected under conditions seen in Kwong et al., Org. Lett., 2002, 4, 581; Zhang et al., J. Org. Chem., 2005, 70, 5164; Jiang et al., J. Org. Chem., 2007, 72, 672; Yang et al., J. Organometallic Chem., 1999, 576, 125; Alen et al., WO 2012/158413; Voss et al., WO 2015/022073; Bartels et al., WO 2017/97728; Albrecht et al., WO 2016/138114; Lohou et al., Synthesis, 2011, 16, 2651; Ioanidis et al., US 2016/0185785 A1; Basha et al., US2005/65178 A1 or other applicable conditions known to the persons skilled in the art. These disclosures are hereby incorporated by reference.

Desired compounds IV (scheme 1) can be obtained by deprotection of intermediates III, under a variety of conditions that depend on the protecting group used and the functionality present in the molecule, via methods known in the literature and to the people skilled in the art.

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Desirable piperidines of the general structure Ia, where X is aryl or heteroaryl, Y is a bond, and Z is CH are commercially available or can easily be synthesized in a variety of methods known to persons skilled in the art. For example, piperidines of the type Ia, where X is aryl or heteroaryl, Y is a bond and Z is CH may be prepared as seen in Eastwood, P. R., Tetrahedron Lett. 2000, 41, 3705; Pasternak et al., Bioorg. Med. Chem. Letters, 2008, 18, 944; Sakhteman et al., Bioorg. Med. Chem., 2009, 17, 6908; Kamei et al., Bior. Med. Chem. Letters, 2005, 15, 2990; Cox et al., ACS Med. Chem. Letters, 2017, 8, 49; Adams et al., WO 2016/001876; Yoshihara et al., WO 2012/124696; Allwood et al., J. Org. Chem., 2014, 79, 328; Conway, R., Bioorg. Med. Chem. Letters, 2012, 2560; Oslob et al., WO 2014/008197 or other suitable methods or combination of conditions/methods available in the literature and known to persons skilled in the art. These disclosures are hereby incorporated by reference.

Piperidines of the general structure Ib, where X is aryl/heteroaryl; Y is O and Z is CH, are commercially available or they can easily be synthesized in a variety of methods available in the literature and known to persons skilled in the art. For example, piperidines of the general structure Ib, where X is aryl/heteroaryl; Y is O and Z is CH, can be prepared as seen in Lawrence et al., WO 2001/077101 A1; Aisaoui et al., WO 2003/048154 A1; Boettcher et al., WO 2008/119741; Eriksson, A., WO 2002/074767; Oberboersch et al., WO 2008/040492; Bodil van Niel et al., WO 2015/177325; Bischoff et al., WO 2009/117676; Liang et al., Molecules, 2014, 19, 6163; Liu, G., ACS Med. Chem. Letters, 2012, 3, 997; Carroll et al., WO 2013/179024 or another suitable method or combination of conditions/methods available in the literature and known to persons skilled in the art. These disclosures are hereby incorporated by reference.

Piperidines of the general structure Ib, where X is aryl/heteroaryl, Y is S and Z is CH are commercially available or they can easily be synthesized in a variety of methods described in the literature. For example, piperidines of the general structure Ib, where X is aryl or heteroaryl, Y is S, and Z is CH may be prepared as seen in Knutsen et al., Bior. Med. Chem. Letters, 1993, 12, 2661; Fletcher et al., J. Med. Chem., 2002, 45, 492-503; Nagase et al., J. Med Chem, 2009, 52, 4111; Zak et al., Bioorg. Med. Chem. Letters, 2015, 25, 529; Nagase et al., WO 2009/038021; Shima et al., WO 2002/055541; Bacani, G., WO 2014/121055; Choi, J., WO 2000/9061131; Chassaing et al., WO 2016/005577; Bair et al., WO 2013/127267; Bromidge et al., WO 2016/001341 or another suitable method or combination of conditions/methods available in the literature and known to persons skilled in the art. These disclosures are hereby incorporated by reference.

Piperidines of the general structure Ib, where X is aryl or heteroaryl Y is SO or SO₂and Z is CH are commercially available or they can be prepared by methods available in the literature and known to those skilled in the art. For example, such piperidines may be prepared from suitable N-protected thio-piperidines of the general structure Ib, where X is aryl/heteroaryl, Y is S and Z is CH, via oxidation of the sulfur atom and then N-deprotection via a variety of methods available in the literature and known to the persons skilled in the art. For example, piperidines of the general structure Ib, where X is aryl/heteroaryl, Y is SO or SO₂, and Z is CH may be prepared as seen in Imamura et al., J. Med. Chem., 2006, 49, 2784; Fletcher et al., J. Med. Chem., 2002, 45, 492; Bacani, G., WO 2014/121055; Bair et al., WO 2013/127267; Bromidge et al. WO 2016/001341; Nagase et al., J. Med Chem., 2009, 52, 4111; Nagase et al., WO 2009/038021; Zak et al., Bioorg. Med. Chem. Letters, 2015, 25, 529; Muhlhausen et al., Nucl. Med. Biology, 2010, 37, 605; Thakur et al., Tetrahedron Asymmetry, 2003, 14, 407 or other suitable combination of conditions/methods available in the literature and known to the persons skilled in the art. These disclosures are hereby incorporated by reference.

Piperidines of the general structure Ib where X is aryl/heteroaryl, Y is CH₂and Z is CH are commercially available or they can be prepared in a variety of methods available in the literature and known to persons skilled in the art. For instance, such piperidines may be prepared as seen in Imamura et al., J. Med. Chem., 2006, 49, 2784; Imamura et al., WO 2001/025200; Ting et al., Bior. Med. Chem. Letters, 2005, 15, 1375; Chun et al., WO 2010/051245; Liu et al., ACS Med. Chem. Letters, 2012, 3, 997; Carroll et al., WO 2013/179024; Pandey et al., WO 2017/147328; Adjabebeng, G, WO 2009/076140; DiFranco et al., Synthesis, 45, 2949; Charvin et al., J. Med. Chem., 2017, 60, 8515 or other suitable combination of conditions/methods available in the literature and known to the persons skilled in the art. These disclosures are hereby incorporated by reference.

Piperazines of the general structure Ic, where X is aryl/heteroaryl, Y is a bond and Z is N are commercially available or can be prepared in a number of methods described in the literature. For example, such piperazines may be prepared as seen in Jpn. Kokai Tokkyo Koho, 57042679; Yong, F. et al. Tetrahedron Lett. 2013, 54, 5332; Jaisinghani, H. et al. Syn. Comm. 1998, 28, 1175; Wodtke, R. et al. J. Med. Chem. J. Med. Chem 2018, 61, 4528; Yoshihara, K. et al. PCT Int. Appl. 2012124696; Duncton, M. et al. Tet. Lett. 2006, 47, 2549; Reilly, S. et al. Org. Lett. 2016, 18, 5272; Pennell, A. et al. PCT Int. Appl. 2003105853 or other suitable method or combination of conditions/methods available in the literature and known to persons skilled in the art. These disclosures are hereby incorporated by reference.

Piperazines of the general structure Ic, where X is aryl/heteroaryl, Y is CH₂and Z is N are commercially available or can be prepared in a number of methods described in the literature. For example, such piperazines may be prepared as seen in Hoveyda, H. et al. Bioorg. Med. Chem. Letters, 2011, 21, 1991; Webster, S. et al. Bioorg. Med. Chem. Lett. 2007, 17, 2838; Bavetsias, V. et al. J. Med. Chem. 2012, 5, 8721 or other suitable method or combination of conditions/methods available in the literature and known to persons skilled in the art. These disclosures are hereby incorporated by reference.

Pyrazoles of the general structure II, where R₁is H or alkyl or fluoro and P a suitable protecting group, can be prepared via the N protection of the corresponding unprotected pyrazoles. THP, trityl, SEM, Methoxybenzyl or other protecting group that will not interfere with the coupling conditions or its deprotection will not unwantedly affect existing functionality may be used. Methods for introducing and removing THP, trityl, SEM or other suitable groups can be seen in Green, T; Wuts, P. Protective Groups in Organic Synthesis, 2^ndedition, Willey Interscience, 1991, the disclosure of which is incorporated by reference, or other literature available to persons skilled in the art.

Unprotected pyrazoles of the general structure II (schemel), where R₁is H or F, or R₁is methyl are commercially available. They also may be prepared via either direct synthesis and/or functionalization of an unprotected pyrazole or via the functionalization of a transiently protected pyrazole substrate followed by deprotection via methods and procedures available in the literature and known to persons skilled in the art. For example, such pyrazoles may be synthesized as seen in Reimlinger et al. Chemische Berichte, 1961, 94, 1036; Sakamoto, T. et al. Heterocycles 1992, 33, 813; Rodriguez-Franco, I. et al. Tet. Lett. 2001, 42, 863; Knorr, Chem. Berichte 1904, 37, 3051; Easton, N. U.S. Pat. No. 2,992,163; Moslin, R. et al. PCT Int. Appl. 201474661; Nicholaou. K. et al. ChemMedChem 2015, 10, 1974; Lahm, G. Bioorg. Med. Chem. Letters 2007, 17, 6274; Miethchen, R. et al. J. Prakt. Chem. 1989, 331, 799; Elguero, J. et al. Bulletin de la Societe Chimique de France, 1966, 2832; Alcalde et al. Anales de Quimica (1968-1979), 1974, 70, 959; Hanamoto, T. et al. Tetrahedron, 2007, 63, 5062; Levchenko, V. et al. J. Org. Chem. 2018, 83, 3265-3274 or other suitable method or combination of conditions/methods available in the literature and known to persons skilled in the art. These disclosures are incorporated by reference.

General Procedure 1: THP Protection of Iodopyrazoles

Desired iodopyrazole (1 eq) in CH₂Cl₂was treated with dihydropyran (1.1 eq) and a p-toluolosulfonic acid monohydrate (0.1 eq) at room temperature. Reaction mixture was allowed to stir until consumption of starting material was seen on TLC and then it was partitioned between CH₂Cl₂and aq. saturated Na₂CO₃solution. Aqueous layer was extracted with CH₂Cl₂(X3) and combined organic layer was dried over Na₂SO₄and concentrated to a crude residue that was chromatographed with silica gel column to afford the desired THP-protected iodopyrazole.

Intermediate 1. THP-Protected 4-iodo-pyrazole

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Prepared from commercially available 4-iodo-1H-pyrazole according to general procedure 1. The crude product was chromatographed using a 0-20% EtOAc in hexanes. The desired compound was isolated as a colorless viscous syrup (80% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.59-1.71 (m, 3H), 1.99-2.11 (m, 3H), 3.65-3.71 (m, 1H), 4.01-4.05 (m, 1H), 5.37 (dd, J=8.4, 3.6 Hz, 1H), 7.54 (s, 1H), 7.66 (s, 1H).

Intermediate 2. THP-Protected 3-iodo-pyrazole

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THP protection of commercially available 3-iodo-1H-pyrazole was carried out according to general method 1. The crude product was chromatographed using a 0-30% EtOAc in hexanes. The desired compound was isolated as a colorless viscous syrup (77% yield). Structure of the THP-protected product has been tentatively assigned as 3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. ¹H NMR (600 MHz, CDCl₃) δ 1.53-1.62 (m, 1H), 1.62-1.72 (m, 2H), 1.99-2.12 (m, 3H), 3.65-3.72 (m, 1H), 4.05-4.10 (m, 1H), 5.36 (dd, J=9.0, 3.0 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H).

Intermediate 3. THP-Protected 4-iodo-3-methyl-1-pyrazole

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THP protection of commercially available 4-iodo-3-methyl-1H-pyrazole was carried out according to general method 1. Crude product was chromatographed using a 0-30% EtOAc in hexanes. Desired compound was isolated as a colorless viscous syrup (72% yield). Structure of the THP-protected product has been tentatively assigned as 4-iodo-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole. ¹H NMR (400 MHz, CDCl₃) δ 1.58-1.72 (m, 3H), 1.97-2.11 (m, 3H), 2.25 (s, 3H), 3.67 (apparent td, J=11.2, 2.8 Hz, 1H), 4.01-4.09 (m, 1H), 5.27 (dd, J=9.6, 2.8 Hz 1H), 7.57 (s, 1H).

Intermediate 4. THP-Protected 3-iodo-5-methyl-1H-pyrazole

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THP protection of commercially available 3-iodo-5-methyl-1H-pyrazole was carried out according to general method 1. Crude product was chromatographed using a 0-30% EtOAc in hexanes. Desired compound was isolated as a pale yellow syrup (99% yield). Structure of the THP-protected product has been tentatively assigned as 3-iodo-5-methyl-1terahydro-2H-pyranyl)-1H-pyrazole ¹H NMR (400 MHz, CDCl₃) δ 1.53-1.75 (m, 3H), 1.89-1.98 (m, 1H), 2.06-2.13 (m, 1H), 2.32 (s, 3H), 2.38-2.48 (m, 1H), 3.62 (distorted td, J=11.2, 2.8 Hz, 1H), 3.98-4.04 (m, 1H), 5.21 (dd, J=10.0, 2.8 Hz, 1H), 6.19 (s, 1H).

Intermediate 5. N-(4-Bromo-3-fluorophenyl)-N-methylacetamide

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4-Bromo-3-fluoroaniline (2.00 g, 10.5 mmol) in CH₂Cl₂(5 mL) was treated with Et₃N (3.20 g, 4.32 mL, 31.5 mmol) and then acetic anhydride (1.30 g, 12.6 mmol). The reaction mixture was stirred at room temperature until TLC indicated that the limiting reagent was consumed. Followed partition between CH₂Cl₂and aq. saturated Na₂CO₃. The organic layer was then dried over Na₂SO₄, filtered and concentrated to a solid residue that was dissolved in CH₂Cl₂. This solution was treated with excess of hexanes to precipitate the corresponding intermediate acetanilide as an off white solid. This solid, after drying, was dissolved in DMF under argon. Followed addition of NaH, as 60% dispersion in mineral oil, (590 mg. 14.8 mmol) in portions. Then followed slow (dropwise) addition of MeI (1.69 g, 11.9 mmol, and 0.74 mL). The reaction mixture was stirred for 4.5 hr and then partitioned between EtOAc and water. Aq. layer was extracted with CH₂Cl₂and the combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was chromatographed with silica gel column and 0-40% EtOAC in CH₂Cl₂gradient to afford the product as a white solid (2.0 g, 77% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.91 (bs, 3H), 3.24 (bs, 3H), 6.91 (bd, J=8.4 Hz, 1H), 7.00 (bd, J=7.8 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H)

Intermediate 6. (R)-1-(1-(4-Bromophenyl)ethyl)pyrrolidin-2-one (LMS-VI-86-II)

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Commercially available (R)-(+)-1-(4-bromophenyl) ethylamine (1.2 g, 5.95 mmol) in THF (20 mL) was treated with Et₃N (0.60 g, 5.95 mmol, and 0.81 mL). Followed slow addition of 4-chlorobutyryl chloride (0.84 g, 5.95 mmol) at 0° C. The reaction mixture was stirred for 30 min and then partitioned between CH₂Cl₂and aq. saturated NH₄Cl. Aq. layer was extracted twice more with CH₂Cl₂and the combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the corresponding (R)-chlorobutanamide intermediate. This intermediate without further purification was then dissolved in dry THF. Followed addition of NaH, as 60% dispersion in mineral oil, (290 mg 7.25 mmol) in portions under argon. The mixture stirred at room temperature under argon for 50 min and then the reaction vessel was sealed and the mixture was heated to 55° C. for 7 hrs. Reaction mixture was then cooled and partitioned between CH₂Cl₂and aq. saturated NH₄Cl. The aqueous layer was extracted with CH₂Cl₂(×3) and combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexane to afford the product as colorless oil (1.48 g, 93% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.50 (d, J=7.2 Hz, 3H), 1.70-1.94 (m, 1H), 1.94-2.03 (m, 1H), 2.35-2.46 (m, 2H), 2.96 (ddd, J=14.4, 9.0, 5.4 Hz, 1H), 5.45 (q, J=7.2 Hz, 1H), 3.31 (ddd, J=15.0, 8.4, 6.0 Hz, 1H), 7.17 (d, J=7.8 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H).

Intermediate 7. (S)-1-(1-(4-Bromophenyl)ethyl)pyrrolidin-2-one (LMS-VI-87-II)

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Commercially available (S)-1-(4-bromophenyl)ethan-1-amine (1.22 g, 6.09 mmol) in dry THF was treated with Et₃N (620 mg, 0.84 mL, 6.09 mmol). Followed slow addition of 4-chlorobutyryl chloride (860 mg, 0.68 mL, 6.09 mmol) at 0° C. The reaction mixture was then stirred for 30 min at room temperature and partitioned between CH₂Cl₂and aq. saturated NH₄Cl. Aq. layer was extracted with CH₂Cl₂(×3) and the combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the corresponding (S)-chlorobutanamide intermediate. This intermediate, without further purification, was dissolved in dry THF. Followed addition of NaH, as 60% dispersion in mineral oil, (300 mg 7.46 mmol) in portions under argon. The mixture stirred at room temperature under argon for 2.5 hr and then partitioned between CH₂Cl₂and aq. saturated NH₄Cl. The aqueous layer was extracted with CH₂Cl₂(×3) and combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes to afford the product as colorless oil (1.52 g, 93% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.49 (d, J=7.2 Hz, 3H), 1.86-1.95 (m, 1H), 1.95-2.03 (m, 1H), 2.36-2.47 (m, 2H), 2.96 (ddd, J=14.4, 9.0, 5.4 Hz, 1H), 3.31 (ddd, J=15.0 Hz, 8.4 Hz, 6.0 Hz, 1H), 5.45 (q, J=7.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H).

Intermediate 8. (4-Bromophenyl)(pyrrolidin-1-yl)methanone. (SHM-I-17-01)

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To a solution of 4-bromobenzoic acid (2.0 g, 9.95 mmol) in THF (12 mL) was added DMAP (121 mg, 0.99 mmol) and then EDCI.HCl (2.5 g, 12.93 mmol). The reaction mixture was stirred for 15 min. Then, pyrrolidine (708 mg, 0.830 mL, 9.95 mmol) was added and the reaction mixture and allowed to stir at room temperature for overnight. The reaction mixture was then diluted with water and extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes gradient to afford the product as a white solid (2.1 g, 83% yield). ¹HNMR (400 MHz, CDCl₃) δ 7.53 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz, 2H), 3.62-3.40 (m, 4H), 1.93-1.90 (m, 4H).

Intermediate 9. (4-Bromo-3-fluorophenyl)(pyrrolidin-1-yl)methanone (SHM-I-39-01)

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To a solution of 4-bromo-3-fluorobenzoic acid (1.5 g, 6.84 mmol) in THF (15 mL), was added DMAP (83 mg, 0.68 mmol) and then EDCI.HCl (1.7 g, 8.90 mmol). The reaction mixture was stirred for 15 min. Then, pyrrolidine (535 mg, 0.627 mL, 7.53 mmol) was added and the reaction mixture was allowed to stir at room temperature for overnight. The reaction mixture was then diluted with water and extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na₂SO₄filtered and evaporated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes to afford the product as white solid (1.4 g, 75% yield). ¹HNMR (400 MHz, CDCl₃) δ 7.60 (t, J=6.5 Hz, 1H), 7.31 (dd, J=9.0, 2.0 Hz, 1H), 7.21 (dd, J=8.0, 1.5 Hz, 1H) 3.64 (s, 2H), 3.43 (s, 2H), 1.97-1.93 (m, 4H).

Intermediate 10. 1-((4-Bromophenyl)sulfonyl)pyrrolidine. (SHM-I-37-01)

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To a solution of pyrrolidine (278 mg, 0.326 mL, 3.92 mmol) and Et₃N (396 mg, 0.545 mL, 3.92 mmol) in CH₂Cl₂, at 0° C. was added 4-bromobenzenesulfonyl chloride (1 g, 3.92 mmol) was added to the reaction mixture and the mixture was stirred and slowly allowed to warm up to rt by itself. After stirring overnight, this reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes gradient to afford the product as white solid (950 mg, 84% yield). ¹HNMR (500 MHz, CDCl₃) δ 7.64-7.59 (m, 4H), 3.18-3.15 (m, 4H), 1.72-1.69 (m, 4H).

Intermediate 11. 5-Bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

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To a solution of 5-bromobenzo[b]thiophene (1.5 g, 7.04 mmol) in CH₂Cl₂, was added mCPBA (3.03 g, 17.60 mmol). The mixture was stirred at room temperature for overnight. Followed addition of 1N aq Na₂SO₃solution and stirred at RT for 20 min. Then the reaction mixture was extracted with CH₂Cl₂(3×50 mL). The combined organic layer was washed with 2N aqueous NaHCO₃solution, dried over Na₂SO₄filtered and concentrated. The crude product (1.1 g, 4.45 mmol) obtained from this operation was dissolved in EtOH and treated with NaBH₄(259 mg, 6.73 mmol). The mixture was stirred at RT for overnight. The reaction mixture was quenched with 1M aq. HCl. Followed evaporation of the volatiles to a residue that was then treated with 2N aq. NaHCO₃solution (pH 9). The mixture was extracted with EtOAc (3×50 mL) and combined organic layer was dried over Na₂SO₄filtered and evaporated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes gradient to afford the product as white solid (800 mg, 46% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 7.84 (d, J=2.1 Hz, 1H), 7.72-7.71 (m, 2H), 3.64-3.59 (m, 2H), 3.38-3.34 (m, 2H).

Intermediate 12. 4-Bromo-N-(1,1,1-trifluoropropan-2-yl)aniline

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To a solution of 4-bromoaniline (2.0 g, 11.62 mmol) in toluene, was added commercially available 2-bromo-3,3,3-trifluoroprop-1-ene (2.44 g, 13.95 mmol). Then added Pd₂(dba)₃(532 mg, 0.58 mmol), dppf (966 mg, 1.74 mmol), and subsequently Cs₂CO₃(13.95 mmol) under Argon. The mixture was then sealed and stirred at 110° C. for overnight. The reaction mixture was cooled and partioned between EtOAc and water. Aqueous layer was extracted with EtOAc (3×50 mL) and then the combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was chromatographed on silica gel using 0-10% EtOAc in Hexanes as gradient. The intermediate (Z)—N-(4-bromophenyl)-1,1,1-trifluoropropan-2-imine obtained from this operation (1 g, 3.75 mmol) was treated with 2M LiAlH₄in THF (214 mg, 2.81 mL 5.6 mmol) in dry THF at 0° C. The mixture was slowly allowed to reach room temperature and stirred for 2 hours. The reaction mixture was then quenched with 1M aq. HCl and stirred for 20 min. The reaction mixture pH was then adjusted to 9 using K₂CO₃aqueous solution. Followed extraction with EtOAc (3×50 mL). The combined organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes gradient to afford the product as white solid (875 mg, 43% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.23-7.20 (m, 2H), 6.48 (d, J=9.0 Hz, 2H), 3.93-3.88 (m, 1H), 3.54-3.53 (m, 1H), 1.33 (d, J=6.6 Hz, 3H).

Intermediate 13. 1-(4-Bromobenzyl)pyrrolidin-2-one. (SHM-I-53-01)

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To a solution of pyrrolidin-2-one (400 mg, 4.7 mmol) in DMF, followed addition of NaH, as 60% dispersion in mineral oil (283 mg, 7.05 mmol) in portions under argon and stirred for 30 min. Then, commercially available 1-bromo-4-(bromomethyl)benzene (1.3 g, 5.17 mmol) was added to the reaction mixture at 0° C. and allowed to stir at room temperature for overnight. The reaction mixture was diluted with water and extracted with EtOAc. Combined organic layer was then dried over Na₂SO₄filtered and concentrated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexane to afford the product as white solid (820 mg, 82% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.38 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 4.32 (s, 2H), 3.18 (t, J=6.6 Hz, 2H), 2.37 (t, J=7.8 Hz, 2H), 1.95-1.91 (m, 2H).

Intermediate 14. 1-(4-Bromo-2-fluorobenzyl)pyrrolidin-2-one

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To a solution of pyrrolidin-2-one (1 g, 11.76 mmol) in DMF, followed addition of NaH, as 60% dispersion in mineral oil (566 mg, 14.11 mmol) in portions under argon and stirred for 30 min. Then, commercially available 4-bromo-1-(bromomethyl)-2-fluorobenzene (1.5 g, 11.76 mmol) was added to the reaction mixture at 0° C. The mixture was allowed warm up at room temperature and stir overnight. The reaction mixture was diluted with water and then extracted with EtOAc. Combined organic layer was dried over Na₂SO₄, filtered and evaporated and the residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes to afford the product as white solid (2.61 g, 82% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.23-7.19 (m, 2H), 7.14 (t, J=8.4 Hz, 1H), 4.42 (s, 2H), 3.27 (t, J=7.2 Hz, 2H), 2.37 (t, J=8.4 Hz, 2H), 1.99-1.94 (m, 2H).

Intermediate 15. 1-(4-Bromo-2-chlorobenzyl)pyrrolidin-2-one. (SHM-I-149-01)

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A solution of pyrrolidin-2-one (300 mg, 3.5 mmol) in DMF, was treated with NaH, as 60% dispersion in mineral oil (169 mg, 4.23 mmol), in portions under argon and stirred for 30 min. Then, commercially available 1-bromo-4-(bromomethyl)-2-chlorobenzene (1 g, 3.5 mmol) was added to the reaction mixture at 0° C. and the mixture was allowed warm up to rt and stir overnight. The mixture was then diluted with water and extracted with EtOAc. Combined organic layer was back extracted with cold water, dried over Na₂SO₄filtered and concentrated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes to afford the product as white solid (530 mg, 52% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.51 (d, J=1.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 4.52 (s, 2H), 3.29 (t, J=7.2 Hz, 2H), 2.42 (t, J=7.8 Hz, 2H), 2.03-1.99 (m, 2H).

Intermediate 16. 1-(4-Bromo-3-fluorobenzyl)pyrrolidin-2-one

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To the solution of pyrrolidin-2-one (1 g, 11.76 mmol) in DMF, followed addition of NaH, as 60% dispersion in mineral oil (566 mg, 14.11 mmol) in portions under argon and stirred for 30 min. Then, commercially available 1-bromo-4-(bromomethyl)-2-fluorobenzene (3.1 g, 11.76 mmol) was added to the reaction mixture at 0° C. The mixture was allowed to warm up to rt and stirred overnight. Followed dilution with water and then extraction with EtOAc. The combined organic layer was back extracted with cold water, dried over Na₂SO₄filtered and concentrated. The residue was chromatographed with a silica gel column with 0-80% EtOAc in hexanes gradient to afford the product as white solid (1.9 g, 60% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.45 (d, J=1.8 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 4.36 (s, 2H), 3.23 (t, J=7.2 Hz, 2H), 2.40 (t, J=7.8 Hz, 2H), 2.01-1.95 (m, 2H).

Intermediate 17. 1-(4-Bromo-3-fluorophenyl)pyrrolidin-2-one (SHM-JJ-64-02)

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Commercially available 4-bromo-3-fluoroaniline (1.5 g, 7.894 mmol) in THF was treated with Et₃N (798 mg, 1.1 mL, 7.89 mmol). Followed slow addition of 4-chlorobutyryl chloride (1.3 g, 1.68 mL, 7.89 mmol) at 0° C. The reaction mixture was then stirred for 30 min at room temperature and partitioned between CH₂Cl₂and aq. saturated NH₄Cl. Aq. layer was extracted with CH₂Cl₂(×3) and the combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the corresponding N-(4-bromo-3-fluorophenyl)-3-chloropropanamide (3.2 g, 10.86 mmol). This intermediate, without further purification, was dissolved in dry THF. Followed addition of NaH, as 60% dispersion in mineral oil, (651 mg, 16.29 mmol) in portions under argon. The mixture stirred at room temperature under argon for 2.5 hr and then partitioned between CH₂Cl₂and aq. saturated NH₄Cl. The aqueous layer was extracted with CH₂Cl₂(×3) and combined organic layer was dried over Na₂SO₄, filtered and concentrated. The residue was chromatographed on a silica gel column with 0-80% EtOAc in hexanes to afford the product as white solid (1.83 g, 90% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.63 (dd, J=11.2, 2.4 Hz, 1H), 7.49 (t, J=8.4 Hz, 1H), 7.25 (dd, J=8.0, 2.0 Hz, 1H), 3.82 (t, J=6.8 Hz, 2H), 2.61 (t, J=8.0 Hz, 2H), 2.21-2.13 (m, 2H).

General Procedure 2. Synthesis of N-Boc-protected 4-aryl/hetroaryl 3,6-dihydropyridines

N-Boc protected 4-aryl-3,6-dihydropyridines were prepared in the general fashion described by Eastwood (Tetrahedron Letters, 2000, 41(19), 3705-3708), this is hereby incorporated by reference, from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1 eq) and a desired arylbromide (1 eq) using PdCl₂dppf as catalyst (0.05 eq), K₂CO₃(3 eq) as base and DMF or dioxane or dioxane/H₂O as solvent.

Intermediate 18. tert-Butyl 4-(4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Prepared via the coupling of commercially available 4-bromoanisole and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 and DMF as solvent. Crude coupling product was purified with silica gel column and 0-50% EtOAc in hexanes gradient to afford tert-butyl 4-(4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a white solid (50% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.50 (apparent bs, 2H), 3.62 (apparent t, J=6.0 Hz, 2H), 3.81 (s, 3H), 4.03-4.08 (m, 2H), 5.93 (s, 1H), 6.88 (d, J=6.8 Hz, 2H), 7.31 (d, J=6.8 Hz, 2H).

Intermediate 19. tert-Butyl 4-(3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Prepared via the coupling of commercially available 3-bromoanisidine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using DMF as solvent. Crude coupling product was purified with silica gel column and 0-10% EtOAc in hexanes gradient to afford tert-butyl 4-(3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (78% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.48 (s, 9H), 2.51 (apparent bs, 2H), 3.63 (apparent distorted t, J=5.6 Hz, 2H), 3.82 (s, 3H), 4.04-4.08 (m, 2H), 6.03 (bs, 1H), 6.80 (dd, J=8.0, 2.0 Hz, 1H), 6.90 (apparent t, J=2.0 Hz, 1H), 6.96 (apparent d, J=8.0 Hz, 1H), 7.25-7.28 (m, 1H).

Intermediate 20. tert-Butyl 4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

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Prepared using commercially available 2-chloropyrimidine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (10/1 ratio) as solvent. Crude coupling product was chromatographed with silica gel column and 0-40% EtOAc in hexanes to afford the desired tert-butyl 4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (88% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 9H), 2.75 (apparent bs, 2H), 3.67 (t, J=4.8 Hz, 2H), 4.20 (apparent broad-based d, J=2.4 Hz, 2H), 7.14 (t, J=4.8 Hz, 1H), 7.23 (bs, 1H), 8.72 (d, J=4.8 Hz, 2H).

Intermediate 21. tert-Butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Prepared from commercially available methyl 4-bromobenzoate and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using DMF as solvent. Crude coupling product was purified with silica gel column and 0-15% EtOAc in Hexanes as elution system to afford desired tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (67% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 9H), 2.57 (apparent bs, 2H), 3.67 (t, J=5.2 Hz, 2H), 3.94 (s, 3H), 4.13 (apparent bs, 2H), 6.19 (bs, 1H), 7.45 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H).

Intermediate 22. tert-Butyl 6-nitro-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

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Prepared from commercially available 5-bromo-2-nitropyridine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane as solvent. Crude coupling product was purified with silica gel column and 0-25% EtOAc in hexanes gradient to afford tert-butyl 6-nitro-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate as a white/off-white solid (73% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H), 2.57 (apparent bs, 2H), 3.69 (t, J=5.6 Hz, 2H), 4.16 (apparent broad based d, J=2.4 Hz, 2H), 6.33 (bs, 1H), 7.94 (dd, J=8.4, 2.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.64 (d, J=2.0 Hz, 1H).

Intermediate 23. tert-Butyl 2′-methoxy-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate

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Compound was prepared from commercially available 4-bromo-2-methoxypyridine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane as solvent. Crude coupling product was purified with silica gel column and 0-50% EtOAc in hexanes to afford, tert-butyl 2′-methoxy-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate, as a light yellow viscous oil (71% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.47 (apparent bs, 2H), 3.63 (t, J=5.6 Hz, 1H), 3.94 (s, 3H), 4.08-4.15 (m, 1H), 6.23 (bs, 1H), 6.68 (apparent s, 1H), 6.88 (dd, J=5.2, 1.6 Hz), 8.10 (dd, J=5.6, 0.8 Hz, 1H).

Intermediate 24. tert-Butyl 4-(2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Synthesized from commercially available 2-bromoanisole and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2. Crude coupling product was chromatographed with silica gel column and 0-100% EtOAc in hex gradient to afford tert-butyl 4-(2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate as colorless liquid (72% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.5 (apparent bs, 2H), 3.59 (apparent t, 2H), 3.81 (s, 3H), 4.04 (s, 2H), 5.75 (s, 1H), 6.85-6.96 (m, 2H), 7.14 (dd, J=7.6, 1.6 Hz, 1H), 7.22-7.26 (m, 1H).

Intermediate 25. tert-Butyl 4-(p-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available 4-bromotoluene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using DMF as solvent. The crude residue was chromatographed with silica gel column using 0-50% EtOAc in hexane gradient to afford the product, tert-butyl 4-(p-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate, as a colorless oil (80% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.34 (apparent s, 3H), 2.51 (apparent bs, 2H), 3.63 (apparent t, 2H), 4.06 (apparent s, 2H), 5.99 (s, 1H), 7.14 (d, J=7.6 Hz, 2H), 7.27 (d, J=7.6 Hz, 2H).

Intermediate 26. tert-Butyl 4-(4-(methoxymethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from 1-bromo-4-(methoxymethyl)benzene (prepared as in Rengan, K. et al. J. Chem. Soc. Perkin Trans. I, 1991, 987, incorporated herein by reference) and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using DMF as solvent. The crude residue was chromatographed with silica gel column using 0-40% EtOAc in hexane gradient to afford the product, tert-butyl 4-(4-(methoxymethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate, as a pale liquid (88% yield). ¹H NMR—(400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.49-2.54 (broad m, 2H), 3.39 (s, 3H), 3.63 (apparent t, J=5.6 Hz, 2H), 4.07 (dd, J=5.6, 2.4 Hz, 2H), 4.45 (s, 2H), 6.04 (apparent bs, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H).

Intermediate 27. tert-Butyl 4-(4-(N-methylacetamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from N-(4-bromophenyl)-N-methylacetamide (prepared as in Shimma, N. et al. WO2008018426, the disclosure is hereby incorporated by reference) and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 2 using DMF as solvent. The crude residue was chromatographed with silica gel and 0-100% EtOAc in hexanes gradient to afford the product, tert-butyl 4-(4-(N-methylacetamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate, as a pale yellow solid (82% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 1.88 (s, 3H), 2.53 (bs, 2H), 3.26 (s, 3H), 3.66 (apparent distorted t, J=4.8 Hz, 2H), 4.09 (bs, 2H), 6.08 (bs, 1H), 7.15 (d, J=7.6 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H).

Intermediate 28. tert-Butyl 4-(4-acetamidophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 4-bromoacetanilide (prepared as in Shimma, N. et al. WO2008018426, the disclosure is hereby incorporated by reference) and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 2 using DMF as solvent. The crude residue was chromatographed with a silica gel column and 0-100% EtOAc in hexanes gradient to afford the product, tert-butyl 4-(4-acetamidophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, as a pale-yellow solid (77% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.18 (s, 3H), 2.49 (apparent bs, 2H), 3.62 (apparent t, J=5.6 Hz, 2H), 4.01-4.08 (m, 2H), 5.99 (bs, 1H), 7.23 (bs, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H).

Intermediate 29. tert-Butyl 6-methoxy-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

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Synthesized from commercially available 5-bromo-2-methoxypyridine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using DMF as solvent. Crude residue was purified with column chromatography and 0-20% EtOAc in CH₂Cl₂gradient to afford the product as a pale liquid. ¹H NMR (400 MHz, CDCl₃) δ 1.48 (s, 9H), 2.48 (apparent bs, 2H), 3.63 (apparent t, J=6.0 Hz, 2H), 3.94 (s, 3H), 4.05-4.08 (m, 2H), 5.95 (bs, 1H), 6.71 (dd, J=8.4, 0.4 Hz, 1H), 7.59 (dd, J=8.8, 2.8 Hz, 1H), 8.16 (d, J=2.0 Hz, 1H).

Intermediate 30. tert-Butyl 4-(m-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available 3-bromotoluene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 2 using DMF as solvent. The crude residue was chromatographed using silica gel column and 0-35% EtOAc in hexanes gradient to afford the product, tert-butyl 4-(m-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate, as a colorless liquid (68% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.36 (s, 3H), 2.52 (apparent bs, 2H), 3.63 (apparent t, J=5.6 Hz, 2H), 4.07 (apparent s, 2H), 6.01 (bs, 1H), 7.07 (d, J=7.2 Hz, 1H), 7.15-7.25 (m, 3H).

Intermediate 31. tert-Butyl 4-(o-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available 2-bromotoluene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 2 using DMF as solvent. The crude residue was chromatographed with silica gel column and 0-20% EtOAc in hexanes gradient to afford the product, tert-butyl 4-(o-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate, as a clear liquid (70% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H), 2.79 (s, 3H), 2.31-2.38 (m, 2H), 3.62 (t, J=5.6 Hz, 2H), 4.03 (dd, J=6.0, 2.8 Hz, 2H), 5.55 (apparent bs, 1H), 7.04-7.09 (m, 1H), 7.13-7.19 (m, 3H).

Intermediate 32. tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available 4-bromo-2-fluoro-1-methoxybenzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 2 using DMF as solvent. The crude residue was chromatographed using silica gel column and 0-15% EtOAc in hexanes gradient to afford the product as a colorless liquid (52% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.48 (s, 9H), 2.46 (s, 2H), 3.62 (t, J=5.6, 2H), 3.89 (s, 3H), 4.04-4.07 (m, 2H), 5.96 (bs, 2H), 6.91 (apparent t, J=8.8 Hz, 1H), 7.06-7.14 (m, 2H).

Intermediate 33. tert-Butyl 4-(2-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available 4-bromo-3-fluoro-1-methoxybenzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 2 using dioxane/H₂O (10:1) as solvent. The crude residue was chromatographed using silica gel column and 0-10% EtOAc in hexanes gradient to afford the product as a colorless liquid (89% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.48 (apparent bs, 2H), 3.60 (t, J=5.6, 2H), 3.80 (s, 3H), 4.04-4.06 (m, 2H), 5.86 (bs, 1H), 6.60 (dd, J=12.8, 2.4 Hz, 1H), 6.66 (dd, J=8.0, 2.4 Hz, 1H), 7.15 (apparent t, J=8.4, 1H).

Intermediate 34. tert-Butyl 4-(2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available 2-fluoro-bromobenzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 2 using dioxane/H₂O (10:1) as solvent. The crude residue was chromatographed using silica gel column and 0-30% EtOAc in hexanes gradient to afford the product, tert-butyl 4-(2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate, as a white solid (94% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H), 2.51 (apparent bs, 2H), 3.62 (t, J=5.6, 2H), 4.05-4.09 (m, 2H), 5.93 (bs, 1H), 7.00-7.07 (m, 1H), 7.07-7.13 (m, 1H), 7.19-7.26 (m, 2H).

Intermediate 35. tert-Butyl 4-(3-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Prepared from commercially available methyl 3-bromobenzoate and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using DMF as solvent. Crude coupling product was purified with silica gel column and 0-100% EtOAc in hexaness gradient to afford tert-butyl 4-(3-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate as a viscous liquid (86% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.55 (apparent bs, 2H), 3.65 (t, J=6.0 Hz, 2H), 3.92 (s, 3H), 4.09 (apparent bs, 2H), 6.11 (bs 1H), 7.40 (distorted t, J=7.6 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.92 (d, J=7.6 Hz, 1H), 8.05 (bs, 1H).

Intermediate 36. tert-Butyl 4-(4-(ethylsulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 1-bromo-4-(ethylsulfonyl)benzene (prepared according to Semple, G. et al. Bioorg. Med. Chem. Letters, 2012, 22(1), 71-75, incorporated herein by reference) according to the general procedure 2 using DMF as solvent. The crude residue was chromatographed using silica gel column and 0-100% Hex:EtOAC) to afford the product as a white solid (94%). ¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.6 Hz, 3H), 1.49 (s, 9H), 2.54 (apparent bs, 2H), 3.11 (q, J=7.6 Hz, 2H), 3.66 (t, J=5.6 Hz, 2H), 4.11-4.13 (m, 2H), 6.20 (bs, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.85 (d, J=6.8 Hz, 2H).

Intermediate 37. tert-Butyl 5-methoxy-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

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Compound was prepared from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 3-bromo-5-methoxypyridine according to general procedure 2 using DMF as solvent. The crude residue was chromatographed using silica gel column and 0-100% EtOAc in hexanes gradient to afford the product as a pale yellow-brown viscous liquid (95% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.51 (apparent bs, 2H), 3.66 (t, J=5.2 Hz, 2H), 3.92 (s, 3H), 4.11 (apparent bs 2H), 6.17 (bs, 1H), 7.31 (bs, 1H), 8.20 (bs, 1H), 8.29 (bs, 1H).

Intermediate 38. tert-Butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 4-chloro-bromobenzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (10:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-20% EtOAc in hexanes gradient to afford the product as pale colorless syrup (86% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.48 (apparent bs, 2H), 3.63 (t, J=5.6 Hz, 2H), 4.04-4.08 (m, 2H), 6.02 (bs, 1H), 7.30 (s, 4H).

Intermediate 39. tert-Butyl 4-(3-chloro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 4-bromo-2-chloro-1-methoxybenzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (10:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-10% EtOAc in hexanes gradient to afford the product as colorless syrup. (78% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.46 (apparent bs, 2H), 3.62 (t, J=5.6, 2H), 3.90 (s, 3H), 4.04-4.07 (m, 2H), 5.96 (bs, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.23 (dd, J=8.4, 2.4, 1H), 7.39 (d, J=2.4 Hz, 1H).

Intermediate 40. tert-Butyl 4-(2-chloro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 4-bromo-3-chloro-1-methoxybenzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (10:1). The residue was purified by silica gel column chromatography and 0-10% EtOAc in hexanes gradient to afford the product as yellowish syrup. (68% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.50 (s, 9H), 2.41 (bs, 2H), 3.60-3.62 (m, 2H), 3.79 (s, 3H), 4.03 (bs, 2H), 5.62 (bs, 1H), 6.77 (dd, J=8.8, 2.8 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 1H).

Intermediate 41. tert-Butyl 4-(2-fluoro-4-(N-methylacetamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and N-(4-bromo-3-fluorophenyl)-N-methylacetamide according to general procedure 2 using dioxane/H2O (10/1) as solvent. The crude residue was purified by silica gel column chromatography and 0-50% EtOAc in hexanes gradient to afford the product as yellowish solid (88% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.51 (s, 9H), 1.93 (s, 3H), 2.52 (bs, 2H), 3.27 (s, 3H), 3.64 (bs, 2H), 4.10 (bs, 2H), 5.99 (bs, 1H), 6.92 (d, J=11.4 Hz, 1H), 6.97 (d, J=7.8 Hz, 1H), 7.29-7.31 (m, 1H).

Intermediate 42. tert-Butyl 4-(3-fluoro-5-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 1-bromo-3-fluoro-5-methoxybenzene according to general procedure 2 using dioxane/H₂O (10:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-20% EtOAc in hexanes gradient to afford the product as yellowish liquid. (88% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.48 (s, 9H), 2.47 (bs, 2H), 3.62 (bs, 2H), 3.80 (s, 3H), 4.06 (bs, 2H), 6.02 (apparent s, 1H), 6.51 (apparent dt, J=4.2, 2.4 Hz, 1H), 6.66-8.68 (m, 2H).

Intermediate 43. tert-Butyl 4-(4-fluoro-3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 4-bromo-1-fluoro-2-methoxybenzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (10:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-15% EtOAc in hexanes gradient to afford the product as white solid. (88% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.49 (s, 1H), 2.49 (bs, 2H), 3.63 (t, J=5.4 Hz, 2H), 3.90 (s, 3H), 4.06 (bs, 2H), 5.96 (bs, 1H), 6.86-6.89 (m, 1H), 6.95 (dd, J=8.4, 2.4 Hz, 1H), 7.00-7.04 (m, 1H).

Intermediate 44. tert-Butyl 4-(4-(pyrrolidine-1-carbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from (4-bromophenyl)(pyrrolidin-1-yl)methanone and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as white solid. (65% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.52 (d, J=6.0 Hz, 2H), 7.41 (d, J=6.0 Hz, 2H), 6.11 (bs, 1H), 4.16-4.13 (m, 2H), 3.66 (bs, 4H), 3.50-3.47 (m, 2H), 2.55 (bs, 2H), 1.98-1.91 (m, 4H), 1.51 (s, 9H).

Intermediate 45: tert-Butyl 4-(2-fluoro-4-(pyrrolidine-1-carbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from (4-bromo-3-fluorophenyl)(pyrrolidin-1-yl)methanone and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (4:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as white solid. (77% yield). ¹HNMR (500 MHz, CDCl₃) δ 7.27-7.26 (m, 2H), 7.21 (d, J_C-F=11.5 Hz, 1H), 5.97 (bs, 1H), 4.07 (d, J=2.0 Hz, 2H), 3.63-3.61 (m, 4H), 3.45 (s, 2H), 2.50 (s, 2H), 1.96-1.89 (m, 4H), 1.49 (s, 9H).

Intermediate 46. tert-Butyl 4-(4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 1-(4-bromobenzyl)pyrrolidin-2-one and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/water (6:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid (78% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.33 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.4 Hz, 2H), 6.02 (bs, 1H), 4.43 (s, 2H), 4.06 (d, J=2.4 Hz, 2H), 3.62 (t, J=5.4 Hz, 2H), 3.25 (t, J=7.2 Hz, 2H), 2.50 (bs, 2H), 2.44 (t, J=8.4 Hz, 2H), 2.01-1.96 (m, 2H), 1.48 (s, 9H).

Intermediate 47. tert-Butyl 4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 1-((4-bromophenyl)sulfonyl)pyrrolidine and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (4:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as white solid. (67% yield). ¹HNMR (500 MHz, CDCl₃) δ 7.76 (d, J=8.5 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 6.15 (bs, 1H), 4.08 (d, J=2.5 Hz, 2H), 3.63 (t, J=5.5 Hz, 2H), 3.23-3.21 (m, 4H), 2.51 (bs, 2H), 1.75-1.72 (m, 4H), 1.47 (s, 9H).

Intermediate 48. tert-Butyl 4-(trifluoromethyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate

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Compound was synthesized from commercially available 2-chloro-4-(trifluoromethyl)pyridine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/water (4:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexaness gradient to afford the product as white solid. (73% yield). ¹HNMR (600 MHz, CDCl₃) δ 8.71 (d, J=4.8 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J=4.8 Hz, 1H), 6.70 (bs, 1H), 4.14 (s, 2H), 3.64 (s, 2H), 2.64 (d, J=1.2 Hz, 2H), 1.47 (s, 9H).

Intermediate 49. tert-Butyl 4-(4-((methylsulfonyl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 1-bromo-4-((methylsulfonyl)methyl)benzene and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/water (3:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid. (78% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.37 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 6.04 (bs, 1H), 4.20 (s, 2H), 4.05 (s, 2H), 3.60 (t, J=5.4 Hz, 2H), 2.72 (s, 3H), 2.48 (bs, 2H), 1.45 (s, 9H).

Intermediate 50. tert-Butyl 5-(trifluoromethyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate

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Compound was synthesized from commercially available 3-bromo-5-(trifluoromethyl)pyridine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (4:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as white solid. (69% yield). ¹HNMR (600 MHz, CDCl₃) δ 8.83-8.77 (m, 2H), 7.86 (s, 1H), 6.21 (bs, 1H), 4.14 (s, 2H), 3.68 (t, J=5.4 Hz, 2H), 2.56 (s, 2H), 1.50 (s, 9H).

Intermediate 51. tert-Butyl 4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 5-bromo-2,3-dihydrobenzo[b]thiophene 1,1-dioxide and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (3:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid. (77% yield). ¹HNMR (300 MHz, CD₃OD) δ 7.65 (d, J=8.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 6.10 (bs, 1H), 4.06 (distorted q, J=2.7 Hz, 2H), 3.61 (t, J=5.7 Hz, 2H), 3.50-3.44 (m, 2H), 3.38-3.32 (m, 2H), 2.48 (bs, 2H), 1.46 (s, 9H).

Intermediate 52. tert-Butyl 4-(4-((1,1,1-trifluoropropan-2-yl)amino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 4-bromo-N-(1,1,1-trifluoropropan-2-yl)aniline and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as yellow liquid. (66% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.20 (d, J=9.0 Hz, 2H), 6.60 (d, J=8.7 Hz, 2H), 5.87 (bs, 1H), 4.04-3.97 (m, 3H), 3.58 (t, J=5.7 Hz, 2H), 2.44 (m, 2H), 1.45 (s, 9H), 1.37 (d, J=6.6 Hz, 3H).

Intermediate 53. tert-Butyl 4-(2,2-dioxido-1,3-dihydrobenzo[c]thiophen-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 5-bromo-1,3-dihydrobenzo[c]thiophene 2,2-dioxide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid (62% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.33 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.2 Hz, 2H), 6.01 (bs, 1H), 4.32 (d, J=3.6 Hz, 4H), 4.04 (s, 2H), 3.59 (t, J=5.4 Hz, 2H), 2.45 (bs, 2H), 1.45 (s, 9H).

Intermediate 54. tert-Butyl 4-(3-fluoro-4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 1-(4-bromo-2-fluorobenzyl)pyrrolidin-2-one and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as gummy liquid (86% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.21-7.20 (m, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.03-7.01 (m, 1H), 6.02 (bs, 1H), 4.47 (s, 2H), 4.04 (s, 2H), 3.59 (s, 2H), 3.28 (t, J=7.2 Hz, 2H), 2.44 (bs, 2H), 2.38 (t, J=4.8 Hz, 2H), 1.99-1.94 (m, 2H), 1.45 (s, 9H).

Intermediate 55. tert-Butyl 4-(3-chloro-4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 1-(4-bromo-2-chlorobenzyl)pyrrolidin-2-one and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid (58% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.34 (s, 1H), 7.23-7.21 (m, 2H), 6.03 (bs, 1H), 4.56 (s, 2H), 4.04 (q, J=2.7 Hz, 2H), 3.60 (t, J=5.7 Hz, 2H), 3.29 (t, J=6.9 Hz, 2H), 2.45-2.39 (m, 4H), 2.04-1.94 (m, 2H), 1.46 (s, 9H).

Intermediate 56. tert-Butyl 4-(2-fluoro-4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 1-(4-bromo-3-fluorobenzyl)pyrrolidin-2-one (SHM-II-11-01) and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid (90% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.15 (t, J=7.8 Hz, 1H), 6.95-6.86 (m, 2H), 5.88 (bs, 1H), 4.37 (s, 2H), 4.01 (q, J=2.7 Hz, 2H), 3.56 (t, J=5.7 Hz, 2H), 3.24 (t, J=7.2 Hz, 2H), 2.43-2.38 (m, 4H), 2.02-1.92 (m, 2H), 1.45 (s, 9H).

Intermediate 57. tert-Butyl 4-(4-morpholinophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 4-(4-bromophenyl)morpholine according to general procedure 2 using dioxane/water (5:1 ratio) as solvent. The crude residue was chromatographed with silica gel column and 0-30% EtOAc in hexanes gradient to afford the product (49% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.48 (s, 9H), 2.49 (apparent s, 2H), 3.16 (t, J=4.8 Hz, 4H), 3.62 (apparent s, 2H), 3.86 (t, J=4.8 Hz, 4H), 4.05 (apparent s, 2H), 5.94 (bs, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.31 (d, J=9.0 Hz, 2H).

Intermediate 58. tert-Butyl 4-(4-(morpholinomethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compounds was synthesized from commercially available 4-(4-bromobenzyl)morpholine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent yellow liquid (61% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.31-7.23 (m, 4H), 6.0 (s, 1H), 7.03 (q, J=2.7 Hz, 2H), 3.67 (d, J=4.8 Hz, 4H), 3.60 (t, J=5.7 Hz, 2H), 3.40 (s, 2H), 2.49 (bs, 2H), 2.41 (t, J=4.5 Hz, 4H), 1.46 (s, 9H).

Intermediate 59. tert-Butyl 4-(4-(3-oxomorpholino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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The compound was prepared from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 4-(4-bromophenyl)morpholin-3-one according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified with silica gel column and 0-50% EtOAc in CH₂Cl₂as eluent to afford the product as an off-white solid. ¹H NMR (600 MHz, CDCl₃) δ 1.49 (s, 9H), 2.51 (bs, 2H), 3.63 (apparent bs, 2H), 3.77 (apparent t, J=4.8 Hz, 2H), 4.03 (distorted t, J=4.8 Hz, 2H), 4.07 (s, 2H), 4.35 (s, 2H), 6.02 (bs, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H).

Intermediate 60. tert-Butyl 4-(3-fluoro-4-morpholinophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared according to general procedure 2 from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and 4-(4-Bromo-2-fluorophenyl)morpholine using dioxane/H₂O (5:1) as solvent. The crude reaction product was purified with a silica gel column and 0-30% EtOAc in hexanes as elution gradient to afford the product as a white/off-white solid (85% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.49 (s, 9H), 2.46 (bs, 2H), 3.09 (apparent t, J=4.8 Hz, 4H), 3.62 (apparent bs, 2H), 3.87 (apparent t, J=4.2 Hz, 4H), 4.06 (bs, 2H), 5.98 (bs, 1H), 6.89 (t, J=8.4 Hz), 7.05-7.12 (m, 2H).

Intermediate 61. tert-Butyl 4-(2-fluoro-4-morpholinophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 4-(4-bromo-3-fluorophenyl)morpholine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid. (86% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.11 (t, J=8.7 Hz, 1H), 6.63-6.51 (m, 2H), 5.85 (s, 1H), 3.83 (t, J=4.5 Hz, 4H), 3.69 (t, J=6.3 Hz, 1H), 3.58 (t, J=5.7 Hz, 2H), 3.13 (t, J=5.1 Hz, 4H), 2.44-2.40 (m, 3H), 1.46 (s, 9H).

Intermediate 62. tert-Butyl (S)-4-(4-(1-(2-oxopyrrolidin-1-yl)ethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and (S)-1-(1-(4-bromophenyl)ethyl)pyrrolidin-2-one according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified with 0-40% EtOAc in CH₂Cl₂to afford the product as pale yellow very viscous syrup (72% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.49 (s, 9H), 1.86-1.94 (m, 1H), 1.94-2.02 (m, 1H), 2.36-2.48 (m, 2H), 2.51 (bs, 2H), 2.98 (ddd, J=14.4, 9.0, 5.4 Hz, 1H), 3.32 (ddd, J=15.0, 9.0, 6.0 Hz, 1H), 3.63 (apparent bs, 2H), 4.07 (bs, 2H), 5.48 (q, J=7.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H).

Intermediate 63. tert-Butyl (R)-4-(4-(1-(2-oxopyrrolidin-1-yl)ethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was prepared from commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and (R)-1-(1-(4-bromophenyl)ethyl)pyrrolidin-2-one according to general procedure 2 using dioxane/H₂O (5:1) as solvent. The crude residue was purified with 0-40% EtOAc in CH₂Cl₂to afford the product as pale yellow very viscous sirup (34% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.49 (s, 9H), 1.51 (d, J=6.6 Hz, 2H), 1.86-1.94 (m, 1H), 1.94-2.02 (m, 1H), 2.35-2.47 (m, 2H), 2.51 (bs, 2H), 2.98 (ddd, J=13.8, 8.4, 4.8 Hz, 1H), 3.32 (ddd, J=15.6, 9.0, 6.6 Hz, 1H), 3.63 (apparent bs, 2H), 4.07 (bs, 2H), 5.49 (q, J=7.2 Hz, 1H), 6.03 (bs, 1H), 7.26 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H).

Intermediate 64. tert-Butyl 4-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from 1-(4-bromo-3-fluorophenyl)pyrrolidin-2-one and commercially available tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (6:1) as solvent. The crude residue was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid. (71% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.50 (dd, J=13.5 Hz, 2.1 Hz, 1H), 7.35-7.31 (m, 1H), 7.23 (t, J=8.7 Hz, 1H), 5.94 (bs, 1H), 4.08 (q, J=3.0 Hz, 2H), 3.85 (t, J=7.2 Hz, 2H), 3.62 (t, J=5.7 Hz, 2H), 2.63 (t, J=7.8 Hz, 2H), 2.50 (bs, 2H), 2.23-2.13 (m, 2H), 1.50 (s, 9H).

Intermediate 65. tert-Butyl 4-(4-(1,1-dioxidothiomorpholino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 4-(4-bromophenyl)thiomorpholine 1,1-dioxide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H₂O (6:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid. (46% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.31 (d, J=6.9 Hz, 2H), 6.86 (d, J=6.9 Hz, 2H), 5.95 (s, 1H), 4.04 (distorted q, J=2.7 Hz, 2H), 3.85 (t, J=5.1 Hz, 4H), 3.61 (t, J=5.7 Hz, 2H), 3.09 (t, J=5.1 Hz, 4H), 2.47 (bs, 2H), 1.47 (s, 9H).

Intermediate 66. tert-Butyl 4-(4-(2-oxopyrrolidin-1-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate

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Compound was synthesized from commercially available 1-(4-bromophenyl)pyrrolidin-2-one and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 2 using dioxane/H2O (5:1) as solvent. The crude residue was purified by silica gel column chromatography and 0-100% EtOAc in hexanes gradient to afford the product as transparent liquid (67% yield). 1HNMR (300 MHz, CDCl3) δ 7.56 (d, J=8.7 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 6.00 (bs, 1H), 4.05 (distorted q, J=3.0 Hz, 2H), 3.85 (dt, J=6.9, 3.9 Hz, 2H), 3.61 (t, J=5.7 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H), 2.49 (bs, 2H), 2.21-2.11 (m, 2H), 1.48 (s, 9H).

General Procedure 3. Synthesis of 4-aryl/heteroaryl piperidines from N-Boc-protected 4-aryl/hetroaryl 3,6-dihydropyridines

A slurry of NBoc-4-aryl/heteroaryl-3.6-dihydrpyridine of interest and Pd/C (0.1 eq) or PtO₂(0.05 eq) in EtOH was hydrogenated at atmospheric pressure until consumption of starting material was judged to be complete by LCMS or TLC. The solids were then filtered and washed with EtOH and EtOAc or 10% MeOH in CH₂Cl₂. The combined organic layer was then concentrated to afford the corresponding N-Boc-protected 4-aryl/heteroaryl piperidine reduced intermediate which was purified, if needed, with silica gel column chromatography. This intermediate was then dissolved in 4 N HCl in dioxane at room temperature and stirred until TLC indicated that Boc deprotection was complete. Volatiles were evaporated and the resulting residue was partitioned between CH₂Cl₂and aq. saturated Na₂CO₃. The aqueous layer was extracted with CH₂Cl₂until no UV absorbance was detected in the organic layer and then the combined organic layer was dried over Na₂SO₄and concentrated to afford the corresponding 4-aryl-piperidine of interest.

Intermediate 67. 4-(3-Methoxyphenyl)piperidine

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Prepared from tert-butyl 4-(3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to the general procedure 3 using 3% Pd/C as hydrogenation catalyst (66% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.71 (apparent qd, J=12.4, 2.8 Hz, 2H), 1.87 (apparent d, J=12.8 Hz, 2H), 2.50 (bs, 1H), 2.63 (tt, J=12.0, 3.6 Hz), 2.78 (apparent t, J=11.2, 2H), 3.24 (apparent d, J=11.2 Hz, 2H), 3.82 (s, 3H), 6.73-6.88 (m, 3H), 7.25 (t, J=8.0 Hz, 1H).

Intermediate 68. 2-(Piperidin-4-yl)pyrimidine

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Prepared from tert-butyl 4-(pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to the general procedure 3 using 3% Pd/C as hydrogenation catalyst. Intermediate hydrogenation product was purified with silica gel column and 0-100% EtOAc gradient prior to addition of 4N HCl. Desired product was isolated as an off-white light brown solid (73% yield) ¹H NMR (400 MHz, CDCl₃) δ 1.81 (apparent qd, J=12.0, 4.0 Hz, 2H), 2.01 (apparent disorted d, J=12.8 Hz, 2H), 2.68 (bs, 1H), 2.79 (td, J=12.4, 2.0 Hz, 2 Hz), 3.02 (tt, J=11.6, 3.6 Hz, 1H), 3.22 (apparent distorted d, J=12.4 Hz, 2H), 7.12 (t, J=5.2 Hz, 1H), 8.68 (d, J=4.8 Hz, 2H).

Intermediate 69. Methyl 4-(piperidin-4-yl)benzoate

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Prepared from tert-butyl 4-(4-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to the general procedure 3 using 3% Pd/C as hydrogenation catalyst. Isolated as a white solid (96% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.64 (apparent qd, J=12.8, 4.0 Hz, 2H), 1.83 (apparent d, J=12.4 Hz, 2H), 2.63-2.79 (m, 3H), 3.19 (apparent d, J=12.0 Hz, 2H), 3.89 (s, 3H), 7.28 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H).

Intermediate 70. N-Methyl-N-(5-(piperidin-4-yl)pyridin-2-yl)acetamide

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A mixture of tert-butyl 6-nitro-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (550 mg, 1.80 mmol), 3% Pd/C (320 mg, 0.09 mmol) in 10 mL of EtOH and 3 mL of EtOAc was hydrogenated at 1 atm of pressure for 3 h. The reaction mixture was then filtered through a pad of celite and the solids washed with EtOH and EtOAc (1:1 mixture) until no UV was detected in the washings. The combined organic layer was evaporated to a light-brown solid. This solid was then dissolved in CH₂Cl₂(13 mL) and then treated with Et₃N (0.5 mL, 3.60 mmol) and then acetic anhydride (0.20 mL, 2.16 mmol). The reaction mixture was stirred until consumption of limiting reagent (as suggested by TLC) and partitioned between CH₂Cl₂and water. The water layer was extracted with CH₂Cl₂(×3) and the combined organic layer was dried over Na₂SO₄filtered and concentrated. Silica gel column with 0-50% EtOAC in hexanes gradient yielded the corresponding intermediate tert-butyl 4-(6-acetamidopyridin-3-yl)piperidine-1-carboxylate, as an off-white solid (340 mg, 59% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.51 (s, 9H), 1.56-1.69 (m, 2H), 1.83 (apparent d, J=12.8 Hz, 2H), 2.22 (s, 3H), 2.67 (tt, J=12.0, 3.6 Hz, 1H), 2.82 (t, J=11.2 Hz, 2H), 4.28 (bs, 2H), 7.56 (dd, J=8.8, 2.4 Hz, 1H), 7.91 (s, 1H), 8.13-8.16 (m, 2H).

This intermediate (340 mg, 1.06 mmol) was then dissolved in in DMF (5 mL) and treated with NaH (60% dispersion, 64 mg, 1.59 mmol) and MeI (180 mg, 80 μL, 1.28 mmol). The reaction mixture stirred until consumption of the limited reagent (as indicated by TLC) and then partitioned between CH₂Cl₂and water. The water layer was extracted with CH₂Cl₂(×3) and the combined organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was chromatographed with silica gel column and 0-100% gradient to afford the corresponding N-methylated derivative, tert-butyl 4-(6-(N-methylacetamido)pyridin-3-yl)piperidine-1-carboxylate, as a white solid (330 mg, 93% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.48 (s, 9H), 1.49-1.68 (m, 2H), 1.83 (apparent d, J=12.8 Hz, 2H), 2.07 (bs, 3H), 2.71 (tt, J=12.0, 3.2 Hz, 1H), 2.82 (apparent t, J=12.0 Hz), 3.36 (s, 3H), 4.27 (bs, 2H), 7.24 (bs, 1H), 7.56 (dd, J=8.4, 2.4 Hz, 1H), 8.33 (d, J=2 Hz, 1H).

This N-methylated intermediate was then deprotected using 4N HCl in dioxane as described in general procedure 3 to afford the desired compound, N-methyl-N-(5-(piperidin-4-yl)pyridin-2-yl)acetamide, as light brown solid (93% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.67 (qd, J=12.8, 4.4 Hz, 2H), 1.87 (apparent d, J=13.6 Hz, 2H), 2.09 (s, 3H), 2.70 (tt, J=12.4, 4.0 Hz, 1H), 2.79 (td, J=12.0, 2.4 Hz, 2H), 3.23 (apparent d, J=12.4 Hz, 2H), 3.38 (s, 3H), 7.23 (bs, 1H), 7.62 (dd, J=8.0, 2.4 Hz, 1H), 8.37 (d, J=2.0 Hz, 1H).

Intermediate 71. 2-Methoxy-4-(piperidin-4-yl)pyridine

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Synthesized from tert-butyl 2′-methoxy-3,6-dihydro-[4,4′-bipyridine]-1(2H)-carboxylate according to general procedure III using 10% Pd/C as hydrogenation catalyst. Isolated as a honey-like sirup (93% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.64 (qd, J=12.0, 4.0 Hz, 2H), 1.83 (apparent d, J=12.4 Hz, 2H), 2.39 (bs, 1H), 2.58 (tt, J=12.0, 4.0 Hz, 1H), 2.74 (apparent td, J=12.4, 2.4 Hz, 2H), 3.19-3.24 (m, 2H), 3.92 (s, 3H), 6.58 (apparent d, J=0.4 Hz, 1H), 6.74 (dd, J=5.6, 0.8 Hz, 1H), 8.07 (d, J=5.2 Hz, 1H).

Intermediate 72. 4-(4-Methoxyphenyl)piperidine

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Prepared from tert-butyl 4-(4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 3% Pd/C as hydrogenation catalyst. Isolated as a thick sirup (76% yield) ¹H NMR (400 MHz, CDCl₃) δ 1.61 (qd, J=12.4 Hz, 4.0 Hz, 2H), 1.81 (apparent d, J=13.6 Hz, 2H), 2.56 (tt, J=12.4, 3.6 Hz, 1H), 2.73 (td, J=12.4, 2.4 Hz, 2H), 3.18 (apparent d, J=12.0 Hz, 2H), 3.79 (s, 3H), 6.85 (d, J=8.4 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H).

Intermediate 73. 4-(2-Methoxyphenyl)piperidine

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Synthesized from tert-butyl 4-(2-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 3 using 10% Pd/C as hydrogenation catalyst (66% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.47 (qd J=12.0, 3.6 Hz, 2H), 1.61 (apparent d, J=12.0 Hz, 2H), 2.60 (apparent td, J=12.0, 1.6 Hz, 2H), 2.90-3.03 (m, 3H), 3.77 (s, 3H), 6.86-6.96 (m, 2H), 7.12-7.20 (m, 2H).

Intermediate 74. 4-(p-Tolyl)piperidine

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Synthesized from tert-butyl 4-(p-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 3 using 10% Pd/C as hydrogenation catalyst. Isolated as a colorless/pale liquid (78% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.75 (qt, J=12.4, 4.4 Hz, 2H), 1.86 (apparent d, J=12.0 Hz, 2H), 2.32 (s, 3H), 2.61 (tt, J=12.0, 4.0 Hz, 1H), 2.79 (td, J=12.4, 2.8 Hz, 2H), 3.31 (apparent d, J=12.4 Hz, 2H), 4.77 (bs, 1H), 7.12 (s, 4H).

Intermediate 75. 4-(4-(Methoxymethyl)phenyl)piperidine

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Synthesized from tert-butyl 4-(4-(methoxymethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate by following the general procedure 3 using 10% Pd/C as hydrogenation catalyst. Isolated as a pale solid (89% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.72 (apparent qd, J=12.4, 3.6 Hz, 2H), 1.86 (apparent d, J=12.4 Hz), 2.59-2.69 (m, 1H), 2.78 (apparent td, J=12.4, 2.0 Hz, 2H), 3.26 (apparent d, J=12.0 Hz, 2H), 3.39 (s, 3H), 4.24 (s, 2H), 7.20 (distorted d, J=8.0 Hz, 2H), 7.28 (distorted d, J=8.0 Hz, 2H).

Intermediate 76. N-Methyl-N-(4-(piperidin-4-yl)phenyl)acetamide

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Synthesized from tert-butyl 4-(4-(N-methylacetamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate by following the general procedure 3 using 10% Pd/C as hydrogenation catalyst. Isolated as a pale yellow oil (62% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.59-1.73 (m, 2H), 1.83-1.91 (s merged with apparent d, 5H), 2.67 (tt, J=12.0, 4 Hz, 1H), 2.78 (td, J=12.0, 2.4 Hz, 2H), 3.23 (apparent d, J=11.6 Hz, 2H), 3.27 (s, 3H), 7.10 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H).

Intermediate 77. N-(4-(Piperidin-4-yl)phenyl)acetamide

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Synthesized from tert-butyl 4-(4-acetamidophenyl)-3,6-dihydropyridine-1(2H)-carboxylate following the general procedure 3 using 10% Pd/C as hydrogenation catalyst. Isolated as a pale yellow solid (73% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.54-1.66 (m, 2H), 1.80 (distorted apparent d, J=12.8 Hz, 2H), 2.16 (s, 3H), 2.54-2.63 (m, 1H), 2.73 (apparent td, J=13.6, 2.0 Hz J=2H), 3.18 (apparent d, 2H), 7.13 (s, 1H), 7.17 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H).

Intermediate 78. 2-Methoxy-5-(piperidin-4-yl)pyridine

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Synthesized from tert-butyl 6-methoxy-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate following general procedure 3 using 3% Pd/C as hydrogenation catalyst. Isolated as pale-yellow solid (52% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.61 (qd, J=12.4, 4.0 Hz, 2H), 1.79 (apparent d, J=13.6 Hz, 2H), 2.57 (tt, J=12.0 Hz, 4.0 Hz, 1H), 2.74 (td, J=12.4 Hz, 2.4 Hz, 2H), 3.18-3.21 (apparent d, 2H), 3.91 (s, 3H), 6.69 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.4 Hz, 2.4 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H).

Intermediate 79. 4-(m-Tolyl)piperidine

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Synthesized from tert-butyl 4-(m-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 3 using 10% Pd/C as hydrogenation catalyst. Isolated as a pale-yellow liquid (83% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.67 (qd, J=12.4, 3.6 Hz, 2H), 1.83 (apparent d, J=12.8 Hz, 2H), 2.33 (s, 3H), 2.60 (tt, J=12.0 Hz, 3.6 Hz, 1H), 2.78 (td, J=12.4 Hz, 2.4 Hz, 2H), 3.22 (apparent d, J=12.0 Hz, 2H), 6.99-7.05 (m, 3H), 7.19 (t, J=7.2 Hz, 1H).

Intermediate 80. 4-(o-Tolyl)piperidine

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Synthesized from tert-butyl 4-(o-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate, following the general procedure 3 using 10% Pd/C as hydrogenation catalyst. Isolated as a pale-yellow liquid (85% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.65 (apparent qd, J=12.8, 4.0 Hz, 2H), 1.76 (apparent d, J=13.2 Hz, 2H), 2.35 (s, 3H), 2.78 (td, J=12.0, 2.4 Hz, 3H), 3.21 (apparent d, J=12.0 Hz, 2H), 7.06-7.25 (m, 4H).

Intermediate 81. 4-(3-Fluoro-4-methoxyphenyl)piperidine

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Synthesized from tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate following general procedure 3 using 3% Pd/C as catalyst. The product was isolated as a colorless liquid (75% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.51-1.63 (m, 4H), 1.77-1.84 (m, 2H), 2.55 (apparent tt, J=12.0, 3.6 Hz, 1H), 2.72 (apparent td, J=12.0, 2.4 Hz, 2H), 3.15-3.20 (m, 2H), 3.87 (s, 3H), 6.85-6.97 (m, 3H).

Intermediate 82. 4-(2-fluoro-4-methoxyphenyl)piperidine

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Prepared from tert-butyl 4-(2-fluoro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 3% Pd/C as hydrogenation catalyst. The product was isolated as colorless liquid (59% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.62 (qd, J=12.4, 4.0 Hz, 2H), 1.74-1.81 (m, 2H), 2.75 (td, J=12.4, 2.8 Hz, 2H), 2.90 (tt, J₁=12.4, 3.6 Hz, 1H), 3.15-3.19 (m, 2H), 3.77 (s, 3H), 6.58 (dd, J=12.0, 2.4 Hz, 1H), 6.65 (apparent dd, J=8.8, 2.4 Hz, 1H), 7.13 (t, J=8.8 Hz, 1H).

Intermediate 83. 4-(2-Fluorophenyl)piperidine

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Synthesized from tert-butyl 4-(2-fluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 3% Pd/C as hydrogenation catalyst. The product was isolated as pale, light yellow syrup (78% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.66 (qd, J=12.4, 4.0 Hz, 2H), 1.78-1.85 (m, 2H), 2.78 (td, J=12.0, 2.4 Hz, 2H), 2.99 (tt, J₁=12.0, 3.6 MHz, 1H), 3.16-3.22 (m, 2H), 6.97-7.04 (m, 1H), 7.07-7.12 (m, 1H), 7.13-7.20 (m, 1H), 7.21-7.26 (m, 1H).

Intermediate 84. Methyl 3-(piperidin-4-yl)benzoate

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Synthesized from tert-butyl 4-(3-(methoxycarbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate by following general procedure 3 using 10% Pd/C as hydrogenation catalyst. Isolated as a light yellow viscous liquid (80% yield). ¹H NMR (400 MHz, dmso-d6) δ 1.50 (apparent qd, J=12.4, 3.6 Hz, 2H), 1.69 (apparent d, J=12.0 Hz, 2H), 2.58 (td, J=12.0, 1.6 Hz, 2H), 2.63-2.71 (m, 1H), 3.02 (apparent d, J=12.0 Hz, 2H), 3.84 (s, 3H), 7.43-7.47 (distorted t, J=7.6 Hz, 1H), 7.52 (distorted d, J=7.6 Hz, 1H), 7.77-7.80 (m, 2H).

Intermediate 85. 4-(4-(Ethylsulfonyl)phenyl)piperidine

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Prepared from tert-butyl 4-(4-(ethylsulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as an off white solid (75% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.6 Hz, 3H), 1.78 (qd, J=12.4, 4.0 Hz, 2H), 1.89 (apparent d, J=12.0 Hz, 2H), 2.72-2.85 (m, 3H), 3.11 (q, J=7.6 Hz, 2H), 3.27-3.33 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.83 (d, J=8.4 Hz, 2H).

Intermediate 86. 3-Methoxy-5-(piperidin-4-yl)pyridine

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Prepared from tert-butyl 5-methoxy-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate according to general procedure 3 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as light brown-yellow viscus oil (42% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.53 (apparent qd, J=11.6, 2.8 Hz, 2H), 1.68 (apparent d, J=11.2 Hz, 2H), 2.54-2.73 (m, 3H), 3.02 (apparent d, J=11.6 Hz, 2H), 3.81 (3, 3H), 7.20 (s, 1H), 8.06 (s, 1H), 8.11 (s, 1H).

Intermediate 87. 4-(4-Chloro-phenyl)-piperidine

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Synthesized from tert-butyl 4-(4-chlorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using PtO₂as hydrogenation catalyst. The reduced N-Boc-protected piperidine intermediate was purified by silica gel column chromatography and 0-20% Et₂O in hexanes gradient before deprotection by treatment with 4N HCl. The product was obtained as colorless syrup (53% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.55-1.68 (m, 2H), 1.78-1.90 (bs overlapping with apparent d, J=9.2 Hz, 3H), 2.59 (tt, J=12.0, 3.6 Hz, 1H), 2.74 (apparent t, J=12.0 Hz, 2H), 3.20 (apparent broad based d, J=11.6 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H).

Intermediate 88. 4-(3-Chloro-4-methoxyphenyl)piperidine

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Synthesized from tert-butyl 4-(3-chloro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using PtO₂as hydrogenation catalyst. The reduced N-Boc-protected piperidine intermediate was purified by silica gel column chromatography and 0-20% Et₂O in hexanes gradient before deprotection with by treatment with 4N HCl. The product was obtained as colorless very viscous syrup/waxy solid (48% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.50-1.62 (m, 2H), 1.80 (apparent d, J=13.6 Hz, 2H), 2.54 (tt, J=12.0, 3.6 Hz, 1H), 2.72 (td, J=12.0, 2.4 Hz, 2H), 3.15-3.19 (m, 2H), 3.88 (s, 3H), 6.86 (d, J=8.4 Hz, 1H), 7.07 (ddd, J=8.4, 2.4, 0.4 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H).

Intermediate 89. 4-(2-Chloro-4-methoxyphenyl)piperidine

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Synthesized from tert-butyl 4-(2-chloro-4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using PtO₂as hydrogenation catalyst. The reduced N-Boc-protected piperidine intermediate was purified by silica gel column chromatography and 0-20% Et₂O in hexanes gradient before deprotection by 4N HCl treatment. The product was obtained as yellowish very viscous syrup/waxy solid (40% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.52-1.61 (m, 4H), 1.83 (apparent d, J=11.4 Hz, 2H), 2.79 (td, J=12.0, 2.4 Hz, 2H), 3.20 (d, J=11.4 Hz, 1H), 3.79 (s, 3H), 6.82 (dd, J=8.4, 2.4 Hz, 1H), 6.92 (d, J=3.0 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H).

Intermediate 90. N-(3-Fluoro-4-(piperidin-4-yl)phenyl)-N-methylacetamide

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Prepared from tert-butyl 4-(2-fluoro-4-(N-methylacetamido)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as yellowish waxy solid syrup (96% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.69 (qd, J=12.0, 4.2 Hz, 2H), 1.84 (apparent d, J=10.8 Hz, 2H), 1.91 (s, 3H), 2.80 (td, J=12.0, 2.4 Hz, 2H), 2.97-3.03 (m, 1H), 3.21-3.24 (m, 2H), 3.25 (s, 3H)), 6.88 (d, J=10.2 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 7.26-7.31 (m, 1H).

Intermediate 91. 4-(3-Fluoro-5-methoxyphenyl)piperidine

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Prepared from tert-butyl 4-(3-fluoro-5-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The reduced N-Boc-protected piperidine intermediate was purified by silica gel column chromatography and 0-20% EtOAc in hexanes gradient before deprotection with 4N HCl treatment. The product was isolated as yellowish waxy solid (67% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.65 (qd, J=12.6 Hz, 3.6 Hz, 2H), 1.85 (apparent distorted d, J=12.0 Hz, 2H), 2.34 (bs, 1H), 2.60 (tt, J=18.0, 3.9 Hz, 1H), 2.76 (apparent t, J=11.7 Hz, 2H), 3.23 (apparent d, J=12.0 Hz, 2H), 3.80 (s, 3H), 6.45-6.58 (m, 3H).

Intermediate 92. 4-(4-Fluoro-3-methoxyphenyl)piperidine

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Prepared from tert-butyl 4-(4-fluoro-3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a yellowish very viscous sirup/waxy solid (58% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.59 (qd, J=11.7, 3.9 Hz, 2H), 1.78 (apparent broad d, J=12.3 Hz, 2H), 2.42 (bs, 1H), 2.52 (tt, J=12.0, 3.6 Hz, 1H), 2.69 (td, J=12.0, 2.1 Hz, 2H), 3.16 (apparent d, J=11.7 Hz, 2H), 3.81 (s, 3H), 6.63-6.69 (m, 1H), 6.76 (dd, J=8.1, 2.1 Hz, 1H), 6.92 (dd, J=11.4, 9.6 Hz, 1H).

Intermediate 93. (4-(Piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone

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Prepared from tert-butyl 4-(4-(pyrrolidine-1-carbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The reduced N-Boc-protected piperidine intermediate was purified by silica gel column chromatography and 0-10% EtOAc in hexanes gradient. The product was isolated as a white solid (47% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.39 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 3.57 (t, J=6.6 Hz, 2H), 3.38 (t, J=6.6 Hz, 2H), 3.14-3.12 (m, 2H), 2.68 (dt, J=12.6, 2.4 Hz, 1H), 2.57 (tt, J=12.0, 3.6 Hz, 1H), 1.91-1.86 (m, 3H), 1.81-1.74 (m, 4H), 1.61-1.54 (m, 2H).

Intermediate 94. (3-Fluoro-4-(piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone

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Prepared from tert-butyl 4-(2-fluoro-4-(pyrrolidine-1-carbonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (73% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.51-7.21 (m, 2H), 7.18 (d, J=7.2 Hz, 1H), 3.66 (t, J=6.6 Hz, 2H), 3.47 (t, J=6.6 Hz, 2H), 3.25-3.23 (m, 2H), 3.03 (tt, J=12.6, 2.4 Hz, 1H), 2.81 (dt, J=12.0, 2.4 Hz, 1H), 2.10 (s, 1H), 2.0-1.96 (m, 2H), 1.93-1.88 (m, 2H), 1.85-1.83 (m, 2H), 1.76-1.69 (m, 2H).

Intermediate 95. 1-(4-(Piperidin-4-yl)benzyl)pyrrolidin-2-one

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Prepared from tert-butyl 4-(4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (72% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.15 (s, 4H), 4.39 (s, 2H), 3.24 (t, J=7.2 Hz, 2H), 3.19-3.17 (m, 2H), 2.72 (td, J=12.0, 2.4 Hz, 2H), 2.59 (tt, J=9.0, 3.6 Hz, 1H), 1.99-1.94 (m, 4H), 1.81-1.79 (m, 2H), 1.66-1.59 (m, 2H).

Intermediate 96. 4-(4-(Pyrrolidin-1-ylsulfonyl)phenyl)piperidine

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Prepared from tert-butyl 4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (93% yield). ¹HNMR (500 MHz, CDCl₃) δ 7.73 (d, J=8.5 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 3.23-3.19 (m, 6H), 2.76-2.64 (m, 3H), 2.19 (s, 1H), 1.83-1.81 (m, 2H), 1.74-1.72 (m, 4H), 1.69-1.61 (m, 2H).

Intermediate 97. 2-(Piperidin-4-yl)-4-(trifluoromethyl)pyridine

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Prepared from tert-butyl 4-(trifluoromethyl)-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (60% yield). ¹HNMR (600 MHz, CDCl₃) δ 8.69 (d, J=4.8 Hz, 1H), 7.37 (s, 1H), 7.32 (d, J=4.8 Hz, 1H), 3.22-3.20 (m, 2H), 2.91 (tt, J=12.0, 3.6 Hz, 1H), 2.76 (dt, J=12.0, 2.4 Hz, 2H), 1.94-1.92 (m, 2H), 1.74-1.67 (m, 2H), 1.62 (bs, 1H).

Intermediate 98. 4-(4-((Methylsulfonyl)methyl)phenyl)piperidine

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Prepared from tert-butyl 4-(4-((methylsulfonyl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (83% yield). ¹HNMR (600 MHz, CD₃OD) δ 7.40 (d, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 4.40 (s, 2H), 3.17-3.15 (m, 2H), 2.86 (s, 3H), 2.77-2.69 (m, 3H), 1.85-1.83 (m, 2H), 1.72-1.65 (m, 2H).

Intermediate 99. 3-(Piperidin-4-yl)-5-(trifluoromethyl)pyridine

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Prepared from tert-butyl 5-(trifluoromethyl)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (72% yield). ¹HNMR (600 MHz, CDCl₃) δ 8.76 (d, J=1.2 Hz, 1H), 8.71 (d, J=1.8 Hz, 1H), 7.79 (s, 1H), 3.29-3.27 (m, 2H), 2.83-2.76 (m, 3H), 2.24 (bs, 1-NH), 1.91-1.89 (m, 2H), 1.76-1.69 (m, 2H).

Intermediate 100. 1-(4-(Piperidin-4-yl)phenyl)pyrrolidin-2-one

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Prepared from tert-butyl 4-(4-(2-oxopyrrolidin-1-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (76% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.48 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 3.85-3.79 (m, 2H), 3.14 (d, J=12.0 Hz, 2H), 2.70 (dt, J=12.6, 2.4 Hz, 1H), 2.59-2.54 (m, 3H), 2.14-2.09 (m, 2H), 1.78-1.76 (m, 2H), 1.61-1.53 (m, 3H).

Intermediate 101. 5-(Piperidin-4-yl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

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Prepared from tert-butyl 4-(1,1-dioxido-2,3-dihydrobenzo[b]thiophen-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (79% yield). ¹HNMR (300 MHz, CD₃OD) δ 7.69 (d, J=8.1 Hz, 1H), 7.48-7.45 (s, 2H), 3.58-3.51 (m, 4H), 3.43-3.39 (m, 2H), 3.18-3.01 (m, 3H), 2.15-2.11 (m, 2H), 2.01-1.87 (m, 2H).

Intermediate 102. 4-(piperidin-4-yl)-N-(1,1,1-trifluoropropan-2-yl)aniline

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Prepared from tert-butyl 4-(4-((1,1,1-trifluoropropan-2-yl)amino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3. The product was isolated as a white solid (72% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.03 (d, J=8.7 Hz, 2H), 6.59 (d, J=8.4 Hz, 2H), 3.99-3.92 (m, 1H), 3.46 (d, J=9.0 Hz, 1H), 3.18-3.14 (m, 2H), 2.70 (td, J=12.0, 2.4 Hz, 2H), 2.49 (dt, J=12.0, 3.6 Hz, 1H), 1.80-1.75 (m, 2H), 1.64-1.51 (m, 2H), 1.35 (d, J=6.9 Hz, 3H).

Intermediate 103. 5-(Piperidin-4-yl)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide

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Prepared from tert-butyl 4-(2,2-dioxido-1,3-dihydrobenzo[c]thiophen-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (96% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.25-7.15 (m, 3H), 4.33 (d, J=3.3 Hz, 4H), 3.23-3.18 (m, 2H), 2.78-2.56 (m, 3H), 1.82-1.79 (m, 3H), 1.69-1.56 (m, 2H).

Intermediate 104. 1-(2-Fluoro-4-(piperidin-4-yl)benzyl)pyrrolidin-2-one

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Prepared from tert-butyl 4-(3-fluoro-4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate) according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (79% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.18 (t, J=7.8 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.89-6.87 (m, 1H), 4.45 (s, 2H), 3.67 (s, 1H), 3.17-3.15 (m, 2H), 2.70 (dt, J=12.6, 2.4 Hz, 2H), 2.57 (td, J=12.6, 3.6 Hz, 1H), 2.39 (t, J=8.4 Hz, 2H), 1.99-1.94 (m, 2H), 1.80-1.78 (m, 3H), 1.60-1.56 (m, 2H).

Intermediate 105. 1-(2-Chloro-4-(piperidin-4-yl)benzyl)pyrrolidin-2-one

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Prepared from tert-butyl 4-(3-chloro-4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as white solid (63% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.19-7.16 (m, 2H), 7.06-7.05 (m, 1H), 4.53 (s, 2H), 3.28 (t, J=7.2 Hz, 2H), 3.16-3.14 (m, 2H), 2.2.69 (dt, J=12.0 Hz, 1.8 Hz, 2H), 2.58 (tt, J=12.0, 3.0 Hz, 1H), 2.41 (t, J=8.4 Hz, 2H), 2.01-1.97 (m, 2H), 1.78-1.66 (m, 3H), 1.59-1.55 (m, 2H).

Intermediate 106. 1-(3-Fluoro-4-(piperidin-4-yl)benzyl)pyrrolidin-2-one

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Prepared from tert-butyl 4-(2-fluoro-4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as white solid (65% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.20-7.17 (m, 1H), 6.99-6.88 (m, 2H), 4.39 (s, 2H), 3.58-3.54 (m, 2H), 3.25 (t, J=6.9 Hz, 2H), 3.07-2.97 (m, 3H), 2.43 (t, J=7.8 Hz, 2H), 2.18-1.88 (m, 6H).

Intermediate 107. 4-(4-(Piperidin-4-yl)phenyl)morpholine

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Prepared from tert-butyl 4-(4-morpholinophenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as white solid (70% yield). ¹HNMR (600 MHz, CDCl₃) δ 1.61 (apparent qd, J=12.6, 3.6 Hz, 2H), 1.81 (bd, J=13.2 Hz, 2H), 2.55 (tt, J=12.0, 3.6 Hz, 1H), 2.73 (td, J=12.0, 1.8 Hz, 2H), 3.13 (apparent t, J=4.8 Hz, 4H), 3.18 (d, J=12.0 Hz, 2H), 3.85 (apparent t, J=4.8 Hz, 4H), 6.87 (d, J=9.0 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H).

Intermediate 108. 4-(4-(Piperidin-4-yl)benzyl)morpholine

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Prepared from tert-butyl 4-(4-(morpholinomethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as viscous liquid (24% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.21 (d, J=6.0 Hz, 2H), 7.13 (d, J=8.1 Hz, 2H), 3.67 (t, J=4.5 Hz, 4H), 3.43 (s, 2H), 3.17-3.13 (m, 2H), 2.70 (td, J=12.0 Hz, 2.1 Hz, 2H), 2.56 (tt, J=8.7 Hz, 3.6 Hz, 1H), 2.4 (t, J=4.5 Hz, 4H), 1.81-1.77 (m, 2H), 1.65-1.54 (m, 3H).

Intermediate 109. 4-(4-(Piperidin-4-yl)phenyl)morpholin-3-one

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Prepared from tert-butyl 4-(4-(3-oxomorpholino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as an off-white solid (79% yield). ¹HNMR (600 MHz, CDCl₃) δ 1.57-1.66 (m, 2H), 1.82 (apparent d, J=13.2 Hz), 2.62 (tt, J=12.0, 3.6 Hz, 1H), 2.73 (td, J=12.6, 2.4 Hz, 2H), 3.18 (apparent d, J=12.0 Hz, 2H), 3.75 (apparent t, J=5.4 Hz, 2H), 4.02 (apparent t, J=5.4 Hz, 2H), 4.34 (s, 2H), 7.23-7.28 (m, 4H).

Intermediate 110. 4-(2-fluoro-4-(piperidin-4-yl)phenyl)morpholine

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Prepared from tert-butyl 4-(3-fluoro-4-morpholinophenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as a white solid (68% yield). ¹HNMR (600 MHz, CDCl₃) δ 1.58 (apparent qd, J=12.6, 3.6 Hz, 2H), 1.80 (apparent d, J=13.2 Hz, 2H), 2.55 (tt, J=12.0, 3.6 Hz, 1H), 2.73 (td, J=12.0, 1.8 Hz, 2H). 3.06 (apparent t, J=4.8 Hz, 4H), 3.18 (apparent d, J=12.0 Hz, 2H), 3.86 (apparent t, J=4.8 Hz, 4H), 6.85-6.94 (m, 3H).

Intermediate 111. 4-(3-Fluoro-4-(piperidin-4-yl)phenyl)morpholine

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Prepared from tert-butyl 4-(2-fluoro-4-morpholinophenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as white solid (37% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.13-7.06 (m, 1H), 6.61 (dd, J=8.1 Hz, 2.8 Hz 1H), 6.55-6.50 (m, 1H), 4.26 (s, 1H), 3.81 (t, J=4.8 Hz, 4H), 3.28-3.24 (m, 1H), 3.09 (t, J=5.1 Hz, 4H), 2.96-2.75 (m, 3H), 1.83-1.68 (m, 4H).

Intermediate 112. (S)-1-(1-(4-(Piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one

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Prepared from tert-butyl (S)-4-(4-(1-(2-oxopyrrolidin-1-yl)ethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as an off-white solid (81% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.49 (d, J=7.2 Hz, 1.65 (apparent qt, J=12.6, 3.0 Hz, 2H), 1.82 (apparent d, J=12.6 Hz, 2H), 1.86-1.93 (m, 1H), 1.93-2.01 (m, 1H), 2.25 (bs, 1H), 2.35-2.47 (m, 2H), 2.75 (td, J=12.0, 1.8 Hz, 2H), 3.00 (ddd, J=14.4, 8.4, 5.4 Hz, 1H), 3.21 (apparent d, J=12.0 Hz, 2H), 3.31 (ddd, J=15.0, 9.0, 6.0 Hz, 1H), 5.47 (q, J=7.2 Hz, 1H), 7.18 (distorted d, J=8.4 Hz, 2H), 7.23 (distorted d, J=8.4 Hz, 2H).

Intermediate 113. (R)-1-(1-(4-(Piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one

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Prepared from tert-butyl (R)-4-(4-(1-(2-oxopyrrolidin-1-yl)ethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as an off-white solid (75% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.52 (d, J=7.2 Hz, 3H), 1.68 (apparent qt, J=12.6, 3.0 Hz, 2H), 1.84 (apparent d, J=12.6 Hz, 2H), 1.90-1.94 (m, 1H), 1.94-2.03 (m, 1H), 2.21 (bs, 1H), 2.37-2.48 (m, 2H), 2.63 (tt, J=12.0, 3.6 Hz, 1H), 2.77 (td, J=12.6, 2.4 Hz, 2H), 3.02 (ddd, J=14.4, 9.0, 5.4 Hz, 1H), 3.23 (apparent bd, J=12.0 Hz, 2H), 3.34 (ddd, J=15.0, 9.0, 6.0 Hz), 5.48 (q, J=7.2 Hz, 1H), 7.20 (distorted d, J=8.4 Hz, 2H), 7.25 (distorted d, J=8.4 Hz, 2H).

Intermediate 114. 1-(3-Fluoro-4-(piperidin-4-yl)phenyl)pyrrolidin-2-one

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Prepared from tert-butyl 4-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as white solid (70% yield). ¹HNMR (400 MHz, CDCl₃) δ 7.43 (dd, J=12.4, 2.0 Hz, 1H), 7.26-7.17 (m, 2H), 3.80 (t, J=6.8 Hz, 2H), 3.16-3.13 (m, 2H), 2.92 (tt, J=12.4, 8.4 Hz, 1H), 2.74 (dt, J=12.4, 2.4 Hz, 2H), 2.58 (t, J=8.0 Hz, 2H), 2.17-2.09 (m, 2H), 1.78-1.74 (m, 2H), 1.65-1.56 (m, 3H).

Intermediate 115. 4-(4-(piperidin-4-yl)phenyl)thiomorpholine 1,1-dioxide

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Prepared from tert-butyl 4-(4-(1,1-dioxidothiomorpholino)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate according to general procedure 3 using 10% Pd/C as hydrogenation catalyst. The product was isolated as white solid (72% yield). ¹H NMR (300 MHz, CDCl₃) δ 7.12 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 3.78 (t, J=7.2 Hz, 4H), 3.18-3.14 (m, 2H), 3.09 (t, J=8.0 Hz, 4H), 2.70 (dt, J=12.3, 2.7 Hz, 2H), 2.53 (tt, J=12.3, 3.6 Hz, 1H), 1.80-1.75 (m, 2H), 1.64-1.52 (m, 2H).

General Procedure 4. Synthesis of 4-(thioaryl/thio-heteroaryl)piperidines

A mixture of a desired aryl/heteroaryl thiol (1.1 eq.) and K₂CO₃(1.1 eq) in DMF was treated at room temperature with tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1 eq), prepared according to De Crescezo, G. et al. WO 2000046221 A1 and Iyobe, A. et al. Chem. Pharm. Bull. 2001, 49(7) 822, disclosures incorporated here in by reference. The reaction vessel was then sealed, warmed up to 70° C. and stirred until TLC indicated consumption of the limiting reagent. The mixture was then cooled and partitioned between CH₂Cl₂and water. The aq. layer was extracted with CH₂Cl₂and combined organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was chromatographed with silica gel column to afford the corresponding intermediate N-Boc protected 4-thioaryl/4-thio heteroaryl piperidine. This intermediate was then treated with 4 N HCl in dioxane at room temperature and stirred until TLC indicated consumption of the starting material. Followed evaporation of the volatiles and partition of the residue between aq. saturated Na₂CO₃and CH₂Cl₂. The aq. layer was extracted with CH₂Cl₂and the combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the corresponding 4-thioary/4-thioheteroaryl piperidine of interest.

Intermediate 116. 4-((4-Methoxyphenyl)thio)piperidine

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Prepared from commercially available 4-methoxybenzenethiol according to general procedure 4. The crude intermediate N-Boc-4-((4-methoxy-phenyl)thio)piperidine was purified with silica gel column and 0-50% EtOAc in hexanes gradient prior to treatment/deprotection with 4N HCl in dioxane. The desired compound, 4-((4-methoxy-phenyl)thio)piperidine, was isolated as a white solid (49% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.43-1.51 (m, 2H), 1.85-1.95 (m, 3H), 2.58-2.63 (m, 2H), 2.98 (tt, J=10.8, 3.6 Hz, 1H), 3.09 (dt, J=13.2, 3.6 Hz, 2H), 3.79 (s, 3H), 6.84 (apparent d, J=9.0 Hz, 2H), 7.39 (apparent d, J=8.4 Hz, 2H).

Intermediate 117. 4-((4-Fluorophenyl)thio)piperdine

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Prepared according to general procedure 4 from commercially available 4-fluorobenzenethiol. The crude intermediate N-Boc-4-((4-fluorophenyl)thio)piperidine was purified with silica gel column and 0-25% EtOAc in hexanes prior to treatment/deprotection with 4N HCl in dioxane. The desired compound, 4-((4-fluorophenyl)thio)piperdine, was isolated as colorless viscous oil (58% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.47-1.55 (m, 2H), 1.93 (apparent dd, J=13.2, 3.0 Hz, 2H), 2.19 (bs, 1H), 2.61-2.67 (m, 2H), 3.07 (tt, J=6.6, 4.2 Hz, 1H), 3.12 (dt, J=13.2, 3.6 Hz, 2H), 7.00 (apparent t, J=9.0 Hz, 2H), 7.40-7.43 (m, 2H).

Intermediate 118. 4-((3-methoxyphenyl)thio)piperidine

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Prepared from commercially available 3-methoxybenzenethiol according to general procedure 4. The crude intermediate N-Boc-4-((3-methoxyphenyl)thio)piperidine was purified with silica gel column and 0-30% EtOAc in hexanes gradient prior to treatment/deprotection with 4N HCl in dioxane. The desired compound, 4-((3-methoxyphenyl)thio)piperidine, was isolated as light yellow oil (50% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.49-1.56 (m, 2H), 1.97 (apparent dd, J=13.8, 3.6 Hz, 2H), 2.65 (ddd, J=13.2, 10.8, 2.4 Hz, 2H), 3.11 (dt, J=13.2, 3.6 Hz, 2H), 3.20 (tt, J=10.8, 3.6 Hz, 1H), 6.78 (ddd, J=7.8, 2.4, 0.6 Hz), 6.95-6.96 (m, 1H), 6.99 (ddd, J=7.8, 1.8, 1.2 Hz, 1H), 7.21 (apparent t, J=7.8 Hz, 1H).

Intermediate 119. 2-(Piperidin-4-ylthio)pyrimidine

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Prepared from commercially available pyrimidine-2-thiol according to general procedure 4. The crude intermediate N-Boc-2-(piperidin-4-ylthio)pyrimidine was purified with silica gel column and 0-100% EtOAc in hexanes gradient prior to treatment/deprotection with 4N HCl in dioxane. The desired compound, 2-(piperidin-4-ylthio)pyrimidine, was isolated as pale yellow viscous sirup (40% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.62-1.70 (m, 2H), 2.10-2.15 (m, 2H), 2.79 (ddd, J=13.2, 10.8, 3.0 Hz, 2H), 3.12 (dt, J=13.2, 3.6 Hz, 2H), 3.86-3.92 (m, 2H), 6.93 (t, J=4.8 Hz, 1H), 8.50 (d, J=4.8 Hz, 2H).

Intermediate 120. 4-((2-Fluorophenyl)thio)piperidine

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Prepared from commercially available 2-fluorobenzenethiol according to general procedure 4. The crude intermediate N-Boc-4-((2-fluorophenyl)thio)piperidine, was purified with silica gel column and 0-25% EtOAc in hexanes gradient prior to treatment/deprotection with 4N HCl in dioxane. The desired compound, 4-((2-fluorophenyl)thio)piperidine, was obtained as clear, pale yellow, sirup (35% yield). ¹H NMR (300 MHz, CD₃OD) δ 1.46-1.60 (m, 2H), 1.89-1.97 (m, 2H), 2.64 (ddd, J=13.8, 11.1, 2.7 Hz, 2H), 3.07 (dt, J=13.2, 3.9 Hz, 2H), 3.25-3.30 (m, 1H), 7.10-7.19 (m, 2H), 7.31-7.39 (m, 1H), 7.51 (apparent td, J=7.2, 1.8 Hz).

General Procedure 5. Synthesis of 4-(benzyl/heterobenzyl)piperidines

To commercially available tert-butyl 4-methylenepiperidine-1-carboxylate (1 mmol) was added 9-BBN (1.1 mmol, 0.5 M in THF). The mixture was refluxed for 2.5 hours under inert atmosphere then cooled and transfer slowly (under inert atmosphere) to a mixture of a desired arylbromide (1.1 mmol), K₂CO₃(3 mmol) and PdCl₂(dppf) (0.04 mmol) in dioxane:water (2:1). The resulting mixture was stirred for 48 h at 90° C., then cooled to room temperature, quenched with 1N NaOH and extracted with EtOAc (3×30 mL). The combined organic layer was dried over Na₂SO₄filtered and concentrated to a residue that was chromatographed on a silica gel column using 0-50% EtOAc in hexanes to afford the corresponding N-Boc-4-(benzyl/heterobenzyl)piperidine. This intermediate was then treated with 4 N HCl in dioxane at room temperature until TLC indicated consumption of the starting material. Followed evaporation of the volatiles and partition of the residue between aq. saturated K₂CO₃and CH₂Cl₂. The aq. layer was extracted with either EtOAc or CH₂Cl₂or 10% MeOH in CH₂Cl₂and the combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the corresponding 4-(benzyl/heterobenzyl)piperidine of interest.

Intermediate 121. 4-(3-chlorobenzyl)piperidine

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Prepared from commercially available 1-bromo-3-chlorobenzene and tert-butyl 4-methylenepiperidine-1-carboxylate according to general procedure 5. The product was isolated as a transparent liquid (23% yield). ¹HNMR (600 MHz, CD₃OD) δ 7.30 (t, J=7.8 Hz, 1H), 7.26-7.20 (m, 2H), 7.15 (d, J=7.8 Hz, 1H), 3.39-3.36 (m, 2H), 2.98-2.94 (m, 2H), 2.64 (d, J=7.2 Hz, 2H), 1.96-1.85 (m, 3H), 1.47-1.40 (m, 2H).

Intermediate 122 4-(4-chlorobenzyl)piperidine hydrochloride

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Prepared from commercially available 1-bromo-4-chlorobenzene and tert-butyl 4-methylenepiperidine-1-carboxylate according to general procedure 5. The piperidine product was characterized as the HCl salt (39% yield). ¹HNMR (600 MHz, CD₃OD) δ 7.31 (d, J=8.4 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 3.39-3.37 (m, 2H), 2.98-2.93 (m, 2H), 2.62 (d, J=6.6 Hz, 2H), 1.95-1.86 (m, 3H), 1.47-1.40 (m, 2H).

Intermediate 123. 4-(3-Methylbenzyl)piperidine

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Prepared from commercially available 1-bromo-3-methylbenzene and tert-butyl 4-methylenepiperidine-1-carboxylate according to the general procedure 5. The product was isolated as a transparent liquid (57% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.16-7.13 (m, 1H), 7.00-6.97 (m, 1H), 6.94-6.92 (m, 2H), 3.08-3.06 (m, 2H), 2.55 (td, J=12.0, 1.8 Hz, 2H), 2.47 (d, J=6.6 Hz, 2H), 2.32 (s, 3H), 1.65-1.57 (m, 3H), 1.27-1.16 (m, 2H).

Intermediate 124. 2-Methoxy-4-(piperidin-4-ylmethyl)pyridine

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Prepared from commercially available 4-bromo-2-methoxypyridine and tert-butyl 4-methylenepiperidine-1-carboxylate according to general procedure 5. The product was isolated as a white solid (55% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 8.02 (d, J=5.4 Hz, 1H), 6.82 (dd, J=5.4, 1.5 Hz, 1H), 6.64 (d, J=0.6 Hz, 1H), 3.89 (s, 3H), 3.22-3.06 (m, 2H), 2.62 (td, J=12.6, 2.7 Hz, 2H), 2.56 (d, J=7.2 Hz, 2H), 1.87-1.73 (m, 1H) 1.68 (apparent d, J=13.5, 2H), 1.26 (qd, J=12.3, 3.9 Hz, 2H).

Intermediate 125. 1-(4-(Piperidin-4-ylmethyl)phenyl)pyrrolidin-2-one

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Prepared from commercially available tert-butyl 4-methylenepiperidine-1-carboxylate and commercially available 1-(4-bromophenyl)pyrrolidin-2-one according to the general procedure 5. The product was isolated as a viscous liquid (41% yield). ¹HNMR (300 MHz, CDCl₃) δ 7.47 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 3.82 (t, J=7.0 Hz, 2H), 3.02-2.98 (m, 2H), 2.61-2.52 (m, 2H), 2.51-2.46 (m, 3H), 2.12 (m, 2H), 1.62-1.51 (m, 4H), 1.18-1.04 (m, 2H).

Intermediate 126. 4-(4-methylbenzyl)piperidine

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Prepared from commercially available tert-butyl 4-methylenepiperidine-1-carboxylate and 1-bromo-4-methylbenzene according to the general procedure 5. The product was isolated as transparent liquid (49% yield). ¹HNMR (600 MHz, CDCl₃) δ 7.06 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.4 Hz, 2H), 3.02-3.00 (m, 2H), 2.53-2.46 (m, 4H), 2.30 (s, 3H), 1.62-1.53 (m, 4H), 1.15-1.08 (m, 2H).

General Procedure 6. Synthesis of piperidine/piperazine pyrazoles IV

A mixture of the desired substituted piperidine or substituted piperazine (2 eq), desired THP-protected iodopyrazole (1 eq) and K₂CO₃(3-5 eq) in DMSO was treated with CuI (0.2 eq) and proline (0.4 eq) and then heated at 95-100° C. until TLC indicated consumption of the limiting reagent. The reaction mixture was then cooled and partitioned between EtOAc and aq saturated NH₄Cl or dilute aqueous ammonia. The aq. layer was extracted with CH₂Cl₂until no UV absorption in the organic extract. The combined organic layer was dried over Na₂SO₄and evaporated to the crude THP-protected coupling product that was chromatographed with silica gel column. The THP-protected coupling intermediate obtained after column purification was then dissolved in 4N HCl in dioxane at room temperature and stirred until TLC indicated consumption of the starting material. Evaporation of volatiles and partitioning of the resulting residue between CH₂Cl₂or EtOAC and aq. saturated Na₂CO₃or direct addition of EtOAc to the dioxane mixture and then addition of aq saturated Na₂CO₃to pH 10-11 in aq layer followed. The aqueous layer was extracted with EtOAc or CH₂Cl₂until no UV absorption in the organic extract. The combined organic layer was then dried over Na₂SO₄, evaporated to afford the crude THP deprotection product that was purified via silica gel column.

Compound 1. 4-Phenyl-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from the coupling of THP-protected 4-iodo-pyrazole with commercially available 4-phenylpiperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-60% EtOAc in hexanes gradient. The crude THP deprotection product was chromatographed with silica gel column and 0-100% EtOAc in CHCl₃gradient to afford the product as a white solid (32% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.0-2.02 (m, 4H), 2.55-2.72 (m, 3H), 3.49-3.53 (m, 2H), 7.18-7.35 (m, 7H), 9.68 (bs, 1H).

Compound 2. 4-Benzyl-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and commercially available 4-benzylpiperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-70% EtOAc in hexanes gradient. The product, 4-benzyl-1-(1H-pyrazol-5-yl)piperidine, was isolated as a semisolid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in CH₂Cl₂(33% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.37-1.46 (m, 2H), 1.61-1.76 (m, 3H), 2.57 (d, J=6.8 Hz, 2H), 2.67 (td, J=12.4, 2.8 Hz, 2H), 3.65-3.72 (m, 2H), 5.74 (d, J=2.0 Hz, 1H), 7.10-7.23 (m, 3H), 7.27-7.32 (m, 2H), 7.38 (d, J=2.4 Hz).

Compound 3. 4-Benzyl-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and commercially available 4-benzylpiperidine according to the general procedure 6. The crude THP protected coupling intermediate was chromatographed with silica gel column and 0-70% EtOAc in hexanes gradient. The desired product, 4-benzyl-1-(1H-pyrazol-4-yl)piperidine, was isolated as an off white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in CH₂Cl₂and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes ¹H NMR (400 MHz, CDCl₃) δ 1.45 (apparent qd, J=11.6, 4.0 Hz, 2H), 1.58-1.67 (m, 1H), 1.73 (apparent d, J=13.2 Hz, 2H), 2.50 (td, J=11.6, 2.4 Hz, 2H), 2.59 (d, J=7.2 Hz, 2H), 3.31-3.36 (m, 2H), 7.13-7.24 (m, 5H), 7.27-7.32 (m, 2H).

Compound 4. 2-(4-(1H-Pyrazol-4-yl)piperazin-1-yl)pyrimidine

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Synthesized from THP-protected 4-iodo-pyrazole and commercially available 2-(1-piperazinyl)pyrimidine as described in the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product 2-(4-(1H-pyrazol-4-yl)piperazin-1-yl)pyrimidine, was isolated as white solid after purification of the crude THP deprotection product with silica gel column and 0-5% MeOH in EtOAc and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (10% yield). ¹H NMR (400 MHz, DMSO-d6) δ 2.89 (t, J=5.2 Hz, 4H), 3.83 (t, J=5.2 Hz, 4H), 6.63 (t, J=4.8 Hz, 1H), 7.29 (s, 2H), 8.36 (d, J=4.8 Hz), 12.30 (bs, 1H).

Compound 5. 1-Phenyl-4-(1H-pyrazol-4-yl)piperazine

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Synthesized from THP-protected 4-iodo-pyrazole and commercially available 1-phenylpiperazine according to general procedure 6. The crude THP-protected intermediate was chromatographed with silica gel column and 0-60% EtOAc in hexanes gradient. The desired product 1-phenyl-4-(1H-pyrazol-4-yl)piperazine, was isolated as an off-white solid after purification of the crude THP deprotection product with silica gel column with 0-2.5% MeOH in EtOAc and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (18% yield). 1H NMR (400 MHz, CDCl₃) δ 3.11-3.16 (m, 4H), 3.31-3.36 (m, 4H), 6.89 (apparent t, J=7.6 Hz, 1H), 6.98 (d, J=8.0 Hz, 2H), 7.26-7.32 (m, 5H).

Compound 6. 1-(4-Methoxyphenyl)-4-(1H-pyrazol-4-yl)piperazine

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Synthesized from THP-protected 4-iodo-pyrazole and commercially available 1-(4-methoxyphenyl)piperazine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-80% EtOAc in hexanes. The desired product 1-(4-methoxyphenyl)-4-(1H-pyrazol-4-yl)piperazine was isolated as a white solid after purification of the crude THP deprotection product with silica gel column and 0-5% MeOH in EtOAc in hexanes gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (8% yield). ¹H NMR (400 MHz, CDCl₃) δ 3.10-3.15 (m, 4H), 3.20-3.26 (m, 4H), 3.78 (s, 3H), 6.85 (d, J=9.2 Hz), 6.95 (d, J=8.8 Hz, 2H), 7.29 (bs, 2H).

Compound 7. 4-(3-Methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(3-methoxyphenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-30% EtOAc in hexanes. The desired product, 4-(3-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as an off-white solid after purification of the THP deprotection product with 0-100% EtOAc in hexanes gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes. ¹H NMR (400 MHz, CDCl₃) δ 1.82-1.97 (m, 4H), 2.59-2.68 (m, 1H), 2.85 (apparent td, J=11.6, 3.2 Hz, 2H), 3.81 (s, 3H), 3.85 (apparent d, J=12.4 Hz, 2H), 5.80 (d, 1H), 6.66-6.77 (m, 1H), 6.79-6.82 (m, 1H), 6.83-6.87 (m, 1H), 7.24 (apparent t, J=8.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H).

Compound 8. 4-(3-Methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(3-methoxyphenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-40% EtOAc in hexanes. The desired product, 4-(3-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as an off-white solid after purification of the THP deprotection product with 0-100% EtOAc in hexanes gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexaness. ¹H NMR (400 MHz, CDCl₃) δ 1.93-2.07 (m, 4H), 2.56-2.66 (m, 1H), 2.73 (apparent td, J=12.0, 3.6 Hz, 2H), 3.52 (apparent d, J=11.6 Hz, 2H), 3.81 (s, 3H), 6.75-6.79 (m, 1H), 6.80-6.82 (m, 1H), 6.85 (apparent d, J=7.6 Hz, 1H), 7.25 (apparent t, J=8 Hz, 1H), 7.35 (bs, 2H).

Compound 9. 2-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)pyrimidine

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Synthesized from THP-protected 3-iodo-pyrazole and 2-(piperidin-4-yl)pyrimidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 2-(1-(1H-pyrazol-5-yl)piperidin-4-yl)pyrimidine, was isolated as an off-white solid after purification of the THP deprotection product with silica gel column and 0-10% MeOH in EtOAc and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (39% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.00-2.17 (m, 4H), 2.92 (td, J=12.0, 2.8 Hz, 2H), 3.03 (apparent tt, J=11.6, 4.0 Hz, 1H), 3.83-3.89 (m, 2H), 5.80 (d, J=2.0 Hz, 1H), 7.14 (t, J=4.8 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 8.70 (d, J=5.2 Hz, 2H).

Compound 10. 2-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)pyrimidine

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Synthesized from THP-protected 4-iodo-pyrazole and 2-(piperidin-4-yl)pyrimidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 2-(1-(1H-pyrazol-4-yl)piperidin-4-yl)pyrimidine, was isolated as an off-white solid after purification of the THP deprotection product with silica gel column and 0-10% MeOH in EtOAc and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (28% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.06-2.17 (m, 4H), 2.76 (apparent td, J=11.6, 3.6 Hz, 2H), 2.95-3.10 (m, 1H), 3.45-3.53 (m, 2H), 7.15 (t, J=4.8 Hz, 1H), 7.29 (s, 2H), 8.70 (d, J=4.8 Hz, 2H).

Compound 11. Methyl 4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)benzoate

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Synthesized from THP-protected 3-iodo-pyrazole and methyl 4-(piperidin-4-yl)benzoate according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-70% EtOAc in hexanes gradient. The desired product, methyl 4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)benzoate, was isolated as a white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (20% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.83-1.97 (m, 4H), 2.67-2.77 (m, 1H), 2.86 (apparent td, 2H), 3.85-3.93 (s and m overlapping, 5H), 5.81 (d, J=1.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.42 (d, J=2.4 Hz, 1H), 7.98 (d, J=8.0 Hz, 2H), 9.11 (bs, 1H).

Compound 12. Methyl 4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)benzoate

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Synthesized from THP-protected 4-iodo-pyrazole and methyl 4-(piperidin-4-yl)benzoate according to general procedure 6. The crude THP-protected intermediate was chromatographed with column and 0-90% EtOAc in hexanes gradient. The desired product, methyl 4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)benzoate, was isolated as a white solid after purification of the THP deprotection product with silica gel column and 0-5% MeOH in EtOAc gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes. ¹H NMR (400 MHz, DMSO-d₆) δ 1.78-1.89 (m, 4H), 2.50-2.68 (m, 2H), 2.68-2.75 (m, 1H), 3.45 (apparent d, J=10.0 Hz, 2H), 3.85 (s, 3H), 7.28 (s, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.91 (d, J=8.0 Hz, 2H), 12.26 (bs, 1H).

Compound 13. N-(5-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)pyridin-2-yl)-N-methylacetamide

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Synthesized from THP-protected 4-iodo-pyrazole and N-methyl-N-(5-(piperidin-4-yl)pyridin-2-yl)acetamide according to general procedure IV. The crude THP-protected intermediate was chromatographed with column and 0-10% MeOH in EtOAc gradient and then 0-30% EtOH in hexanes gradient. The desired product, N-(5-(1-(1H-pyrazol-4-yl)piperidin-4-yl)pyridin-2-yl)-N-methylacetamide, was isolated as a white solid after purification of the THP deprotection product with silica gel column and 0-5% MeOH in EtOAc gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (27% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 1.80-1.87 (m, 4H), 2.00 (s, 3H), 2.50-2.58 (m, 2H), 2.65-2.75 (m, 1H), 3.25 (s, 3H), 3.42-3.48 (m, 2H), 7.27 (s, 1H), 7.30 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.81 (dd, J=8.4, 2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 2H), 12.29 (s, 1H).

Compound 14. 4-Phenoxy-1-(1H-pyrazol-4-yl)piperidine

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Synthesized according to general procedure 6 from THP-protected 4-iodo-1-pyrazole and 4-phenoxypiperidine (prepared as described in Hudskins, R. L. et al. Biorg. Med. Chem. Lett 2014, 24 (5), 1303-1306, incorporated herein by reference). The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 4-phenoxy-1-(1H-pyrazol-4-yl)piperidine, was isolated as an off-white solid after purification of the THP deprotection product with silica gel column and 0-5% MeOH in EtOAc gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (11% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.67-1.78 (m, 2H), 1.96-2.06 (m, 2H), 2.71-2.78 (distorted t, 2H), 3.15-3.22 (m, 2H), 4.45-4.51 (m, 1H), 6.91 (t, J=7.2 Hz, 1H), 6.96 (d, J=8.0 Hz, 2H), 7.23-7.31 (m, 4H), 12.26 (bs, 1H).

Compound 15. 4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-2-methoxypyridine

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Synthesized from THP-protected 4-iodo-pyrazole and 2-methoxy-4-(piperidin-4-yl)pyridine according to general procedure 6. The crude THP-protected intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-2-methoxypyridine, was isolated as an off-white solid after purification of the THP deprotection product with silica gel column and 0-5% MeOH in EtOAc gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (45% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.83-1.95 (m, 4H), 2.52-2.61 (m, 1H), 2.64-2.71 (m, 2H), 3.45-3.51 (m, 2H), 3.93 (s, 3H), 6.61-6.62 (m, 1H), 6.77 (dd, J=5.2, 1.2 Hz, 1H), 7.27 (s, 2H), 8.09 (d, J=5.2 Hz, 1H), 9.73 (bs, 1H).

Compound 16. 4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-2-methoxypyridine

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Synthesized from THP-protected 3-iodo-pyrazole and 2-methoxy-4-(piperidin-4-yl)pyridine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-70% EtOAc in hexanes gradient. The desired product, 4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)-2-methoxypyridine, was isolated as an off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (13% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.78-1.95 (m, 4H), 2.62 (tt, J=12.0, 4.0 Hz, 1H), 2.89 (td, J=12.0, 2.8 Hz, 2H), 3.87 (apparent d, J=12.8 Hz, 2H), 3.93 (s, 3H), 5.78 (s, 1H), 6.61 (s, 1H), 6.76 (d, J=5.2 Hz, 1H), 7.44 (s, 1H), 8.08 (d, J=5.6, 1H).

Compound 17. 4-(4-Fluorophenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and commercially available 4-(4-fluorophenyl)piperidine according to the general procedure 6. The crude THP-protected intermediate was chromatographed with column and 0-70% EtOAc in hexanes gradient. The desired product, 4-(4-fluorophenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as a white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in CH₂Cl₂gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (18% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.84-1.93 (m, 4H), 2.54-2.64 (m, 1H), 2.64-2.72 (m, 2H), 3.46-3.51 (m, 2), 6.97-7.04 (m, 2H), 7.17-7.23 (m, 2H), 7.29 (s, 2H), 9.76 (bs, 1H).

Compound 18. 4-(4-Fluorophenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and commercially available 4-(4-fluorophenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-45% EtOAc in hexanes gradient. The desired product, 4-(4-fluorophenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as a white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in CH₂Cl₂gradient and a precipitation of the chromatographed product out of CH₂Cl₂with excess of hexanes (10% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.78-1.93 (m, 4H), 2.64 (tt, J=12.0, 4.0 Hz, 1H), 2.84 (td, J=12.0, 3.2 Hz, 2H), 3.86 (apparent d, J=12.0 Hz, 2H), 5.80 (d, J=2.4 Hz, 1H), 6.96-7.03 (m, 2H), 7.17-7.30 (m, 2H), 7.42 (d, J=2.4 Hz, 1H), 9.20 (bs, 1H).

Compound 19. 4-(4-Methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(4-methoxyphenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-50% EtOAc in hexanes gradient. The desired product, 4-(4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (21% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.78-1.95 (m, 4H), 2.56-2.66 (m, 1H), 2.85 (apparent t, J=12.0 Hz, 2H), 3.80 (s, 3H), 3.85 (apparent d, J=11.6 Hz, 2H), 5.80 (s, 1H), 6.86 (d, J=7.6 Hz, 2H), 7.17 (d, J=7.2 Hz, 2H), 7.42 (s, 1H).

Compound 20. 4-(4-Methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(4-methoxyphenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in CH₂Cl₂gradient (15% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.86-1.96 (m, 4H), 2.50-2.62 (m, 1H), 2.63-2.73 (m, 2H), 3.48 (apparent d, J=11.6 Hz, 2H), 3.80 (s, 3H), 6.87 (d, J=8.8 Hz, 2H), 7.17 (d, J=8.4 Hz, 2H), 7.29 (s, 2H).

Compound 21. 4-(2-Methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(2-methoxyphenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product 4-(2-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (20% Yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.67-1.82 (m, 4H), 2.60-2.71 (apparent t, J=9.6 Hz, 2H), 2.90-3.05 (m, 1H), 3.70-3.85 (m, 5H), 5.70 (s, 1H), 6.85-6.99 (m, 2H), 7.15-7.20 (m, 2H), 7.44 (s, 1H), 11.76 (s, 1H).

Compound 22. 4-(2-Methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(2-methoxyphenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(2-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (11% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.85-1.95 (m, 4H), 2.65-2.77 (m, 2H), 2.99-3.11 (m, 1H), 3.44-3.51 (m, 2H), 3.84 (s, 3H), 6.88 (d, J=8.4 Hz, 1H), 6.95 (apparent t, J=7.6 Hz, 1H), 7.16-7.25 (m, 2H), 7.28 (s, 2H).

Compound 23. 1-(1H-Pyrazol-5-yl)-4-(p-tolyl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(p-tolyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-50% EtOAc in hexanes gradient. The desired product, 1-(1H-pyrazol-5-yl)-4-(p-tolyl)piperidine, was isolated as off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (7% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.62-1.81 (m, 4H), 2.26 (s, 3H), 2.57 (tt, J=12.0, 3.6 Hz, 1H), 2.62-2.72 (apparent td, 2H), 3.74 (apparent bd, J=11.6 Hz, 2H), 5.71 (s, 1H), 7.09 (d, J=8.0 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.44 (s, 1H), 11.76 (bs, 1H).

Compound 24. 1-(1H-Pyrazol-4-yl)-4-(p-tolyl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(p-tolyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-50% EtOAc in hexanes gradient. The desired product, 1-(1H-pyrazol-4-yl)-4-(p-tolyl)piperidine, was isolated as an off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (10% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.88-1.97 (m, 2H), 2.33 (s, 3H), 2.51-2.63 (m, 1H), 2.63-2.73 (m, 2H), 3.45-3.52 (m, 2H), 7.10-7.19 (apparent s, 4H), 7.28 (s, 2H).

Compound 25. 4-(4-(Methoxymethyl)phenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(4-(methoxymethyl)phenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-(methoxymethyl)phenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as an off-white fluffy solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (13% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.65-1.84 (m, 4H), 2.58-2.73 (m, 3H), 3.27 (s, 3H), 3.75 (apparent d, J=11.2 Hz, 2H), 4.36 (s, 2H), 5.71 (s, 1H), 7.24 (s, 4H), 7.44 (s, 1H), 11.78 (bs, 1H).

Compound 26. 4-(4-(Methoxymethyl)phenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(4-(methoxymethyl)phenyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-(methoxymethyl)phenyl)-1-(1H-pyrazol-4-yl)piperidine, was obtained as an off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (6% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.71-1.81 (m, 4H), 2.50-2.63 (m, 3H), 3.27 (s, 3H), 3.42 (apparent d, J=11.6 Hz, 2H), 4.36 (s, 2H), 7.24-7.27 (s overlapping, 6H), 12.23 (bs, 1H).

Compound 27. N-(4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)phenyl)-N-methylacetamide

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Synthesized from THP-protected 3-iodo-pyrazole and N-methyl-N-(4-(piperidin-4-yl)phenyl)acetamide according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-10% MeOH in CH₂Cl₂gradient. The desired product, N-(4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)phenyl)-N-methylacetamide, was obtained as a white solid after purification of the THP deprotection product with silica gel column and 0-10% EtOH in DCM gradient (8% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.80-1.98 (m, 7H), 2.64-2.74 (m, 1H), 2.86 (apparent td, J=12.0, 2.4 Hz, 2H), 3.25 (s, 3H), 3.87 (apparent d, J=12.8 Hz, 2H), 5.81 (s, 1H), 7.12 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.43 (s, 1H).

Compound 28. N-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)-N-methylacetamide

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Synthesized from THP-protected 4-iodo-pyrazole and N-methyl-N-(4-(piperidin-4-yl)phenyl)acetamide according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-10% EtOH in CH₂Cl₂gradient. The desired product, N-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)-N-methylacetamide, was obtained as an off-white solid after purification of the THP deprotection product with silica gel column and 0-20% EtOH in CH₂Cl₂(10% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.90 (s, 3H), 1.95-2.11 (m, 4H), 2.63-2.83 (m, 3H), 3.28 (s, 3H), 3.56 (apparent d, J=11.6 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 7.40 (s, 2H). ¹HNMR (400 MHz, DMSO-d6) δ 1.70-1.90 (s and m overlaping, 7H), 2.53-2.67 (m, 3H), 3.12 (s, 3H), 3.43 (apparent d, J=11.8 Hz, 2H); 7.22-7.27 (s overlapping with d, 4H), 7.33-7.35 (d, J=7.2 Hz, 2H), 12.21 (bs, 1H).

Compound 29. N-(4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)phenyl)acetamide

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Synthesized from THP-protected 3-iodo-pyrazole and N-(4-(piperidin-4-yl)phenyl)acetamide according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-10% EtOH in CH₂Cl₂gradient. The desired product, N-(4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)phenyl)acetamide, was obtained as an off-white solid after purification of the THP deprotection product with silica gel column and 0-10% EtOH in CH₂Cl₂gradient (8% yield). ¹H NMR (400 MHz, CD₃OD) δ 1.78-1.91 (m, 4H), 2.10 (s, 3H), 2.59-2.68 (m, 1H), 2.82 (td, J=12.0 Hz, 3.6 Hz, 2H), 3.79 (apparent d, J=12.4 Hz, 2H), 5.81 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.43-7.49 (m, 3H).

Compound 30. N-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)acetamide

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Synthesized from THP-protected 4-iodo-pyrazole and N-(4-(piperidin-4-yl)phenyl)acetamide according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-10% MeOH in CH₂Cl₂gradient. The desired product, N-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)acetamide, was obtained as an off-white solid after purification of the THP deprotection product with silica gel column and 0-10% MeOH in CH₂Cl₂gradient (18% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.86-1.96 (m, 4H), 2.18 (s, 3H), 2.52-2.64 (m, 1H), 2.64-2.73 (m, 2H), 3.48 (apparent d, J=10.8 Hz, 2H), 7.09 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 7.27 (s, 2H), 7.43 (d, J=8.0 Hz, 2H).

Compound 31. 5-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-2-methoxypyridine

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Synthesized from THP-protected 3-iodo-pyrazole and 2-methoxy-5-(piperidin-4-yl)pyridine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 5-(1-(1H-pyrazol-5-yl)piperidin-4-yl)-2-methoxypyridine, was obtained as an off-white solid after purification of the THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (9% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.76-1.93 (m, 4H), 2.56-2.66 (m, 1H), 2.81-2.88 (m, 2H), 3.86 (apparent d, J=12.0 Hz, 2H), 3.92 (s, 3H), 5.80 (s, 1H), 6.70 (d, J=8.4 Hz, 1H), 7.42 (s, 1H), 7.46 (dd, J=8.8, 2.4 Hz, 2H), 8.04 (d, 1H).

Compound 32. 5-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-2-methoxypyridine

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Synthesized from THP-protected 4-iodo-pyrazole and 2-methoxy-5-(piperidin-4-yl)pyridine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in CH₂Cl₂gradient. The desired product, 5-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-2-methoxypyridine, was obtained as an off-white solid after purification of the THP deprotection product with silica gel column and 0-15% MeOH in CH₂Cl₂gradient (12% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.70-1.93 (m, 4H), 2.52-2.62 (m, 1H), 2.63-2.73 (m, 2H), 3.46-3.52 (m, 2H), 3.92 (s, 3H), 6.71 (d, J=8.8 Hz, 1H), 7.28 (bs, 2H), 7.47 (dd, J=8.4 Hz, 2.4 Hz, 8.05 (d, J=2.0 Hz, 1H).

Compound 33. 1-(1H-Pyrazol-5-yl)-4-(m-tolyl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(m-tolyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-50% EtOAc in hexanes gradient. The desired product, 1-(1H-pyrazol-5-yl)-4-(m-tolyl)piperidine, was obtained as an oil after purification of the crude THP deprotection product with silica gel column and 0-70% EtOAc in hexanes gradient (20% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.83-1.93 (m, 4H), 2.34 (s, 3H), 2.57-2.67 (m, 1H), 2.87 (apparent t, J=11.6 Hz, 2H), 3.86 (apparent d, J=12.4 Hz, 2H), 5.79 (s, 1H), 7.00-7.09 (m, 3H), 7.17-7.25 (m, 1H), 7.42 (s, 1H).

Compound 34. 1-(1H-Pyrazol-4-yl)-4-(m-tolyl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(m-tolyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-70% EtOAc in hexanes gradient. The desired product, 1-(1H-pyrazol-4-yl)-4-(m-tolyl)piperidine, was obtained as an off-white solid after purification of the crude THP deprotection product with silica gel column and 0-10% MeOH in CH₂Cl₂gradient (7% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.88-2.00 (m, 4H), 2.35 (s, 3H), 2.51-2.63 (m, 1H), 2.64-2.73 (m, 2H), 3.45-3.52 (m, 2H), 7.01-7.08 (m, 3H), 7.22 (t, J=7.2 Hz, 1H), 7.28 (s, 2H).

Compound 35. 1-(1H-Pyrazol-5-yl)-4-(o-tolyl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(o-tolyl)piperidine according to general procedure 6. The crude THP-protected intermediate was chromatographed with silica gel column and 0-60% EtOAc in hexanes gradient. The desired product 1-(1H-pyrazol-5-yl)-4-(o-tolyl)piperidine was isolated as an oil after purification of the crude THP deprotection product with silica gel column and 0-50% EtOAc in CH₂Cl₂(8% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.82-1.93 (m, 4H), 2.38 (s, 3H), 2.82-2.92 (m, 3H), 3.88 (apparent d, J=12.4 Hz, 2H), 5.82 (s, 1H), 7.07-7.28 (m, 4H), 7.43 (s, 1H).

Compound 36. 1-(1H-Pyrazol-4-yl)-4-(o-tolyl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(o-tolyl)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 1-(1H-pyrazol-4-yl)-4-(o-tolyl)piperidine, was isolated as an off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (8% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.82-2.01 (m, 4H), 2.36 (s, 3H), 2.71 (td, J=11.6, 2.4 Hz), 2.76-2.87 (m, 1H), 3.51 (apparent d, J=11.2 Hz, 2H), 7.08-7.24 (m, 4H), 7.28 (s, 2H).

Compound 37. 1-(3-Methyl-1H-pyrazol-4-yl)-4-phenylpiperidine

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Synthesized from THP-protected 4-iodo-3-methyl-pyrazole and commercially available 4-phenylpiperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 1-(3-methyl-1H-pyrazol-4-yl)-4-phenylpiperidine, was isolated as an off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (15% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.76-1.83 (m, 4H), 2.12 (s, 3H), 2.53-2.62 (m, 3H), 3.17 (apparent d, J=11.2 Hz, 2H), 7.15-7.22 (m, 1H), 7.27-7.35 (m, 5H), 12.03 (bs, 1H).

Compound 38. 1-(5-Methyl-1H-pyrazol-5-yl)-4-phenylpiperidine

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Synthesized from THP-protected 3-iodo-5-methyl-pyrazole and commercially available 4-phenylpiperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-50% EtOAc in hexanes gradient. The desired product, 1-(5-methyl-1H-pyrazol-5-yl)-4-phenylpiperidine, was isolated as an off-white solid after silica gel column chromatography with 0-100% EtOAc in hexanes and a precipitation out of CH₂Cl₂with excess of hexanes (27% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.64-1.82 (m, 4H), 2.12 (s, 3H), 2.55-2.68 (m, 3H), 3.7 (apparent d, J=11.2 Hz, 2H), 5.47 (s, 1H), 7.17-7.20 (m, 1H), 7.24-7.31 (m, 4H), 11.43 (bs, 1H).

Compound 39. 4-(Phenylthio)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized according to the general procedure 6 from THP-protected 3-iodo-pyrazole and 4-(phenylthio)piperidine (prepared according to general procedure 4 using benzenethiol as the arylthiol of choice). The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-50% EtOAc in hexanes gradient. The desired product, 4-(phenylthio)-1-(1H-pyrazol-5-yl)piperidine, was isolated as an oil after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (15% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.50-1.59 (m, 2H), 1.93 (apparent d, J=11.2 Hz, 2H), 2.76 (apparent t, 2H), 3.34-3.42 (m, 1H), 3.56 (apparent d, J=12.0 Hz, 2H), 5.68 (s, 1H), 7.25 (apparent distorted t, J=7.2 Hz, 1H), 7.35 (apparent t, J=7.2 Hz, 2H), 7.39-7.46 (m, 3H), 11.76 (bs, 1H).

Compound 40. 4-(Phenylthio)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized according to the general procedure 6 from THP-protected 4-iodo-pyrazole and 4-(phenylthio)piperidine (prepared according to general procedure 4 using benzenethiol as the arylthiol of choice). The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-50% EtOAc in hexanes gradient. The desired product, 4-(phenylthio)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (23% yield). ¹H NMR (400 MHz, DMSO-d6) 1.54-1.65 (m, 2H), 1.92-1.98 (m, 2H), 2.59 (apparent t, J=9.6 Hz, 2H), 3.23-3.38 (m, 3H), 7.22-7.28 (s overlapping with m, 3H), 7.30-7.37 (m, 2H), 7.40-7.42 (m, 2H), 12.29 (bs, 1H).

Compound 41. 4-(Phenylsulfonyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized according to the general procedure 6 from THP-protected 3-iodo-pyrazole and 4 (phenylsulfonyl)piperidine (prepared from tert-butyl 4-(phenylthio)piperidine-1-carboxylate, Buchanan, J. L. et al. WO2010022055, the disclosure hereby incorporated by reference, via an mCPBA oxidation and then Boc deprotection with 4N HCl). The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(phenylsulfonyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes (22% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.83 (qd, 12.4, 4.4 Hz, 2H), 2.09 (apparent d, J=13.2 Hz, 2H), 2.72 (td, J=12.4 Hz, 2.4 Hz, 2H), 3.05 (tt, J=12.4 Hz, 3.2 Hz, 1H), 3.86 (apparent d, J=12.4 Hz, 2H), 5.72 (d, J=2.4 Hz, 1H), 7.39 (d, J=2.8 Hz, 1H), 7.58 (distorted t, J=7.2 Hz, 2H), 7.64-7.68 (m, 1H), 7.90 (apparent d, J=7.2 Hz, 2H).

Compound 42. 4-(Phenylsulfonyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized according to the general procedure 6 from THP-protected 4-iodo-pyrazole and 4-(phenylsulfonyl)piperidine (prepared from tert-butyl 4-(phenylthio)piperidine-1-carboxylate, Buchanan, J. L. et al. WO2010022055, the disclosure hereby incorporated by reference, via an mCPBA oxidation and then Boc deprotection with 4N HCl). The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes. The desired product, 4-(phenylsulfonyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes and a precipitation out of CH₂Cl₂with excess of hexanes (5% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.80-1.93 (m, 2H), 2.09 (apparent d, J=18.8 Hz, 2H), 2.49-2.58 (m, 2H), 2.99 (apparent tt, J=12.4 Hz, 2.8 Hz, 1H), 3.43 (apparent d, J=11.6 Hz, 2H), 7.20 (s, 2H), 7.55-7.62 (distorted t, J=7.6 Hz, 2H), 7.68 (distorted t, J=7.6 Hz, 1H), 7.89 (d, J=8.0 Hz, 2H).

Compound 43. 4-(3-Fluoro-4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(3-fluoro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-30% EtOAc in hexanes gradient. The desired product, 4-(3-fluoro-4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as an off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes (19% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.81 (qd, J=12.0, 4.0 Hz, 2H), 1.91 (distorted apparent d, J=12.8, 2H), 2.58 (tt, J=11.6, 4.0 Hz, 1H), 2.83 (td, J=12.4, 2.8 Hz, 2H), 3.82-3.88 (s overlap with d, 5H), 5.79 (d, J=2.4, 1H), 6.85-7.01 (m, 3H), 7.41 (d, J=2.4, 1H).

Compound 44. 4-(3-Fluoro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4′-iodo-pyrazole and 4-(3-fluoro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP protected coupling intermediate was chromatographed with silica gel column and 0-60% EtOAc in hexanes. The desired product, 4-(3-fluoro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-10% MeOH in CH₂Cl₂(14% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.83-1.94 (m, 4H), 2.50-2.59 (m, 1H), 2.66 (apparent td, J=11.6, 4.0 Hz, 2H), 3.45-3.50 (m, 2H), 3.88 (s, 3H), 6.87-7.00 (m, 3H), 7.27 (s, 2H), 9.71 (bs, 1H). ¹H NMR (400 MHz, DMSO-d6) δ 1.66-1.82 (m, 4H), 2.49-2.59 (m, 3H), 3.40 (apparent d, J=11.6, 2H), 3.80 (s, 3H), 7.01-7.15 (m, 3H), 7.25 (s, 2H), 12.24 (s, 1H).

Compound 45. 4-(3-Methoxybenzyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and commercially available 4-(3-methoxybenzyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(3-methoxybenzyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-10% MeOH in EtOAc (15% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.45 (qd, J=12.0, 4.0 Hz, 2H), 1.60-1.67 (m, 1H), 1.73 (apparent d, J=12.8 Hz, 2H), 2.50 (td, J=11.6, 2.4 Hz, 2H), 2.55 (d, J=7.2 Hz, 2H), 3.31-3.36 (m, 2H), 3.81 (s, 3H), 6.71-6.79 (m, 3H), 7.18-7.23 (m, 3H), 9.65 (bs, 1H).

Compound 46. 4-(2-Fluoro-4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(2-fluoro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(2-fluoro-4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as an off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (9% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.71-1.81 (m, 4H), 2.45-2.73 (m, 2H), 2.79-2.86 (m, 1H), 3.73-3.80 (s overlapping with d, 5H), 5.71 (d, J=2.4 Hz, 1H), 6.72-6.80 (m, 2H), 7.23 (t, J=8.8 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 11.86 (bs, 1H).

Compound 47. 4-(2-Fluoro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(2-fluoro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(2-fluoro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (17% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.86-1.98 (m, 4H), 2.64-2.74 (m, 2H), 2.84-2.93 (m, 1H), 3.48 (apparent d, J=11.6 Hz, 2H), 3.78 (s, 3H), 6.61 (dd, J=12.4, 2.4 Hz, 1H), 6.67 (dd, J=8.8, 2.4 Hz, 1H), 7.15 (t, J=8.4 Hz, 1H), 7.27 (s, 2H) 9.74 (bs, 1H).

Compound 48. 4-(3-Fluorophenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and commercially available 4-(3-fluorophenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The product, 4-(3-fluorophenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (27% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.80-1.97 (m, 4H), 2.66 (tt, J=12.0, 4.0 Hz, 1H), 2.86 (td, J=12.0, 2.8 Hz, 2H), 3.87 (apparent d, J=12.4 Hz, 2H), 5.79 (d, J=2.4 Hz, 1H), 6.86-6.97 (m, 2H), 7.02 (d, J=7.6 Hz, 1H), 7.23-7.30 (m, 1H), 7.42 (d, J=2.4, 1H).

Compound 49. 4-(3-Fluorophenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and commercially available 4-(3-fluorophenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The product, 4-(3-fluorophenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (22% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.92-2.03 (m, 4H), 2.58-2.67 (m, 1H), 2.67-2.76 (m, 2H), 3.51 (apparent d, J=12.0 Hz, 2H), 6.80-6.98 (m, 2H), 7.03 (d, J=7.6 Hz, 1H), 7.25-7.31 (m, 1H), 7.32 (s, 2H).

Compound 50. 4-(2-Fluorophenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(2-fluorophenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(2-fluorophenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as white solid after purification of the crude THP deprotection product with 0-100% EtOAc in hexanes gradient (13% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.75-1.82 (m, 4H), 2.66-2.72 (m, 2H), 2.87-2.97 (m, 1H), 3.77 (d, J=12.0 Hz, 2H), 5.72 (s, 1H), 7.11-7.19 (m, 2H), 7.23-7.30 (m, 1H), 7.31-7.38 (m, 1H), 7.45 (s, 1H), 11.78 (s, 1H).

Compound 51. 4-(2-Fluorophenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(2-fluorophenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes. The desired product, 4-(2-fluorophenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc gradient (13% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.90-2.05 (m, 4H), 2.74 (td, J=11.6, 2.8 Hz, 2H), 2.99 (apparent tt J=12.0, 4.0 Hz, 1H), 3.51 (d, J=11.6 Hz, 2H), 7.00-7.06 (m, 1H), 7.09-7.14 (m, 1H), 7.16-7.23 (m, 1H), 7.27-7.32 (m and s overlapping, 3H).

Compound 52. 4-(4-(Ethylsulfonyl)phenyl)-1-(1H-pyrazol-4-yl)piperidine

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Synthesized from THP-protected 4-iodo-pyrazole and 4-(4-(ethylsulfonyl)phenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in DCM gradient. The desired product, 4-(4-(ethylsulfonyl)phenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white/beige solid after purification of the crude THP deprotection product with silica gel column and 0-5% MeOH in CH₂Cl₂gradient and a precipitation out of CH₂Cl₂with excess of hexanes (14% yield). ¹H NMR (400 MHz, CD₃CN) δ 1.17 (t, J=7.2 Hz, 3H), 1.85-1.91 (m, 4H), 2.59-2.65 (m, 2H), 2.72-2.80 (m, 1H), 3.13 (q, J=7.2 Hz, 2H), 3.45-3.52 (m, 2H), 7.22 (s, 2H), 7.53 (apparent d, J=8.0 Hz, 2H), 7.80 (apparent d, J=8.4 Hz, 2H), 10.57 (bs, 1H).

Compound 53. 1-Phenyl-4-(1H-pyrazol-5-yl)piperazine

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Synthesized from THP-protected 3-iodo-pyrazole and commercially available 1-phenylpiperazine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 1-phenyl-4-(1H-pyrazol-5-yl)piperazine, was isolated as off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in CH₂Cl₂(37% yield). ¹H NMR (600 MHz CDCl₃) δ 3.31-3.33 (m, 4H), 3.39-3.41 (m, 4H), 5.83 (s, 1H), 6.89 (t, J=7.2 Hz, 1H), 6.99 (d, J=8.4 Hz, 2H), 7.29 (t, J=7.2 Hz, 2H), 7.43 (s, 1H).

Compound 54. 4-Phenyl-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and commercially available 4-phenylpiperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-50% EtOAc in hexanes gradient. The desired product, 4-phenyl-1-(1H-pyrazol-5-yl)piperidine, was isolated as white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in CH₂Cl₂(13% yield). ¹H NMR (600 MHz CDCl₃) δ 1.86-1.95 (m, 4H), 2.65 (apparent tt, J=12.0, 4.2 Hz, ¹H), 2.86 (td, J=12.0, 3.0 Hz, 2H), 3.86 (apparent d, J=12.0 Hz, 2H), 5.81 (s, 1H), 7.20-7.23 (m, 2H), 7.29-7.33 (m, 2H), 7.42 (s, 1H).

Compound 55. 4-Phenoxy-1-(1H-pyrazol-5-yl)piperidine

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Synthesized according to general method 6 from THP-protected 3-iodo-pyrazole and 4-phenoxypiperidine (prepared as in Hudskins, R. L. et al. Biorg. Med. Chem. Lett 2014, 24 (5), 1303-1306, incorporated herein by reference). The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The desired product, 4-phenoxy-1-(1H-pyrazol-5-yl)piperidine, was isolated after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient. ¹H NMR (600 MHz, CDCl₃) δ 1.91-1.93 (m, 2H), 2.05-2.11 (m, 2H), 3.09-3.12 (m, 2H), 3.56-3.59 (m, 2H), 4.40-4.50 (m, 1H), 5.78 (s, 1H), 6.90-6.96 (m, 3H), 7.23-7.30 (m, 2H), 7.40 (s, 1H).

Compound 56. Methyl 3-(1-(1H-pyrazol-5-yl)piperidin-4-yl)benzoate

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Synthesized from THP-protected 3-iodo-pyrazole and methyl 3-(piperidin-4-yl)benzoate according to general method 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, methyl 3-(1-(1H-pyrazol-5-yl)piperidin-4-yl)benzoate, was isolated as off-white solid after silica gel column chromatography with 0-100% Hex in EtOAC gradient (23% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.66-1.78 (m, 2H), 1.83 (apparent d, J=11.2 Hz, 2H), 2.67-2.79 (m, 3H), 3.77 (apparent d, J=11.2 Hz, 2H), 3.85 (s, 3H), 5.72 (s, 1H), 7.44-7.49 (m, 2H), 7.57 (d, J=7.6 Hz, 1H), 7.78-7.84 (m, 2H), 11.80 (bs, 1H).

Compound 57. Methyl 3-(1-(1H-pyrazol-4-yl)piperidin-4-yl)benzoate

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Synthesized from THP-protected 4-iodo-pyrazole and methyl 3-(piperidin-4-yl)benzoate according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, methyl 3-(1-(1H-pyrazol-4-yl)piperidin-4-yl)benzoate, was isolated as an off-white solid after purification of the THP deprotection product with 0-100% EtOAc in CH₂Cl₂and a precipitation out of CH₂Cl₂with excess of hexanes (23% yield). ¹H NMR (400 MHz, DMSO-d6) δ 1.73-1.85 (m, 4H), 2.54-2.60 (m, 2H), 2.67-2.72 (m, 1H), 3.44 (apparent d, J=10.0 Hz, 2H), 3.85 (s, 3H), 7.24-7.29 (m, 2H), 7.47 (apparent t, J=7.6 Hz, 1H), 7.57-7.60 (m, 1H), 7.79-7.86 (m, 2H), 12.28 (bs, 1H).

Compound 58. 4-(4-(Ethylsulfonyl)phenyl)-1-(1H-pyrazol-5-yl)piperidine

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Synthesized from THP-protected 3-iodo-pyrazole and 4-(4-(ethylsulfonyl)phenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with column and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-(ethylsulfonyl)phenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as an off-white solid after purification of the THP deprotection product with 0-5% MeOH in CH₂Cl₂and a precipitation out of CH₂Cl₂with excess of hexanes (25% yield). ¹H NMR (400 MHz, CD₃CN) δ 1.16 (t, J=7.2, 3H), 1.73-1.88 (m, 4H), 2.73-2.85 (m, 3H), 3.13 (q, 7.6 Hz, 2H), 3.81-3.84 (m, 2H), 5.74 (d, J=2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H).

Compound 59. 3-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-5-methoxypyridine

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Synthesized from THP-protected 4-iodo-pyrazole and 3-methoxy-5-(piperidin-4-yl)pyridine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-10% MeOH in EtOAc. The desired product, 3-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-5-methoxypyridine, was isolated as off-white/beige solid after purification of the THP deprotection product with silica gel column and 0-10% MeOH in CH₂Cl₂and a precipitation out of CH₂Cl₂with excess of hexanes (18% yield). ¹H NMR (400 MHz, CD₃OD) δ 1.91-1.98 (m, 4H), 2.69-2.73 (m, 3H), 3.52 (apparent d, J=11.2 Hz, 2H), 3.89 (s, 3H), 7.33 (bs, 1H), 7.37 (bs, 2H), 8.07-8.09 (m, 2H).

Compound 60. 3-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-5-methoxypyridine

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Synthesized from THP-protected 3-iodo-pyrazole and 3-methoxy-5-(piperidin-4-yl)pyridine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-5% MeOH in EtOAc gradient. The desired product, 3-(1-(1H-pyrazol-5-yl)piperidin-4-yl)-5-methoxypyridine, was isolated as off-white/beige solid after purification of the THP deprotection product with silica gel column and 0-10% MeOH in CH₂Cl₂and a precipitation out of CH₂Cl₂with excess of hexanes (25% yield). ¹H NMR (600 MHz, DMSO-d6) δ 1.70-1.90 (m 4H), 2.66-2.68 (m, 3H), 3.70-3.90 (m, 5H), 5.72 (s, 1H), 7.25-7.30 (m, 1H), 7.45 (s, 1H), 8.12-8.14 (m, 2H), 11.78 (bs, 1H).

Compound 61. 4-(3-Chlorophenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and commercially available 4-(3-chlorophenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-5% MeOH in EtOAc gradient. The desired product, 4-(3-chlorophenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as off-white/beige solid after purification of the THP deprotection product with silica gel column and 0-10% MeOH in CH₂Cl₂and a precipitation out of CH₂Cl₂with excess of hexanes (8% yield). ¹HNMR (500 MHz, CD₃OD) δ 7.38 (s, 2H), 7.32-7.29 (m, 2H), 7.23-7.21 (m, 2H), 3.54-3.51 (m, 2H), 2.72-2.65 (m, 3H), 1.95-1.88 (m, 4H).

Compound 62. 4-(4-chlorophenyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was synthesized from THP-protected 3-iodo-pyrazole and 4-(4-chloro-phenyl)-piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-40% EtOAc in hexanes gradient. The desired product, 4-(4-chlorophenyl)-1-(1H-pyrazol-3-yl)piperidine, was isolated as an off-white solid after purification of the THP deprotection product with silica gel column chromatography and 0-100% EtOAc in hexanes gradient (18% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.77-1.93 (m, 4H), 2.63 (apparent tt, J=11.6 Hz, 4.0 Hz, 1H), 2.83 (td, J=12.4 Hz, 3.6 Hz, 2H), 3.83-3.89 (m, 2H), 5.80 (d, J=2.4 Hz, 1H), 7.18 (apparent d, J=8.4 Hz, 2H), 7.28 (apparent d, J=8.4 Hz, 2H), 7.42 (d, J=2.4 Hz, 1H).

Compound 63. 4-(4-chlorophenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was synthesized from THP-protected 4-iodo-pyrazole and 4-(4-chloro-phenyl)-piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-60% EtOAc in hexanes gradient. The product, 4-(4-chlorophenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as an off-white solid after purification of the crude THP deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (23% yield). ¹H NMR (400 MHz, CDCl₃) δ 1.86-1.93 (m, 4H), 2.53-2.63 (m, 1H), 2.63-2.72 (m, 2H), 3.45-3.51 (m, 2H), 7.18 (apparent d, J=8.0 Hz, 2H), 7.28 (apparent d, J=8.4 Hz, 2H); ¹H NMR (400 MHz, DMSO-d6) δ 1.68-1.82 (m, 4H), 2.50-2.57 (m, 2H), 2.57-2.64 (m, 1H), 3.42 (apparent d, J=11.6 Hz, 2H), 7.26 (s, 2H), 7.29-7.37 (m, 4H), 12.24 (s, 1H).

Compound 64. 4-(3-Chloro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was synthesized from THP-protected 4-iodo-1H-pyrazole and 4-(3-chloro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-35% EtOAc in hexanes gradient. The product, 4-(3-chloro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as a as white solid after purification of the crude THP deprotection product with silica gel column chromatography and 0-100% EtOAc in hexanes gradient (16% yield). ¹H NMR (600 MHz, CD₃OD) δ 1.80-1.91 (m, 4H), 2.58 (apparent tt, J=12.0, 3.6 Hz, 1H), 2.66 (td, J=12.0, 2.4 Hz, 2H), 3.49 (apparent d, J=11.4 Hz, 2H), 3.85 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.16 (dd, J=12.0, 1.8 Hz, 1H), 7.26 (d, J=2.4 Hz, 1H), 7.37 (s, 2H); H NMR (600 MHz, CDCl₃) δ 1.86-1.92 (m, 4H), 2.51-2.57 (m, 1H), 2.67 (td, J=10.8, 4.2 Hz, 2H), 3.48 (d, J=11.4 Hz, 1H), 3.89 (s, 3H), 6.89 (d, J=8.4 Hz, 1H), 7.10 (dd, J=8.4, 2.4 Hz, 2H).

Compound 65. 4-(2-Chloro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was synthesized from THP-protected 4-iodo-pyrazole and 4-(2-chloro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-35% EtOAc in hexanes. The product, 4-(2-chloro-4-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine was isolated as a white solid after purification of the crude THP deprotection product with silica gel column chromatography and 0-100% EtOAc in hexanes gradient (13% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.73-1.79 (m, 4H), 2.54-2.59 (m, 2H), 2.87-2.97 (m, 1H), 3.45 (apparent d, J=11.7 Hz, 2H), 3.76 (s, 3H), 6.92 (dd, J=8.7, 2.7 Hz, 1H), 7.02 (d, J=2.7, 1H), 7.28 (s, 2H), 7.32 (d, J=8.7 Hz, 1H), 12.14 (bs, 1H).

Compound 66. 4-(2-Chloro-4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was synthesized from THP-protected 3-iodo-pyrazole and 4-(2-chloro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-30% EtOAc in hexanes. The product, 4-(2-chloro-4-methoxyphenyl)-1-(1H-pyrazol-3-yl)piperidine was isolated as a white solid after purification of the crude THP deprotection product with silica gel column chromatography and 0-100% EtOAc in hexanes gradient (16% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.81 (apparent qd, J=12.0 Hz, 3.6 Hz, 2H), 1.92-1.94 (m, 2H), 3.11 (tt, J=12.0 Hz, 3.6, 1H), 2.90 (td, J=12.0 Hz, 2.4, 2H), 3.80 (s, 3H), 3.86-3.90 (m, 2H), 5.82 (s, 1H), 6.82 (dd, J=9.0 Hz, 3.0 Hz, 1H), 6.94 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.43 (d, J=2.4 Hz, 1H), 9.25 (bs, 1H).

Compound 67. 4-(3-Chloro-4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 4-(3-chloro-4-methoxyphenyl)piperidine according to the general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-40% EtOAc in hexanes gradient. The product, 4-(3-chloro-4-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as a white solid after purification of the crude THP deprotection product with silica gel column chromatography and 0-100% EtOAc in hexanes gradient (18% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.82 (apparent qd, J=11.4, 4.2 Hz, 2H), 1.90 (apparent distorted d, J=13.2 Hz, 2H), 2.59 (tt, J=12.6, 3.6 Hz, 1H), 2.83 (td, J=12.0, 3.0 Hz, 2H), 3.83-3.86 (m, 2H), 3.89 (s, 3H), 5.80 (d, J=1.8 Hz, 1H), 6.88 (d, J=9.0 Hz, 1H), 7.10 (dd, J=8.4, 2.4 Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H).

Compound 68. 4-((4-Methoxyphenyl)thio)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 4-((4-methoxy-phenyl)thio)piperidine according to general procedure 6. The crude THP-protected coupling intermediate was chromatographed with silica gel column and 0-100% EtOAc in hexanes gradient. The crude THP deprotection product was chromatographed with 0-100% EtOAc in hexanes to afford the desired product, 4-((4-methoxyphenyl)thio)-1-(1H-pyrazol-3-yl)piperidine, as a white/off-white solid (22% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.67-1.74 (m, 2H), 1.80-2.05 (m, 2H), 2.81 (ddd, J=13.8, 9.6, 3.0 Hz, 2H), 3.02 (tt, J=10.8, 3.6, 1H), 3.68 (apparent dt, J=13.2, 3.6 Hz, 2H), 3.81 (s, 3H), 5.73 (broad d, J=1.8 Hz, 1H), 6.85 (apparent d, J=8.4, 2H), 7.38 (broad d, J=2.4 Hz, 1H), 7.42 (apparent d, J=8.4, 2H).

Compound 69. N-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)-N-methylacetamide

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Compound was prepared from THP-protected 4-iodo-pyrazole and N-(3-fluoro-4-(piperidin-4-yl)phenyl)-N-methylacetamide according to the general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, N-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)-N-methylacetamide, was obtained as a white solid after purification of the crude THP deprotection product with silica gel column chromatography and 0-5% MeOH in CH₂Cl₂gradient (9% yield). ¹H NMR (600 MHz, CD₃OD) δ 1.88-2.01 (m overlap with s, 7H), 2.72-2.76 (m, 2H), 3.00-3.04 (m, 1H), 3.23 (s, 3H), 3.54 (d, J=11.4 Hz, 2H), 7.12 (apparent d, J=9.0 Hz, 2H), 7.40-7.45 (m overlap with s, 3H).

Compound 70. 4-((4-Fluorophenyl)thio)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-((4-fluorophenyl)thio)piperdine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-65% EtOAc in hexanes gradient. The desired product, 4-((4-fluorophenyl)thio)-1-(1H-pyrazol-4-yl)piperidine, was isolated as an off-white solid after purification of the crude THP deprotection product with silica gel column chromatography and 0-100% EtOAc in hexanes gradient (11% yield). ¹H NMR (500 MHz, DMSO-d6) 1.53-1.62 (m, 2H), 1.89-1.93 (m, 2H), 3.21-3.28 (m, 3H), 7.17-7.20 (m, 4H), 7.48 (apparent dd, J=8.5, 5.5 Hz, 2H), 12.25 (bs, 1H).

Compound 71. N-(4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-3-fluorophenyl)-N-methylacetamide

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Compound was prepared from THP-protected 3-iodo-pyrazole and N-(3-fluoro-4-(piperidin-4-yl)phenyl)-N-methylacetamide according to the general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, N-(4-(1-(1H-pyrazol-3-yl)piperidin-4-yl)-3-fluorophenyl)-N-methylacetamide, was obtained as a white solid after purification of the crude THP deprotection product with 0-100% EtOAc in hexanes gradient (22% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.78-1.83 (m, 7H), 2.66-2.77 (m, 2H), 2.88-2.99 (m, 1H), 3.16 (s, 3H), 3.78 (apparent d, J=12.3 Hz, 2H), 5.73 (d, J=2.1 Hz, 1H), 7.16 (apparent d, J=7.8 Hz, 1H), 7.26 (apparent d, J=11.7 Hz, 1H), 7.41 (apparent t, J=8.4 Hz, 1H), 7.47 (d, J=1.8 Hz, 1H), 11.81 (bs, 1H).

Compound 72. 4-(3-Fluoro-5-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(3-fluoro-5-methoxyphenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-45%. EtOAc in hexanes gradient. The desired product, 4-(3-fluoro-5-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine was isolated as an off-white solid after purification of the crude THP-deprotection product with silica gel column chromatography and 0-100% EtOAc in hexaness gradient (23% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.91-2.03 (m, 4H), 2.53-2.64 (m, 1H), 2.67-2.76 (m, 2H), 3.47-3.54 (m, 2H), 3.80 (s, 3H), 6.48 (dt, J=10.5, 2.4 Hz, 1H), 6.54-6.61 (m, 2H), 7.33 (s, 2H).

Compound 73. 4-(3-Fluoro-5-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 4-(3-fluoro-5-methoxyphenyl)piperidine according to general procedure 6. The THP-protected coupling intermediate was purified with silica gel column chromatography and 0-35% EtOAc in hexanes gradient. The desired product, 4-(3-Fluoro-5-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as an off white/tan solid after purification of the crude THP-deprotection product with silica gel column chromatography and 0-100% EtOAc in hexanes gradient (38% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.76-1.95 (m, 4H), 2.62 (apparent tt, J=11.7, 3.9 Hz, 1H), 2.87 (td, J=12.4, 3.0 Hz, 2H), 3.78 (s, 3H), 3.83-3.89 (m, 2H), 5.78 (d, J=2.4 Hz, 1H), 6.47 (apparent dt, J=10.5, 2.4 Hz, 1H), 6.53-6.59 (m, 2H), 6.84 (bs, 1H), 7.43 (d, J=2.4 Hz, 1H).

Compound 74. 4-(4-Fluoro-3-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 4-(4-fluoro-3-methoxyphenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-50% EtOAc in hexanes gradient. The desired product, (4-fluoro-3-methoxyphenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as a white solid after purification of the crude THP deprotection product with 0-100% EtOAc in hexanes gradient (24% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 1.66-1.83 (m, 4H), 2.57-2.72 (m, 3H), 3.76 (apparent d, J=12.0 Hz, 2H), 3.84 (s, 3H), 5.72 (d, J=2.4 Hz, 1H), 6.78-6.84 (m, 1H), 7.04-7.14 (m, 2H), 7.45 (d, J=2.1 Hz, 1H), 11.79 (bs, 1H).

Compound 75. 4-(4-Fluoro-3-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-fluoro-3-methoxyphenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-50% EtOAc in hexanes gradient. The desired product, 4-(4-fluoro-3-methoxyphenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as a white solid after purification of the crude THP deprotection product with 0-10% MeOH in CH₂Cl₂(29% yield). ¹H NMR (300 MHz, CDCl₃) δ 1.90-2.02 (m, 4H), 2.53-2.63 (m, 1H), 2.66-2.75 (m, 2H), 3.47-3.52 (m, 2H), 3.89 (s, 3H), 6.73-6.79 (m, 1H), 6.84 (dd, J=8.4 Hz, 2.1 Hz, 1H), 7.01 (dd, J=11.1, 8.1 Hz, 1H), 7.31 (s, 2H).

Compound 76. 4-((3-Methoxyphenyl)thio)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-((3-methoxyphenyl)thio)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-((3-methoxyphenyl)thio)-1-(1H-pyrazol-4-yl)piperidine, was isolated as a white solid after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient (32% yield). ¹H NMR (600 MHz, CDCl₃) δ 1.76-1.85 (m, 2H), 2.05-2.10 (m, 2H), 2.69 (ddd, J=13.2, 11.4, 3.0 Hz, 2H), 3.20 (tt, J=10.2, 3.6 Hz, 1H), 3.33 (dt, J=12.2, 4.0 Hz, 2H), 3.81 (s, 3H), 6.79 (ddd, J=8.4, 3.0, 1.2 Hz, 1H), 6.97 (apparent dd, J=2.4, 1.8 Hz 1H), 7.00-7.03 (m, 1H), 7.20-7.24 (m, 3H).

Compound 77. (4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone

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Compound was prepared from THP protected 4-iodo-pyrazole and (4-(piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, (4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone, was isolated as a white/off-white solid after purification of the crude THP deprotection product with silica gel column and 0-12% CH₂Cl₂in CH₃OH gradient (8% yield). ¹HNMR (400 MHz, CD₃OD) δ 7.44 (distorted d, J=8.4 Hz, 2H), 7.33 (distorted t, J=3.2 Hz, 4H), 3.55 (t, J=6.8 Hz, 2H), 3.49-3.42 (m, 4H), 2.69-2.62 (m, 3H), 1.97-1.84 (m, 8H).

Compound 78. (4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone

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Compound was prepared from THP-protected 3-iodo-pyrazole and (4-(piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, (4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone, was isolated as a white solid after purification of the crude THP deprotection product with silica gel column and 0-12% CH₂Cl₂in CH₃OH gradient (23% yield). ¹HNMR (400 MHz, CD₃OD) δ 7.50-7.47 (m, 3H), 7.37 (d, J=8.0 Hz, 2H), 5.84 (bs, 1H), 3.83 (d, J=9.0 Hz, 2H), 3.60 (t, J=7.0 Hz, 2H), 3.49 (t, J=6.5 Hz, 2H), 2.84 (dt, J=11.5, 2.0 Hz, 2H), 2.75 (tt, J=11.5, 4.5 Hz, 1H), 2.02-1.98 (m, 2H), 1.94-1.86 (m, 6H).

Compound 79. 4-(4-Methoxybenzyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and commercially available 4-(4-methoxybenzyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-methoxybenzyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as a gummy colorless solid after silica gel column purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient (10% yield). ¹HNMR (400 MHz, CD₃OD) δ 7.42 (s, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 5.75 (bs, 1H), 3.78 (s, 3H), 3.64 (d, J=12.0 Hz, 2H), 2.63 (t, J=11.2.0 Hz, 2H), 2.52 (d, J=6.8 Hz, 2H), 1.72-1.61 (m, 3H), 1.40-1.31 (m, 2H).

Compound 80. 4-((4-Methoxyphenyl)thio)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-((4-methoxyphenyl)thio)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-((4-methoxyphenyl)thio)-1-(1H-pyrazol-4-yl)piperidine, was isolated as a white/off-white solid after silica gel column purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient (15% yield). ¹HNMR (600 MHz, DMSO-d₆) δ 12.25 (s, 1-NH), 7.41-7.39 (m, 2H), 7.23-7.19 (m, 2H), 6.94 (d, J=9.0 Hz, 2H), 3.76 (s, 3H), 3.27-3.23 (m, 2H), 3.08 (tt, J=10.8, 4.2 Hz, 1H), 2.54-2.53 (m, 2H), 1.89-1.86 (m, 2H), 1.58-1.52 (m, 2H).

Compound 81. (4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)(pyrrolidin-1-yl)methanone

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Compound was prepared from THP-protected 4-iodo-pyrazole and (3-fluoro-4-(piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, (4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)(pyrrolidin-1-yl)methanone, was isolated as a white/off-white solid after purification of the crude THP deprotection product with silica gel column and 0-15% CH₂Cl₂in MeOH gradient (10% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 12.28 (s, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.34-7.25 (m, 4H), 3.47-3.39 (m, 6H), 2.90 (tt, J=11.5, 3.5 Hz, 1H), 2.55 (td, J=12.0, 2.5 Hz, 2H), 1.87-1.78 (m, 8H).

Compound 82. ((4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)-3-fluorophenyl)(pyrrolidin-1-yl)methanone

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Compound was prepared from THP-protected 3-iodo-pyrazole and (3-fluoro-4-(piperidin-4-yl)phenyl)(pyrrolidin-1-yl)methanone according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, (4-(1-(1H-pyrazol-3-yl)piperidin-4-yl)-3-fluorophenyl)(pyrrolidin-1-yl)methanone, was isolated as a white/off-white solid after silica gel column purification of the crude THP deprotection product with 0-15% CH₂Cl₂in MeOH gradient (7% yield). ¹HNMR (600 MHz, CD₃OD) δ 7.48-7.42 (m, 2H), 7.34 (dd, J=7.8 Hz, 1.2 Hz, 1H), 7.27 (d, J=10.8 Hz, 2.4 Hz, 1H), 5.86 (bs, 1H), 3.85 (bs, 2H), 3.60 (t, J=7.2 Hz, 2H), 3.50 (t, J=6.6 Hz, 2H), 3.10-3.05 (m, 1H), 2.86 (t, J=9.6 Hz, 2H), 2.03-1.99 (m, 2H), 1.96-1.91 (m, 6H).

Compound 83. 1-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)benzyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 1-(4-(piperidin-4-yl)benzyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)benzyl)pyrrolidin-2-one, was isolated as a white/off-white solid after silica gel column purification of the crude THP deprotection product using 0-15% CH₂Cl₂in MeOH gradient (25% yield): ¹HNMR (600 MHz, CD₃OD) δ 7.39 (s, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 4.44 (s, 2H), 3.54-3.52 (m, 2H), 3.37-3.34 (m, 2H), 2.72-2.65 (m, 3H), 2.46 (t, J=7.8 Hz, 2H), 2.06-2.01 (m, 2H), 1.93-1.88 (m, 4H).

Compound 84. 1-(4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)benzyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 3-iodo-pyrazole and 1-(4-(piperidin-4-yl)benzyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)benzyl)pyrrolidin-2-one, was isolated as a white/off-white solid after silica gel column purification of the crude THP deprotection product using 0-15% CH₂Cl₂in MeOH gradient (26% yield): ¹HNMR (500 MHz, CD₃OD) δ 7.46 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 5.82 (bs, 1H), 4.44 (s, 2H), 3.81 (d, J=11.0 Hz, 2H), 3.36-3.35 (m, 2H), 2.83 (td, J=12.0 Hz, 3.0 Hz, 2H), 2.71-2.65 (m, 1H), 2.45 (t, J=8.0 Hz, 2H), 2.06-2.00 (m, 2H), 1.90-1.81 (m, 4H).

Compound 85. 1-(1H-Pyrazol-4-yl)-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(1H-pyrazol-4-yl)-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)piperidine, was isolated as a white/off-white solid after silica gel column purification of the crude THP deprotection product using 0-15% CH₂Cl₂in MeOH gradient (8% yield): ¹HNMR (600 MHz, CD₃OD) δ 7.81-7.79 (m, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.39 (s, 2H), 3.56-3.54 (m, 2H), 3.26-3.23 (m, 4H), 2.82-2.78 (m, 1H), 2.73 (td, J=11.5, 3.6 Hz, 2H), 1.98-1.92 (m, 4H), 1.78-1.75 (m, 4H).

Compound 86. 2-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-4-(trifluoromethyl)pyridine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 2-(piperidin-4-yl)-4-(trifluoromethyl)pyridine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 2-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-4-(trifluoromethyl)pyridine, was isolated after purification of the crude THP deprotection product with 0-15% CH₂Cl₂in MeOH gradient as a white/off-white solid (16% yield): ¹HNMR (600 MHz, DMSO-d₆) δ 12.28 (s, 1-NH), 8.81 (d, J=5.4 Hz, 1H), 7.70 (s, 1H), 7.61 (d, J=5.4 Hz, 1H), 7.30-7.26 (m, 2H), 3.46-3.42 (m, 2H), 2.95-2.90 (m, 1H), 2.59-2.54 (m, 2H), 1.94-1.90 (m, 4H).

Compound 87. 2-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-4-(trifluoromethyl)pyridine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 2-(piperidin-4-yl)-4-(trifluoromethyl)pyridine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 2-(1-(1H-pyrazol-5-yl)piperidin-4-yl)-4-(trifluoromethyl)pyridine, was isolated after purification of the crude THP deprotection product with 0-15% CH₂Cl₂in MeOH gradient as a white/off-white solid (22% yield): ¹HNMR (600 MHz, DMSO-d₆) δ 11.77 (s, 1H), 8.80 (d, J=4.8 Hz, 1H), 7.69 (s, 1H), 7.60 (dd, J=4.8, 1.2 Hz, 1H), 7.49 (s, 1H), 5.75 (bs, 1H), 3.78 (s, 2H), 2.97 (tt, J=11.4, 4.2 Hz, 1H), 2.72 (t, J=10.8 Hz, 2H), 1.91-1.83 (m, 4H).

Compound 88. 2-((1-(1H-Pyrazol-4-yl)piperidin-4-yl)thio)pyrimidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 2-(piperidin-4-ylthio)pyrimidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes. The desired product, 2-((1-(1H-pyrazol-4-yl)piperidin-4-yl)thio)pyrimidine, was isolated as off-white solid after silica gel column purification of the THP deprotection product with 0-10% MeOH in CH₂Cl₂(28% yield). ¹H NMR (500 MHz, DMSO-d6) δ 1.71-1.80 (m, 2H), 2.10-2.14 (m, 2H), 2.67 (m, 2H), 3.25 (dt, J=12.0, 4.0 Hz, 2H), 3.77-3.84 (m, 1H), 7.21 (t, J=5.0 Hz, 1H), 7.25 (bs, 2H), 8.64 (d, J=5.0 Hz, 2H), 12.28 (bs, 1H).

Compound 89. 4-(4-((methylsulfonyl)methyl)phenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-((methylsulfonyl)methyl)phenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-((methylsulfonyl)methyl)phenyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient as a white/off-white solid (12% yield): ¹HNMR (400 MHz, DMSO-d₆) δ 12.27 (s, 1H), 7.35-7.27 (m, 6H), 4.44 (s, 2H), 3.45-3.42 (m, 2H), 2.90 (s, 3H), 2.64-2.55 (m, 3H), 1.82-1.74 (m, 4H).

Compound 90. 4-(3-chlorobenzyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(3-chlorobenzyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-(3-chlorobenzyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient to afford the product as a white/off-white solid (17% yield). ¹HNMR (600 MHz, DMSO-d₆) δ 12.21 (s, 1H), 7.34-7.31 (m, 1H), 7.28-7.25 (m, 2H), 7.20-7.16 (m, 3H), 3.29-3.27 (m, 2H), 2.54 (d, J=7.2 Hz, 2H), 2.37-2.34 (m, 2H), 1.59-1.57 (m, 3H), 1.34-1.27 (m, 2H).

Compound 91. 4-(3-Chlorobenzyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 4-(3-chlorobenzyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-(3-chlorobenzyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient as a white solid (15% yield). ¹HNMR (600 MHz, DMSO-d₆) δ 12.21 (s, 1H), 7.34-7.31 (m, 1H), 7.28-7.25 (m, 2H), 7.20-7.16 (m, 3H), 3.29-3.27 (m, 2H), 2.54 (d, J=7.2 Hz, 2H), 2.37-2.34 (m, 2H), 1.59-1.57 (m, 3H), 1.34-1.27 (m, 2H).

Compound 92. 4-((2-Fluorophenyl)thio)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-((2-fluorophenyl)thio)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes. The desired compound, 4-((2-fluorophenyl)thio)-1-(1H-pyrazol-4-yl)piperidine was isolated as an off-white solid after purification of the THP deprotection product with 0-9% MeOH in CH₂Cl₂(18% yield). ¹H NMR (500 MHz, DMSO-d6) δ 1.55-1.64 (m, 2H), 1.90-1.94 (m, 2H), 2.58 (apparent td, J=13.0, 2.5 Hz, 2H), 3.25 (apparent dt, J=12.5, 3.0 Hz, 2H), 7.18-7.29 (m, 4H), 7.32-7.39 (m, 1H), 7.54 (td, J=7.5, 1.5 Hz, 1H), 12.25 (bs, 1H).

Compound 93. 4-(4-Chlorobenzyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-chlorobenzyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-chlorobenzyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient as a white solid (20% yield): ¹HNMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.22-7.19 (m, 4H), 3.28-3.25 (m, 2H), 2.53-2.52 (m, 2H), 2.34 (t, J=10.4 Hz, 2H), 1.59-1.52 (m, 3H), 1.33-1.24 (m, 2H).

Compound 94. 4-(3-Methylbenzyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(3-methylbenzyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-(3-methylbenzyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as a white solid after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient (29% yield). ¹HNMR (500 MHz, DMSO-d₆) δ 12.21 (s, 1H), 7.19-7.15 (m, 3H), 7.00-6.95 (m, 3H), 3.28-3.25 (m, 2H), 2.49-2.48 (m, 2H), 2.34 (td, J=11.5, 2.0 Hz, 2H), 2.28 (s, 3H), 1.61-1.53 (m, 3H), 1.33-1.26 (m, 2H).

Compound 95. 4 3-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-5-(trifluoromethyl)pyridine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 3-(piperidin-4-yl)-5-(trifluoromethyl)pyridine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 3-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-5-(trifluoromethyl) pyridine, was isolated as a white solid after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient (24% yield). ¹HNMR (300 MHz, DMSO-d6) δ 12.29 (s, 1-NH), 8.84 (dd, J=8.7, 1.8 Hz, 2H), 8.12 (s, 1H), 7.30-7.26 (m, 2H), 3.47-3.43 (m, 2H), 2.86-2.76 (m, 1H), 2.58-2.53 (m, 2H), 1.95-1.85 (m, 4H).

Compound 96. 1-(1H-Pyrazol-5-yl)-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(1H-pyrazol-5-yl)-4-(4-(pyrrolidin-1-ylsulfonyl)phenyl)piperidine, was isolated as a white solid after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient to afford the product as a white solid (10% yield): ¹HNMR (300 MHz, CDCl₃) δ 7.36-7.29 (m, 2H), 7.68 (d, J=8.4 Hz, 3H), 5.71 (d, J=2.4 Hz, 1H), 3.83-3.79 (m, 2H), 3.19-3.14 (m, 4H), 2.80 (td, J=11.7 Hz, 3.6 Hz, 2H), 2.72-2.61 (m, 1H), 1.89-1.78 (m, 4H), 1.71-1.66 (m, 4H).

Compound 97. 4-(3-Methylbenzyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 4-(3-methylbenzyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(3-methylbenzyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated after purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient as a white solid (12% yield): ¹HNMR (300 MHz, DMSO-d₆) δ 11.73 (s, 1H), 7.41 (s, 1H), 7.19-7.14 (m, 1H), 7.00-6.95 (m, 3H), 5.64 (br, 1H), 3.61-3.57 (m, 2H), 2.54-2.47 (m, 4H), 2.28 (s, 3H), 1.61-1.57 (m, 3H), 1.30-1.18 (m, 2H).

Compound 98. 4-((1-(1H-Pyrazol-4-yl)piperidin-4-yl)methyl)-2-methoxypyridine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 2-methoxy-4-(piperidin-4-ylmethyl)pyridine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-((1-(1H-pyrazol-4-yl)piperidin-4-yl)methyl)-2-methoxypyridine, was isolated as a transparent liquid after the purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient to afford the product as a white solid (36% yield): ¹HNMR (300 MHz, CDCl₃) δ 8.04 (d, J=5.4 Hz, 1H), 7.31 (s, 2H), 6.67 (dd, J=5.1 Hz, 1.2 Hz, 1H), 6.53 (s, 1H), 3.91 (s, 3H), 3.38-3.34 (m, 2H), 2.61-2.51 (m, 4H), 1.75-1.55 (m, 5H).

Compound 99. 4-((1-(1H-Pyrazol-5-yl)piperidin-4-yl)methyl)-2-methoxypyridine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 2-methoxy-4-(piperidin-4-ylmethyl)pyridine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-((1-(1H-pyrazol-5-yl)piperidin-4-yl)methyl)-2-methoxypyridine, was isolated as a white solid after the purification of the crude THP deprotection product with 0-100% EtOAc in CH₂Cl₂gradient (10% yield). ¹HNMR (300 MHz, CDCl₃) δ 8.04 (d, J=5.4 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 6.68 (dd, J=5.1 Hz, 1.2 Hz, 1H), 6.53 (s, 1H), 5.71 (d, J=2.4 Hz, 1H), 3.91 (s, 3H), 3.70-3.66 (m, 2H), 2.66 (td, J=12.3 Hz, 2.1 Hz, 2H), 2.50 (d, J=6.6 Hz, 2H), 1.74-1.63 (m, 3H), 1.44-1.30 (m, 2H).

Compound 100. 1-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 1-(4-(piperidin-4-yl)phenyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)pyrrolidin-2-one, was isolated as a white solid after the purification of the crude THP deprotection product with 0-15% MeOH in CH₂Cl₂gradient (15% yield): ¹HNMR (600 MHz, DMSO-d₆) δ 12.26 (s, 1-NH), 7.56 (d, J=9.0 Hz, 2H), 7.26 (d, J=8.4 Hz, 4H), 3.81 (t, J=7.2 Hz, 2H), 3.43-3.41 (m, 2H), 3.30-3.28 (m, 1H), 2.58-2.53 (m, 2H), 2.48-2.47 (m, 2H), 2.07-2.02 (m, 2H), 1.78-1.72 (m, 4H).

Compound 101. 1-(4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)phenyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 3-iodo-pyrazole and 1-(4-(piperidin-4-yl)phenyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(4-(1-(1H-pyrazol-5-yl)piperidin-4-yl)phenyl)pyrrolidin-2-one, was isolated after purification of the crude THP deprotection product with 0-15% MeOH in CH₂Cl₂gradient as a white solid (7% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 11.78 (s, 1-NH), 7.56 (d, J=8.4 Hz, 2H), 7.45 (d, J=1.8 Hz, 1H), 7.26 (d, J=8.7 Hz, 2H), 5.71 (d, J=2.1 Hz, 1H), 3.83-3.73 (m, 4H), 2.72-2.57 (m, 3H), 2.48-2.45 (m, 2H), 2.10-2.00 (m, 2H), 1.81-1.68 (m, 4H).

Compound 102. 5-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

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Compound was prepared from THP-protected 4-iodo-pyrazole and 5-(piperidin-4-yl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes. The desired product, 1-(4-(1-(1H-pyrazol-3-yl)piperidin-4-yl)phenyl)pyrrolidin-2-one, was isolated after the purification of the crude THP deprotection product with 0-15% MeOH in gradient t as a white solid (13% yield): ¹HNMR (300 MHz, CDCl₃) δ 7.66 (d, J=8.1 Hz, 1H), 7.40 (s, 2H), 7.32 (d, J=8.4 Hz, 1H), 7.24 (s, 1H), 3.55-3.52 (m, 2H), 3.50-3.44 (m, 2H), 3.38-3.32 (m, 2H), 2.83-2.67 (m, 3H), 2.10-2.06 (m, 2H), 1.94-1.90 (m, 2H).

Compound 103. 3-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-5-(trifluoromethyl)pyridine

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Compound was prepared from THP-protected 3-iodo-pyrazole and 3-(piperidin-4-yl)-5-(trifluoromethyl)pyridine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 3-(1-(1H-pyrazol-5-yl)piperidin-4-yl)-5-(trifluoromethyl)pyridine, was isolated after the purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient as a white solid (36% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 11.79 (s, 1-NH), 8.83 (dd, J=6.0 Hz, 1.2 Hz, 2H), 8.10 (s, 1H), 7.47 (s, 1H), 5.74 (s, 1H), 3.80-3.76 (s, 2H), 2.91-2.80 (m, 1H), 2.69 (td, J=11.7 Hz, 3.3 Hz, 2H), 1.88-1.79 (m, 4H).

Compound 104. 4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-N-(1,1,1-trifluoropropan-2-yl)aniline

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(piperidin-4-yl)-N-(1,1,1-trifluoropropan-2-yl)aniline according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-N-(1,1,1-trifluoropropan-2-yl)aniline, was isolated after the purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient as a white solid (8% yield): ¹HNMR (300 MHz, DMSO-d₆) δ 12.25 (s, 1-NH), 7.25 (s, 2H), 6.99 (d, J=8.4 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 5.76 (d, J=9.0 Hz, 1H), 4.29-4.19 (m, 1H), 3.42-3.38 (m, 2H), 2.48-2.38 (m, 3H), 1.74-1.62 (m, 4H), 1.28 (d, J=6.9 Hz, 3H).

Compound 105. 4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)aniline

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Compound was prepared from THP-protected 4-iodo-pyrazole and commercially available 4-(4-nitrophenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. This intermediate was then hydrogenated at atmospheric pressure using 10% Pd/C (0.1 eq) in ethanol. When starting material deemed consumed by TLC the catalyst was filtered off and washed with 10% MeOH in CH₂Cl₂. Combined organic layer was evaporated to afford the crude reduced product that was treated with 4N HCl as described in general procedure 6. The desired product 4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)aniline, was isolated as a white solid after purification of the THP-deprotection product with silica gel column and 0-100% EtOAc in hexanes gradient (10% yield). ¹HNMR (600 MHz, DMSO-d₆) δ 12.22 (s, 1-NH), 7.24 (s, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.50 (d, J=8.4 Hz, 2H), 4.89 (s, 2H), 3.40-3.38 (m, 2H), 2.48-2.46 (m, 2H), 2.37 (tt, J=11.4, 4.2 Hz, 1H), 1.73-1.66 (m, 4H).

Compound 106. 5-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

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Compound was prepared from THP-protected 3-iodo-pyrazole and 5-(piperidin-4-yl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 5-(1-(1H-pyrazol-5-yl)piperidin-4-yl)-2,3-dihydrobenzo[b]thiophene 1,1-dioxide, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (8% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 11.79 (s, 1-NH), 7.65 (d, J=8.4 Hz, 1H), 7.44-7.42 (m, 3H), 5.73 (s, 1H), 3.79-3.75 (m, 2H), 3.57 (t, J=6.6 Hz, 2H), 3.32 (d, J=6.6 Hz, 2H), 2.77-2.66 (m, 3H), 1.84-1.69 (m, 4H).

Compound 107. 1-(4-((1-(1H-Pyrazol-4-yl)piperidin-4-yl)methyl)phenyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 1-(4-(piperidin-4-ylmethyl)phenyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(4-((1-(1H-pyrazol-4-yl)piperidin-4-yl)methyl)phenyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (5% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 12.21 (s, 1-NH), 7.55 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.4 Hz, 4H), 3.81 (t, J=6.9 Hz, 2H), 3.29-3.25 (m, 2H), 2.49-2.45 (m, 4H), 2.33 (dt, J=11.7 Hz, 2.1 Hz, 2H), 2.10-2.00 (m, 2H), 1.61-1.51 (m, 3H), 1.34-1.23 (m, 2H).

Compound 108. 5-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide

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Compound was prepared from THP-protected 4-iodo-pyrazole and 5-(piperidin-4-yl)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 5-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using a 0-15% MeOH in CH₂Cl₂gradient (6% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 12.21 (s, 1-NH), 7.26-7.20 (m, 5H), 4.38 (d, J=6.0 Hz, 4H), 3.38-3.35 (m, 2H), 2.56-2.47 (m, 3H), 1.75-1.64 (m, 4H).

Compound 109. 1-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-2-fluorobenzyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 1-(2-fluoro-4-(piperidin-4-yl)benzyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-2-fluorobenzyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using a 0-15% MeOH in CH₂Cl₂gradient (10% yield) ¹HNMR (300 MHz, CDCl₃) δ 7.31 (s, 2H), 7.19-7.17 (m, 1H), 6.98-6.88 (m, 2H), 4.45 (s, 2H), 3.49-3.44 (m, 2H), 3.29 (t, J=6.9 Hz, 3H), 2.74-2.54 (m, 3H), 2.38 (t, J=8.1 Hz, 2H), 2.01-1.88 (m, 6H).

Compound 110. 1-(4-(1-(1H-Pyrazol-5-yl)piperidin-4-yl)-2-fluorobenzyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 3-iodo-pyrazole and 1-(2-fluoro-4-(piperidin-4-yl)benzyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 1-(4-(1-(1H-pyrazol-3-yl)piperidin-4-yl)-2-fluorobenzyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (12% yield): ¹HNMR (300 MHz, CDCl₃) δ 7.40 (s, 1H), 7.22-7.17 (m, 1H), 6.98-6.88 (m, 2H), 5.76 (s, 1H), 4.46 (s, 2H), 3.86-3.82 (m, 2H), 3.29 (t, J=6.9 Hz, 2H), 2.87-2.79 (m, 2H), 2.62 (tt, J=11.7, 4.2 Hz, 1H), 2.42-2.37 (m, 2H), 2.0-1.77 9m, 6H).

Compound 111. 4-(4-Nitrophenyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound 112. 4-(4-Nitrophenyl)-1-(1H-pyrazol-5-yl)piperidine

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Compound was prepared from THP-protected 3-iodo-pyrazole and commercially available 4-(4-nitrophenyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(4-nitrophenyl)-1-(1H-pyrazol-5-yl)piperidine, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (17% yield): ¹HNMR (300 MHz, DMSO-d₆) δ 11.70 (s, 1-NH), 8.12-8.08 (m, 2H), 7.50 (d, J=8.7 Hz, 2H), 7.42 (s, 1H), 5.69 (s, 1H), 3.74-3.70 (m, 2H), 2.77-2.59 (m, 3H), 1.78-1.61 (m, 4H).

Compound 113. N-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)methanesulfonamide

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THP-protected 4-iodo-pyrazole and commercially available 4-(4-nitrophenyl)piperidine were coupled according to general procedure 6. The resulting THP-protected coupling intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. This THP protected intermediate was then reduced using 10% Pd/C (0.1 eq) in ethanol and hydrogen gas at atmospheric pressure. When reduction deemed complete by TLC the catalyst was removed and washed with 10% MeOH in DCM and the combined organic layer was concentrated. The residue was sulfonylated in DCM with CH₃SO₂Cl (1.2 eq) in the presence of Et₃N as base (1.2 eq). Upon consumption of the starting material the reaction mixture was partitioned between DCM and water. The organic layer was dried over Na₂SO₄filtered and concentrated and the reside was purified with silica gel column using EtOAc in hexanes as eluent. This intermediate obtained from this purification was then stirred with 50% KOH aq. solution in THF/H₂O (1:1) overnight. Then the mixture was neutralized with 1N HCl aq. to pH 6. Water was added and the mixture extracted with 10% MeOH in DCM. Organic layer was dried over Na₂SO₄, filtered and concentrated to a residue that was treated with 4N HCl in dioxane as described in general procedure 6. The desired product, N-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)methanesulfonamide, was isolated as a white solid after silica gel column purification of the crude THP deprotection product with 0-15% MeOH in CH₂Cl₂gradient (7% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 12.18 (s, 1-NH), 9.52 (s, 1-NH), 7.18-7.06 (m, 4H), 7.08-7. 06 (m, 2H), 3.36-3.32 (m, 2H), 2.87 (s, 3H), 2.52-2.44 (m, 3H), 1.72-1.60 (m, 4H).

Compound 114. N-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)cyclopropanesulfonamide

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THP-protected 4-iodo-pyrazole and commercially available 4-(4-nitrophenyl)piperidine were coupled according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. This intermediate was then reduced using ethanol, 10% Pd/C (0.1 eq) and H₂gas at atm pressure. When reaction deemed complete by TLC the catalyst was removed, washed with 10% MeOH in DCM and the combined organic layer was evaporated to a residue that was sulfonylated with cyclopropanesulfonyl chloride (1.1 eq) in CH₂Cl₂and in the presence of Et₃N (1.1 eq) as base. When sulfonylation deemed complete by TLC the mixture was diluted with water and extracted with CH₂Cl₂. Combined organic layer was dried over Na₂SO₄filtered and concentrated and the residue was treated with 4 N HCl in dioxane as described in general procedure 6. The desired product N-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)methanesulfonamide, was isolated as a white solid after purification of the crude THP deprotection product with silica gel column and 0-15% MeOH in CH₂Cl₂gradient (18% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 1-NH), 9.51 (s, 1-NH), 7.20-7.08 (m, 6H), 3.36-3.32 (m, 2H), 2.54-2.47 (m, 4H), 1.72-1.61 (m, 4H), 0.84 (d, J=6.3 Hz, 4H).

Compound 115. 4-(4-Chlorobenzyl)-1-(1H-pyrazol-4-yl)piperidine hydrochloride

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4-(4-Chlorobenzyl)-1-(1H-pyrazol-4-yl)piperidine (prepared from THP-protected 4-iodopyrazole and 4-(4-chlorobenzyl)piperidine according to general procedure 6, 1 eq) in dioxane was treated with 1.2 eq of 4N HCl in dioxane and stirred overnight. The volatiles were then evaporated and the resulting solid residue was washed with CH₂Cl₂and dried to afford the product as a white solid (46% yield). ¹H NMR (300 MHz, CD₃OD) δ 8.04 (s, 2H), 7.32 (dd, J=6.8 Hz, 2.1 Hz, 2H), 7.23 (dd, J=4.8 Hz, 2.1 Hz, 2H), 3.82-3.78 (m, 2H), 3.51 (dt, J=12.6 Hz, 2.7 Hz, 2H), 2.69 (d, J=6.9 Hz, 2H), 2.08-1.99 (m, 3H), 1.80-1.67 (m, 2H).

Compound 116. 4-(4-Methylbenzyl)-1-(1H-pyrazol-4-yl)piperidine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-methylbenzyl)piperidine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(4-methylbenzyl)-1-(1H-pyrazol-4-yl)piperidine, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (12% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 12.20 (s, 1-NH), 7.18 (s, 2H), 7.10-7.04 (m, 4H), 3.28-3.24 (m, 2H), 2.49-2.47 (m, 2H), 2.37-2.26 (m, 5H), 1.56-1.47 (m, 3H), 1.34-1.21 (m, 2H).

Compound 117. 1-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-2-chlorobenzyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 1-(2-chloro-4-(piperidin-4-yl)benzyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-2-chlorobenzyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (3% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 12.27 (s, 1H), 7.36 (d, J=1.5 Hz, 1H), 7.28-7.25 (m, 3H), 7.19 (d, J=7.8 Hz, 1H), 4.42 (s, 2H), 3.44-3.40 (m, 2H), 3.26 (t, J=6.2 Hz, 2H), 2.66-2.54 (m, 3H), 2.30 (t, J=7.8 Hz, 2H), 2.00-1.90 (m, 2H), 1.81-1.73 (m, 4H).

Compound 118. 1-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-3-fluorobenzyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 1-(3-fluoro-4-(piperidin-4-yl)benzyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-3-fluorobenzyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂(18% yield): ¹HNMR (400 MHz, CD₃OD) δ 7.27 (s, 2H), 7.22 (t, J=7.6 Hz, 1H), 6.96 (dd, J=8.0 Hz, 1.2 Hz, 1H), 6.87 (d, J_H-F=11.2 Hz, 1H), 4.33 (s, 2H), 3.43-3.40 (m, 2H), 3.26 (d, J=6.8 Hz, 2H), 2.86 (tt, J=12.0, 4.0 Hz, 1H), 2.59 (td, J=11.6, 3.2 Hz, 2H), 2.35 (t, J=7.6 Hz, 2H), 1.96-1.77 (m, 6H).

Compound 119. 1-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)pyrrolidin-2-one hydrochloride

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1-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)pyrrolidin-2-one (prepared from THP protected 4-iodopyrazole and 1-(4-(piperidin-4-yl)phenyl)pyrrolidin-2-one according to general procedure 6, 1 eq) in dioxane was treated with 4N HCl in dioxane (1.2 eq) and the mixture was stirred overnight. The volatiles were then evaporated and the residue was washed with CH₂Cl₂several times and then dried to afford the product as a white solid. ¹HNMR (300 MHz, DMSO-d₆) δ 8.09 (s, 2H), 7.62 (t, J=8.7 Hz, 2H), 7.27 (t, J=8.7 Hz, 2H), 3.85-3.72 (m, 4H), 3.55-3.48 (m, 2H), 2.97-2.89 (m, 1H), 2.49-2.46 (m, 2H), 2.26-2.22 (m, 2H), 2.11-2.01 (m, 4H).

Compound 120. 4-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)morpholine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-(piperidin-4-yl)phenyl)morpholine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)morpholine, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (5% yield): ¹HNMR (300 MHz, DMSO-d₆) δ 12.25 (s, 1-NH), 7.25 (s, 2H), 7.12 (t, J=8.4 Hz, 2H), 6.87 (t, J=8.7 Hz, 2H), 3.73 (t, J=4.5 Hz, 4H), 3.43-3.39 (m, 2H), 3.05 (t, J=4.8 Hz, 4H), 2.55-2.43 (m, 3H), 1.78-1.65 (m, 4H).

Compound 121. 4-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)benzyl)morpholine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-(piperidin-4-yl)benzyl)morpholine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)benzyl)morpholine, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (6% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 12.26 (s, 1H), 7.27-7.23 (m, 6H), 3.56 (t, J=9 Hz, 4H), 3.44-3.42 (m, 4H), 2.56-2.53 (m, 3H), 2.33 (t, J=8.4 Hz, 4H), 1.80-1.67 (m, 4H).

Compound 122. 4-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)morpholin-3-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-(piperidin-4-yl)phenyl)morpholin-3-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)morpholin-3-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (4% yield) ¹H NMR (300 MHz, DMSO-d₆) δ 12.19 (s, 1H), 7.24-7.19 (m, 6H), 4.12 (s, 2H), 3.91-3.87 (m, 2H), 3.65-3.62 (m, 2H), 3.38-3.34 (m, 2H), 2.58-2.46 (m, 3H), 1.76-1.65 (m, 4H).

Compound 123. 4-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-2-fluorophenyl)morpholine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(2-fluoro-4-(piperidin-4-yl)phenyl)morpholine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-2-fluorophenyl)morpholine, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (8% yield). ¹H NMR (600 MHz, CDCl₃) δ 7.29 (bs, 2H), 6.94-6.90 (m, 2H), 6.86 (t, J=4.2 Hz, 1H), 3.84 (t, J=4.2 Hz, 4H), 3.47-3.45 (m, 2H), 3.03 (t, J=4.8 Hz, 4H), 2.69-2.66 (m, 2H), 2.55-2.51 (m, 1H), 1.93-1.88 (m, 4H).

Compound 124. 4-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)morpholine

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(3-fluoro-4-(piperidin-4-yl)phenyl)morpholine according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product, 4-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)morpholine, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (4% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 7.26 (d, J=9.2 Hz, 2H), 7.17 (t, J=8.8 Hz, 1H), 6.74-6.70 (m, 2H), 3.72 (t, J=4.4 Hz, 4H), 3.43-3.40 (m, 2H), 3.09 (t, J=4.8 Hz, 4H), 2.77-2.71 (m, 1H), 2.55-2.54 (m, 2H), 1.83-1.71 (m, 4H).

Compound 125. (R)-1-(1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and (R)-1-(1-(4-(piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product (R)-1-(1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (16% yield). ¹H NMR (300 MHz, DMSO-d6): δ 12.18 (bs, 1H), 7.19-7.11 (m, 6H), 5.13 (q, J=7.5 Hz, 1H), 3.37-3.28 (m, 3H), 2.93-2.85 (m, 2H), 2.55-2.47 (m, 2H), 2.21-2.16 (m, 2H), 1.86-1.77 (m, 2H), 1.74-1.66 (m, 4H), 1.36 (d, J=7.2 Hz, 3H).

Compound 126. (S)-1-(1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and (S)-1-(1-(4-(piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product (S)-1-(1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)ethyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product using 0-15% MeOH in CH₂Cl₂gradient (26% yield): ¹H NMR (300 MHz, DMSO-d₆): δ 12.26 (bs, 1H), 7.26-7.19 (m, 6H), 5.21 (q, J=7.2 Hz, 1H), 3.44-3.35 (m, 3H), 3.00-2.93 (m, 1H), 2.59-2.55 (m, 3H), 2.29-2.23 (m, 2H), 1.92-1.85 (m, 2H), 1.85-1.73 (m, 4H), 1.44 (d, J=7.2 Hz, 3H).

Compound 127. 4-[(4-Methoxyphenyl)methyl]-1-(1H-pyrazol-4-yl)piperidine

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Synthesized according to general procedure 6 from THP-protected 4-iodopyrazole and commercially available 4-(4-methoxybenzyl)piperidine. The crude THP protected coupling intermediate was chromatographed with 0-80% EtOAc in hexanes. The product 4-[(4-methoxyphenyl)methyl]-1-(1H-pyrazol-4-yl)piperidine was isolated as an off-white solid after silica gel column purification of the crude THP-deprotected product with 0-10% MeOH in EtOAc gradient and a precipitation out of CH₂Cl₂with excess of hexanes (24% yield). ¹H NMR (600 MHz, CD₃OD) δ 1.40 (qd, J=12.6, 3.6 Hz, 2H), 1.54-1.65 (m, 1H), 1.72 (apparent d, J=13.2 Hz, 2H), 2.49 (td, J=12.0, 1.8 Hz, 2H), 2.52 (d, J=7.2 Hz, 2H), 3.36 (apparent d, J=11.4 Hz, 2H), 3.78 (s, 3H), 6.84 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 7.32 (s, 2H).

Compound 128. 1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)pyrrolidin-2-one

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Compound was prepared from THP-protected 4-iodo-pyrazole and 1-(3-fluoro-4-(piperidin-4-yl)phenyl)pyrrolidin-2-one according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 1-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)-3-fluorophenyl)pyrrolidin-2-one, was isolated as a white solid after silica gel column purification of the crude THP deprotection product with 0-15% MeOH in CH₂Cl₂gradient (13% yield): ¹H NMR (300 MHz, DMSO-d₆) δ 12.27 (s, 1-NH), 7.64-7.59 (m, 1H), 7.37-7.32 (m, 2H), 7.26 (d, J_C-F=9.9 Hz, 2H), 3.82 (t, J=6.9 Hz, 2H), 3.45-3.41 (m, 2H), 2.87-2.80 (m, 1H), 2.58-2.48 (m, 4H), 2.10-2.00 (m, 2H), 1.89-1.74 (m, 4H).

Compound 129. 4-(4-(1-(1H-Pyrazol-4-yl)piperidin-4-yl)phenyl)thiomorpholine 1,1-dioxide

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Compound was prepared from THP-protected 4-iodo-pyrazole and 4-(4-(piperidin-4-yl)phenyl)thiomorpholine 1,1-dioxide according to general procedure 6. The THP-protected intermediate was purified with silica gel column chromatography and 0-100% EtOAc in hexanes gradient. The desired product 4-(4-(1-(1H-pyrazol-4-yl)piperidin-4-yl)phenyl)thiomorpholine 1,1-dioxide, was isolated as a white solid after silica gel column purification of the crude THP deprotection product with 0-15% MeOH in CH₂Cl₂gradient (13% yield). ¹HNMR (300 MHz, DMSO-d₆) δ 12.25 (s, 1-NH), 7.25 (d, J=5.7 Hz, 2H), 7.15 (t, J=8.1 Hz, 2H), 6.96 (t, J=8.4 Hz, 2H), 3.72 (bs, 4H), 3.43-3.39 (m, 2H), 3.11 (bs, 4H), 2.50 (m, 3H), 1.76-1.71 (m, 4H).

Example 2: Determination of Compound Inhibition and Selectivity Against 20-HETE Formation

Inhibition of 20-HETE Formation Determination at 250 or 500 nM

To screen the inhibitory effects against 20-HETE formation, compounds were screened in HLM, RLM, RKM and rCYP4F2 microsomal incubations. Compounds dissolved in either 100% methanol or 100% DMSO to yield 10 mM stock solution. Microsomal incubations containing HLM, RLM, RKM (300 μg/ml) or rCYP4F2 (25 pmol/mL), AA (100 M), NADPH (1 mM) treated with test compounds at various concentrations (500 nM or 250 nM) in a 1 ml total volume in incubation buffer (0.12 M potassium phosphate buffer containing 5 mM magnesium chloride). Reaction was started by adding NADPH to the incubates and was carried out at 37° C. in a shaking water bath for 20 min. Reaction was stopped by placing tubes on ice, followed by adding 125 μl 20-HETE-d₆as internal standard to each sample. Microsomal incubations were extracted with 3 ml ethyl ether twice, dried down under nitrogen gas and reconstituted in 125 μl 80:20 methanol:deionized H₂O for analysis. 20-HETE formation was quantified using a validated UPLC-MS/MS assay and normalized by vehicle group. Each compound had three replications (n=3). Vehicle group was used as control to calculate percentage of 20-HETE formation rate. HET0016 (250 nM) was used as positive control. Incubates without NADPH group served as the negative control. An Acquity ultra performance LC autosampler (Waters, Milford, Mass.) was used to isolate 20-HETE on an UPLC BEH C18, 1.7 μm (2.1×100 mm) reversed-phase column (Waters, Milford, Mass.) protected by a guard column (2.1×5 mm; Waters, Milford, Mass.) of the same packing material. Column temperature was maintained at 55° C. Mobile phases consisted of 0.005% acetic acid, 5% acetonitrile in deionized water (A) and 0.005% acetic acid in acetonitrile (B). The flow rate for mobile phases is 0.5 ml/min. The initial mixture of mobile phase was 65:35 of A and B. Mobile phase B increased at 0.4 minutes after injection from 35% to 70% in a linear gradient over 4 minutes, and again increased to 95% over 0.5 minutes where it remained for 0.3 minutes. This was followed by a linear return to initial conditions over 0.1 minutes with a 1.5 minute pre-equilibration period prior to the next sample run. Total run time was 6.4 minutes for each injection. Injection volumes were 7.5 μl. Mass spectrometric analysis was carried out using a TSQ Quantum Ultra (Thermo Fisher Scientific, San Jose, Calif.) triple quadrupole mass spectrometer using heated electrospray ionization (HESI). Mass spectrometer was operated in negative selective reaction monitoring (SRM) mode with unit resolutions at both Q1 and Q3 set at 0.70 Da full width at half maximum. Scan time was set at 0.01 s and collision gas pressure was 1.3 mTorr. Quantitation of 20-HETE by SRM was performed by monitoring the m/z. Analytical data was acquired and analyzed using Xcaliber 3.0 data system (ThermoFinnigan, San Jose, Calif.).

IC₅₀Determinations

Microsomal incubations contained HLM, RLM (300 μg/ml), AA (100 μM), NADPH (1 mM) and test compounds at 12 concentrations (0.1 nM-50 μM) in a 1 ml total volume in microsomal incubation buffer (0.12 M potassium phosphate buffer containing 5 mM magnesium chloride). Reaction was started by adding NADPH to the incubates and was carried out at 37° C. in a shaking water bath for 20 min. Reaction was stopped by placing tubes on ice, followed by adding 12.5 μl 20-HETE-d₆as internal standard to each sample. Microsomal incubations were extracted with 3 ml ethyl ether twice, dried down under nitrogen gas and reconstituted in 125 μl 80:20 methanol:deionized H₂O for analysis. 20-HETE formation was quantified using the validated UPLC-MS/MS assay described above and normalized by vehicle group. HET0016 (250 nM) was used as positive control. Incubates without NADPH group served as the negative control. IC₅₀was determined by fitting the dose-response curve using Graphpad Prism nonlinear regression.

Determination of Selectivity of Compounds for 20-HETE Formation Inhibition Vs EETs and DiHETs

Selectivity of compounds for inhibition of 20-HETE formation vs inhibition of formation of 8,9-, 11,12-, 14,15-EET and 5,6-, 8,9-, 11,12-, 14,15-DiHETs was assessed via the simultaneous monitor of formation of 20-HETE and those metabolites under the UPLC-MS/MS assay conditions described above using HLM incubations and the same 12 test compound concentrations (0.1 nM-50 mM) used for the IC₅₀determination experiments. At each of the 12 concentrations, the selectivity of 20-HETE inhibition over the other metabolites was compared. Epoxygenase activity was assessed by the sum of EETs and DiHETEs as percentage of control.

Example 3: Determination of Blood Brain Barrier Penetration Potential

BBB penetration potential assessment data in Table 1 was obtained as follows. MDR1-MDCK cell monolayers were grown to confluence on collagen-coated, microporous membranes in 12-well assay plates. Atenolol, propranolol and digoxin were used as control to assess plate quality. The permeability assay buffer was Hanks' balanced salt solution containing 10 mM HEPES and 15 mM glucose at a pH of 7.4. The buffer in the receiver chamber also contained 1% bovine serum albumin. The dosing solution concentration was 5 μM of test article in the assay buffer. Cell monolayers were dosed on the apical side (A-to-B) or basolateral side (B-to-A) and incubated at 37° C. with 5% CO₂in a humidified incubator. Samples were taken from the donor and receiver chambers at 120 minutes. Each determination was performed in duplicate the flux of lucifer yellow was also measured post-experimentally for each monolayer to ensure no damage was inflicted to the cell monolayers during the flux period. All samples were assayed by LC-MS/MS using electrospray ionization using a PE SCIEX API 4000 spectrometer and total run time of 1 min. Analytical method/conditions were: Liquid Chromatography Column: Waters ACQUITY UPLC BEH Phenyl 30×2.1 mm, 1.7 m; M.P. Buffer: 25 mM ammonium formate buffer, pH 3.5; Aqueous Reservoir (A): 90% water, 10% buffer; Organic Reservoir (B): 90% acetonitrile, 10% buffer; Flow Rate: 0.7 mL/minute; gradient program: 99% A (t=0 min), 1% A (t=0.65 min), 1% A (t=0.75 min), 99% A (t=0.8 min), 99% A (t=1 min); 5 μL injection volume

The apparent permeability (P_app) and percent recovery were calculated as follows:

P
_app=(dC_r/dt)×V_r/(A×C_A) (1)

Percent Recovery=100×((V_r×C_r^final)+(V_d×C_d^final))/(V_d×C_N) (2)

wherein:

dC_r/dt is the slope of the cumulative concentration in the receiver compartment versus time in μMs⁻¹;

V_ris the volume of the receiver compartment in cm³;

V_dis the volume of the donor compartment in cm³;

A is the area of the insert (1.13 cm²for 12-well);

C_Ais the average of the nominal dosing concentration and the measured 120 minute donor concentration in μM;

C_Nis the nominal concentration of the dosing solution in μM;

C_r^finalis the cumulative receiver concentration in μM at the end of the incubation period;

C_d^finalis the concentration of the donor in μM at the end of the incubation period. Efflux ratio (ER) is defined as P_app(B-to-A)/P_app(A-to-B)

Interpretation

Brain Penetration Potential Classification:

P_app(A-to-B)≥3.0 and ER<3.0: High

P_app(A-to-B)≥3.0 and 10>ER≥3.0: Moderate

P_app(A-to-B)≥3.0 and ER≥10, or P_app(A-to-B)<3.0 Low

Example 4 HLM Stability Determinations

HLM stability determinations shown in Table 3 were obtained as follows. Microsomal incubates contained HLM (500 μg/ml), test compounds (1 μM) and NADPH (1.3 mM) in a 1 ml total volume of microsomal incubation buffer (0.12 M potassium phosphate buffer containing 5 mM magnesium chloride). Reaction was started by adding NADPH to the incubates and was carried out at 37° C. in a shaking water bath for 60 min. At 0, 15, 30, 45, 60 min, a 50 μl aliquot of incubates was taken out and reaction was stopped by adding aliquot into 200 μl ice-cold acetonitrile. After centrifugation at 14000×g for 5 min, 200 μl supernatant was taken out for UPLC-MS/MS analysis as described above. Values at 0 min were used as corresponding control for test compounds. Varapamil, metoprolol, and warfarin, categorized as fast, moderate and slow metabolism, were used as positive control. Incubates without NADPH group served as negative control.

Example 5 Solubility Determination

Solubility determinations shown in Table 3 were obtained turbidometrically and in a manner similar to the one described in Perez et al., J. Biomol. Screen, 2015, 20(2), 254-64. The method requires small volumes of 100× stock concentration drug solution to be prepared in DMSO 0, 0.23, 0.47, 0.94, 1.88, 3.75, 7.5, 15.0, 30.0 and 50.0 mM. The stock drug concentrations are then diluted 1:100 added into triplicate wells containing PBS in a clear bottom 384 well microtiter to achieve final testing concentrations of 0, 2.3, 4.7, 9.4, 18.8, 37.5, 75, 150, 300, 600 μM in 1% DMSO. The plate is allowed to equilibrate with constant shaking for 2 hours at room temperature. The plate is then placed in a SpectroMax V plate reader to measure absorbance at 620 nm. Increase in absorbance is evident in test wells which precipitation of the compound is evident. The plot of OD₆₂₀vs. drug concentration is used to calculate the maximum solubility limit as determined by a statistically significant increase in absorbance above the background levels.

TABLE 3

BBB penetration

potential

Human Potency Data
Stability
MDCK
MDCK

HLM %
HLM %
IC50
rCYP4F2
rCYP4F2
EETs
HLM
A-B
B-A

Compound
inh. @
inh. @
(uM)
% inh. @
% inh. @
Inhibition
% @
10−6
10−6

#
250 nM
500 nM
HLM
250 nM
500 nM
(nM)
30 min
cm/s
cm/s

1
64.29
78.80
0.19
78.50

>10,000
100

2

59.90
0.15

47.60
>50,000
61

3

77.30
0.05

77.00
>25,000
85
62.00
60.00

4

0.00

0.00

5

24.50

2.60

6

31.80

6.10

7

51.70
0.19

6.50
2.6% @ 50,000

8

62.70
0.17

48.90
>50,000

9

0.00

0.00

10

0.00

0.00

11

0.00

66.50

12

0.00

63.70

13

29.00

1.00

14

53.00
0.22

60.00

97

15

39.00

54.00

16

27.00

28.00

17

80.00

83.00

18

66.00

70.00

19

72.30
0.14

41.40
>25,000
89

20

73.10
0.07

67.70
3.1%@ 50,000
92
32.00
25.70

21

8.80

2.00

22

0.00

0.00

23

67.40
0.11

70.80

61

24

73.80
0.08

79.90

92

25

56.40
0.28

67.80

100

26

71.70
0.20

81.70

100

27

20.00

14.00

28

75.00
0.10

58.00

18.40
40.20

29

60.00
0.17

55.00

30

86.00
0.05

95.00

0

31

35.00

44.00

32

59.00
0.13

67.00

33

72.00
0.18

69.00

34

80.00
0.11

86.00

60.10
48.60

35

20.00

20.00

36

46.00
0.65

61.00

37

0.00

31.90

38

0.00

22.30

39

6.00

22.70

40

65.80
0.10

75.90

82

41

32.00

0.00

42

5.00

28.00

43

82.00

79.00

44

85.00
0.05

86.00

100

45

71.00

73.00

46

78.00

88.00

47

82.00
0.08

88.00

100

48

67.00

63.00

49

80.00

90.00

50

47.00

69.00

51

77.00

94.00

52

84.10
0.08

74.80

100

53
14.90

3.90

54
31.60
47.40
0.44
53.60

>50,000
91

55
12.11

0.00

56

0.00

11.40

57

0.00

41.20

58

67.40
0.11

70.60

97

59

63.30
0.19

73.70

98

60

3.70

38.40

100

61

77.5

81.3

62

60.0

45

63

74.3

73.8

64

88

72

46.4
34.8

65

57.00

35

66

36

58

67

83.2

90.86

68

48

70.9

69

85.6

57.9

22.3
44.4

70

84.8

80.5

71

82

52.2

72

77

77

73

61

54.7

74

55

32

75

61.10

74.50

76

84

71

77

84.4

55

78

83.6

31

79

60

62

80

86

90

81

83.1
0.0474

66

82

75

36

83

91.6
0.0542

96.2
>50
91
5.16
41.6

84

79.4

80.3

85

81.3

64

86

37.9

49.4

87

15.6

7.4

88

39.8

26.4

89

34.8

72.9

90

67

70.3

91

40.4

39.1

92

77.3

87.1

93

93.03
0.017

97.02
50% @ 10 μM
85
44.3
40

94

61.3

60.3

95

42.8

26.3

96

63.10

16.40

97

35.30

22.90

98

37.20

25.00

99

17.70

0.00

100

76.1
0.054

81.2
>50
95
22.20
46.90

101

79.00

80.00

33.80
46.70

102

36.50

27.90

103

0.00

0.00

104

86.1

78.00

50.40
48.90

105

77.30

78.00

106

0.00

0.00

107

78.90

82.30

108

90.00

83.00

109

90.30

86.00

10.80
77.50

110

80.4

84.1

111

43.5

60.10

112

21.90

41.30

113

30.5

67.6

114

68.7

87.4

115

85.50

84.20

116

86.40

89.30

77.40
70.30

117

118

119

120

121

122

123

124

125

126

127

128

129

TABLE 4

Rat Potency Data

RKM %
RKM %
RLM %
RLM %
RLM

Compound
inh. @
inh. @
inh. @
inh. @
IC50
Solubility_ug/
Max Solub

#
250 nM
500 nM
250 nM
500 nM
(uM)
mL
(uM)

1
18.00

27.40

28.00
121

2

0.00

0.00

oil

3

0.00

2.40

122.00
505

4

0.00

0.00

5

0.00

0.00

6

1.20

0.00

7

0.00

42.30

127.00
494

8

0.00

45.50

29.00
111

9

0.00

0.00

10

0.00

0.00

11

1.60

3.60

12

6.40

18.30

13

27.00

3.00

14

0.00

15

27.00

16.00

16

0.00

29.00

17

25.00

57.00

18

0.00

41.00

19

0.00

31.80

27.30
106

20

4.90

25.90

9.00
35

21

0.00

22

0.00

23

0.00

40.10
166.2

24

16.30

20.60
85.4

25

21.30

63.90
235.3

26

27.80

99.40
366.4

27

0.00

8.00

179.00
>600

28

43.00

52.00

179.00
>600

29

7.00

38.00

170.60
>600

30

40.00

37.00

137.00
481.8

31

9.00

0.00

155.00
>600

32

25.00

0.00

101.00
391

33

16.00

12.00

oil

34

36.00

44.00

144.80
>600

35

4.00

0.00

oil

36

4.00

0.00

752

37

0.00

38

0.00

39

0.00

40

7.80

24.80
95.5

41

0.00

0.00

107.60
369.2

42

0.00

0.00

43

31.00

17.00

44

21.00

42.00
0.34

45

0.00

24.00

46

0.00

47.00

47

0.00

63.00

48

8.00

0.00

49

28.00

31.00

50

18.00

16.00

51

26.00

53.00

52

13.40

78.00
244.1

53
8.20

4.30

54
0.00

12.00

137.00
>600

55
0.00

0.00

56

0.00

57

43.10

58

0.00

125.70
393.6

59

64.40

155.00
>600

60

0.00

61

61.00

121

62

0.00

42.4

63

10.30

13.3

64

49.00

19.5

65

0.00

18.7

66

0.00

133

67

30.20

204.9

68

0

69

27.70

304

70

35.70

109

71

25.00

>600

72

11.00

234

73

0.00

164

74

0.00

201

75

0.00

127

76

0.00

77

13.80

78

0.00

79

4.00

80

42.00

89

81

19.30

353

82

2.00

83

49.60
0.72

>600

84

42.70

>600

85

0.00

86

18.10

87

2.70

88

0.00

89

0.00

324.3

90

20.80

91

0.00

92

0.00

93

64.30
0.12

117

94

13.50

95

15.40

96

0.00

97

0.00

98

5.00

99

0.00

100

42.90
0.57

74

101

48.70

158

102

0.00

103

0.00

104

36.00

31

105

17.00

106

0.00

107

63.60

216

108

41.70

187

109

62.70

>600

110

63.60

421

111

22.30

112

20.30

113

14.30

114

36.70

74

115

74.30

74

116

59.60

71

117

118

443

119

63

120

121

122.3

122

247.2

123

85.5

124

26.6

125

>600

126

>600

127

151

128

129

* * *

In one embodiment, one or more compounds ofany disclosure of Table 3, or a pharmaceutically acceptable salt or solvate thereof, is excluded from the compound of formula I.

The entire disclosure of each disclosure tabulated in Table 4 is hereby incorporated by reference.

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While certain embodiments have been illustrated and described, it should be understood that changes and modifications can be made therein in accordance with ordinary skill in the art without departing from the technology in its broader aspects as defined in the following claims.

The embodiments, illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claimed technology. Additionally, the phrase “consisting essentially of” will be understood to include those elements specifically recited and those additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase “consisting of” excludes any element not specified.

The present disclosure is not to be limited in terms of the particular embodiments described in this application. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and compositions within the scope of the disclosure, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

As will be understood by one skilled in the art, for any and all purposes, particularly in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

All publications, patent applications, issued patents, and other documents referred to in this specification are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually indicated to be incorporated by reference in its entirety. Definitions that are contained in text incorporated by reference are excluded to the extent that they contradict definitions in this disclosure.

Other embodiments are set forth in the following claims.

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