HK1239691B - 1,3-thiazol-2-yl substituted benzamides - Google Patents

Description

1,3-Thiazol-2-yl substituted benzamides

The present invention relates to 1,3-thiazol-2-yl substituted benzamide compounds of general formula (I) as described and defined herein, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds as sole agents or in combination with other active ingredients for the preparation of pharmaceutical compositions for the treatment or prevention of diseases, in particular neurological disorders.

Background Art

The present invention relates to compounds that inhibit P2X3 receptors. P2X purinoceptor 3 is a protein encoded by the human P2RX3 gene (Garcia-Guzman M, Stuhmer W, Soto F (September 1997) "Molecular characterization and pharmacological properties of the human P2X3 purinoceptor." Brain Res Mol Brain Res 47(1-2): 59-66). The gene product belongs to the ATP purinoceptor family. This receptor functions as a ligand-gated ion channel and transduces ATP-induced nociceptor activation.

P2X purinergic receptors are a family of ligand-gated ion channels activated by ATP. To date, seven members of this family have been cloned, including P2X1-7 [Burnstock 2013, front Cell Neurosci 7:227]. These channels can exist as homopolymers and heteropolymers [Saul 2013, front Cell Neurosci 7:250]. Purines (such as ATP) have been recognized as important neurotransmitters and, through their respective receptor actions, have been associated with a variety of physiological and pathophysiological effects [Burnstock 1993, Drug Dev Res 28:196-206; Burnstock 2011, Prog Neurobiol 95:229-274; Jiang 2012, Cell Health Cytoskeleton 4:83-101].

Among the P2X family members, the P2X3 receptor is particularly recognized as an important mediator of nociception [Burnstock 2013, Eur J Pharmacol 716:24-40; North 2003, J Phyiol 554:301-308; Chizh 2000, Pharmacol Rev 53:553-568]. It is primarily expressed in the dorsal root ganglion, a subset of nociceptive sensory neurons. During inflammation, the expression of the P2X3 receptor increases, and activation of the P2X3 receptor has been described as sensitizing peripheral nerves [Fabretti 2013, Front Cell Neurosci 7:236].

The significant role of P2X3 receptors in nociception has been described in a variety of animal models, including mouse and rat models for acute, chronic, and inflammatory pain. P2X3 receptor knockout mice exhibit reduced pain responses [Cockayne 2000, Nature 407:1011-1015; Souslova 2000, Nature 407:1015-1017]. In various pain and inflammatory pain models, P2X3 receptor antagonists have been shown to have antinociceptive effects [Ford 2012, Purin Signal 8(Suppl 1):S3-S26]. P2X3 receptors have also been shown to integrate different nociceptive stimuli. Hyperalgesia triggered by PGE2, ET-1, and dopamine has been shown to be mediated by the release of ATP and activation of P2X3 receptors [Prado 2013, Neuropharm 67:252-258; Joseph 2013, Neurosci 232C:83-89].

In addition to their prominent role in nociception and pain-related diseases, including chronic and acute pain, P2X3 receptors have also been shown to be associated with genitourinary, gastrointestinal, and respiratory conditions and disorders, including overactive bladder and chronic cough [Ford 2013, front Cell Neurosci 7:267; Burnstock 2014, Purin Signal 10(1):3-50]. ATP release occurs in these two instances from epithelial cells, which in turn activates P2X3 receptors and induces contraction of the bladder and lung muscles, leading to premature urination or coughing, respectively.

P2X3 subunits and P2X2 subunits not only form homotrimers, but also form heterotrimers. P2X3 subunits and P2X2 subunits are also expressed on nerve fibers that stimulate the tongue (taste buds therein) [Kinnamon 2013, front Cell Neurosci 7:264]. In a physiological environment, receptors containing P2X3 and/or P2X2 subunits are related to the transmission of taste (bitter, sweet, salty, fresh and sour) from the tongue. Recent data show that although blocking P2X3 homopolymeric receptors alone is important for achieving the effect of anti-nociception, the non-selective blocking of P2X3 homopolymeric receptors and P2X2/3 heteropolymeric receptors causes taste changes, which can limit the therapeutic use of non-selective P2X3 and P2X2/3 receptor antagonists [Ford 2014, Purines 2014, abstractbook p15]. Therefore, it is very desirable to distinguish compounds that can bind P2X3 and P2X2/3 receptors.

Compounds that block both ion channels containing only P2X3 subunits (P2X3 homomers) and ion channels composed of P2X2 and P2X3 subunits (P2X2/3 heterotrimers) are called P2X3 and P2X2/3 non-selective receptor antagonists [Ford, Pain Manag 2012]. Clinical PhII trials have shown that AF-219, a P2X3 antagonist, causes taste disturbances in treated subjects by affecting taste on the tongue [e.g., Abdulqawi et al., Lancet 2015; Strand et al., 2015 ACR/ARMP Annual Meeting, Abstract 2240]. This side effect has been attributed to the blockage of P2X2/3 channels (i.e., heterotrimers) [A. Ford, London 2015 Pain Therapeutics Conference, congress report]. Both P2X2 and P2X3 subunits are expressed on sensory nerve fibers that stimulate the tongue. Animals deficient for both P2X2 and P2X3 subunits exhibit a weakened sense of taste, or even a loss of taste [Finger et al., Science 2005], whereas deletion of the P2X3 subunit alone shows mild or no changes in taste. Furthermore, two distinct neuronal populations have been described in the geniculate ganglion expressing both P2X2 and P2X3 subunits, or the P2X3 subunit alone. In an in vivo assessment of taste preferences for artificial sweeteners using a lickometer, an effect on taste was observed only at very high free plasma levels (>100 μM), suggesting that, unlike the population expressing the P2X3 subunit, the population expressing the P2X2 and P2X3 subunits plays a major role in taste [Vandenbeuch et al., J Physiol. 2015]. Therefore, since improving taste has a profound impact on patients' quality of life, P2X3-homomeric receptor selective antagonists are considered to be superior to non-selective receptor antagonists and are believed to represent a solution to the problem of insufficient patient compliance during chronic disease treatment, as indicated by increased drop-out rates during PhII trials [Strand et al., 2015 ACR/ARMP Annual Meeting, Abstract 2240 and A. Ford, London 2015 Pain Therapeutics Conference, congress report].

The prior art has disclosed benzamide derivative compounds for treating or preventing various diseases:

WO 2009/058298 and WO 2009/058299 (Merck) disclose novel P2X3 type receptor antagonists having a benzamide core structure substituted with phenyl or pyridyl moieties instead of thiazole, making said compounds different from the compounds of the present invention.

WO2008/000645 (Roche) relates to P2X3 and/or P2X2/3 receptor antagonist compounds for treating diseases associated with P2X purinergic receptors. According to the general formula of claim 1, the benzamide compounds are substituted with tetrazolyl. Furthermore, they may have substituents such as phenyl, pyridyl, pyrimidyl, pyridazinyl, or thienyl. However, a thiazolyl substituent is not disclosed.

WO2009/077365, WO2009/077366, WO2009/077367, and WO2009/077371 (Roche) disclose a series of benzamide derivatives substituted with imidazole, triazole, pyrazole, or tetrazole, which are believed to be useful for treating diseases associated with P2X purinergic receptors, more specifically as P2X3 receptor antagonists and/or P2X2/3 receptor antagonists. According to the general formula of claim 1, the benzamide compound may have additional substituents ^R6 , ^R7 , and ^R8 , each of which is a _C1 - _C6 alkyl group, a _C1 - _C6 alkoxy group, a _C1 - _C6 haloalkyl group, a halogen atom, or a cyano group. However, ethers substituted with functional groups such as -C2 _{- C6} -alkyl- ^OR4 , -( _CH2 ) _q- ( _C3 - _C7 -cycloalkyl), -(CH2) _q- (6- to 12-membered heterobicycloalkyl), -( _CH2 ) _q- (4- to 7-membered heterocycloalkyl), - _{( CH2} ) _q- (5- to 10-membered heteroaryl) or -C2- _C6 -alkynyl are _not disclosed.

US20100152203 (Roche) discloses substituted benzamides (wherein R ¹ is thiadiazolyl and R ² is phenyl, pyridyl, pyrimidinyl, pyridazinyl or thienyl) as compounds for treating diseases associated with P2X purinergic receptors, and more particularly relates to P2X3 receptor antagonists and/or P2X2/3 receptor antagonists that can be used to treat diseases, conditions and disorders of the urogenital, pain, inflammation, gastrointestinal and respiratory tracts. More specifically, the benzamide compounds may be further substituted with C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkyl, halogen atoms or cyano groups. However, ethers substituted with functional groups such as -C2 _{- C6} -alkyl- ^OR4 , -( _CH2 ) _q- ( _C3 - _C7 -cycloalkyl), -(CH2) _q- (6- to 12-membered heterobicycloalkyl), -( _CH2 ) _q- (4- to 7-membered heterocycloalkyl), - _{( CH2} ) _q- (5- to 10-membered heteroaryl) or -C2- _C6 -alkynyl are _not disclosed.

US20100324056 (Roche) discloses substituted benzamides (wherein R ¹ is phenyl, thienyl, pyrimidinyl, pyridazinyl, or pyridinyl) as compounds useful for treating diseases associated with P2X purinergic receptors, and more particularly, P2X3 receptor antagonists and/or P2X2/3 receptor antagonists useful for treating diseases, conditions, and disorders of the urogenital, pain, inflammation, gastrointestinal, and respiratory tracts. Ethers substituted with functional groups such as -C ₂ -C ₆ -alkyl-OR ⁴ , -(CH ₂ ) _q -(C ₃ -C ₇ -cycloalkyl), -(CH ₂ ) _q -(6- to 12-membered heterobicycloalkyl), -(CH ₂ ) _q -(4- to 7-membered heterocycloalkyl), -(CH ₂ ) _q -(5- to 10-membered heteroaryl), or -C ₂ -C ₆ -alkynyl are not disclosed.

US20100324069 (Genentech) discloses oxazolone- and pyrrolidone-substituted benzamides and their use for preventing and/or treating diseases associated with P2X3 receptors and/or P2X2/3 receptor antagonists. According to the general formula of claim 1, the benzamide compound is additionally substituted with a pyridine or phenyl group. Ether groups attached to the benzamide core structure are not disclosed.

WO2006119504 (Renovis) relates to fused heterocyclic compounds of the tetrahydronaphthothiazine and tetrahydropyrido[4,3-d]pyrimidine classes and pharmaceutical compositions containing the same.

WO2008123963 (Renovis) relates to fused heterocyclic compounds of the tetrahydropyrido[4,3-d]pyrimidine class and pharmaceutical compositions comprising the compounds. Also provided are methods of using the fused heterocyclic compounds and pharmaceutical compositions thereof to prevent and/or treat mammalian disorders, such as (but not limited to) arthritis, Parkinson's disease, Alzheimer's disease, asthma, myocardial infarction, pain syndromes (acute and chronic or neurological), neurodegenerative diseases, schizophrenia, cognitive impairment, anxiety disorders, depression, inflammatory bowel disease, and autoimmune diseases, as well as promoting neuroprotection.

WO2008130481 (Renovis) discloses 2-cyanophenyl-fused heterocyclic compounds of the tetrahydropyrido[4,3-d]pyrimidine class and pharmaceutical compositions comprising the same.

WO2010033168 (Renovis) discloses a series of benzamides substituted with phenyl or pyridyl groups, which are believed to be useful for treating diseases associated with P2X purinergic receptors, more particularly P2X3 receptor antagonists and/or P2X2/3 receptor antagonists. However, benzamides having additional ether groups are not disclosed.

WO2009110985 (Renovis) relates to phenyl and pyridyl substituted benzamide compounds and pharmaceutical compositions comprising said compounds, but not thiazole substituted benzamides, making said compounds distinct from the compounds of the present invention.

WO2008/055840 (Roche) relates to thiazole- and oxazole-substituted benzamides (wherein the substituent ^R2 is phenyl, pyridyl, pyrimidinyl, pyridazinyl or thienyl) which are useful for treating diseases associated with P2X purinergic receptors, and more particularly as P2X3 and/or P2X2/3 receptor antagonists. However, the thiazole-substituted benzamides do in fact have C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -haloalkyl, halo-C ₁ -C ₆ -alkoxy, a halogen atom or a cyano group, but there is no disclosure of ethers substituted with, for example, -C ₂ -C ₆ -alkyl-OR ⁴ , -(CH ₂ ) _q -(C ₃ -C ₇ -cycloalkyl), -(CH ₂ ) _q -(6- to 12-membered heterobicycloalkyl), -(CH ₂ ) _q -(4- to 7-membered heterocycloalkyl), -(CH ₂ ) _q -(5- to 10-membered heteroaryl) or -C ₂ -C ₆ -alkynyl.

Therefore, the above-mentioned prior art does not describe the specific thiazole-substituted benzamide compounds of the general formula (I) of the present invention as defined herein, or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, or their pharmacological activities, as described and defined herein and referred to hereinafter as "compounds of the present invention".

It has now been found that the compounds according to the invention have unexpected and advantageous properties, and this forms the basis of the present invention.

In particular, it has been unexpectedly found that the compounds of the present invention effectively inhibit P2X3 receptors and are therefore useful in treating or preventing the following diseases:

Genitourinary, gastrointestinal, respiratory, and pain-related diseases, conditions, and disorders;

Gynecological disorders, including dysmenorrhea (primary and secondary), dyspareunia, endometriosis, and adenomyosis; pain associated with endometriosis; symptoms associated with endometriosis, particularly dysmenorrhea, dyspareunia, dysuria, or constipation; endometriosis-associated hyperplasia; and pelvic irritability.

Urinary tract conditions associated with bladder outlet obstruction; urinary incontinence disorders, such as reduced bladder capacity, increased frequency of urination, urge incontinence, stress incontinence, or hypersensitive bladder; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms associated with overactive bladder, particularly increased frequency, nocturia, urgency, or urge incontinence; pelvic irritability; urethritis; prostatitis; prostatodynia; cystitis, particularly interstitial cystitis; idiopathic irritable bladder [Ford 2014, Purines 2014, abstract bookp 15];

Pain syndromes (including acute, chronic, inflammatory and neuropathic pain), preferably inflammatory pain, back pain, surgical pain, visceral pain, toothache, periodontitis, premenstrual pain, pain associated with endometriosis, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headache, pain due to nerve damage, pain due to neuritis, neuralgia, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viral, parasitic or bacterial infection, pain due to traumatic nerve damage, pain due to post-traumatic injury (including fractures and pain associated with a motor or sports injury, pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic low back pain, neck pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, pain associated with gastrointestinal distension, chronic arthritis pain and related neuralgia, pain associated with cancer, morphine-resistant pain, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; pain associated with a disease or condition selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (e.g., irritable bowel syndrome), and arthritis (e.g., osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis);

Epilepsy, both partial and generalized;

Respiratory diseases, including chronic obstructive pulmonary disease (COPD) [Ford 2013, European Respiratory Society Annual Congress 2013], asthma [Ford 2014, 8th Pain & Migraine Therapeutics Summit], bronchospasm, pulmonary fibrosis, acute cough, and chronic cough (including chronic spontaneous and chronic refractory cough);

Gastrointestinal diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary diseases, renal colic, diarrhea-predominant IBS, gastroesophageal reflux, gastrointestinal bloating, Crohn’s disease, etc.

Neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, cerebral ischemia, and traumatic brain injury;

Myocardial infarction, dyslipidemia;

a pain-related disease or condition selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis [Ford 2014, 8th Pain & Migraine Therapeutics Summit], rheumatoid arthritis, and ankylosing spondylitis), cough syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injury (including fractures and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgia, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing, and bone diseases such as joint degeneration

Itching.

The compounds of the present invention show high P2X3 receptor inhibition, and in addition, selectivity over P2X2/3 receptors. Selective inhibition of P2X3 receptors over P2X2/3 receptors means a selectivity of at least 3 times over P2X2/3 receptors. Preferred compounds of the present invention show a selectivity of at least 10 times over P2X2/3 receptors. In addition, more preferred compounds of the present invention show other favorable properties that are conducive to their use as drugs, such as the desired pharmacokinetic profiles that provide suitable metabolic stability and oral bioavailability. In addition, even more preferred compounds of the present invention show other favorable properties that are conducive to their use as drugs, such as the desired pharmacokinetic profiles that provide suitable metabolic stability and oral bioavailability, and at least one other favorable property selected from favorable cardiovascular characteristics and suitable CYP inhibition characteristics.

Summary of the Invention

The present invention encompasses compounds of the general formula (I) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof:

in

R ¹ represents a halogen atom, C ₁ -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl, where C ₁ -C ₄ -alkyl is optionally substituted by 1 to 5 identical or different halogen atoms;

R ² represents -C ₂ -C ₆ -alkyl-OR ⁴ , -(CH ₂ ) _q -(C ₃ -C ₇ -cycloalkyl), -(CH ₂ ) _q -(6- to 12-membered heterobicycloalkyl), -(CH ₂ ) _q -(4- to 7-membered heterocycloalkyl), -(CH ₂ ) _q -(5- to 10-membered heteroaryl) or -C ₂ -C ₆ -alkynyl; and

wherein said -(CH ₂ ) _q -(C ₃ -C ₇ -cycloalkyl), -(CH ₂ ) _q -(6- to 12-membered heterobicycloalkyl) and -(CH ₂ ) _q -(4- to 7-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or more identical or different substituents selected from the group consisting of: C ₁ -C ₄ alkyl optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b , -COOR ⁵ and oxo (═O); and

wherein in said -(CH ₂ ) _q -(6- to 12-membered heterobicycloalkyl) and -(CH ₂ ) _q -(4- to 7-membered heterocycloalkyl), if any ring nitrogen atoms are present, any ring nitrogen atoms are independently substituted by R ^c ; and

wherein said -(CH ₂ ) _q -(5- to 10-membered heteroaryl) is optionally substituted by one or more identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ;

R ³ represents hydrogen or C ₁ -C ₄ -alkyl, which is optionally substituted by 1 _{to 5} identical or different halogen atoms;

R ⁴ and R ⁵ represent hydrogen or C ₁ -C ₄ -alkyl;

R ^a and R ^b represent hydrogen or C ₁ -C ₄ -alkyl;

R ^c represents hydrogen, C ₁ -C ₄ -alkyl, —C(O)OC ₁ -C ₄ -alkyl or —C(O)—C ₁ -C ₄ -alkyl which is optionally substituted by 1 to 5 identical or different halogen atoms;

A represents a 5- to 10-membered heteroaryl group, which is optionally substituted by one or more identical or different substituents selected from halogen atoms, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy groups, wherein C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy groups are optionally substituted by 1 to 5 identical or different halogen atoms;

q represents an integer 0, 1, or 2.

The present invention also relates to compounds of general formula (Ia) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof:

wherein A, R ¹ , R ² and R ³ have the meanings as defined for formula (I), preferably R ³ represents C ₁ -C ₄ -alkyl, more preferably methyl.

The invention also relates to pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for the preparation of medicaments for the treatment or prevention of diseases or disorders, and for the treatment of pain associated with these diseases.

DETAILED DESCRIPTION

As mentioned herein, the terms preferably have the following meanings:

The term "halogen atom", "halo-" or "halo (Hal-)" is understood to mean a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

The term "alkyl" is understood to mean a linear or branched, saturated, monovalent hydrocarbon radical having the indicated number of carbon atoms and generally having from 2 to 6 carbon atoms in the case of ^R and from 1 to 4 (preferably from 1 to 3) carbon atoms for all other alkyl substituents, such as, for example and preferably, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or an isomer thereof. In particular, such radicals have 1, 2, 3 or 4 carbon atoms (“C ₁ -C ₄ -alkyl”), for example methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly 1, 2 or 3 carbon atoms (“C ₁ -C ₃ -alkyl”), for example methyl, ethyl, n-propyl or isopropyl, even more particularly 1 or 2 carbon atoms (“C ₁ -C ₂ -alkyl”), for example methyl or ethyl.

The term "Ci _{- C4} -alkyl radical optionally substituted by 1 to 5 halogen atoms" or similarly "Ci- _C3 -alkyl radical optionally substituted by ₁ to 5 halogen atoms" or "Ci- _C2 -alkyl radical optionally substituted by 1 to ₅ halogen atoms" is understood to mean a linear or branched saturated monovalent hydrocarbon radical wherein the term " _Ci - _C4 -alkyl", "Ci- _{C3 -} alkyl" or "Ci- _{C2 -} alkyl" is as defined above and wherein one or more hydrogen atoms are replaced by identical or different halogen atoms, i.e. one halogen atom is independent of another. In particular, halogen is fluorine or chlorine.

The term "C ₁ -C ₄ -alkyl radical optionally substituted by 1 to 5 fluorine atoms" or similarly "C ₁ -C ₃ -alkyl radical optionally substituted by 1 to 5 fluorine atoms" or "C ₁ -C ₂ -alkyl radical optionally substituted by 1 to 5 fluorine atoms" is understood to mean a linear or branched saturated monovalent hydrocarbon radical wherein the term "C ₁ -C ₄ -alkyl radical", "C ₁ -C ₃ -alkyl radical" or "C ₁ -C ₂ -alkyl radical" is as defined above and wherein one or more hydrogen atoms are replaced by fluorine atoms.

The “C ₁ -C ₄ -alkyl group optionally substituted by 1 to 5 fluorine atoms” or the “C ₁ -C ₄ -alkyl group optionally substituted by 1 to 5 halogen atoms” is, for example, —CH ₂ CH ₂ CH ₂ CF ₃ .

Similarly, the above applies to “C ₁ -C ₃ -alkyl optionally substituted by 1 to 5 halogen atoms” or “C ₁ -C ₂ -alkyl optionally substituted by 1 to 5 halogen atoms” or “C ₁ -C ₃ -alkyl optionally substituted by 1 to 5 fluorine atoms” or “C ₁ -C ₂ -alkyl optionally substituted by 1 to 5 fluorine atoms”. Thus, the “C ₁ -C 3 -alkyl optionally substituted by 1 to 5 halogen atoms” or “C ₁ -C ₃ -alkyl optionally substituted by 1 to ₅ fluorine atoms” is, for example, -CH ₂ CH ₂ CF ₃ .

The "C ₁ -C ₂ -alkyl group optionally substituted by 1-5 halogen atoms" or "C ₁ -C ₂ -alkyl group optionally substituted by 1-5 fluorine atoms" is, for example, -CF ₃ , -CHF ₂ , -CH ₂ F, -CF ₂ CF ₃ , -CH ₂ CHF ₂ or -CH ₂ CF ₃ .

Where R ² in formula (I) or (Ia) is -C ₂ -C ₆ -alkyl-OR ⁴ , "C ₂ -C ₆ -alkyl" is understood to be a C ₁ -C ₅ -alkylene group bonded to a phenolic oxygen group via a -CH ₂ - group. For example, C ₁ -C ₅ -alkylene is methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, tert-butylene, isopentylene, 2-methylbutylene, 1-methylbutylene, 1-ethylpropylene, 1,2-dimethylpropylene, neopentylene, and 1,1-dimethylpropylene.

Where R ² in formula (I) or (Ia) is —C ₂ -C ₆ -alkyl-OR ⁴ , “C ₂ -C ₆ -alkyl” is also understood to mean a C ₁ -C ₄ -alkylene group bonded to the phenolic oxygen via a —CH—CH ₃ group.

Where R ² in formula (I) or (Ia) is -C ₂ -C ₄ -alkyl-OR ⁴ , "C ₂ -C ₄ -alkyl" is understood to mean a C ₁ -C ₃ -alkylene group bonded to the phenoxide oxygen group via a -CH ₂ - group. Where R ² in formula (I) or (Ia) is -C ₂ -C ₄ -alkyl-OR ⁴ , "C ₂ -C ₄ -alkyl" is also understood to mean a C ₁ -C ₂ -alkylene group bonded to the phenoxide oxygen group via a -CH-CH ₃ group.

Where R ² in formula (I) or (Ia) is -C ₂ -C ₄ -alkyl-OH, "C ₂ -C ₄ -alkyl" is understood to mean a C ₁ -C ₃ -alkylene group bonded to the phenoxide oxygen group via a -CH ₂ - group. Where R ² in formula (I) or (Ia) is -C ₂ -C ₄ -alkyl-OH, "C ₂ -C ₄ -alkyl" is also understood to mean a C ₁ -C ₂ -alkylene group bonded to the phenoxide oxygen group via a -CH-CH ₃ group.

Where R ² in formula (I) or (Ia) is —C ₂ -C ₆ -alkyl-OR ⁴ , “—OR ⁴ ” is located at a tertiary, secondary or primary carbon atom of the —C ₂ -C ₆ -alkyl chain.

Where R ² in formula (I) or (Ia) is -C ₂ -C ₄ -alkyl-OR ⁴ , "-OR ⁴ " is located at a tertiary, secondary or primary carbon atom of the -C ₂ -C ₄ -alkyl chain.

Where R ² in formula (I) or (Ia) is -C ₂ -C ₄ -alkyl-OH, "-OH" is located at a tertiary, secondary or primary carbon atom of the -C ₂ -C ₄ -alkyl chain.

For example, the -C ₂ -C ₆ -alkyl-OR ⁴ is 3-hydroxybutan-2-yl, (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl, (2R,3S)-3-hydroxybutan-2-yl, (2S,3R)-3-hydroxybutan-2-yl, (2R,3R)-3-methoxybutan-2-yl, (2S,3S)-3-methoxybutan-2-yl, (2R,3S)-3-methoxybutan-2-yl, (2S,3R)-3 -methoxybutyl-2-yl, 3-methoxybutyl-2-yl, 2-hydroxy-2-methylprop-1-yl, 2-methoxy-2-methylprop-1-yl, 3-hydroxyprop-1-yl, 3-hydroxybutyl-1-yl, 3-hydroxy-3-methylbutyl-1-yl, 3-hydroxy-2-methylbutyl-1-yl, 3-hydroxy-2,2-dimethylprop-1-yl, 4-hydroxy-3-methylbutyl-2-yl, 4-hydroxy-3-methylpent-1-yl, 4 -hydroxy-4-methylpentan-1-yl, 2-hydroxy-2-methylpropyl-1-yl, 2-methoxy-2-methyl-propyl-1-yl, 2-methoxyethyl-1-yl, 3-methoxypropyl-1-yl, 4-methoxybutyl-1-yl, 2-ethoxyethyl-1-yl, 3-ethoxypropyl-1-yl, 4-ethoxybutyl-1-yl, 2-isopropoxyethyl-1-yl, 3-isopropoxypropyl-1-yl, 4-isopropoxybutyl-1-yl, 2-hydroxy 3-Hydroxybutan-2-yl, (2R, 3R)-3-hydroxybutan-2-yl, (2S, 3S)-3-hydroxybutan-2-yl, (2R, 3S)-3-hydroxybutan-2-yl, (2S, 3R)-3-hydroxybutan-2-yl, more preferably (2R, 3R)-3-hydroxybutan-2-yl, (2S, 3S)-3-hydroxybutan-2-yl.

For example, the -C ₂ -C ₄ -alkyl-OR ⁴ or -C ₂ -C ₄ -alkyl-OH is preferably 3-hydroxybutan-2-yl, (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl, (2R,3S)-3-hydroxybutan-2-yl, (2S,3R)-3-hydroxybutan-2-yl, more preferably (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl.

The term "alkoxy" is understood to mean a linear or branched saturated monovalent hydrocarbon radical of the formula -O-alkyl, wherein the term "alkyl" is defined to mean a linear or branched saturated monovalent hydrocarbon radical having the indicated number of carbon atoms and generally having 1 to 3, preferably 1 to 2, alkyl substituents, particularly preferably 1 carbon atom. In particular, such radicals have 1, 2 or 3 carbon atoms (" _Ci - _C3 -alkoxy"), such as methoxy, ethoxy, n-propoxy or isopropoxy radicals, and even more particularly 1 or 2 carbon atoms ("Ci _{- C2} -alkoxy"), such as methoxy or ethoxy radicals.

The term "C ₁ -C ₃ -alkoxy optionally substituted by 1 to 5 halogen atoms" is understood to mean a linear or branched saturated monovalent hydrocarbon radical, wherein the term "C ₁ -C ₃ -alkoxy" is as defined above and wherein one or more hydrogen atoms are replaced by identical or different halogen atoms, i.e. one halogen atom is independent of another. In particular, halogen is fluorine or chlorine.

The "C ₁ -C ₃ -alkoxy" group is optionally substituted by 1 to 5 fluorine atoms, for example -OCF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₂ CF ₃ , -OCH ₂ CHF ₂ , -OCH ₂ CF ₃ , -OCH ₂ CH ₂ CF ₃ or -OCH ₂ CF ₂ CF ₃ . In particular, the optionally fluorine-substituted "C ₁ -C ₃ -alkoxy" group is -OCF ₃ .

The term "C ₂ -C ₆ -alkynyl" is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more triple bonds, preferably one triple bond, and containing 2, 3, 4, 5 or 6 carbon atoms, in particular a linear or branched monovalent hydrocarbon radical containing 3 or 4 carbon atoms ("C _{3 -C 4 -alkynyl} "). -alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4 In some embodiments, the alkynyl group is 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methyl-pent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is prop-1-ynyl or prop-2-ynyl.

The term "cycloalkyl" is understood to mean a saturated monovalent monocyclic hydrocarbon ring having the indicated number of carbon atoms and typically having 3 to 7 or 3 to 6 ring carbon atoms, preferably 3 to 4 ring carbon atoms.

"C ₃ -C ₇ -cycloalkyl" is understood to mean a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5, 6 or 7 carbon atoms. Such C ₃ -C ₇ -cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a further substituent as specified. In particular, the ring contains 3, 4, 5 or 6 carbon atoms ("C ₃ -C ₆ -cycloalkyl"), preferably 3 or 4 carbon atoms ("C ₃ -C ₄ -cycloalkyl").

In the case of R ² in formula (I) or (Ia), unless otherwise stated, the "C ₃ -C ₇ -cycloalkyl" in "(CH ₂ ) _q -(C ₃ -C ₇ -cycloalkyl)" is optionally substituted on any ring carbon atom by one or more identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b , COOR ⁵ and oxo (═O). In the case of R ² in formula (I) or (Ia), unless otherwise stated, the “C ₃ -C ₄ -cycloalkyl” itself or the “C _{3 -C 4} -cycloalkyl” in “CH ₂ -(C ₃ -C ₄ -cycloalkyl)” is optionally substituted on any ring carbon atom by one or more identical or different substituents selected from the group consisting of C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b , -COOR ⁵ and oxo (═O).

The term "heterocycloalkyl" is understood to mean a saturated monovalent monocyclic hydrocarbon ring having the specified number of ring atoms, wherein one, two or three ring atoms of the hydrocarbon ring are replaced by one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O) ₂ or N.

"4- to 7-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic "heterocycloalkyl" ring as defined above containing 4, 5, 6 or 7 ring atoms.

Similarly, "4- to 6-membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic "heterocycloalkyl" ring as defined above containing 4, 5 or 6 ring atoms.

In the case of R ² in formula (I) or (Ia), unless otherwise specified, the 4- to 7-membered heterocycloalkyl or 4- to 6-membered heterocycloalkyl is optionally substituted on any ring carbon atom by one or more identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b , COOR ⁵ and oxo (═O); and wherein in the 4- to 7-membered or 4- to 6-membered heterocycloalkyl, if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; the 4- to 7-membered or 4- to 6-membered heterocycloalkyl may be attached to the remainder of the molecule via any of the carbon atoms or, if present, the nitrogen atom. Thus, in the 4- to 7-membered or 4- to 6-membered heterocycloalkyl, if a ring nitrogen atom is present, any ring nitrogen atom is substituted only by R ^c , provided that the normal valence of the designated atom for the existing instance is not exceeded.

Specifically, the 4- to 7-membered heterocycloalkyl group may contain 3, 4, 5, or 6 carbon atoms and one or two heteroatoms or heteroatom-containing groups as described above, provided that the total number of ring atoms is not greater than 7. More specifically, the heterocycloalkyl group may contain 3, 4, or 5 carbon atoms and one or two heteroatoms or heteroatom-containing groups as described above, provided that the total number of ring atoms is not greater than 6 ("4- to 6-membered heterocycloalkyl").

In particular, without limitation thereto, the heterocycloalkyl group may be a 4-membered ring, such as azetidinyl, oxetanyl; or a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithioxanyl, thiomorpholinyl, piperazinyl; or a 7-membered ring, such as diazepanyl.

In particular, without being limited thereto, in another preferred embodiment, the heterocycloalkyl group may be (3R)-tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl, 4-methylmorpholin-2-yl, (2R)-4-methylmorpholin-2-yl, (2S)-4-methylmorpholin-2-yl, 4-methylmorpholin-3-yl, (3R)-4-methylmorpholin-3-yl or (3S)-4-methylmorpholin-3-yl, most preferably (2R)-4-methylmorpholin-2-yl.

The term "6- to 12-membered heterobicycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical wherein the two rings share one or two common ring atoms, wherein the bicyclic hydrocarbon radical contains 5, 6, 7, 8, 9 or 10 carbon atoms and one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O) ₂ or N, with the proviso that the total number of ring atoms is not greater than 12. Unless otherwise specified, the 6- to 12-membered heterobicycloalkyl group is optionally substituted on any ring atom by one or more identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b , COOR ⁵ and oxo (═O); and wherein in the 6- to 12-membered heterobicycloalkyl group, if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; the 6- to 12-membered heterobicycloalkyl group may be attached to the remainder of the molecule via any of the carbon atoms or, if present, the nitrogen atom. Thus, in the 6- to 12-membered heterobicycloalkyl group, if a ring nitrogen atom is present, any ring nitrogen atom is substituted only by R ^c , provided that the normal valence of the designated atom for the existing situation is not exceeded. The 6- to 12-membered heterobicycloalkyl group is, for example, azabicyclo[3.3.0]octyl, azabicyclo[4.3.0]nonyl, diazabicyclo[4.3.0]nonyl, oxazabicyclo[4.3.0]nonyl, thiazabicyclo[4.3.0]nonyl or azabicyclo[4.4.0]decyl.

Heterospirocycloalkyl and bridged heterocycloalkyl groups, as defined below, are also included within the scope of this definition.

The term "heterospirocycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical in which the two rings share one common ring atom, wherein the bicyclic hydrocarbon radical contains 5, 6, 7, 8, 9 or 10 carbon atoms and one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O) ₂ or N, with the proviso that the total number of ring atoms is not greater than 12. The heterospirocycloalkyl radical may be linked to the remainder of the molecule via any of the carbon atoms or, if present, the nitrogen atom. The heterospirocycloalkyl group is, for example, azaspiro[2.3]hexyl, azaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, oxazaspiro[3.3]heptyl, oxazaspiro[5.3]nonyl, oxazaspiro[4.3]octyl, oxazaspiro[5.5]undecyl, diazaspiro[3.3]heptyl, thiazaspiro[3.3]heptyl, thiazaspiro[4.3]octyl or azaspiro[5.5]decyl.

The term "bridged heterocycloalkyl" is understood to mean a saturated monovalent bicyclic hydrocarbon radical in which the two rings share two common non-directly adjacent ring atoms, wherein the bicyclic hydrocarbon radical contains 5, 6, 7, 8, 9 or 10 carbon atoms and one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O) ₂ or N, with the proviso that the total number of ring atoms is not greater than 12. The bridged heterocycloalkyl radical may be linked to the remainder of the molecule via any of the carbon atoms or, if present, the nitrogen atom. The bridged heterocycloalkyl group is, for example, azabicyclo[2.2.1]heptyl, oxazabicyclo[2.2.1]heptyl, thiazabicyclo[2.2.1]heptyl, diazabicyclo[2.2.1]heptyl, azabicyclo[2.2.2]octyl, diazabicyclo[2.2.2]octyl, oxazabicyclo[2.2.2]octyl, thiazabicyclo[2.2.2]octyl, azabicyclo[3.2.1]octyl, diazabicyclo[3.2.1]octyl, oxazabicyclo[3.2.1]octyl, thiazabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, diazabicyclo[3.3.1]nonyl, oxazabicyclo[3.3.1]nonyl, thiazabicyclo[3.3.1]nonyl, azabicyclo[4.2.1]nonyl, diazabicyclo[4.2.1]nonyl, oxazabicyclo[4.2.1]nonyl, thiazabicyclo[4.2.1]nonyl, azabicyclo[3.3.2]decyl, diazabicyclo[3.3.2]decyl, oxazabicyclo[3.3.2]decyl, thiazabicyclo[3.3.2]decyl or azabicyclo[4.2.2]decyl.

The term "heteroaryl" is understood to mean a monovalent monocyclic or bicyclic hydrocarbon ring system having at least one aromatic ring containing the specified number of ring system atoms, wherein one, two or three ring atoms of the monovalent monocyclic or bicyclic hydrocarbon ring system are replaced by one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(=O), S(=O) ₂ or N.

“5- to 10-membered heteroaryl” is understood to mean a heteroaryl radical having 5, 6, 7, 8, 9 or 10 ring atoms (“5- to 10-membered heteroaryl”) and in which one, two or three ring atoms of the monovalent monocyclic or bicyclic hydrocarbon ring system are replaced by one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(═O), _S (═O) or N. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like, and benzo derivatives thereof, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof, for example, quinolyl, quinazolinyl, isoquinolyl and the like; indolizinyl and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and the like.

In the case of R ² in formula (I) or (Ia), unless otherwise stated, the 5- to 10-membered heteroaryl group is optionally substituted by one or more identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ .

In the case of R ² in formula (I) or (Ia), the abovementioned optionally substituted 5- to 10-membered heteroaryl may in particular be substituted on any ring N, if present, by C ₁ -C ₂ -alkyl.

In the case of A in formula (I) or (Ia), unless otherwise stated, the 5- to 10-membered heteroaryl group is optionally substituted by one or more identical or different substituents selected from the group consisting of: halogen atoms, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy are optionally substituted by 1 to 5 identical or different halogen atoms.

In the case of A in formula (I) or (Ia), "5- or 6-membered heteroaryl" is understood to mean a heteroaryl group having 5 or 6 ring atoms, and in which one, two or three ring atoms of the hydrocarbon ring system are replaced by one, two or three heteroatoms or heteroatom-containing groups independently selected from O, S, S(═O), S(═O) ₂ or N. Unless otherwise stated, the "5- or 6-membered heteroaryl" group is optionally substituted by one or more identical or different substituents selected from the group consisting of halogen atoms, C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy, wherein C ₁ -C ₃ -alkyl and C ₁ -C ₃ -alkoxy are optionally substituted by 1 to 5 identical or different halogen atoms.

The 5-membered heteroaryl group is preferably selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl.

The 6-membered heteroaryl group is preferably selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

In particular, the 5- or 6-membered heteroaryl is optionally substituted by preferably one or two identical or different substituents selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy optionally substituted by 1 to 5 fluorine atoms.

In particular, the 5- or 6-membered heteroaryl group is a 6-membered heteroaryl group having one or two nitrogen atoms and is optionally substituted by one or two identical or different substituents selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy optionally substituted by 1 to 5 fluorine atoms.

The 6-membered heteroaryl group is preferably CF ₃ -pyrimidinyl, most preferably 2-CF ₃ -pyrimidin-5-yl. Also preferred is CF ₃ -pyridazinyl, most preferably 6-CF ₃ -pyridazin-3-yl.

In general, unless otherwise indicated, the term "heteroaryl" includes all possible isomeric forms thereof, for example, positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term pyrimidinyl includes pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl; or the term pyridazinyl includes pyridazin-3-yl and pyridazin-4-yl; or the term thiazolyl includes 1,3-thiazol-5-yl, 1,3-thiazol-4-yl, and 1,3-thiazol-2-yl.

The term "C ₁ -C ₄ " as used throughout this document is understood to mean a group having a finite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms, e.g. in the context of the definition of "C ₁ -C ₄ -alkyl", it is understood to mean an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1, 2, 3 or 4 carbon atoms.

As used herein, the term "C ₂ -C ₆ " is understood to mean a group having a finite number of carbon atoms of 2 to 6 (i.e., 2, 3, 4, 5 or 6 carbon atoms), for example, in the context of defining "C ₂ -C ₆ -alkyl", it is understood to mean an alkyl group having a finite number of carbon atoms of 2 to 6 (i.e., 2, 3, 4, 5 or 6 carbon atoms). It is also understood that the term "C ₂ -C ₆ " is to be interpreted as any subrange subsumed therein, for example, C ₂ -C ₆ , C ₃ -C ₅ , C ₃ -C ₄ , C ₂ -C ₃ , C ₂ -C ₄ , C ₂ -C ₅ ; in particular, C ₂ -C ₃ .

The term "C ₁ -C ₃ " used in the context of the definition of "C 1 _{-C 3} -alkoxy" is understood to mean an alkoxy group having a finite number of carbon atoms of 1 to 3, ie 1, 2 or 3 carbon atoms.

The foregoing applies to otherwise referred to "alkyl," "alkynyl," or "alkoxy" groups as described herein, and is understood by those skilled in the art.

It will also be understood that, for example, the term " _C1 - _C6 " is to be interpreted as any sub-range subsumed therein, e.g., _C1 - _C6 , _C2 - _C3 , _C2 - _C6 , _{C3 - C4} , C1 _{- C2} , _C1 - _C3 , C1- _C4 , _C1 - _C5 ; particularly _C1 - _C2 , _{C1 - C3} , C1- _C4 , _C1 - _C5 , _C1 - _C6 ; more particularly _C1 - _C4 .

Similarly, the above applies to "C ₁ -C ₄ -alkyl", "C 1 -C 3 -alkyl", "C ₁ -C ₃ -alkoxy", "C ₁ -C ₂ -alkyl" or "C ₁ -C ₂ -alkoxy" optionally substituted by 1 _to 5 identical or _different halogens.

Similarly, as used herein, the term " _C2 - _C6 " as used throughout this document (e.g., in the context of defining " _C2 - _C6 -alkynyl") is to be understood as meaning an alkynyl group having a finite number of carbon atoms of 2 to 6, i.e., 2, 3, ₄ , ₅ , or 6 carbon atoms. It is also to be understood that the term " _C2 - _C6 " is to be interpreted as including any subranges subsumed therein, e.g., _C2 - _C6 , C3- _C5 , _{C3 - C4} , C2-C3, _C2 - _C4 , _C2 - _C5 ; in particular, _C2 - _C3 and _C2 - _C4 .

Furthermore, as used herein, the term "C ₃ -C ₇ " as used throughout this document is understood to mean a group having a finite number of carbon atoms from 3 to 7 (i.e., 3, 4, 5, 6, or 7 carbon atoms), for example, in the context of defining "C ₃ -C ₇ -cycloalkyl", it is understood to mean a cycloalkyl group having a finite number of carbon atoms from 3 to 7 (i.e., 3, 4, 5, 6, or 7 carbon atoms). It is also understood that the term "C ₃ -C ₇ " is to be interpreted as any subrange included therein, for example, C ₃ -C ₆ , C ₄ -C ₅ , C ₃ -C ₅ , C ₃ -C ₄ , C ₄ -C ₆ , C ₅ -C ₇ ; in particular, C ₃ -C ₆ .

The term "substituted" means that one or more hydrogen atoms on a designated atom are replaced with a selected designated radical, provided that the designated atom's normal valency is not exceeded and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "optionally substituted" means that the number of substituents may be zero. Unless otherwise indicated, an optionally substituted group may be substituted with a number of optional substituents, which may be performed by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon atom or nitrogen atom. Typically, the number of optional substituents (if present) ranges from 1 to 5, particularly from 1 to 3.

As used herein, for example in the definition of substituents of compounds of the general formula of the invention, the term "one or more" is understood to mean "one, two, three, four or five, in particular one, two, three or four, more in particular one, two or three, even more in particular one or two".

The present invention also includes all suitable isotopic modifications of the compounds of the present invention. An isotopic modification of a compound of the present invention is defined as a compound in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that common or primarily present in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine, such as, respectively, ² H (deuterium), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ O, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, and ³⁶ Cl. Certain isotopic modifications of the compounds of the present invention, such as those wherein one or more radioactive isotopes such as ³ H or ¹⁴ C are introduced, are used for drug and/or substrate tissue distribution studies. Tritium isotopes and carbon-14 (i.e., ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures known to those skilled in the art using appropriate isotopic variations of suitable reagents, for example, by the illustrative methods or by the preparative methods described in the Examples hereinafter.

Optical isomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by forming diastereomeric salts using optically active acids or bases, or by forming covalent diastereoisomers. Examples of suitable acids are tartaric acid, diacetyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. A mixture of diastereoisomers can be separated into their respective diastereoisomers based on their physical and/or chemical differences by methods known in the art (for example, by chromatography or fractional crystallization). Then, the optically active base or acid is released from the separated diastereomeric salts. A different method of separating optical isomers includes using chiral chromatography (for example, a chiral HPLC column) with or without conventional derivatization, optimally selected to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, for example, including Chiracel OD and Chiracel OJ, all of which can be conventionally selected. Enzymatic separation can also be used with or without derivatization. The optically active compounds of the present invention can also be obtained by utilizing chiral synthesis of optically active raw materials.

In order to distinguish different types of isomers from each other, reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

Furthermore, the compounds of the present invention may exist in the form of tautomers.

The present invention includes all possible tautomers of the compounds of the present invention, either as single tautomers or as any mixture of said tautomers in any ratio.

The present invention also relates to useful forms of the compounds disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts (particularly pharmaceutically acceptable salts), and coprecipitates.

When the word compounds, salts, polymorphs, hydrates, solvates etc. is used in the plural herein, this is to be understood as referring also to a single compound, salt, polymorph, isomer, hydrate, solvate etc.

By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The compounds of the present invention can exist in the form of hydrates or solvates, wherein the compounds of the present invention include, for example, polar solvents, particularly water, methanol or ethanol, as structural elements of the compound lattice. The amount of polar solvents, particularly water, can be present in a stoichiometric ratio or a non-stoichiometric ratio. In the case of stoichiometric solvates such as hydrates, these can be hemisolvates or hydrates, (semisolvates or hydrates), monosolvates or hydrates, sesquisolvates or hydrates, disolvates or hydrates, trisolvates or hydrates, tetrasolvates or hydrates, pentasolvates or hydrates, etc. The present invention includes all such hydrates or solvates.

Furthermore, the compounds of the present invention may exist in free form, for example as a free base, a free acid or a zwitterion, or in the form of a salt. The salt may be any salt, organic or inorganic, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmacy.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of a compound of the present invention. For example, see S.M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Suitable pharmaceutically acceptable salts of the compounds of the present invention may be, for example, acid addition salts of compounds of the present invention having a nitrogen atom in the chain or ring, for example, which have sufficient basicity, such as acid addition salts formed with the following inorganic acids: for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, bisulfuric acid, phosphoric acid or nitric acid; or acid addition salts formed with the following organic acids: for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid acid), 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid, or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of the compound of the present invention having sufficient acidity is: an alkali metal salt, such as a sodium salt or a potassium salt; an alkaline earth metal salt, such as a calcium salt or a magnesium salt; an ammonium salt; or a salt formed with an organic base which provides a physiologically acceptable cation, such as a salt formed with the following substances: N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexanediamine, ethanolamine, glucosamine, sarcosine, serinol, trihydroxy-methyl-aminomethane, aminopropylene glycol, sovak's base, 1-amino-2,3,4-butanetriol. In addition, basic nitrogen-containing groups can be quaternized using the following reagents: lower alkyl halides, such as the chlorides, bromides and iodides of methyl, ethyl, propyl and butyl; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and diamyl sulfate; long chain halides, such as the chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; aralkyl halides, such as the bromides of benzyl and phenethyl, etc.

Those skilled in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid by any of a number of known methods. Alternatively, alkali metal and alkaline earth metal salts of the acidic compounds of the invention can be prepared by reacting the compounds of the invention with a suitable base by a variety of known methods.

The present invention includes all possible salts of the compounds according to the invention, either as individual salts or as any mixture of said salts in any ratio.

Unless otherwise indicated, the compounds of the present invention also refer to isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts thereof, or mixtures thereof.

As used herein, the term "in vivo hydrolysable ester" is understood to mean an in vivo hydrolysable ester of a compound of the invention containing a carboxyl or hydroxy group, for example, a pharmaceutically acceptable ester which hydrolyses in the human or animal body to produce the parent acid or parent alcohol. Suitable pharmaceutically acceptable esters of carboxyl groups include the following esters and may be formed at any carboxyl group of the compounds of the invention: for example, alkyl esters, cycloalkyl esters and optionally substituted phenylalkyl esters (particularly benzyl esters), C ₁ -C ₆ alkoxymethyl esters (for example methoxymethyl ester), C ₁ -C ₆ alkanoyloxymethyl esters (for example pivaloyloxymethyl ester), phthalate esters, C ₃ -C ₈ cycloalkyloxy-carbonyloxy-C ₁ -C ₆ alkyl esters (for example 1-cyclohexylcarbonyloxyethyl ester); 1,3-dioxolen-2-onylmethyl ester, for example 5-methyl-1,3-dioxolen-2-onylmethyl ester; and C ₁ -C ₆ -alkoxycarbonyloxyethyl esters, for example 1-methoxycarbonyloxyethyl ester. In vivo hydrolyzable esters of compounds of the present invention containing hydroxyl groups include inorganic esters such as phosphates and [α]-acyloxyalkyl ethers and related compounds that break down to form the parent hydroxyl group upon in vivo hydrolysis of the esters. Examples of [α]-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. Selections of groups that form in vivo hydrolyzable esters with hydroxyl groups include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, alkoxycarbonyl (to form alkyl carbonates), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to form carbamates), dialkylaminoacetyl and carboxyacetyl. All of these esters are encompassed by the present invention.

Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as single polymorphs or as mixtures of more than one polymorph in any ratio.

According to a first aspect, the present invention covers compounds of general formula (Ia) or isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts thereof, or mixtures thereof:

wherein A, R ¹ , R ² and R ³ have the meanings as defined in formula (I), preferably R ³ represents C ₁ -C ₄ -alkyl, more preferably methyl.

Also preferred are compounds of general formula (I) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl, preferably an optionally substituted 6-membered heteroaryl; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (I).

Also preferred are compounds of formula (Ia) or isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts thereof, or mixtures thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl, preferably an optionally substituted 6-membered heteroaryl; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (Ia).

Additionally preferred are compounds of the general formula (I) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, wherein

R ¹ represents C ₁ -C ₄ -alkyl, preferably methyl or ethyl; and

wherein A, R ² and R ³ have the same meanings as defined in the general formula (I).

Additionally preferred are compounds of the general formula (Ia) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, wherein

R ¹ represents C ₁ -C ₄ -alkyl, preferably methyl or ethyl; and

wherein A, R ² and R ³ have the same meanings as defined in the general formula (Ia).

Additionally preferred are compounds of the general formula (I) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, wherein

^R1 represents a halogen atom, preferably chlorine; and

wherein A, R ² and R ³ have the same meanings as defined in the general formula (I).

Additionally preferred are compounds of the general formula (Ia) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, wherein

^R1 represents a halogen atom, preferably chlorine; and

wherein A, R ² and R ³ have the same meanings as defined in the general formula (Ia).

Also preferred are compounds of formula (I), more preferably compounds of formula (Ia) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, wherein

R ³ represents C ₁ -C ₄ -alkyl, preferably methyl; and

wherein R ¹ , R ² and A have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl; and

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted with one or more identical or different substituents on any ring carbon atom; and

wherein in the -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ;

q represents the integer 0; and

wherein A, R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -C ₂ -C ₃ -alkyl-OR ⁴ , -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or -C ₂ -C ₄ -alkynyl; and

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted with one or more identical or different substituents on any ring carbon atom; and

wherein in the -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ;

q represents the integer 0; and

wherein A, R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl; and

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted with one or more identical or different substituents on any ring carbon atom; and

wherein in the -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ;

q represents the integer 0; and

wherein A, R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -C ₂ -C ₃ -alkyl-OR ⁴ , -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or -C ₂ -C ₄ -alkynyl; and

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted with one or more identical or different substituents on any ring carbon atom; and

wherein in the -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ;

q represents the integer 0; and

wherein A, R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted by one or more substituents which may be the same or different on any ring carbon atom; and

wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl; and

q represents the integer 1; and

wherein A, R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group;

q represents the integer 1; and

wherein A, R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted by one or more substituents which may be the same or different on any ring carbon atom; and

wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl; and

q represents the integer 1; and

wherein A, R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group;

q represents the integer 1; and

wherein A, R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -C ₂ -C ₄ -alkyl-OH; and

wherein A, R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

R ² represents -C ₂ -C ₄ -alkyl-OH; and

wherein A, R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group; and

R ¹ represents -C ₁ -C ₄ -alkyl, preferably methyl or ethyl; and

wherein R ² and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group; and

R ¹ represents -C ₁ -C ₄ -alkyl, preferably methyl or ethyl; and

wherein R ² and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group; and

^R1 represents a halogen atom, preferably chlorine; and

wherein R ² and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group; and

^R1 represents a halogen atom, preferably chlorine; and

wherein R ² and R ³ have the same meanings as defined in the general formula (Ia).

Also preferred are compounds of formula (I), more preferably compounds of formula (Ia) or their isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts, or mixtures thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group; and

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl; and

wherein R ¹ and R ² have the same meanings as defined in the general formula (I).

Additionally preferred are compounds of formula (I), more preferably compounds of formula (Ia) or isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts thereof, or mixtures thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group;

R ¹ represents -C ₁ -C ₄ -alkyl, preferably methyl or ethyl; and

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl; and

wherein R ² has the same meaning as defined in the general formula (I).

Additionally preferred are compounds of formula (I), more preferably compounds of formula (Ia) or isomers, enantiomers, diastereomers, racemates, hydrates, solvates or salts thereof, or mixtures thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group;

^R1 represents a halogen atom, preferably chlorine; and

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl; and

wherein R ² has the same meaning as defined in the general formula (I).

A preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group;

R ¹ represents -C ₁ -C ₄ -alkyl, preferably methyl or ethyl;

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl; and

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted with one or more identical or different substituents on any ring carbon atom; and

wherein in the -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ;

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl; and

q represents the integer 0,

wherein R ^c is as defined in formula (I).

A preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group;

R ¹ represents -C ₁ -C ₄ -alkyl, preferably methyl or ethyl;

R ² represents -C ₂ -C ₃ -alkyl-OR ⁴ , -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or -C ₂ -C ₄ -alkynyl; and

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted with one or more identical or different substituents on any ring carbon atom; and

wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if any ring nitrogen atom is present, then any ring nitrogen atom is independently substituted by R ^c ; and

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl; and

q represents the integer 0,

wherein R ^c is as defined in formula (I).

A preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group;

R ¹ represents -C ₁ -C ₄ -alkyl, preferably methyl or ethyl;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted by one or more substituents which may be the same or different on any ring carbon atom; and

wherein in the -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ; wherein -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl; and

q represents the integer 1;

wherein R ^c is as defined in formula (I).

A preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group;

R ¹ represents -C ₁ -C ₄ -alkyl, preferably methyl or ethyl;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group;

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl; and

q represents the integer 1.

A preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents an optionally substituted 5- or 6-membered heteroaryl group, preferably an optionally substituted 6-membered heteroaryl group;

R ¹ represents a halogen atom, preferably chlorine;

R ² represents -C ₂ -C ₄ -alkyl-OH, preferably 3-hydroxybutan-2-yl;

R ³ represents -C ₁ -C ₄ -alkyl, preferably methyl.

Another preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5- or 6-membered heteroaryl group containing at least one or two nitrogen atoms, preferably a 6-membered heteroaryl group containing one or two nitrogen atoms;

wherein the 5- or 6-membered heteroaryl group is optionally substituted once or twice with substituents selected, identically or differently, from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted with 1 to 5 fluorine atoms, or C ₁ -C ₂ -alkoxy groups optionally substituted with 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -C ₂ -C ₃ -alkyl-OR ⁴ , unsubstituted -CH ₂ -(C ₃ -C ₄ -cycloalkyl), unsubstituted C ₃ -C ₄ -cycloalkyl, unsubstituted (CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), or -C ₂ -C ₄ -alkynyl;

R ³ represents a methyl group; and

q represents the integer 0.

Another preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5- or 6-membered heteroaryl group containing at least one or two nitrogen atoms, preferably a 6-membered heteroaryl group containing one or two nitrogen atoms;

wherein the 5- or 6-membered heteroaryl group is optionally substituted once or twice with substituents selected, identically or differently, from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted with 1 to 5 fluorine atoms, or C ₁ -C ₂ -alkoxy groups optionally substituted with 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents optionally substituted -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted by one or more identical or different substituents on any ring carbon atom; and

wherein in the -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ; wherein -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

R ³ represents a methyl group; and

q represents the integer 1;

wherein R ^c is as defined in formula (I).

Another preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5- or 6-membered heteroaryl group containing at least one or two nitrogen atoms, preferably a 6-membered heteroaryl group containing one or two nitrogen atoms;

wherein the 5- or 6-membered heteroaryl group is optionally substituted once or twice with substituents selected, identically or differently, from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted with 1 to 5 fluorine atoms, or C ₁ -C ₂ -alkoxy groups optionally substituted with 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c as defined in formula (I), preferably by methyl;

R ³ represents a methyl group; and

q represents the integer 1.

Another preferred embodiment relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5- or 6-membered heteroaryl group containing at least one or two nitrogen atoms, preferably a 6-membered heteroaryl group containing one or two nitrogen atoms;

wherein the 5- or 6-membered heteroaryl group is optionally substituted once or twice with substituents selected, identically or differently, from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted with 1 to 5 fluorine atoms, or C ₁ -C ₂ -alkoxy groups optionally substituted with 1 to 5 fluorine atoms;

R ¹ represents a chlorine atom;

R ² represents -C ₂ -C ₄ -alkyl-OH, preferably 3-hydroxybutan-2-yl; and

R ³ represents a methyl group.

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl, thiazolyl or thiadiazolyl, preferably pyrimidinyl, pyridazinyl, thiazolyl or thiadiazolyl, more preferably pyrimidinyl, pyridazinyl or thiadiazolyl, wherein the pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl, thiazolyl and thiadiazolyl are optionally substituted; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl, thiazolyl or thiadiazolyl, preferably pyrimidinyl, pyridazinyl, thiazolyl or thiadiazolyl, more preferably pyrimidinyl, pyridazinyl or thiadiazolyl, wherein the pyrimidinyl, pyridazinyl, pyridinyl, pyrazinyl, thiazolyl and thiadiazolyl are optionally substituted; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents CF ₃ -pyrimidinyl, preferably 2-CF ₃ -pyrimidin-5-yl; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents CF ₃ -pyrimidinyl, preferably 2-CF ₃ -pyrimidin-5-yl; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents CF ₃ -pyridazinyl, preferably 6-CF ₃ -pyridazin-3-yl; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents CF ₃ -pyridazinyl, preferably 6-CF ₃ -pyridazin-3-yl; and

wherein R ¹ , R ² and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents an optionally substituted cyclopropylmethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, prop-2-yn-1-yl, but-2-yn-1-yl, oxetan-3-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-ylmethyl, pyridin-4-yl, pyridin-3-yl, 1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl, 2,2-dimethyl-2-methoxyethyl, methoxyethyl, piperidin-4-yl, pyrrolidin-3-yl or azetidin-3-yl, preferably unsubstituted cyclopropylmethyl, unsubstituted oxetan-3-yl, unsubstituted tetrahydrofuran-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents 3-hydroxybutan-2-yl, propan-2-yn-1-yl, butan-2-yn-1-yl, 2,2-dimethyl-2-methoxyethyl, methoxyethyl; or

optionally substituted cyclopropylmethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-ylmethyl, (4-methylmorpholin-2-yl)methyl, pyridin-4-yl, pyridin-3-yl, 1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl, piperidin-4-yl, pyrrolidin-3-yl or azetidin-3-yl,

Preferably, unsubstituted cyclopropylmethyl, unsubstituted oxetan-3-yl, unsubstituted (3R)-tetrahydrofuran-3-yl, unsubstituted (3S)-tetrahydrofuran-3-yl, [(2R)-4-methylmorpholin-2-yl]methyl, [(2S)-4-methylmorpholin-2-yl]methyl, (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl, (2S,3R)-3-hydroxybutan-2-yl or (2R,3S)-3-hydroxybutan-2-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents an optionally substituted cyclopropylmethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, prop-2-yn-1-yl, but-2-yn-1-yl, oxetan-3-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-ylmethyl, pyridin-4-yl, pyridin-3-yl, 1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl, 2,2-dimethyl-2-methoxyethyl, methoxyethyl, piperidin-4-yl, pyrrolidin-3-yl or azetidin-3-yl, preferably unsubstituted cyclopropylmethyl, unsubstituted oxetan-3-yl, unsubstituted tetrahydrofuran-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents 3-hydroxybutan-2-yl, propan-2-yn-1-yl, butan-2-yn-1-yl, 2,2-dimethyl-2-methoxyethyl, methoxyethyl; or

optionally substituted cyclopropylmethyl, tetrahydrofuran-3-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, oxetan-3-yl, tetrahydropyran-4-yl, tetrahydro-2H-pyran-4-ylmethyl, (4-methylmorpholin-2-yl)methyl, pyridin-4-yl, pyridin-3-yl, 1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl, piperidin-4-yl, pyrrolidin-3-yl or azetidin-3-yl,

Preferably, unsubstituted cyclopropylmethyl, unsubstituted oxetan-3-yl, unsubstituted (3R)-tetrahydrofuran-3-yl, unsubstituted (3S)-tetrahydrofuran-3-yl, [(2R)-4-methylmorpholin-2-yl]methyl, [(2S)-4-methylmorpholin-2-yl]methyl, (2R,3R)-3-hydroxybutan-2-yl, (2S,3S)-3-hydroxybutan-2-yl, (2S,3R)-3-hydroxybutan-2-yl or (2R,3S)-3-hydroxybutan-2-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents unsubstituted tetrahydrofuran-3-yl or unsubstituted oxetan-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents unsubstituted (3R)-tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl or unsubstituted oxetan-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents unsubstituted (3R)-tetrahydrofuran-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents [(2R)-4-methylmorpholin-2-yl]methyl, (2R,3R)-3-hydroxybutan-2-yl or (2S,3S)-3-hydroxybutan-2-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents [(2R)-4-methylmorpholin-2-yl]methyl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents (2R,3R)-3-hydroxybutan-2-yl or (2S,3S)-3-hydroxybutan-2-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents unsubstituted tetrahydrofuran-3-yl or unsubstituted oxetan-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents unsubstituted (3R)-tetrahydrofuran-3-yl, (3S)-tetrahydrofuran-3-yl or unsubstituted oxetan-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents unsubstituted (3R)-tetrahydrofuran-3-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents [(2R)-4-methylmorpholin-2-yl]methyl, (2R,3R)-3-hydroxybutan-2-yl or (2S,3S)-3-hydroxybutan-2-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents [(2R)-4-methylmorpholin-2-yl]methyl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

^R2 represents (2R,3R)-3-hydroxybutan-2-yl or (2S,3S)-3-hydroxybutan-2-yl; and

wherein R ¹ , A and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group; and

wherein R ² and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group; and

wherein R ² and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ³ represents a methyl group; and

wherein R ¹ and R ² have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a Rb and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if any ring nitrogen atom is present, then any ring nitrogen atom is independently substituted by R ^c ; and wherein said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl; and

q represents the integer 1; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group; and

q represents the integer 1; and

wherein R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice, identically or differently, by substituents selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if any ring nitrogen atom is present, then any ring nitrogen atom is independently substituted by R ^c ; and wherein said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl; and

q represents the integer 1; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group; and

q represents the integer 1; and

wherein R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -C ₂ -C ₄ -alkyl-OH; and

wherein R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -C ₂ -C ₄ -alkyl-OH; and

wherein R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group; and

wherein R ² and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group; and

wherein R ² and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ³ represents a methyl group; and

wherein R ¹ and R ² have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein (CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and wherein said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

q represents the integer 1; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein (CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and wherein said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

q represents the integer 1; and

wherein R ^c , R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -C ₂ -C ₄ -alkyl-OH; and

wherein R ¹ and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ² represents -C ₂ -C ₄ -alkyl-OH; and

wherein R ¹ and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ³ represents a methyl group; and

wherein R ² has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

^R1 represents chlorine;

R ³ represents a methyl group; and

wherein R ² has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ³ represents a methyl group;

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) are optionally substituted once or twice on any ring carbon atom by substituents selected from: C ₁ -C _{4 -alkyl} optionally substituted with 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b or -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c and R ¹ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ³ represents a methyl group;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) are optionally substituted once or twice on any ring carbon atom by substituents selected from: C ₁ -C _{4 -alkyl} optionally substituted with 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b or -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c and R ¹ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ³ represents a methyl group;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and wherein said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

q represents the integer 1; and

wherein R ^c and R ¹ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ³ represents a methyl group;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group;

q represents the integer 1; and

wherein R ¹ has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from the group consisting of fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups optionally substituted by 1 to 5 fluorine atoms;

R ³ represents a methyl group;

R ² represents C ₂ -C ₄ -alkyl-OH, preferably 3-hydroxybutan-2-yl; and

wherein R ¹ has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₄ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

q represents the integer 0; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and wherein said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

q represents the integer 1; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group;

q represents the integer 1; and

wherein R ³ has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein (CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and wherein said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

q represents the integer 1; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group;

q represents the integer 1; and

wherein R ³ has the same meaning as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents chlorine;

R ² represents C ₂ -C ₄ -alkyl-OH, preferably 3-hydroxybutan-2-yl; and

wherein R ³ has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl or pyridazinyl group, wherein the 6-membered heteroaryl group is optionally substituted once or twice by substituents, which are identical or different, selected from fluorine or chlorine atoms, C ₁ -C ₂ -alkyl groups which are optionally substituted by 1 to 5 fluorine atoms or C ₁ -C ₂ -alkoxy groups which are optionally substituted by 1 to 5 fluorine atoms;

^R1 represents chlorine;

R ² represents C ₂ -C ₄ -alkyl-OH, preferably 3-hydroxybutan-2-yl; and

wherein R ³ has the same meaning as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ³ represents a methyl group; and

wherein R ² has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents chlorine;

R ³ represents a methyl group;

wherein R ² has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , —CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl;

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ;

R ³ represents a methyl group;

q represents the integer 0; and

wherein R ^c and R ¹ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ; wherein said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

R ³ represents a methyl group;

q represents the integer 1; and

wherein R ^c and R ¹ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) are optionally substituted once or twice on any ring carbon atom by substituents which are the same or different and are selected from: C ₁ -C ₄ -alkyl optionally substituted with 1 to 5 same or different halogen atoms, halogen atoms, -NR ^a R ^b or -COOR ⁵ ; and wherein any ring nitrogen atom of said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is independently substituted with R ^c ; and

q represents the integer 0;

wherein R ^c and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) are optionally substituted once or twice on any ring carbon atom by substituents which are the same or different and are selected from: C ₁ -C ₄ -alkyl optionally substituted with 1 to 5 same or different halogen atoms, halogen atoms, -NR ^a R ^b or -COOR ⁵ ; and wherein any ring nitrogen atom of said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is independently substituted with R ^c ;

q represents the integer 0; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein (CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ; and wherein -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

q represents the integer 1; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group, wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein (CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ; and wherein -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

q represents the integer 1; and

wherein R ^c and R ³ have the same meanings as defined in the general formula (Ia).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1-5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

R ³ represents a methyl group; and

q represents the integer 0,

wherein R ^c has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein (CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ; and wherein -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

R ³ represents a methyl group; and

q represents the integer 1,

wherein R ^c has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -morpholinyl, wherein the ring nitrogen atom is substituted by R ^c ; and

R ^c represents a methyl group;

R ³ represents a methyl group; and

q represents the integer 1.

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 6-membered heteroaryl group, in particular a pyrimidinyl group or a pyridazinyl group; wherein the 6-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents chlorine;

R ² represents -C ₂ -C ₄ -alkyl-OH, preferably 3-hydroxybutan-2-yl; and

R ³ represents a methyl group.

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents —C ₂ -C ₃ -alkyl-OR ⁴ , CH ₂ —(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl, —(CH ₂ ) _q -(4- to 6-membered heterocycloalkyl) or —C ₂ -C ₄ -alkynyl,

wherein said -CH ₂ -(C ₃ -C ₄ -cycloalkyl), C ₃ -C ₄ -cycloalkyl and -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) are optionally substituted on any ring carbon atom by one or more identical or different substituents selected from the group consisting of: C ₁ -C _{4 -alkyl} optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and wherein in said -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl), if a ring nitrogen atom is present, any ring nitrogen atom is independently substituted by R ^c ; and

R ³ represents a methyl group; and

q represents the integer 0,

wherein R ^c has the same meaning as defined in the general formula (I).

In another preferred embodiment, the present invention relates to a compound of formula (I), more preferably a compound of formula (Ia) or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate or salt thereof, or a mixture thereof, wherein

A represents a 5-membered heteroaryl group, in particular a thiazolyl group or a thiadiazolyl group; wherein the 5-membered heteroaryl group is optionally substituted by one or two identical or different substituents selected from the group consisting of a fluorine or chlorine atom, a C ₁ -C ₂ -alkyl group optionally substituted by 1 to 5 fluorine atoms or a C ₁ -C ₂ -alkoxy group optionally substituted by 1 to 5 fluorine atoms;

^R1 represents a methyl group or an ethyl group;

R ² represents -(CH ₂ ) _q -(4 to 6 membered heterocycloalkyl); and wherein (CH ₂ ) _q -(4 to 6 membered heterocycloalkyl) is optionally substituted on any ring carbon atom by one or two identical or different substituents selected from the group consisting of: C ₁ -C ₄ -alkyl optionally substituted by 1 to 5 identical or different halogen atoms, halogen atoms, -NR ^a R ^b and -COOR ⁵ ; and

wherein in said -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl), if a ring nitrogen atom exists, any ring nitrogen atom is independently substituted by R ^c ; and wherein -(CH ₂ ) _q -(4 to 6-membered heterocycloalkyl) is preferably -(CH ₂ ) _q -morpholinyl;

and

R ³ represents a methyl group; and

q represents the integer 1,

wherein R ^c has the same meaning as defined in formula (I).

The following compounds are disclosed, namely

1) 3-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

2) 3-(Cyclopropylmethoxy)-N-[(6-methylpyridazin-3-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

3) 3-(Cyclopropylmethoxy)-N-[(5-methylpyrazin-2-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

4) 3-(Cyclopropylmethoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

5) N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide

6) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide

7) 3-(Cyclopropylmethoxy)-N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

8) 3-(Cyclopropylmethoxy)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

9) 3-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

10) 3-(Cyclopropylmethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

11) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

12) N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

13) N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

14) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

15) N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

16) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

17) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

18) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

19) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

20) N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

21) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{[6-(trifluoromethyl)pyridazin-3-yl]methyl}benzamide

22) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide

23) N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

24) N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

25) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

26) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

27) N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

28) N-[(1R)-1-(5-methylpyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

29) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

30) N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

31) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide

32) N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide

33) N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide

34) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide

35) N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide

36) 3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

37) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide

38) 3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

39) N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzamide

40) 3-(But-2-yn-1-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

41) 3-(But-2-yn-1-yloxy)-N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

42) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

43) N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

44) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

45) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

46) N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

47) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

48) 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

49) N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

50) N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

51) N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

52) 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{[6-(trifluoromethyl)pyridazin-3-yl]methyl}benzamide

53) 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide

54) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

55) N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

56) N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

57) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

58) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

59) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

60) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

61) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

62) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

63) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

64) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

65) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

66) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

67) N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

68) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

69) N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

70) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

71) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

72) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

73) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

74) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

75) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

76) N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

77) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

78) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

79) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

80) N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

81) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

82) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

83) N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

84) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

85) 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

86) N-[(1R)-1-(6-methoxypyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

87) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

88) N-[(6-methoxypyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

89) 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

90) 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide

91) N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

92) N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

93) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

94) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

95) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

96) N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

97) N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

98) 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

99) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

100) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

101) N-[(6-methylpyridazin-3-yl)methyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

102) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

103) 3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

104) N-[(5-methylpyrazin-2-yl)methyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

105) 3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

106) 3-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

107) N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-[(2-methylpyridin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

108) 3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

109) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

110) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

111) 3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

112) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzamide

113) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzamide

114) N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzamide

115) N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzamide

116) 3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

117) 3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]benzamide

118) N-[(6-methylpyridazin-3-yl)methyl]-3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzamide

119) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

120) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

121) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

122) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

123) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

124) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

125) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

126) N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

127) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

128) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

129) 3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

130) N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

131) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

132) N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

133) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

134) N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

135) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

136) 3-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

137) tert-Butyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

138) 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

139) 3-[(1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

140) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

141) 3-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

142) 3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

143) 3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

144) 3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

145) 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

146) tert-Butyl 6-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate

147) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[5-(trifluoromethyl)pyrazin-2-yl]ethyl}benzamide

148) 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

Also disclosed are the following compounds:

149) 3-(1-Azabicyclo[2.2.2]oct-4-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

150) 3-[(1-acetylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

151) N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

152) N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

153) N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

154) N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

155) 3-{[(3S)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

156) 3-[(3-methyloxetan-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

157) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

158) 3-{[(3R)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

159) 3-(5-methyl-1,3-thiazol-2-yl)-5-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

160) 3-(5-methyl-1,3-thiazol-2-yl)-5-[2-(1H-1,2,4-triazol-1-yl)ethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

161) 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

162) Trans Isomer 1; 3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

163) Trans isomer 2; 3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

164) N-{(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

165) 3-{[trans-3-(dimethylamino)cyclobutyl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

166) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide

167) 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide

168) 3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

169) 3-(5-ethyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

170) 3-[(6-methylpyridazin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

171) N-{(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

172) 3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

173) 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

174) 3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

175) 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

176) 3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

177) 3-[(2R)-1,4-dioxane-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

178) 3-[(2R)-1,4-dioxane-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

179) 3-[(2R)-1,4-dioxane-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

180) 3-[(2S)-1,4-dioxane-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

181) 3-[(2S)-1,4-dioxane-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

182) 3-[(2S)-1,4-dioxane-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

183) Trans Isomer 1; 3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

184) Trans Isomer 1; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

185) Cis Isomer 1; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

186) Trans Isomer 1; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

187) Cis Isomer 2; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

188) Trans isomer 2; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

189) Trans isomer 2; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

190) (3R)-tert-butyl 3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate as a mixture of diastereoisomers

191) 3-(But-2-yn-1-yloxy)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

192) 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

193) Enantiomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

194) Enantiomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

195) Enantiomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

196) Enantiomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

197) Diastereomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

198) Diastereomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

199) Diastereomer 2; 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

200) Diastereomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

201) 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

202) 3-(2-Azaspiro[3.3]hept-6-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

203) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-pyrrolidin-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

204) 3-{[3-fluoropiperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of cis isomers

205) Diastereomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

206) Diastereomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

207) Cis Isomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

208) Cis Isomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

209) 3-{[2-methyl-2-azabicyclo[2.2.1]hept-5-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

210) 3-[(1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

211) 3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

212) 3-[(3-fluoro-1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide as a single unknown isomer

213) 3-{[1-(dimethylamino)cyclopropyl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

214) 3-[(2-methyl-2-azaspiro[3.3]hept-6-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

215) N-{(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl}-3-[(1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

216) 3-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

217) 3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

218) 3-{[(4aS,7R,7aR)-4-methyloctahydrocyclopenta[b][1,4]oxazin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

219) 3-{[(4aS,7S,7aR)-4-methyloctahydrocyclopenta[b][1,4]oxazin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

220) Diastereomer 1; 3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

221) Diastereomer 2; 3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

222) Cis Isomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

223) Cis Isomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

224) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

225) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3S)-1-(propan-2-yl)pyrrolidin-3-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

226) Methyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

227) Ethyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

228) (3S)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]pyrrolidine-1-carboxylic acid ethyl ester

229) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propyl-2-yl)azetidin-3-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

230) Cis-isomer 1; 3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

231) Cis-isomer 2; 3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

232) 3-[(1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

233) 3-[(1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

234) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

235) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

236) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

237) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

238) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

239) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

240) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

241) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

242) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

243) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

244) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

245) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

246) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

247) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

248) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

249) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

250) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

251) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

252) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

253) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

254) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

255) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

256) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

257) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

258) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

259) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

260) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

261) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

262) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

263) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

264) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

265) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzamide

266) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

267) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

268) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

269) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

270) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

271) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

272) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

273) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

274) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

275) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

276) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

277) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

278) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

279) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

280) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

281) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

282) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

283) 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

284) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

285) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

286) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

287) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

288) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

289) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

290) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

291) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

292) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

293) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

294) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

295) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

296) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

297) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

298) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

299) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

300) 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

301) 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

302) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

303) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

304) 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

305) 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

306) 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

307) 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(6-methylpyridazin-3-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

308) 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

309) 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

310) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

311) N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide

312) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

313) N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide

314) N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide

315) N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzamide

316) 3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

317) 3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

318) 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

319) 3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

320) 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

321) 3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

322) 3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

323) 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

324) 3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

325) 3-(5-chloro-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

326) 3-(5-chloro-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

327) 3-[(3-methyloxetan-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

328) 3-(2-Hydroxy-2-methylpropoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

329) 3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

330) Diastereomer 1; 3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

331) Diastereomer 2; 3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

332) 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

333) Diastereomer 1; 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

334) Diastereomer 2; 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

335) 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

336) Diastereomer 1; 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

337) Diastereomer 2; 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

338) 3-[(3-Hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of cis isomers

339) Cis Isomer 1; 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

340) Cis-isomer 2; 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

341) 3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two stereoisomers

342) Stereoisomer 1; 3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

343) Stereoisomer 2; 3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

344) 3-[(7-Isopropyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two stereoisomers

345) 9-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylic acid methyl ester, as a mixture of two stereoisomers

346) (2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylic acid tert-butyl ester

347) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

348) 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

349)(2S)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylic acid tert-butyl ester

350) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

351) 3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

352) 3-(5-Methyl-1,3-thiazol-2-yl)-5-[morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of diastereoisomers

353) 3-{[4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of diastereoisomers

354) Diastereomer 1; 3-(fluoropiperidin-3-yl)methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

355) Diastereomer 2; 3-(fluoropiperidin-3-yl)methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

356) Diastereomer 1; 3-{[3-fluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

357) Diastereomer 2; 3-{[3-fluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

358) 3-[(3-Fluoroazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

359) 3-{[4,4-difluoropiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

360) 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

361) 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

362) 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

363) 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

364) 3-{[4-fluoro-1-methylpyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of stereoisomers

365) 3-{[4-fluoro-1-methylpyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide, as a mixture of stereoisomers

366) 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

367) 3-(5-chloro-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

368) 3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide

369) N-{(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}-3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzamide

370) 3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

371) 3-[(3-fluoro-1-methylazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

372) 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{[2-(trifluoromethyl)pyrimidin-5-yl]methyl}benzamide

373) 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

374) 3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

375) 3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2S)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

376) 3-(5-chloro-1,3-thiazol-2-yl)-5-{[(2S)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

377) 3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

378) 3-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

379) 3-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

380) 3-[(1-methylpiperidin-4-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

381) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2R)-4-(propyl-2-yl)morpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

382) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2S)-4-(propan-2-yl)morpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

383) 3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

384) Diastereomer 1; 3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

385) Diastereomer 2; 3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

386) 3-[(3-fluoro-1-methylazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

387) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3-fluoro-1-methylazetidin-3-yl)methoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

388) 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

389) 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

390) 3-{[(2R)-4-ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

391) 3-{[(2R)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

392) (2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylic acid methyl ester

393)(2S)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylic acid methyl ester

394) 3-(azetidin-3-ylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

395) 3-{[(3R)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

396) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3R)-5-oxomorpholin-3-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

397) 3-{[(5S)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

398) 3-{[(5R)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

399) 3-{[(2R)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

400) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2S)-5-oxomorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

401) 3-{[(2S)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

402) 3-{[(3S)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

403) 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3S)-5-oxomorpholin-3-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

404) tert-Butyl 1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate, as a mixture of two diastereoisomers

405) 3-[(5-Isopropyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

406) 3-[(5-methyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

407) 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-1-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

408) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(5-propyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two diastereoisomers

409) 1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid methyl ester, as a mixture of two diastereoisomers

410) 1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid ethyl ester, as a mixture of two diastereoisomers

411) 3-{[(2S)-4-ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

412)(2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylic acid tert-butyl ester

413) 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

414) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

415) 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

416) 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

417) 3-{[(2S)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

418) 3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2S)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

419) 3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

Also disclosed are the following compounds, namely

3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-ethyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;

3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide.

The preferred compounds are

3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide.

An even more preferred compound is 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide.

Also preferred are compounds, namely

3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

3-(5-ethyl-1,3-thiazol-2-yl)-5-{[(2R)-4-methylmorpholin-2-yl]methoxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide.

An even more preferred compound is 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}-benzamide.

Also preferred are compounds, namely

Trans isomer 2; 3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

Trans isomer 1; 3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;

Trans isomer 1; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

Cis isomer 1; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

Cis isomer 2; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

Trans isomer 2; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

Cis isomer 1; 3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;

Cis isomer 2; 3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide;

Cis isomer 1; 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide;

Cis isomer 2; 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide.

An even more preferred compound is cis isomer 1; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}-benzamide.

It will be understood that the present invention also relates to any combination of the preferred embodiments described above.

Synthesis of the compounds of formula (I)/(Ia) of the present invention

Compounds of general formula (I) having the meanings of R ¹ -R ³ and A as defined in general formula (I) can be synthesized according to the general steps described in Scheme 1 starting from synthons of formula (II) or (IV), respectively.

Similarly, compounds of general formula (Ia) having the meanings of R ¹ -R ³ and A as defined in general formula (Ia) can be synthesized starting from synthons of formula (II) or (IV), respectively, according to the general steps described in Scheme 1. The intermediates having the ester moiety -C(O)OR' described in Schemes 2 and 3 are referred to as methyl esters, ethyl esters or propyl esters (R': methyl, ethyl, propyl), respectively.

Carboxylic acids of formula (II) can be reacted with amines of formula (III) by methods known to those skilled in the art to give compounds of general formula (I).

The reaction is carried out, for example, by activating the carboxylic acid of formula (II) with a reagent such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N-hydroxybenzotriazole (HOBT), N-[(dimethylamino)-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanamine hexafluorophosphate (HATU) or propylphosphonic anhydride (T3P). For example, the reaction with HATU is carried out in an inert solvent such as N,N-dimethylformamide, dichloromethane or dimethyl sulfoxide in the presence of an appropriate amine of formula (III) and a tertiary amine such as triethylamine or diisopropylethylamine at a temperature of -30°C to +60°C.

The carboxylic acid of formula (II) can also be converted into the corresponding carboxylic acid chloride using an inorganic acid chloride (e.g. phosphorus pentachloride, phosphorus trichloride or thionyl chloride), and then converted into the target compound of general formula (I) in pyridine or an inert solvent (e.g. N,N-dimethylformamide) in the presence of an appropriate amine of formula (III) and a tertiary amine (e.g. triethylamine) at a temperature of -30°C to +60°C.

Completely analogously, carboxylic acids of the formula (II) can be reacted with amines of the formula (IIIa) by methods known to those skilled in the art to give compounds of the general formula (Ia).

In the same manner, compounds of the general formula (I) can be obtained by methods known to those skilled in the art by reacting a pinacol borate of the general formula (IV) with a bromo-thiazole of the formula (V) in a suitable solvent (e.g., N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and optionally water) with the addition of a base (e.g., triethylamine, potassium carbonate, cesium carbonate) and a catalyst-ligand mixture (e.g., palladium(II) acetate/triphenylphosphine, tetrakis(triphenylphosphine)palladium(0), bis(diphenylphosphino)ferrocenedichloropalladium(II)).

Similarly, compounds of the general formula (Ia) can be obtained from boronic acid pinacol esters of the general formula (IVa) by reaction with bromo-thiazoles of the formula (V).

Carboxylic acids of the general formula (II) can be obtained, for example, from esters of the formula (VI) by ester saponification in a suitable solvent or solvent mixture (e.g. methanol, ethanol or tetrahydrofuran) with the addition of an aqueous solution of an alkali metal hydroxide (e.g. sodium hydroxide or lithium hydroxide) at a temperature of 10° C. to 60° C. (Scheme 2).

In the same way, carboxylic acids of the formula (XII) can be obtained from esters of the formula (X) (Scheme 3), and carboxylic acids of the formula (XX) can be obtained from esters of the formula (XXI) (Scheme 4).

Alternatively, carboxylic acids of formula (II) can be obtained from nitriles of formula (XXXIV) by hydrolysis of the nitrile in a suitable solvent or solvent mixture, such as dimethyl sulfoxide or ethanol, with the addition of an aqueous alkali metal hydroxide, such as sodium hydroxide, at a temperature of 80° C. to 130° C. (Scheme 5).

Compounds of formula (VI) can be obtained from pinacol boronic acid esters of formula (IX) by reaction with bromo-thiazoles of formula (V) (Scheme 2), analogously to the synthesis of compounds of formula (I) from compounds of formula (IV).

In the same way, compounds of formula (VII) can be obtained from boronic acid pinacol esters of formula (VIII) and bromo-thiazoles of formula (V) (Scheme 2).

Alternatively, compounds of the general formula (VI) can be obtained by reacting phenols of the general formula (VII) with electrophilic reagents R 2 -LG (LG: leaving group) of the general formula (XXIV) in a suitable solvent (e.g., N,N ^- dimethylformamide, acetonitrile, acetone, dimethyl sulfoxide) in the presence of a base (e.g., potassium carbonate and cesium carbonate) at a temperature of 10° C. to 120° C. by methods known to those skilled in the art (Scheme 2).

Suitable leaving groups may include, for example, chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy or nonafluorobutanesulfonyloxy.

Alternatively, phenols of general formula (VII) can be reacted with alcohols R 2 -LG (LG:OH) in a suitable solvent (e.g., dichloromethane or tetrahydrofuran) in the presence of triphenylphosphine and diisopropyl azodicarboxylate at temperatures between ^-20 °C and 40°C to give compounds of general formula (VI) (Scheme 2).

Alternatively, compounds of the general formula (VI) can be obtained by reacting phenols of the general formula (VII) with oxiranes of the general formula (XXV) (wherein R″, R′″ can independently be H or C ₁ -C ₄ -alkyl) as electrophiles in a suitable solvent (e.g. N,N-dimethylformamide, acetonitrile or dimethyl sulfoxide) in the presence of a base (e.g. potassium carbonate or cesium carbonate) at a temperature of 10° C. to 120° C. (Scheme 2).

In the same manner as above, the compound of formula (X) can be obtained from 3-bromo-5-hydroxybenzoate of formula (XXVI) and a compound of formula (XXIV) or a compound of formula (XXV), respectively (Scheme 2).

In addition, compounds of formula (VI) can also be obtained by reacting aryl bromides of general formula (XXVIII) with heteroaromatic alcohols of formula (XXIV) (LG: OH, R2: 5-10 membered heteroaromatic system) by methods known to those skilled in the art in a suitable solvent (e.g. N-methyl- ² -pyrrolidone) in the presence of a base (e.g. potassium carbonate or cesium carbonate) and copper (I) chloride, by heating the reaction mixture in a microwave oven at a temperature of 100°C to 220°C (Scheme 2).

After workup and purification, it may happen that, by said steps, carboxylic acids of the general formula (II) are obtained instead of the aforementioned esters of the formula (VI).

Compounds of general formula (XXXIV) can be obtained by methods known to those skilled in the art from aryl fluorides of general formula (XXXII) by reaction with alcohols R ² —OH of general formula (XXXIII) in a suitable solvent such as N,N-dimethylformamide in the presence of a base such as sodium hydride at a temperature of 10° C. to 80° C. (Scheme 5).

Compounds of general formula (XXXII) can be obtained from boronic acid pinacol esters of general formula (XXXI) by reaction with bromo-thiazoles of formula (V) (Scheme 5), analogously to the synthesis of compounds of formula (I) from compounds of formula (IV).

Compounds of general formula (IV) can be obtained by reacting aryl bromides of general formula (XI) with bis(pinacolato)diborane in a suitable solvent such as 1,4-dioxane in the presence of potassium acetate and a catalyst such as 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II)-dichloromethane complex or [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) at a temperature of 60° C. to 100° C. (Scheme 3).

Similarly, compounds of general formula (IVa) can be obtained from aryl bromides of general formula (XIa).

In the same way, compounds of formula (IX) can be obtained from aryl bromides of formula (X), and likewise compounds of formula (VIII) can be obtained from 3-bromo-5-hydroxybenzoic acid esters of formula (XXVI) (Scheme 2).

Analogously, compounds of general formula (XXXI) can be obtained from aryl bromides of general formula (XXX) (Scheme 5).

Compounds of general formula (XI) can be obtained from carboxylic acids of general formula (XII) by reaction with amines of general formula (III) (Scheme 3), analogously to the synthesis of compounds of formula (I) from carboxylic acids of formula (II) and amines of formula (III).

Similarly, compounds of the general formula (XIa) can be obtained from carboxylic acids of the general formula (XII) by reaction with amines of the general formula (IIIa).

Compounds of the general formula (XXVIII) can be obtained by reacting aryl bromides of the general formula (XXVII) with thiazoles of the formula (XXIX) (Met: for example, tributylstannanyl) in a suitable solvent (for example, N,N-dimethylformamide) with the addition of a base (for example, potassium carbonate or cesium carbonate) and a catalyst-ligand mixture (for example, palladium(II) acetate/triphenylphosphine, tetrakis(triphenylphosphine)palladium(0)) at a temperature of 40°C to 120°C (Scheme 2).

Amines of general formula (IIIa) can be obtained from sulfinamides of general formula (XIII) or (XIV) by methods known to those skilled in the art in a suitable solvent (e.g., methanol, 2-propanol, diethyl ether) and with the addition of an acid (e.g., hydrochloric acid) at an appropriate concentration (e.g., 4 M in dioxane, 3 M in 2-propanol, 2 M in diethyl ether, 12 M in water) at a temperature of 0° C. to 40° C. (Scheme 4). Amines of general formula (IIIa) can be obtained as mono-, di-, or tri-salts (e.g., hydrochloride/dihydrochloride). Alternatively, the amine salt can be converted to the free base by methods known to those skilled in the art.

Amines of formula (III) and (IIIa) can be used as free bases or salts of undefined stoichiometry to obtain compounds of formula (I)/(Ia) and formula (XI)/(XIa), in accordance with but not limited to the synthetic disclosure herein.

Sulfenamides of general formula (XIII) can be obtained from ketones of general formula (XVII) by methods known to those skilled in the art in a suitable solvent (e.g., diethyl ether, tetrahydrofuran) with the addition of titanium (IV) ethoxide and (S)-2-tert-butylsulfenamide, and the conversion of ketones of general formula (XVII) into sulfenyl imines of general formula (XV) in situ at temperatures of 10° C. to 80° C. Sulfenyl imines (XV) can be directly converted into sulfenamides of formula (XIII) by methods known to those skilled in the art in a suitable solvent (e.g., tetrahydrofuran) with the addition of lithium tri-sec-butylborohydride (L-selectride) at temperatures of −80° C. to −70° C. (Scheme 4).

Sulfenamides of general formula (XIV) can be obtained from aldehydes of general formula (XVIII) by methods known to those skilled in the art in a suitable solvent (e.g., dichloroethane) with the addition of copper (II) sulfate and (R)-2-tert-butylsulfenamide at a temperature of 10° C. to 80° C. The sulfenyl imines (XVI) can be converted to sulfenamides of formula (XIV) by methods known to those skilled in the art in a suitable solvent (e.g., tetrahydrofuran, diethyl ether) with the addition of a Grignard reagent R ³ MgX (X: Cl, Br) at a temperature of −70° C. to −20° C. (Scheme 4).

Amines having a stereochemistry opposite to that described for amines of general formula (IIIa) can be synthesized in a similar manner to that described for amine (IIIa) starting from ketone (XVII) and using (R)-2-tert-butylsulfenamide instead of (S)-2-tert-butylsulfenamide. In a similar manner, starting from aldehyde (XVIII) and using (S)-2-tert-butylsulfenamide instead of (R)-2-tert-butylsulfenamide.

Ketones of general formula (XVII) can be obtained from Weinreb amides of general formula (XIX) by methods known to those skilled in the art in a suitable solvent (e.g. tetrahydrofuran, diethyl ether, tert-butyl methyl ether or toluene) with the addition of a Grignard reagent R ³ MgX (X: Cl, Br, I) at a temperature of -20°C to 0°C (Scheme 4).

Likewise, ketones of the general formula (XVII) can be obtained from nitriles of the general formula (XXII) and Grignard reagents R ³ MgX (X: Cl, Br, I).

Furthermore, ketones of general formula (XVII) can be obtained from halides of general formula (XXIII) (Hal: Cl, Br) by methods known to those skilled in the art in a suitable solvent (e.g. N,N-dimethylformamide) in tributyl(1-ethoxy-vinyl)stannane and a catalyst (e.g. dichlorobis(triphenylphosphine)-palladium(II)) at a temperature of 40°C to 100°C, followed by cleavage of the enol ether intermediate under acidic conditions (e.g. aqueous hydrochloric acid solution) in a suitable solvent (e.g. tetrahydrofuran) at a temperature of 10°C to 40°C (Scheme 4).

Weinreb amides of the general formula (XIX) can be obtained from carboxylic acids of the general formula (XX) and N-methoxymethaneamine in an analogous manner to that described for the synthesis of amides of the formula (I) from carboxylic acids of the formula (II).

Aldehydes of general formula (XVIII) can be obtained from amides of formula (XIX) by reduction methods known to those skilled in the art in a suitable solvent (e.g. tetrahydrofuran) and a reducing agent (e.g. lithium aluminum hydride) at a temperature of -80°C to -70°C (Scheme 4).

Bromo-thiazoles of general formula (V) can be generated from amino-thiazoles of formula (XXXV) by methods known to those skilled in the art in a suitable reaction medium (e.g. aqueous hydrobromic acid/sodium nitrite, copper(II) bromide/tert-butyl nitrite) in acetonitrile or N,N-dimethylformamide at temperatures between 0°C and 40°C (Scheme 4).

Furthermore, compounds of formula Ia, IIIa, IVa and XIa can be obtained directly from the racemic diastereoisomer mixtures of formula I, III, IV and XI, respectively, by separating said mixtures using methods known to those skilled in the art (e.g. preparative chiral HPLC).

Solution 1

Option 2

Option 3

Option 4

Option 5

Experimental part

The exemplary test experiments described herein serve to illustrate the present invention, but the present invention is not limited to the examples given.

The following table lists the abbreviations used in this paragraph and the Examples section.

Analytical methods

LC-MS, Method A: Conventional High-Throughput Analysis

LC-MS, Method B: Conventional high-throughput analysis

LC-MS, Method C: Routine high-throughput analysis at high pH

LC-MS, analytical method D

LC-MS, Analytical Method E: High pH

LC-MS, analytical method F:

Analytical LCMS Method 1, Low pH:

Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEHC18 1.750x2.1 mm; eluent A: water + 0.1% by volume formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Analytical LCMS Method 2, High pH:

Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC BEHC18 1.750x2.1 mm; eluent A: water + 0.2% by volume ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow rate 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Chiral analysis method:

Analytical chiral HPLC method

Method A:

Instrument: Agilent HPLC 1260; Column: Chiralpak IE 3μ 100×4.6 mm; Eluent A: tert-butyl methyl ether + 0.1% by volume diethylamine (99%); Eluent B: ethanol; Isocratic solvent: 95% A + 5% D; Flow rate: 1.4 ml/min; Temperature: 25°C; DAD 325 nm

Method B:

Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IF 5 μm 100×4.6 mm; Eluent A: CO ₂ ; Eluent B: ethanol; Isocratic solvent: 16% B; Flow rate: 4.0 ml/min; Temperature: 37.5°C; BPR: 100 bar; MWD@254 nm

Method C:

Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μ 100 × 4.6 mm; Eluent A: Hexane; Eluent B: 2-propanol; Isocratic solvent: 70% A + 30% B; Flow rate: 1.0 ml/min; Temperature: 25°C; DAD @ 254 nm

Method D:

Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μ 100×4.6 mm; Eluent A: Hexane + 0.1% by volume diethylamine (99%); Eluent B: Ethanol; Isocratic solvent: 80% A + 20% B; Flow rate: 1.0 ml/min; Temperature: 25°C; DAD 254 nm

Method E:

Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μ 100×4.6 mm; Eluent A: Hexane + 0.1% by volume diethylamine (99%); Eluent B: Ethanol; Isocratic solvent: 50% A + 50% B; Flow rate: 1.0 ml/min; Temperature: 25°C; DAD 254 nm

Method F:

Instrument: Agilent: 1260, Aurora SFC-Modul; Column: LUNA HILIC 5μm 100×4.6mm; Eluent A: CO ₂ , Eluent B: Methanol + 0.2% by volume diethylamine (99%); Isocratic: 20% B; Flow rate: 4.0ml/min; Temperature: 37.5°C; BPR: 100 bar; MWD@254nm

Method G:

Instrument: Agilent HPLC 1260; Column: Chiralpak IF 3μ 100 × 4.6 mm; Eluent A: water, Eluent B: acetonitrile; Isocratic solvent: 70% A + 30% B; Flow rate: 1.4 ml/min; Temperature: 25°C; MWD @ 220 nm

Purification method:

A Biotage Isolera ^™ chromatography system using pre-packed silica gel columns and pre-packed modified silica gel columns was used.

Preparative HPLC, Method A: High pH

Preparative HPLC, Method B: Low pH

Preparative HPLC method

Preparative HPLC, Method 1:

System: Waters automated purification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5 μm 100×30 mm; Solvent: A=H ₂ O+0.1 vol% formic acid (99%), B=acetonitrile; Gradient: 0-8 min 10-100% B, 8-10 min 100% B; Flow rate: 50 mL/min; Temperature: Room temperature; Solution: up to 250 mg/up to 2.5 mL DMSO o.DMF; Injection: 1×2.5 mL; Detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m/z.

Preparative HPLC, Method 2:

System: Waters automated purification system: Pump 2545, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD; Column: XBrigde C18 5 μm 100×30 mm; Solvent: A=H ₂ O+0.1 vol% ammonia (99%), B=acetonitrile; Gradient: 0-8 min 10-100% B, 8-10 min 100% B; Flow rate: 50 mL/min; Temperature: room temperature; Solution: up to 250 mg/up to 2.5 mL DMSO o.DMF; Injection: 1×2.5 mL; Detection: DAD scan range 210-400 nm; MS ESI+, ESI-, scan range 160-1000 m/z.

Chiral purification method:

Preparative chiral HPLC method

Method A:

Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Chiralpak IE 5μ 250x30mm; Eluent A: ethanol + 0.1% by volume diethylamine (99%); Eluent B: tert-butyl methyl ether; Isocratic solvent: 5% A + 95% B; Flow rate 50.0ml/min; UV 325nm

Method B:

Instrument: Sepiatec:Prep SFC ₁ 00; Column: Chiralpak IF 5 μm 250x30 mm; Eluent A: CO ₂ , Eluent B: ethanol; Isocratic solvent: 16% B; Flow rate: 100.0 ml/min; Temperature: 40°C; BPR: 150 bar; MWD@254 nm

Method C:

Instrument: Agilent PrepHPLC 1200, column: Chiralpak IC 5μ 250x20mm; eluent A: hexane; eluent B: 2-propanol; isocratic solvent: 70% A + 30% B; flow rate: 15.0 ml/min; UV @ 254 nm

Method D:

Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Chiralpak IC 5μ 250x30mm; Eluent A: Hexane + 0.1% by volume diethylamine (99%); Eluent B: Ethanol; Isocratic solvent: 80% A + 20% B; Flow rate 50.0ml/min; UV 254nm

Method E:

Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: Chiralpak IC 5μ 250x30mm; Eluent A: Hexane + 0.1% by volume diethylamine (99%); Eluent B: Ethanol; Isocratic solvent: 70% A + 30% B; Flow rate 50.0ml/min; UV 254nm

Method F:

Instrument: Sepiatec: Prep SFC ₁ 00; Column: LUNA HILIC IF 5 μm 250x30 mm; Eluent A: CO ₂ , Eluent B: Methanol + 0.5 vol% ammonia (32%); Isocratic: 20% B; Flow rate: 100.0 ml/min; Temperature: 40° C.; BPR: 90 bar; MWD@254 nm

Example

Chemical nomenclature of the examples and intermediates was performed by ACD/LABS using ACD software or by ChemAxon using Marvin software.

Reaction times are specified in the protocols in the experimental section or are allowed to proceed until completion. Chemical reactions are monitored and judged to be complete using methods well known to those skilled in the art, such as thin layer chromatography on silica gel coated plates or by LCMS methods.

Intermediate 1: Methyl 3-bromo-5-hydroxybenzoate

A solution of 3-bromo-5-hydroxybenzoic acid (47.7 g, 0.22 mol) and acetyl chloride (31.5 mL, 0.44 mol) in methanol (500 mL) was stirred at reflux for 16 hours. TLC analysis showed complete conversion to a single product. The solvent was removed under reduced pressure to give 49.9 g (98% yield) of the title compound as an off-white powder, which was used in the next step without further purification.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 7.74 (t, J=1.5 Hz, 1H), 7.46 (dd, J=2.4, 1.3 Hz, 1H), 7.25-7.16 (m, 1H), 5.57 (s, 1H), 3.92 (s, 3H).

Intermediate 2: Methyl 3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Methyl 3-bromo-5-hydroxybenzoate (26 g, 112.5 mmol), bis(pinacolato)diborane (31.4 g, 123.8 mmol) and potassium acetate (33.1 g, 337.6 mmol) were dissolved in 1,4-dioxane (450 mL), and the solution was degassed with a nitrogen stream for 10 minutes. Pd(dppf)Cl ₂ CH ₂ Cl ₂ (4.6 g, 5.62 mmol) was added, and the resulting solution was degassed with a nitrogen stream for another 5 minutes, and then the reaction mixture was stirred at 100 ° C for 16 hours. The reaction mixture was filtered and concentrated in vacuo to give a brown solid. The crude material was purified by dry flash chromatography (eluting with 0-25% EtOAc in heptane). The fractions containing the product were concentrated, the material was slurried in heptane and the solid was collected by filtration to give the title compound 30.1 g (96% yield) as a milky white powder.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 8.04 (s, 1H), 7.60 (dd, J=2.7, 1.5 Hz, 1H), 7.47-7.41 (m, 1H), 4.95 (s, 1H), 3.90 (s, 3H), 1.35 (s, 12H).

Intermediate 3: Methyl 3-hydroxy-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 2 (1.0 g, 3.60 mmol) and 2-bromo-5-methylthiazole (0.451 mL, 4.32 mmol) were dissolved in 1M _{K₂CO₃ aqueous} solution (8.63 mL) and THF (58.7 mL). The solution was degassed with a nitrogen stream for 10 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (395.3 mg, 0.539 mmol) was added. The reaction mixture was heated at 90°C for 17 hours until the reaction was complete (monitored by TLC). The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were dried (over _MgSO₄ ) and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 12-80% EtOAc in heptane on _a 25 g pre-packed KP-SiO2 column) to afford 359.7 mg (40% yield) of the title compound as an off-white powder.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 8.06 (t, J = 1.4 Hz, 1H), 7.67-7.62 (m, 1H), 7.54 (dd, J = 2.5, 1.4 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 5.84 (s, 2H), 3.93 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H).

Intermediate 3A: methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-hydroxybenzoate

A mixture of intermediate 2 (7.08 g, 25.5 mmol), 2-chloro-5-ethyl-1,3-thiazole (4.51 g, 30.5 mmol), [1,1-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride (3.12 g, 3.82 mmol), and _{KCO (} 31 ml, 2.0 M, 61 mmol) was stirred in THF (420 mL) under reflux until complete conversion. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution and evaporated to dryness under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EtOAc gradient) to give 2.54 g (38% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ [ppm] 1.26-1.32 (m, 3H) 2.89 (m, 2H) 3.87 (s, 3H) 7.39 (dd, 1H) 7.52 (dd, 1H) 7.66 (t, 1H) 7.87 (t, 1H) 10.24 (s, 1H).

Intermediate 3B: methyl 3-(5-chloro-1,3-thiazol-2-yl)-5-hydroxybenzoate

A mixture of intermediate 2 (30.1 g, 50% purity, 54.2 mmol), 2-bromo-5-chloro-1,3-thiazole (14.0 g, 70.4 mmol), [1,1-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride (6.63 g, 8.13 mmol), and _K₂CO₃ (65 mL, 2.0 M, 130 mmol) was stirred in THF (890 mL) under reflux until complete conversion _. The solvent was evaporated under reduced pressure, water was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution and evaporated to dryness under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EtOAc gradient) to give 5.21 g (34% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ [ppm] 3.85-3.90 (m, 3H) 7.44 (dd, 1H) 7.51 (dd, 1H) 7.84 (t, 1H) 7.99 (s, 1H) 10.35 (br.s., 1H).

Intermediate 4A: Methyl 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 3 (500 mg, 2.0 mmol), (bromomethyl)cyclopropane (331 uL, 3.41 mmol) and potassium carbonate (554 mg, 4.01 mmol) were stirred in acetonitrile at 100 ° C for 4 hours. The reaction was treated again with (bromomethyl)cyclopropane (331 uL, 3.41 mmol) and stirred at 100 ° C for another 4 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 1-40% EtOAc in heptane on a 50 g pre-packed HP-SiO ₂ column) to give the title compound 498.4 mg (74% yield) as a light yellow semi-crystalline solid.

¹ H NMR (250MHz, chloroform-d): δ[ppm]8.10(t,J＝1.4Hz,1H),7.73-7.64(m,1H),7.59(dd,J＝2.5,1.4Hz,1H),7.51(d,J＝1.1H z,1H),3.92(d,J＝6.9Hz,5H),2.52(d,J＝1.1Hz,3H),1.35-1.26(m,1H),0.73-0.60(m,2H),0.38(q,J＝4.7Hz,2H).

LCMS (Analytical Method A): Rt=1.48 min, MS (ESIpos): m/z=304 (M+H)+.

Intermediate 5A: 3-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4A (498.4 mg, 1.48 mMol) was dissolved in MeOH (5 mL) and THF (5 mL). 1 M LiOH (2.2 mL) was added, and the reaction was stirred at room temperature for 2 hours. 1 M LiOH (1 mL) was added, and the reaction was stirred for 1 hour. The reaction mixture was concentrated to dryness, and the residue was dissolved in water (5 mL) and washed with EtOAc (2 x 5 mL). The aqueous layer was acidified to pH 4 with 1 M HCl and extracted with DCM (4 x 10 mL). The combined organics were dried (MgSO ₄ ), filtered, and concentrated to afford 389.5 mg (91% yield) of the title compound as a white powder.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.27 (s, 1H), 7.68 (d, J = 1.5Hz, 1H), 7.65 (d, J = 1.3Hz, 1H), 7.57 (d, J = 1.1Hz, 1H), 3. 94(d,J＝6.9Hz,2H), 2.54(d,J＝1.0Hz,3H), 1.28(d,J＝14.7Hz,1H), 0.68(q,J＝6.1Hz,2H), 0.39(q,J＝4.8Hz,2H).

LC-MS (Analytical Method A) Rt = 1.32 min, MS (ESIpos): m/z = 290 (M+H) ⁺ .

Intermediate 6B: (3S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

A solution of (3S)-tetrahydrofuran-3-ol (23.6.0 g, 268 mmol), TEA (56 ml, 402 mmol), and trimethylamine hydrochloride (2.6 g, 27 mmol) was stirred in DCM (500 mL) and cooled to 0°C. 4-Methylbenzenesulfonyl chloride (63.8 g, 335 mmol) was added portionwise, and the mixture was stirred at room temperature for 4 hours. TLC (50% EtOAc in heptane) indicated complete consumption of the ethanol. Excess 4-methylbenzenesulfonyl chloride was reacted with N,N-dimethylethane-1,2-diamine (8.8 ml, 80 mmol). The crude reaction mixture was washed with 1 M HCl (2 x 500 mL), and the organic portion was dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to afford 64.6 g (99% yield) of the title compound as an orange, viscous oil.

1H NMR (500 MHz, chloroform-d): δ [ppm] 7.79 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 5.11 (tt, J = 4.7, 2.3 Hz, 1H), 3.91-3.78 (m, 4H), 2.45 (s, 3H), 2.12-2.07 (m, 2H).

Intermediate 7: Methyl 3-bromo-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 1 (15 g, 4.33 mmol), Intermediate 6B (20.4 g, 84.4 mmol) and cesium carbonate (42.3 g, 129.8 mmol) in acetonitrile (250 mL) was stirred at 100° C. overnight. The cooled reaction mixture was filtered through celite, washed with EtOAc, and the filtrate was evaporated. The residue was dissolved in EtOAc (200 mL), washed with water (2×200 mL), brine (100 mL), dried ( _MgSO ), filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 1-50% EtOAc in heptane on a 340 g pre-packed HP-SiO ₂ column) to afford the title compound, 18.12 g (92% yield), as a colorless oil.

¹ H NMR (250MHz, chloroform-d): δ[ppm]7.77(t,J＝1.5Hz,1H),7.44(dd,J＝2.4,1.3Hz,1H),7.23-7.19(m,1 H), 4.96 (ddt, J = 6.2, 4.2, 2.0Hz, 1H), 4.06-3.86 (m, 7H), 2.33-2.19 (m, 1H), 2.18-2.05 (m, 1H).

Intermediate 8: Methyl 3-[(3R)-tetrahydrofuran-3-yl]oxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Intermediate 7 (18.1 g, 59.8 mmol), bis(pinacolato)diborane (16.7 g, 65.7 mmol) and potassium acetate (17.6 g, 179.3 mmol) were dissolved in 1,4-dioxane (200 mL), and the solution was degassed with a nitrogen stream for 10 minutes. Pd(dppf) _{Cl₂CH₂Cl₂} ( _{2.4 g} , 2.99 mmol) was added, and the resulting solution was degassed with a nitrogen stream for another 10 minutes, after which the reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature, then filtered and concentrated in vacuo to afford a brown solid. The crude material was purified by dry flash chromatography (eluting with 0-25% EtOAc in heptane). The material was further purified by slurrying in heptane to afford 16.57 g (80% yield) of the title compound as an off-white solid.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.06 (d, J = 1.0 Hz, 1H), 7.61 (dd, J = 2.7, 1.5 Hz, 1H), 7.54-7.45 (m ,1H),5.03(ddt,J=6.4,4.4,2.0Hz,1H),4.07-3.86(m,7H),2.32-2.08(m,2H),1.34(s,12H).

Intermediate 4B: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

Intermediate 8 (5.2 g, 14.9 mmol), 2-bromo-5-methyl-1,3-thiazole (1.87 mL, 17.9 mmol) and cesium carbonate (12.2 g, 37.3 mmol) were dissolved in 4:1 dioxane/water (75 mL). The solution was degassed with a nitrogen stream for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (517.7 mg, 0.45 mmol) was added, and the reaction mixture was heated at 100°C overnight. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organics were dried (MgSO ₄ ), filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 1-40% EtOAc in heptane on a 100 g KP-SiO ₂ column) to give 3.06 g (64% yield) of the title compound as a yellow solid.

¹ H NMR (250MHz, chloroform-d): δ[ppm]8.11(t,J＝1.4Hz,1H),7.67-7.63(m,1H),7.55(dd,J＝2.5,1.4Hz,1H),7.52(d ,J＝1.2Hz,1H),5.07(td,J＝4.1,2.2Hz,1H),4.11-3.86(m,7H),2.53(d,J＝1.1Hz,3H),2.35-2.09(m,2H).

LCMS (Analytical Method A) Rt=1.34 min, MS (ESIpos): m/z=320 (M+H) ⁺ .

Intermediate 5B: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid

Analogously to Intermediate 5A, 8 g (25.0 mmol) of Intermediate 4B was reacted with 1 M lithium hydroxide (20 mL) to give the title compound 5.83 g (76% yield) as a white powder.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 8.30 (s, 1H), 7.69-7.56 (m, 3H), 5.08 (s, 1H), 4.12-3.87 (m, 4H), 2.54 (s, 3H), 2.39-2.11 (m, 2H).

LCMS (Analytical Method A) Rt=1.16 min, MS (ESIpos): m/z=305.9 (M+H) ⁺ .

Intermediate 6C: (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

A solution of (3R)-tetrahydrofuran-3-ol (18.0g, 204mmol), TEA (43mL, 306mmol) and trimethylamine hydrochloride (1.95g, 20mmol) was stirred at room temperature in DCM (625mL). 4-Methylbenzenesulfonyl chloride (42.8g, 2255mmol) was added and the mixture was stirred at room temperature for 20 hours. Excess 4-methylbenzenesulfonyl chloride was reacted with N,N-dimethylethane-1,2-diamine (26ml, 245mmol). Water was added and the crude reaction mixture was extracted three times with DCM. The combined organic portion was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/EE gradient) to obtain 41g (83% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6) δ [ppm] 1.83-1.94 (m, 1H) 2.08 (dtd, J = 14.29, 8.32, 8.32, 6.08Hz, 1H) 2.43 (s, 3H) 3 .61-3.80(m,4H)5.12(ddt,J＝5.83,3.87,1.62,1.62Hz,1H)7.49(d,J＝8.11Hz,2H)7.81(d,J＝8.36Hz,2H).

Intermediate 4C: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

Intermediate 3 (4.5 g, 18.2 mmol), intermediate 6C (5.3 g, 21.8 mmol) and cesium carbonate (8.9 g, 27.3 mmol) were stirred at 90 ° C in DMF (100 mL) for 36 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 3.9 g (67% yield) of the title compound.

1H NMR(400MHz,DMSO-d6)δ[ppm]1.96-2.05(m,1H)2.20-2.31(m,1H)3.74-3.82(m,1H)3.82-3.94(m,6H)5.19-5.26 (m, 1H) 7.48 (dd, J = 2.41, 1.39Hz, 1H) 7.61 (dd, J = 2.28, 1.52Hz, 1H) 7.66 (d, J = 1.27Hz, 1H) 8.00 (t, J = 1.39Hz, 1H).

Intermediate 5C: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid

Intermediate 4C (3.9 g, 12.2 mmol) was dissolved in MeOH (200 mL). 2M NaOH (30.5 mL) was added and the reaction was stirred at room temperature for 3 days. The reaction mixture was neutralized with 2N HCl, the aqueous phase was extracted with DCM, and the combined organics were concentrated to dryness under reduced pressure to give 2.3 g (62% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6) δ [ppm] 1.95-2.05 (m, 1H) 2.19-2.30 (m, 1H) 3.73-3.94 (m, 4H) 5.20 (dd, J = 5.96, 4.44Hz, 1H) 7.46 ( dd,J＝2.41,1.39Hz,1H)7.58(dd,J＝2.41,1.65Hz,1H)7.65(d,J＝1.27Hz,1H)7.98(t,J＝1.39Hz,1H)13.06-13.46(m,1H).

Intermediate 4D: 3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzoate

To a solution of intermediate 3 (300 mg, 1.203 mmol) in acetone (15 mL) was added K ₂ CO ₃ (831.6 mg, 6.017 mmol) and 3-bromoprop-1-yne (201.1 μL, 1.805 mmol). The reaction mixture was stirred at reflux for 2 hours, then cooled to room temperature and evaporated to dryness. The crude material was dissolved in DCM and washed with 1M NaOH (aqueous solution) and brine. The organic phase was evaporated to dryness to give 489 mg (>100% yield) of a dark brown powder. Purification by Biotage Isolera ^™ chromatography (eluting with EtOAC/heptane 0-100% on a pre-filled 10 g silica gel column) gave 335 mg (97% yield) of the title compound as a light yellow powder.

¹ H NMR (250MHz, chloroform-d): δ[ppm]8.16(t,J＝1.4Hz,1H),7.74(dd,J＝2.5,1.6Hz,1H),7.66(dd,J＝2.6,1.4Hz,1H ), 7.53 (d, J = 1.2Hz, 1H), 4.80 (d, J = 2.4Hz, 2H), 3.94 (s, 3H), 2.55 (t, J = 2.4Hz, 1H), 2.53 (d, J = 1.1Hz, 3H).

Intermediate 5D: 3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)benzoic acid

Analogously to Intermediate 5A, 300 mg (0.625 mmol) of Intermediate 4D was reacted with 1 M lithium hydroxide (0.9 mL) to give 159 mg (89% yield) of the title compound.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]8.07-7.94(m,1H),7.74-7.60(m,2H),7.56(dd ,J＝2.4,1.3Hz,1H),4.96(d,J＝2.3Hz,2H),3.63(t,J＝2.3Hz,1H),2.50(s,3H).

Intermediate 4E: Methyl 3-(but-2-yn-1-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

To a solution of intermediate 3 (250 mg, 1.0 mmol) in acetone (10 mL) were added _{K₂CO₃ (} 693 mg, 5.0 mmol) and 1-bromo-2-butyne (175.4 μL, 2.0 mmol), and the reaction mixture was stirred at 60°C in a sealed tube for 2 hours. The reaction mixture was cooled to room temperature, filtered, and evaporated to dryness. The residue was dissolved in DCM and washed with water. The organic phase was dried (over _MgSO₄ ) and evaporated under reduced pressure to give 300.9 mg (98% yield) of the title compound as a brown powder.

¹ H NMR (250MHz, CDCl ₃ )δ[ppm]8.15(t,J＝1.4Hz,1H),7.74-7.70(m,1H),7.65(dd,J＝2.5,1.4Hz,1H),7.54-7.50 (m, 1H), 4.75 (q, J = 2.3Hz, 2H), 3.94 (s, 3H), 2.53 (d, J = 1.1Hz, 3H), 1.87 (t, J = 2.3Hz, 3H).

LCMS (Analytical Method A) Rt=1.43 min, MS (ESIpos): m/z=302 (M+H) ⁺ .

Intermediate 5E: 3-(But-2-yn-1-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To the solution of intermediate 4E (300mg, 1.00mmol) in MeOH (5mL) and THF (5mL), 1M LiOH (2mL) was added, and the reactant was stirred at room temperature for 2 hours. The concentrated reaction mixture was dissolved in water (5mL) and washed with EtOAc (5mL). The water layer was acidified to pH 4 with 1M HCl, and the precipitate was collected by vacuum filtration and dried in a vacuum oven to obtain 245.1mg (85% yield) of the title compound as a white powder.

¹ H NMR (250MHz, DMSO-d6): δ 8.00 (t, J = 1.4 Hz, 1H), 7.65 ( q, J = 1.4 Hz, 2H), 7.54 ( dd, J = 2.5, 1.3 Hz, 1H), 4.89 ( d, J = 2.4 Hz, 2H), 1.84 ( t, J = 2.3 Hz, 3H).

Intermediate 4F: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoate

By intermediate 3 (300mg, 1.2mmol), oxetane-3-yl toluenesulfonate (357mg, 1.56mmol) and cesium carbonate (588mg, 1.81mmol) in acetonitrile (5mL) merge, and at 100 DEG C, in sealed tube, stir 6 hours, then at 110 DEG C, stir 4 hours.Reaction mixture is cooled to room temperature, filtered through diatomite, and washed with EtOAc.Filtrate is concentrated under reduced pressure, and by Biotage ^IsoleraTM chromatography (eluting silica gel with heptane-ethyl acetate 9:1 to 2:3), purifying, obtain 163.5mg (43% yield) title compound, be colorless jelly.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.12 (t, J = 1.4Hz, 1H), 7.52 (d, J = 1.1Hz, 1H), 7.51 (dd, J = 2.5, 1.6Hz, 1H), 7.37 (dd, J = 2.5 ,1.3Hz,1H),5.33(p,J＝5.6Hz,1H),5.07-4.98(m,2H),4.78(dd,J＝7.9,5.1Hz,2H),3.94(s,3H),2.53(d,J＝1.1Hz,3H).

LCMS (Analytical Method A) Rt=1.29 min, MS (ESIpos): m/z=309.95 (M+H) ⁺ .

Intermediate 5F: 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoic acid

Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoate (163.5 mg, 0.52 mmol) was stirred in 1 M LiOH (1 mL), THF (2 mL), and MeOH (2 mL) for 1 hour. The organics were removed under reduced pressure, and the residue was dissolved in water (5 mL) and acidified to pH 3 with 1 M HCl. The resulting precipitate was collected by vacuum filtration to give 151.8 mg (100% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.31 (t, J = 1.4Hz, 1H), 7.59 (d, J = 1.1Hz, 1H), 7.53 (dd, J = 2.4, 1.7Hz, 1H), 7.42 (dd, J =2.4, 1.3Hz, 1H), 5.35 (p, J = 5.6Hz, 1H), 5.05 (t, J = 6.9Hz, 2H), 4.80 (dd, J = 7.7, 5.1Hz, 2H), 2.54 (d, J = 1.0Hz, 3H).

LCMS (Analytical Method A) Rt=1.12 min, MS (ESIpos): m/z=219.95 (M+H) ⁺ .

Intermediate 4G: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

To a solution of intermediate 3 (500 mg, 2.0 mmol), (2S)-tetrahydrofuran-2-ylmethanol (245 mg, 2.4 mmol) and _PPh3 (789 mg, 3.0 mmol) in DCM (20 mL) was added DIAD (0.6 mL, 3.0 mmol) and the resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by Biotage Isolera ^™ chromatography (silica gel, eluting with 20-60% EtOAc in heptane) to give 550 mg (50% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.11(t,J＝1.4Hz,1H),7.70(dd,J＝2.5,1.6Hz,1H),7.61(dd,J＝2.5,1.4Hz,1H),7.51(d,J＝1.2Hz,1H),4.36-4.23(m,1H),4. 12-4.03(m,2H),3.99-3.91(m,4H),3.88-3.81(m,1H),2.52(d,J＝1.1Hz,3H),2.13-2.05(m,1H),2.03-1.89(m,2H),1.84-1.74(m,1H).

LCMS (Analytical Method F): Rt=3.64 min, MS (ESIpos); m/z=33 (M+H) ⁺ .

Intermediate 5G: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid

A mixture of methyl 5-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate (600 mg, 1.83 mmol) and 1M LiOH (10 mmol) in THF (20 mL) was stirred at room temperature for 18 hours. The reaction was neutralized with 1M HCl (10 mL) at 0°C, followed by the addition of 10 mL of buffer (pH = 6.5). The aqueous phase was extracted with _CHCl₃ /iPrOH (1:1, ₄ x 5 mL), and the combined organic layers were dried (over _Na₂SO₄ ) and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with 50% EtOAc in heptane, then 10% MeOH in DCM) to afford 520 mg (84% yield) of the title compound as a yellow gum.

¹ H NMR (500MHz, CDCl ₃ ): δ [ppm] 8.24 (s, 1H), 7.67 (s, 2H), 7.54 (s, 1H), 4.31 (s, 1H), 4.15-3.77 (m, 4H), 2.50 (s, 3H), 2.13-1.66 (m, 4H).

LCMS (Analytical Method A): Rt=1.22 min, MS (ESIpos); m/z=391 (M+H) ⁺ .

Intermediate 4H: methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

To a suspension of intermediate 3 (600 mg, 2.4 mmol) in DCM (10 mL) was added (2R)-tetrahydrofuran-2-ylmethanol (295 mg, 2.9 mmol) and triphenylphosphine (950 mg, 3.6 mmol). DIAD (0.7 mL, 3.6 mmol) was added at ~10°C, and the resulting solution was stirred at room temperature for 20 hours. The reaction mixture was concentrated, and the residue was dissolved in THF (10 mL) and treated again with (2R)-tetrahydrofuran-2-ylmethanol (150 mg, 1.4 mmol), triphenylphosphine (475 mg, 1.8 mmol), DIAD (0.7 mL, 3.6 mmol), and the resulting solution was stirred at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was re-extracted with EtOAc (2 x 20 mL) and the combined organics were dried ( _MgSO4 ) and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 12-100% EtOAc in heptane on _a 55 g pre-packed KP-NHSiO2 column) to afford 973 mg (55% yield) of the title compound.

¹ H NMR (250MHz, CDCl ₃ ): δ[ppm]8.11(t,J＝1.4Hz,1H),7.76-7.67(m,1H),7.66-7.58(m,1H),7.52(d,J＝1.1Hz,1H),4.37-4.2 5(m,1H),4.19-4.04(m,3H),3.93(s,4H),3.91-3.81(m,2H),3.80-3.67(m,2H),2.52(d,J=1.0Hz,3H).

LCMS (Analytical Method A) Rt=1.39, MS (ESIpos): m/z=334.1 (M+H) ⁺ .

Intermediate 5H: 3-(5-methyl-1,3-thiazol-2-yl)-5-[[(2R)-tetrahydrofuran-2-yl]methoxy]benzoic acid

To a solution of methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[[(2R)-tetrahydrofuran-2-yl]methoxy]benzoate (973 mg, ~45% purity, 1.31 mmol) in THF (1.8 mL) and methanol (1.3 mL) was added 1 M LiOH (1.84 mL, 1.84 mmol), and the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove the organic solvent, diluted with 1 M NaOH (13 mL) and washed with ethyl acetate (2 x 20 mL). The aqueous phase was acidified to pH 4 with 1 M HCl, and the resulting precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 258 mg (61% yield) of the title compound as a white powder.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]13.27(s,0.5H),8.05-7.91(m,1H),7.69-7.63(m,1H),7.63-7.57(m,1H),7.54-7.43(m,1H),4.24-4.15(m,1H),4 .15-4.07(m,1H),4.07-3.99(m,1H),3.83-3.76(m,1H),3.72-3.66(m,1H ),2.51(s,3H),2.07-1.96(m,1H),1.96-1.77(m,2H),1.77-1.64(m,1H).

LCMS (Analytical Method A) Rt=1.24 min, MS (ESIpos): m/z=320 (M+H) ⁺ .

Intermediate 4I: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

To a suspension of intermediate 3 (300 mg, 1.2 mmol), (3R)-tetrahydrofuran-3-ylmethanol (185 mg, 1.8 mmol) and triphenylphosphine (475 mg, 1.8 mmol) in DCM (10 mL) was added DIAD (355 μl, 1.8 mmol), and the resulting solution was stirred at room temperature over the weekend (~65 hours). The reaction mixture was washed with water (20 mL) and the aqueous layer was re-extracted with DCM (2×20 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc 1:0 to 35:65) to give 700 mg (91% yield) of the title compound.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.09 (t, J = 1.4Hz, 1H), 7.71-7.67 (m, 1H), 7.58 (dd, J = 2.5, 1.4H z,1H),7.52(d,J＝1.2Hz,1H),4.05(dd,J＝8.9,6.5Hz,1H),4.02-3.97(m,1H),3.94(s,3H),3 .96-3.88(m,5H),3.83-3.77(m,1H),3.72(dd,J＝8.9,5.3Hz,1H),2.77(hept,J＝6.8,6.2Hz, 1H), 2.53(d,J＝1.1Hz,3H), 2.13(dtd,J＝13.5,8.1,5.6Hz,1H), 1.76(td,J＝12.7,6.9Hz,1H).

Intermediate 5I: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoic acid

To a solution of methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate (939 mg, 1.41 mmol, ~50% purity) in THF (3 mL) was added 1 M aqueous sodium hydroxide solution (3 mL). The reaction was vigorously stirred at room temperature for 18 hours. Another portion of 1 M aqueous sodium hydroxide solution (1 mL) was added, and the reaction was vigorously stirred at room temperature for 4 hours. The reaction mixture was acidified to pH 3 with 1 M HCl and extracted into EtOAc (3 x 30 mL). The combined organics were washed with 1 M HCl (4 x 20 mL). The aqueous phase was concentrated (to ~20 mL) and extracted with DCM (4 x 20 mL). The combined DCM and EtOAc organics were dried (over MgSO ₄ ) and concentrated to give 600 mg (86% yield) of the title compound.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.22 (t, J = 1.4Hz, 1H), 7.84 (s, 1H), 7.69 (dd, J = 2.4, 1.3Hz, 1H), 7.66-7.62 (m, 1H), 4.17-4.02 (m, 2H), 4.01-3.91(m,2H),3.87-3.74(m,0H),2.86-2.75(m,1H),2.58(d,J＝0.8Hz,0H),2.23-2.12(m,2H),2.07(s,1H),1.86-1.76(m,1H).

LCMS (Analytical Method A) Rt=1.20 min, MS (ESIpos) m/z=320 (M+H) ⁺ .

Intermediate 4J: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[[(3R)-tetrahydrofuran-3-yl]methoxy]benzoate

To the stirred solution of PPh ₃ (552mg, 2.11mmol) and DIAD (415 μL, 2.11mmol) in THF (8mL) was added intermediate 3 (350mg, 1.40mmol) and (3S)-tetrahydrofuran-3-ylmethanol (215mg, 2.11mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was dissolved in DCM and washed with water, dried (over Na SO ₄ ) and concentrated in vacuo to give an amber viscous oil. The crude material was purified by Biotage Isolera ^TM chromatography (on KP-NH silica gel, eluted with heptane-DCM 1:0 to 7:3) to give 566mg (40% yield) of the title compound as a pale jelly.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.08 (s, 1H), 7.71-7.63 (m, 5H), 7.60-7.50 (m, 4H), 7. 46(td,J＝7.7,2.8Hz,4H),4.07-3.87(m,7H),3.79(q,J＝7.7Hz,1H),3.72(dd,J＝8.9 ,5.3Hz,1H),2.83-2.70(m,J＝7.2,6.4Hz,1H),2.52(s,3H),2.13(dtd,J＝13.6,8.1, 5.6Hz, 1H), 1.76 (dq, J = 12.9, 7.1Hz, 1H), 1.36-1.17 (m, 3H), 0.87 (t, J = 7.0Hz, 1H).

LCMS (Analytical Method A) Rt=1.37 min, MS (ESIpos) m/z=334 (M+H) ⁺ .

Intermediate 5J: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoic acid

To a solution of methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate (566 mg, 0.80 mmol, ~50% purity) in THF (1.2 mL) and methanol (0.5 mL) was added 1 M aqueous lithium hydroxide solution (1.2 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (3 mL) and washed with EtOAc (2×6 mL). The aqueous phase was acidified to pH ~4, resulting in a white solid precipitate. Filtration gave 264 mg (98% yield) of the title compound as a white solid.

LCMS (Analytical Method A) Rt=1.20 min, MS (ESIpos) m/z=320 (M+H) ⁺ .

Intermediate 4K: 3-(5-methyl-1,3-thiazol-2-yl)-5-tetrahydro-2H-pyran-4-yloxy-benzoic acid methyl ester

To a solution of intermediate 3 (700 mg, 2.81 mmol), tetrahydro-2H-pyran-4-ol (0.386 mL, 3.65 mmol) and triphenylphosphine (957 mg, 3.65 mmol) in THF (10 mL) was slowly added DIAD (0.724 mL, 3.65 mmol), and the reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2×30 mL). The combined organic phases were washed with brine (10 ml), dried (over _Na₂SO₄ ), and concentrated in vacuo. The resulting material was purified by chromatography on silica gel (gradient: hexane/EE) _to give 571 mg (54% yield) of the title compound as a yellow oil. The impure fraction from the chromatography was repurified using the same conditions to give an additional 981 mg (25% yield) of the title compound.

¹ H NMR (500MHz, CDCl ₃ ): δ8.11-8.06(m,1H),7.72-7.68(m,1H),7.60-7.58(m,1H),7.53-7.48(m,1H),4.69-4.60(m,1H),4.02- 3.96(m,2H),3.94(s,3H),3.66-3.57(m,2H),2.53(d,J=1.1Hz,3H),2.10-2.00(m,2H),1.87-1.77(m,2H).

Intermediate 5K: 3-(5-methyl-1,3-thiazol-2-yl)-5-tetrahydro-2H-pyran-4-yloxy-benzoic acid

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-tetrahydro-2H-pyran-4-yloxy-benzoic acid methyl ester (565 mg, 1.49 mmol) in THF/MeOH (1:1, 6 mL) was added 1 M LiOH (2.24 mL, 2.24 mmol), and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was adjusted to pH ~3 with 1 M HCl and then extracted with EtOAc (2 x 15 mL). The combined organic phases were washed with brine (5 mL), dried (using a Biotage phase separator), and concentrated in vacuo to give 516 mg (90% yield) of the title compound as an off-white solid.

¹ H NMR (250MHz, CDCl ₃ ): δ[ppm]8.36-8.21(m,1H),7.73-7.63(m,2H),7.61-7.57(m,1H),4.75-4.58(m,1H),4.08- 3.94(m,2H),3.71-3.54(m,2H),2.54(d,J＝1.1Hz,3H),2.17-1.99(m,2H),1.94-1.73(m,2H).

LCMS (Analytical Method A) Rt=1.16 min, MS (ESIpos): m/z=320 (M+H) ⁺ .

Intermediate 4L: methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

To the solution of stirred intermediate 3 (250mg, 1mmol) and 4-(bromomethyl)tetrahydro-2H-pyrans (449mg, 2.51mmol) in anhydrous MeCN (7mL), dipotassium carbonate (347mg, 2.51mmol) was added. The reaction mixture was stirred overnight at 100°C, cooled to room temperature, filtered and concentrated under reduced pressure. Silica gel (gradient: hexane/EE) purification of the obtained material was used by chromatography to obtain 1.0g (76% yield) of the title compound as a colorless oil.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.08(t,J＝1.4Hz,1H),7.69-7.67(m,1H),7.57(dd,J＝2.5,1.4Hz,1H),7.53-7.51(m,1H),4.05-4.00(m,2H),3.94( s,3H),3.92(d,J＝6.5Hz,2H),3.49-3.42(m,2H),2.53-2.52(m,3H),2.14-2.03(m,1H),1.80-1.75(m,2H),1.53-1.43(m,2H).

LCMS (Analytical Method A) Rt=1.45 min, MS (ESIpos): m/z=348 (M+H) ⁺ .

Intermediate 5L: 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid

To a solution of methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate (1 g, 2.88 mmol) in THF (6 mL) and MeOH (6 mL) was added 1 M LiOH (4.3 mL) at room temperature, and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and acidified to pH 4 with 1 M HCl, resulting in the formation of a precipitate. The precipitate was collected by vacuum filtration, washed with ethyl acetate and dried under vacuum to give 179 mg (16% yield) of the title compound as a white solid. The filtrate was extracted again with IPA/chloroform 50:50, and the combined organic layers were washed with brine, dried (over Na ₂ SO ₄ ) and concentrated to give 302 mg (27% yield) of a second batch of the title compound as a white solid.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]7.97(s,1H),7.66-7.64(m,1H),7.62-7.60(m,1H),7.50(s,1H),3.97(d,J＝6.4Hz,2H ),3.92-3.86(m,2H),3.38-3.34(m,2H),2.54-2.49(m,3H),2.10-1.99(m,1H),1.75-1.68(m,2H),1.42-1.32(m,2H).

LCMS (Analytical Method A) Rt=1.24 min, MS (ESIpos): m/z=334 (M+H) ⁺ .

Intermediate 5M: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2-methylpyridin-4-yl)oxy]benzoic acid

A mixture of intermediate 3 (1.0 g, 3.81 mmol), 4-fluoro-2-methylpyridine (0.63 g, 5.71 mmol) and Cs ₂ CO ₃ (2.48 g, 7.6 mmol) was heated in DMSO (10 mL) at 100° C. for 6 hours. The reaction mixture was treated with 1 M aqueous NaOH solution (5 mL) and stirred for 30 minutes. The solution was diluted with water (30 mL) and acidified to pH 4 with 1 M aqueous HCl. Upon addition of EtOAc (40 mL), a precipitate formed which was collected by vacuum filtration to afford 722 mg (56% yield) of the title compound as an orange powder.

¹ H NMR (500MHz, MeOH-d4): δ [ppm] = 8.39 (t, J = 1.5Hz, 1H), 8.35 (d, J = 6.0Hz, 1H), 7.90-7.85 (m, 1H), 7.77 (dd, J = 2.3, 1.4 Hz,1H),7.58(d,J＝1.2Hz,1H),6.98(d,J＝2.4Hz,1H),6.93(dd,J＝6.0,2.5Hz,1H),2.55(d,J＝1.1Hz,3H),2.52(s,3H).

LCMS (Analytical Method A) Rt=0.96 min, MS (ESIpos) m/z=327 (M+H) ⁺ .

Intermediate 9: Methyl 3,5-dibromobenzoate

A solution of 3,5-dibromobenzoic acid (10.5 g, 37.5 mmol) and acetyl chloride (6.7 mL, 93.8 mmol) in methanol (212 mL) was stirred at reflux for 17 hours. The solvent was removed under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 11.0 g (99% yield) of the title compound.

Intermediate 10: Methyl 3-bromo-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 9 (3.5 g, 11.91 mmol) and 5-methyl-2-(tributyltin alkyl)-1,3-thiazole (4.62 g, 11.91 mmol) were dissolved in DMF (105 mL). The solution was degassed with a nitrogen stream for 10 minutes, tetrakis(triphenylphosphine)palladium(0) (550 mg, 0.476 mmol) was added, and the reaction mixture was heated at 100 ° C for 17 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain the title compound 1.72 g (42% yield).

¹ H NMR (400MHz, DMSO-d6) δ [ppm] 2.53 (d, J = 1.27Hz, 3H) 3.89-3.94 (m, 3H) 7.71 (d, J＝1.27Hz,1H)8.08-8.11(m,1H)8.27(t,J＝1.77Hz,1H)8.35(t,J＝1.52Hz,1H).

Intermediate 5N: 3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 10 (1.29 g, 4.14 mmol), 5-hydroxy-2-methylpyridine (903 mg, 8.28 mmol), 2,2,6,6-tetramethylheptane-3,5-dione (0.11 ml, 0.83 mmol), Cu(I)Cl (165 mg, 1.65 mmol) and Cs ₂ CO ₃ (4.05 g, 12.4 mmol) were stirred in NMP (51 mL) using microwaves at 220° C. for 20 minutes. The reaction mixture was concentrated to dryness under reduced pressure, and the crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 1.0 g (70% purity, 52% yield) of the title compound.

¹ H NMR (300MHz, DMSO-d6) δ [ppm] 7.31 (d, 1H) 7.45 (d, 1H) 7.49 (m, 2H) 7.58 (d, 1H) 8.08-8.16 (m, 1H) 8.31 (d, 1H).

Intermediate 40: Methyl 3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A solution of intermediate 3 (250 mg, 1.0 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (270 mg, 1.5 mmol) and cesium carbonate (654 mg, 2.0 mmol) in DMF (5 mL) was heated overnight at 110 ° C in a sealed tube. The cooled reaction mixture was concentrated under reduced pressure and the residue was distributed between water (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM (10 mL), the combined organic matter was dried (over MgSO ₄ ), and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 4: 1 to 3: 7). The mixed fraction was purified again by Biotage Isolera ^™ chromatography (eluted with heptane-EtOAc 1: 0 to 3: 7). The clean fractions from both purifications were combined and concentrated to give 204.9 mg (59% yield) of the title compound as an off-white solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.39 (t, J = 1.4Hz, 1H), 8.09 (dd, J = 2.3, 1.7Hz, 1H), 7.98 (dd, J＝2.4,1.4Hz,1H),7.54(d,J＝1.1Hz,1H),3.95(s,3H),2.69(s,3H),2.54(d,J＝1.0Hz,3H).

LCMS (Analytical Method A) Rt=1.33 min, MS (ESIpos) m/z=348 (M+H) ⁺ .

Intermediate 50: 3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a stirred solution of methyl 3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate (204.9 mg, 0.59 mmol) in MeOH (2.5 mL) and THF (2.5 mL) was added 1 M LiOH (2.5 mL). After 1 hour, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (5 mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH ~3 with 1 M HCl to form a white precipitate, which was collected by vacuum filtration to give 128.6 mg (58% yield) of the title compound as a white powder.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] = 8.29 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 2.64 (s, 3H), 2.52 (s, 3H).

LCMS (Analytical Method A) Rt=1.15 mins, MS (ESIpos) m/z=334 (M+H) ⁺ .

Intermediate 5P: 3-(5-methyl-1,3-thiazol-2-yl)-5-(1,3-thiazol-2-yloxy)benzoic acid

A solution of intermediate 3 (250 mg, 1.0 mmol), 2-bromothiazole (246.7 mg, 1.5 mmol) and cesium carbonate (654 mg, 2.0 mmol) in DMF (5 mL) was heated overnight at 110° C. in a sealed tube. The cooled reaction mixture was treated with 1 M LiOH (2 mL) and stirred at 110° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (10 mL) and washed with EtOAc (2×10 mL). The aqueous layer was acidified to pH 3 with 1 M HCl, and the solution was extracted with DCM (3×10 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure to give 328.3 mg (86% yield) of the title compound as a brown powder.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] = 8.26 (d, J = 1.3Hz, 1H), 8.08-8.05 (m, 1H), 7.86 (dd, J = 2.2 ,1.4Hz,1H),7.69-7.67(m,1H),7.36(d,J＝3.8Hz,1H),7.34(d,J＝3.8Hz,1H),2.52(s,3H).

LCMS (Analytical Method A) Rt=1.23 min, MS (ESIpos) m/z=319 (M+H) ⁺ .

Intermediate 11: Methyl 3-bromo-5-(2-hydroxy-2-methylpropoxy)benzoate

A mixture of Intermediate 1 (1.92 g, 8.33 mmol), 2,2-dimethyloxirane (3 g, 41.5 mmol), and K ₂ CO ₃ (2.3 g, 16.6 mmol) was stirred in DMSO (23 mL) at 100° C. for 17 hours. The reaction mixture was filtered and washed with DCM. The organics were washed with water and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 2.1 g of the title compound (87% yield).

¹ H NMR (400MHz, DMSO-d6) δ [ppm] 1.16-1.23 (m, 6H) 3.80 (s, 2H) 3.86 (s, 3H) 4.66 (s, 1H) 7.41-7.49 (m, 2H) 7.62 (t, J = 1.52Hz, 1H).

Intermediate 12: 3-Bromo-5-(2-methoxy-2-methylpropoxy)benzoic acid

At room temperature, 637mg NaH (60%, 15.9mmol) is added to a solution of intermediate 11 (1.92g, 6.64mmol) in THF (21mL) and stirred for 30 minutes. Methyl iodide (1.24ml, 19.9mmol) is then added at room temperature. The reaction mixture is stirred at 50°C for 1 hour and stirred at room temperature overnight. The reaction mixture is diluted with water and extracted three times with DCM. The organic matter is concentrated under reduced pressure to obtain the title compound (2.9g,>100% yield), which is used in the next step without further purification.

Intermediate 13: Methyl 3-bromo-5-(2-methoxy-2-methylpropoxy)benzoate

At 90 ° C, a mixture of crude intermediate 12 (2.9 g) and acetyl chloride (1.7 ml, 23.9 mmol) was stirred in MeOH (130 mL). The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give the title compound 1.66 g (79% yield over two steps from intermediate 11).

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.21(s,6H)3.15(s,3H)3.86(s,3H)3.94(s,2H )7.45(dd,J＝2.40,1.39Hz,1H)7.49(t,J＝2.15Hz,1H)7.63(t,J＝1.52Hz,1H).

Intermediate 14Q: methyl 3-(2-methoxy-2-methylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of intermediate 13 (1.66 g, 5.23 mmol), bis(pinacolato)diborane (3.32 g, 13.08 mmol), potassium acetate (1.8 g, 18.3 mmol), and Pd(dppf) _Cl₂ (383 mg, 0.52 mmol) was stirred in 1,4-dioxane (100 mL) at 90°C for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The remaining crude reaction mixture was extracted three times with DCM and concentrated again in vacuo. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 1.2 g (63% yield) of the title compound.

¹ H NMR(300MHz,DMSO-d6)δ[ppm]1.22(s,6H)1.31(s,12H)3.16(s,3H)3.86(s,3H )3.92(s,2H)7.41(d,J＝2.07Hz,1H)7.56(dd,J＝2.64,1.70Hz,1H)7.85(s,1H).

Intermediate 15Q: Methyl 3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzoate

Intermediate 14Q (1.15 g, 3.16 mmol), 2-bromo-5-chloro-1,3-thiazole (752 mg, 3.79 mmol), and Pd(dppf) _Cl₂ (347 mg, 0.47 mmol) were dissolved in 1M _K₂CO₃ aqueous solution ₍ 7.58 mL) and THF (100 mL). The reaction mixture was stirred at room temperature for 4 days and at 90°C for another day. The reaction mixture was concentrated under reduced pressure, and the remaining material was diluted with water and extracted three times with DCM. The combined organics were concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 790 mg (70% yield) of the title compound.

Intermediate 5Q: 3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzoic acid

Intermediate 15Q (790 mg, 2.22 mmol) was dissolved in MeOH (40 mL). 2M NaOH (5.55 mL) was added and the reaction was stirred at room temperature overnight. The reaction mixture was neutralized with 2N HCl, the aqueous phase was extracted with DCM, and the combined organics were concentrated to dryness under reduced pressure to give 460 mg (56% yield) of the title compound.

¹ H NMR(300MHz,DMSO-d6)δ[ppm]1.22-1.25(m,6H)3.17(s,3H)3.99(s,2H)7.57(d d,J＝2.45,1.32Hz,1H)7.62-7.66(m,1H)7.96-8.02(m,2H)13.22-13.43(m,1H).

Intermediate 16: Methyl 3-bromo-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

At 120 ° C, intermediate 1 (5.1 g, 22.1 mmol), 4- (bromomethyl) tetrahydro -2H- pyran (4.35 g, 24.3 mmol) and cesium carbonate (36 g, 110 mmol) were stirred in DMF (150 mL) for 22 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material (7.1 g) contained the title compound and the corresponding carboxylic acid.

At 90 ° C, the mixture was stirred in methanol (150 mL) and acetyl chloride (4.23 g, 53.9 mmol) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 6.02 g (83% yield) of the title compound.

¹ H NMR(400MHz, DMSO-d6)δ[ppm]1.26-1.39(m,2H)1.66(dd,J＝12.80,1.90Hz,2H)1.94-2.06(m,1H)3.29-3.37(m,2H)3 .85-3.90(m,5H)3.92(d,J＝6.34Hz,2H)7.42(dd,J＝2.41,1.39Hz,1H)7.46(t,J＝2.15Hz,1H)7.62(t,J＝1.52Hz,1H).

Intermediate 14R: methyl 3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of intermediate 16 (6.2 g, 18.8 mmol), bis(pinacolato)diborane (11.96 g, 47.1 mmol), potassium acetate (6.47 g, 65.9 mmol), and Pd(dppf) _Cl₂ (1.38 g, 1.88 mmol) was stirred in 1,4-dioxane (150 mL) at 90°C for 17 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The remaining crude reaction mixture was purified by column chromatography (silica gel, hexane/EE gradient) to give 9.2 g of the title compound (quantitative yield).

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.29-1.41(m,14H)1.64-1.72(m,2H)1.93-2.06(m,1H)3.33(d,J＝ 1.52Hz, 2H) 3.84-3.94 (m, 7H) 7.38 (dd, J = 2.79, 0.76Hz, 1H) 7.53-7.55 (m, 1H) 7.83-7.85 (m, 1H).

Intermediate 15R: methyl 3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzoate

Intermediate 14R (717 mg, 1.9 mmol), 2-bromo-5-(trifluoromethyl)-1,3-thiazole (531 mg, 2.29 mmol), and Pd(dppf) _Cl₂ (209 mg, 0.29 mmol) were dissolved in 1M _{K₂CO₃ aqueous} solution (4.5 mL) and THF (30 mL). The reaction mixture was heated in a microwave at 120°C for 90 minutes. The reaction mixture was concentrated under reduced pressure, and the remaining material was diluted with water and extracted three times with DCM. The combined organics were concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give a mixture of the title compound and unreacted boronic acid (300 mg).

Intermediate 5R: 3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzoic acid

Intermediate 15R (300 mg, 0.75 mmol) was dissolved in MeOH (30 mL). 2M NaOH (1.87 mL) was added and the reaction was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, neutralized with 2N HCl, and the aqueous phase was extracted three times with DCM. The combined organic matter was concentrated to dryness under reduced pressure to give 230 mg of the crude title compound (55% purity by LCMS), which was used without further purification.

Intermediate 15S: methyl 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

Intermediate 14R (667 mg, 1.77 mmol), 2-chloro-5-cyclobutyl-1,3-thiazole (369 mg, 2.13 mmol), and Pd(dppf) _Cl₂ (194 mg, 0.27 mmol) were dissolved in 1M _K₂CO₃ aqueous solution ₍ 4.25 mL) and THF (28 mL). The reaction mixture was stirred at 90°C overnight. The reaction mixture was concentrated under reduced pressure, and the remaining material was diluted with water and extracted three times with DCM. The combined organics were concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 180 mg (26% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6) δ [ppm] 1.33-1.43 (m, 2H) 1.70 (dd, J = 12.67, 1.77Hz, 2H) 1.85-1 .95(m,1H)1.96-2.05(m,2H)2.15(td,J＝9.00,2.53Hz,2H)2.40-2.46(m,2H)3.33-3.3 9(m,2H)3.76-3.84(m,1H)3.86-3.91(m,5H)3.97(d,J＝6.34Hz,2H)7.49(dd,J＝2.41,1 .39Hz, 1H) 7.63 (dd, J = 2.28, 1.52Hz, 1H) 7.69 (d, J = 0.76Hz, 1H) 8.00 (t, J = 1.52Hz, 1H).

Intermediate 5S: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid

Intermediate 15S (180 mg, 0.46 mmol) was dissolved in MeOH (20 mL). 2M NaOH (1.16 mL) was added and the reaction was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, neutralized with 2N HCl, and the precipitated solid material was filtered out to obtain 160 mg (92% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.27-1.44(m,2H)1.62-1.74(m,2H)1.83-1.94(m,1H)1. 95-2.07(m,2H)2.08-2.20(m,2H)2.38-2.45(m,2H)3.31-3.38(m,2H)3.81(s,1H)3.88( dd,J＝11.37,2.78Hz,2H)3.96(d,J＝6.57Hz,2H)7.48(dd,J＝2.40,1.39Hz,1H)7.61(dd, J＝2.40,1.64Hz,1H)7.68(d,J＝0.76Hz,1H)7.98(t,J＝1.52Hz,1H)13.17-13.32(m,1H).

Intermediate 17A: (3S)-tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate

At room temperature, a solution of (3R)-tetrahydrofuran-3-ylmethanol (3.0 g, 29.4 mmol), TEA (6.1 mL, 44 mmol) and trimethylamine hydrochloride (281 mg, 2.9 mmol) in DCM (90 mL) was stirred for 10 minutes and cooled to 0 ° C. 4-Methylbenzenesulfonyl chloride (6.16 g, 32 mmol) was added and the mixture was stirred at room temperature for 17 hours. The mixture was treated with N, N-dimethylethane-1,2-diamine (3.8 mL, 35 mmol) and water. The aqueous layer was extracted three times with DCM. The combined organic portions were concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/EE gradient) to give 6.45 g (86% yield) of the title compound.

¹ H NMR(300MHz,DMSO-d6)δ[ppm]1.45(td,J＝13.09,6.97Hz,1H)1.79-1.96(m,1H)1.83-1.83(m,1H)2.43 (s,3H)3.27-3.36(m,1H)3.48-3.68(m,3H)3.88-4.01(m,2H)7.49(d,J=7.91Hz,2H)7.75-7.84(m,2H).

Intermediate 18: Methyl 3-bromo-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Intermediate 1 (4.85 g, 21 mmol), Intermediate 17A (6.45 g, 25.2 mmol) and cesium carbonate (10.2 g, 31.5 mmol) were stirred in DMF (81 mL) at 50° C. for 60 h. The reaction mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give the crude title compound (7.47 g), which was used in the next step without further purification.

Intermediate 14T: methyl 3-[(3S)-tetrahydrofuran-3-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Intermediate 18 (7.47 g, 23.7 mmol), bis(pinacolato)diborane (15.05 g, 59.3 mmol), potassium acetate (8.14 g, 83 mmol), and Pd(dppf) _Cl₂ (1.73 g, 2.37 mmol) were stirred in dioxane (91 mL) at 90°C for 80 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The remaining crude reaction mixture was extracted with DCM, washed with water, and the organic phase was concentrated in vacuo. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 9.3 g of the title compound (quantitative yield).

¹ H NMR(400MHz, DMSO-d6)δ[ppm]1.31(s,12H)1.63-1.75(m,1H)1.95-2.07(m,1H)2.58-2.69(m,1H)3.54(dd,J＝8.59,5.56Hz,1H)3.66(d,J＝6.82Hz ,1H)3.72-3.83(m,2H)3.86(s,3H)3.99(dd,J＝19.07,7.20Hz,2H)7.39(dd,J＝2.78,0.76Hz,1H)7.55(dd,J＝2.65,1.64Hz,1H)7.83-7.87(m,1H).

Intermediate 15T: Methyl 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Intermediate 14T (1 g, 2.76 mmol), 2-chloro-5-cyclobutyl-1,3-thiazole (623 mg, 3.59 mmol), and Pd(dppf) _Cl₂ · _CH₂Cl₂ (338 mg, 0.41 mmol) were dissolved in 1M aqueous _K₂CO₃ (6.63 _mL ) and THF (45 mL). The reaction mixture was heated at reflux for ₂ hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to afford 770 mg (75% yield) of the title compound.

Intermediate 5T: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoic acid

Intermediate 15T (770 mg, 2.06 mmol) was dissolved in MeOH (20 mL) and THF (20 mL). 2M NaOH (4.12 mL) was added, and the reactant was stirred at room temperature. The reaction mixture was concentrated under reduced pressure. Water was added, and the aqueous phase was adjusted to pH 2 with 2NHCl, extracted with EE, and the organic matter was concentrated under reduced pressure to obtain 765 mg (quantitative yield) of the title compound, which was used without further purification.

Intermediate 15U: Methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

Intermediate 14R (1.05 g, 2.79 mmol), 2-chloro-5-ethyl-1,3-thiazole (495 mg, 3.34 mmol) and Pd(dppf) _Cl2 (306 mg, 0.42 mmol) were dissolved in 1M _{K2CO3 aqueous} solution (6.6 mL) and THF (42 mL). The reaction mixture was heated in a microwave at 120°C for 90 minutes. The reaction mixture was concentrated under reduced pressure, and the remaining material was diluted with water and extracted three times with DCM. The combined organics were concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 450 mg (44% yield) of the title compound.

Intermediate 5U: 3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid

Intermediate 15U (450 mg, 1.25 mmol) was dissolved in MeOH (50 mL). 2M NaOH (3.1 mL) was added and the reaction was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, neutralized with 2N HCl, extracted three times with EE, and the combined organic matter was concentrated under reduced pressure. The remaining material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 50 mg (12% yield) of the title compound.

¹ H NMR(400MHz, DMSO-d6)δ[ppm]1.29(t,J＝7.45Hz,3H)1.31-1.43(m,2H)1.65-1.75(m,2H)1.97-2.08(m,1H)2.90(d,J＝7 .58Hz,2H)3.31-3.38(m,2H)3.84-3.92(m,2H)3.95(d,J＝6.32Hz,2H)7.50(s,1H)7.55(s,1H)7.66(s,1H)7.98(s,1H).

Intermediate 15V: Methyl 3-(5-isopropyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoate

Intermediate 14R (716 mg, 1.90 mmol), 2-chloro-5-(propan-2-yl)-1,3-thiazole (370 mg, 2.28 mmol), and Pd ₍ dppf) _Cl₂ · _CH₂Cl₂ (233 mg, 0.29 _mmol ) were dissolved in 1M _K₂CO₃ aqueous solution (4.6 mL) and THF (28 mL). The reaction mixture was heated in a microwave at 120°C for 90 minutes. The reaction mixture was concentrated under reduced pressure, and the remaining material was diluted with water and extracted three times with DCM. The combined organics were concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 330 mg of the title compound (46% yield).

Intermediate 5V: 3-(5-isopropyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzoic acid

Intermediate 15V (330 mg, 0.88 mmol) was dissolved in MeOH (50 mL). 2M NaOH (2.2 mL) was added and the reaction was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, neutralized with 2N HCl, and the mixture was extracted three times with EE, and the combined organic matter was concentrated under reduced pressure. The remaining material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 140 mg (32% yield) of the title compound, which was used without further purification.

Intermediate 17B: Tetrahydro-2H-pyran-4-yl 4-methylbenzenesulfonate

A solution of tetrahydro-2H-pyran-4-ol (25.0 g, 245 mmol), TEA (51 mL, 367 mmol) and trimethylamine hydrochloride (2.34 g, 24.5 mmol) in DCM (750 mL) was stirred at room temperature for 10 minutes and cooled to 0 ° C. 4-Methylbenzenesulfonyl chloride (51.3 g, 269 mmol) was added and the mixture was stirred at room temperature for 17 hours. The mixture was treated with N, N-dimethylethane-1,2-diamine (31.6 mL, 294 mmol) and water. The aqueous layer was extracted three times with DCM. The combined organic portions were concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/EE gradient) to give 58.5 g (93% yield) of the title compound.

¹ H NMR(400MHz, DMSO-d6)δ[ppm]1.51-1.61(m,2H)1.74(dq,J＝13.04,3.65Hz,2H)2.42(s,3H)3.39(ddd,J＝11.75,8.97,3 .03Hz, 2H) 3.71 (dt, J = 11.81, 4.71Hz, 2H) 4.69 (tt, J = 8.65, 4.23Hz, 1H) 7.47 (d, J = 8.08Hz, 2H) 7.81 (d, J = 8.34Hz, 2H).

Intermediate 14W: methyl 3-(tetrahydro-2H-pyran-4-yloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Intermediate 24 (0.85 g, 2.7 mmol), bis(pinacolato)diborane (1.71 g, 6.74 mmol), potassium acetate (0.93 g, 9.44 mmol), and Pd(dppf) _Cl2 (0.20 g, 0.27 mmol) were stirred in dioxane (50 mL) at 80°C until complete conversion. The reaction mixture was cooled to room temperature and concentrated in vacuo. The remaining crude reaction mixture was extracted with DCM, and the organic phase was concentrated in vacuo. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to give 1.06 g of the title compound (quantitative yield).

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.27-1.33(m,12H)1.60(s,2H)1.89-1.98(m,2H)3.51(s,2H)3.78-3.87( m,5H)4.66-4.74(m,1H)7.42(dd,J＝2.76,0.75Hz,1H)7.58(dd,J＝2.51,1.51Hz,1H)7.83-7.86(m,1H).

Intermediate 15W: Methyl 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

Intermediate 14W (500 mg, 1.38 mmol), 2-chloro-5-cyclobutyl-1,3-thiazole (288 mg, 1.66 mmol), and Pd(dppf) _Cl₂ (151 mg, 0.21 mmol) were dissolved in 1M _K₂CO₃ aqueous solution ₍ 3.3 mL) and THF (25 mL). The reaction mixture was heated at 90°C until complete conversion. The reaction mixture was concentrated under reduced pressure, and the remaining material was diluted with water and extracted three times with DCM. The combined organics were concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 320 mg of the title compound (62% yield).

¹ H NMR(400MHz, DMSO-d6)δ[ppm]1.55-1.69(m,2H)1.91(br.s.,1H)1.95-2.04(m,3H)2.12-2.21(m,2H)2.43(dt,J＝8.27,3.19Hz,2H)3.53 (ddd,J＝11.68,9.03,3.03Hz,2H)3.81-3.91(m,6H)4.79(s,1H)7.53(dd,J＝2.40,1.39Hz,1H)7.64-7.72(m,2H)8.00(t,J＝1.52Hz,1H).

Intermediate 5W: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid

Intermediate 15W (320 mg, 0.86 mmol) was dissolved in MeOH. 2M NaOH (2.1 mL) was added and the reaction was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, adjusted to pH 2 with 2N HCl, extracted with EE and concentrated under reduced pressure to give 114 mg (37% yield) of the title compound, which was used without further purification.

Intermediate 15X: Methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

Intermediate 14W (500 mg, 1.38 mmol), 2-chloro-5-ethyl-1,3-thiazole (245 mg, 1.66 mmol) and Pd(dppf) _Cl2 (151 mg, 0.21 mmol) were dissolved in 1M _{K2CO3 aqueous} solution (3.3 mL) and THF (25 mL). The reaction mixture was heated at 90°C until complete conversion. The reaction mixture was concentrated under reduced pressure, and the remaining material was diluted with water and extracted three times with DCM. The combined organics were concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain 320 mg of the title compound (62% yield).

Intermediate 5X: 3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid

Intermediate 15X (450 mg, 1.29 mmol) was dissolved in MeOH. 2M NaOH (2.59 mL) was added and the reaction was stirred at room temperature. The reaction mixture was concentrated under reduced pressure, adjusted to pH 2 with 2N HCl, extracted with EE and concentrated under reduced pressure to give 251 mg (58% yield) of the title compound, which was used without further purification.

Intermediate 15Y: methyl 3-bromo-5-(2-methoxyethoxy)benzoate

A mixture _of intermediate 1 (300 g, 1.3 mol), 2-bromoethyl methyl ether (330 g, 2.37 mol), _K₂CO₃ (330 g, 2.39 mol), and NaI (2 g) was refluxed in acetonitrile (2500 ml) for 12 hours. The suspension was filtered, the solid was washed with acetonitrile (1000 mL), and the combined filtrates were evaporated under reduced pressure to give a dark oil. Petroleum ether (2500 mL) was added, and the resulting solution was filtered through a layer of alumina. The filtrate was evaporated under reduced pressure to give 250.3 g of the title compound (67% yield).

¹ H NMR(300MHz,DMSO-d6)δ[ppm]3.30(s,3H)3.61-3.69(m,2H)3.86(s,3H)4.14-4.24 (m, 2H) 7.43 (dd, J = 2.45, 1.32Hz, 1H) 7.48 (t, J = 2.17Hz, 1H) 7.63 (t, J = 1.51Hz, 1H).

Intermediate 5Y: 3-bromo-5-(2-methoxyethoxy)benzoic acid

Intermediate 15Y (5.0 g, 17.3 mmol) was dissolved in MeOH (52 mL). 2M NaOH (17.3 mL) was added and the reaction was stirred at room temperature. The reaction mixture was adjusted to pH 3 with 1N HCl, extracted with EE, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure to give 5.12 g (>100%) of the title compound, which was used without further purification.

¹ H NMR (300MHz, DMSO-d6) δ [ppm] 3.30 (s, 3H) 3.65 (dd, J = 5.27, 3.58Hz, 2H) 4.18 (dd, J＝5.27,3.58Hz,2H)7.39-7.45(m,2H)7.61(t,J＝1.51Hz,1H)13.26-13.53(m,1H).

Intermediate 19Z: tert-Butyl 4-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

Intermediate 3 (500 mg, 2.0 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (807 mg, 4.0 mmol) and triphenylphosphine (2104 mg, 8.0 mmol) were combined in THF and cooled to 0 ° C in an ice bath. DIAD (0.788 mL, 4.0 mmol) was added dropwise and the reaction mixture was stirred for 10 minutes and then warmed to room temperature. After stirring for 16 hours, the reaction mixture was concentrated in vacuo, dissolved in EtOAc (10 mL), and washed with salt solution (5 mL) and ammonium chloride solution (5 mL). The organic phase was separated, dried (over MgSO ₄ ) and concentrated in vacuo to give a brown oil. Purification was carried out by Biotage Isolera ^™ chromatography (on pre-filled 50 g SiO ₂ , eluted with 0-100% EtOAc in heptane) to give 1000 mg (92% yield) of the title compound as a colorless oil.

¹ H NMR (250MHz, chloroform-d): δ [ppm] = 8.08 (t, J = 1.4Hz, 1H), 7.69 (dd, J = 2.4, 1.6Hz, 1H), 7.58 (dd, J = 2.5, 1.4Hz, 1H), 7.51 (d, J = 1.2Hz, 1H), 4.62 (tt, J ＝6.9,3.5Hz,1H),3.93(s,3H),3.77-3.62(m,2H),3.47-3.31(m,2H),2. 52(d,J＝1.1Hz,3H),2.03-1.88(m,3H),1.87-1.55(m,5H),1.48(s,9H).

LCMS (Analytical Method A) Rt=1.65 min, MS (ESIpos): m/z=433 (M+H) ⁺ .

Intermediate 5Z: 3-{[1-(tert-Butoxycarbonyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of tert-butyl 4-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate (1000 mg, 1.85 mmol) in THF (2.5 mL) was added 1 M LiOH (2.7 mL), and the resulting solution was stirred at room temperature for 16 hours. The organic solvent was removed in vacuo, and the aqueous phase was acidified to pH ~4 with 1 M HCl. The resulting precipitate was collected by filtration and evaporated to give 682 mg (88% yield) of the title compound as a white solid.

LCMS (Analytical Method A) Rt=1.48 min, MS (ESIpos): m/z=419 (M+H) ⁺ .

Intermediate 19AA: methyl 3-[(3R)-1-methylpyrrolidin-3-yl]oxy-5-(5-methyl-1,3-thiazol-2-yl)benzoate

At 0 ° C, DIAD (236 μ L, 1.20 mmol) was added dropwise to a solution of intermediate 3 (150 mg, 0.60 mmol), (3S)-1-methylpyrrolidin-3-ol (121 mg, 1.20 mmol) and triphenylphosphine (631 mg, 2.41 mmol) in THF (3 mL). The solution was stirred for another 5 minutes at 0 ° C, then allowed to warm to room temperature and stirred for another 16 hours. The reaction mixture was concentrated under vacuum, dissolved in DCM, washed with brine, saturated NaHCO ₃ , dried (over MgSO ₄ ), and concentrated under vacuum to give a brown oil. The crude material was purified by Biotage Isolera ^TM chromatography (on a pre-filled KP-NH column, eluted with heptane-acetone 5: 1 to 1: 4) to obtain 143 mg (54% yield) of the title compound as a clear oil.

1H NMR (250 MHz, chloroform-d): δ [ppm] = 8.10 (t, J = 1.5 Hz, 1H), 7.62 (dd, J = 2.5, 1.6 Hz, 1H), 7.56-7.48 (m, 2H), 4.99-4.89 (m, 1H), 3.93 (s, 3H), 2.95-2.76 (m, 3H), 2.52 (d, J = 1.1 Hz, 3H), 2.40 (s, 5H), 2.12-1.95 (m, 1H), 1.69-1.57 (m, 1H).

LCMS (Analytical Method A) Rt=0.93 min, MS (ESIpos) m/z=534 (M+H) ⁺ .

Intermediate 19AB: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-pyrrolidin-3-yloxy]benzoate

To the solution of intermediate 3 (150mg, 0.60mmol), (3R)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (225mg, 1.20mmol) and triphenylphosphine (63mg, 2.40mmol) in THF (3mL) stirred at 0℃, DIAD (236 μL, 1.20mmol) was added dropwise. The solution was stirred at 0℃ for 5 minutes, then allowed to warm to room temperature and stirred for another 16 hours. The reaction mixture was concentrated under vacuum, dissolved in DCM, washed with salt solution, saturated NaHCO ₃ , dried (through MgSO ₄ ) and concentrated under vacuum to obtain a brown oil. Purified by Biotage Isolera ^TM chromatography (pre-filled 10g columns, eluted with heptane-EtOAc 15:3 to 0:1), a colorless oil (620mg) was obtained. The oil was dissolved in DCM (1mL) and TFA (1mL), and the solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, dissolved in DCM (1 mL) and stirred in saturated sodium bicarbonate for 15 minutes.The organic phases were collected, dried ( _MgSO4 ) and concentrated in vacuo to give 400 mg (34% yield) of the title compound as an amber oil.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] = 8.10 (t, J = 1.3 Hz, 1H), 7.73-7.65 (m, 1H), 7.65-7.57 (m, 2H), 3.94 (s, 3H), 2.54 (d, J = 1.0 Hz, 3H), 1.26 (s, 12H), 1.25 (s, 9H).

LCMS (Analytical Method A) Rt=0.96, MS (ESIpos) m/z=319 (M+H) ⁺ .

Intermediate 20: Methyl 3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-pyrrolidin-3-yloxy]benzoate (420 mg, 0.40 mmol), formaldehyde (37% in water, 59 μL, 0.79 mmol), and formic acid (59 μL, 1.58 mmol) were combined in THF and heated under reflux for 4 hours. The reaction mixture was concentrated under vacuum, dissolved in sodium bicarbonate, and extracted with DCM. The organic phase was dried (over MgSO ₄ ) and concentrated under vacuum to give 65 mg (49% yield) of the title compound.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.12 (t, J = 1.4Hz, 1H), 7.64 (dd, J = 2.4, 1.6Hz, 1H), 7.55 (dd, J = 2.5, 1.4Hz, 6H), 7.53 (d, J = 1. 2Hz,1H),5.06-4.93(m,6H),3.95(s,3H),2.92-2.82(m,3H),2.54(d,J=1.1Hz,3H),2.51-2.36(m,5H),2.10-2.00(m,2H).

Intermediate 21: tert-Butyl 3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]azetidine-1-carboxylate

Under nitrogen atmosphere, intermediate 3 (300mg, 1.20mmol), 3-{[(4-methylphenyl)sulfonyl]oxy}azetidine-1-carboxylic acid tert-butyl ester (511mg, 1.80mmol) and cesium carbonate (780mg, 2.39mmol) are combined in anhydrous dimethylformamide (3mL), and are heated to 80 DEG C and kept for 16 hours. The room temperature reaction mixture is poured into brine (3mL) and extracted with ethyl acetate (10mL). The organic phase is washed with brine (3mL), dried (over MgSO ₄ ) and concentrated under vacuum to give a brown oil. The crude material is passed through Biotage Isolera ^TM chromatography (silica gel, eluted with heptane-tert-butyl methyl ether 3: 1 to 0: 1) to purify, and the title compound of 440mg (81% yield) crystallization under standing is obtained, as colorless oil.

¹ H NMR (250MHz, CDCl ₃ ): δ[ppm]=1.45(s,9H),2.52(d,3H),3.94(s,3H),4.02(dd,2H),4.36(dd,2H),5.00(tt,1H),7.41(dd,1H),7.48-7.58(m,2H),8.12(t,1H).

Intermediate 22: Methyl 3-(azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Tert-butyl 3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]azetidine-1-carboxylate (440 mg, 0.98 mmol) was stirred in 4M HCl in dioxane (2.5 mL) for 2 hours. The reaction was concentrated to dryness, and the resulting solid was dissolved in saturated NaHCO ₃ and extracted with DCM/methanol (9:1, 2×25 mL). The organic phase was dried (over MgSO ₄ ) and concentrated to dryness to give 259 mg (87% yield) of the title compound.

LCMS (Analytical Method A) Rt=0.92 min, MS (ESIpos) m/z=305 (M+H) ⁺ .

Intermediate 23: Methyl 3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

To a solution of methyl 3-(azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (255 mg, 0.84 mmol) in DCE (0.5 mL) was added formaldehyde 37% aqueous solution, 1 mL) and acetic acid (0.048 mL), and the resulting mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (213 mg, 1.00 mmol) was added and the mixture was stirred at room temperature for another 16 hours. The reaction mixture was concentrated under vacuum, and the residue was basified to pH 9 with saturated sodium bicarbonate solution and extracted into ethyl acetate. The organic phase was separated, dried (over MgSO ₄ ) and concentrated under vacuum to give a brown oil. The crude material was purified by Biotage Isolera ^™ chromatography to give 80 mg (29% yield) of the title compound as a colorless oil.

¹ H NMR (500MHz, MeOD): δ [ppm] = 2.53 (d, 3H), 3.27-3.31 (m, 2H), 3.83-3.90 (m, 2 H),3.93(s,3H),4.92(p,1H),7.44(dd,1H),7.50-7.57(m,2H),8.04(t,1H).

Intermediate 24: Methyl 3-bromo-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

Intermediate 1 (1.5 g, 6.49 mmol), intermediate 17B (2.5 g, 9.74 mmol) and cesium carbonate (3.17 g, 9.74 mmol) were stirred at room temperature in DMF (25 mL) until complete conversion. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The remaining material was purified by column chromatography (silica gel, hexane/EE gradient) to obtain title compound 0.85 g (42% yield).

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.59(s,2H)1.92-1.99(m,2H)3.49(s,2H)3.80-3.86(m,5H) 4.65-4.81(m,1H)7.45(dd,J＝2.41,1.39Hz,1H)7.52-7.54(m,1H)7.62(t,J＝1.52Hz,1H).

Intermediate 4AC: methyl 3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A solution of intermediate 3 (250 mg, 1.0 mmol), 2-bromo-5-methyl-1,3,4-thiadiazole (270 mg, 1.5 mmol) and cesium carbonate (654 mg, 2.0 mmol) in DMF (5 ml) was heated in a microwave at 120 ° C for 1 hour. The reaction mixture was distributed between brine (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with another EtOAc (2 × 10 mL). The combined organics were washed with brine (20 mL), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by BiotageIsolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 4: 1 to 1: 4) to obtain 226.6 mg (65% yield) of the title compound as a yellow gum.

1H NMR (500MHz, chloroform-d): δ [ppm] 8.39 (t, J = 1.4Hz, 1H), 8.09 (dd, J = 2.3, 1.7Hz, 1H), 7.98 (dd, J =2.4, 1.4Hz, 1H), 7.54 (d, J = 1.1Hz, 1H), 3.95 (s, 3H), 2.69 (s, 3H), 2.54 (d, J = 1.0Hz, 3H).

LCMS (Analytical Method A) Rt=1.23 min, MS (ESIpos): m/z=347.9 (M+H) ⁺ .

Intermediate 5AC: 3-[(5-methyl-1,3,4-thiadiazol-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4AC (226 mg, 0.65 mmol) was stirred in MeOH (2.5 mL), THF (2.5 mL), and 1 M LiOH (2.5 mL) for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (5 mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH ~3 with 1 M HCl, and the resulting precipitate was collected by vacuum filtration to afford 198.6 mg (92% yield) of the title compound as an off-white powder.

¹ H NMR (250MHz, DMSO-d6): δ [ppm] 8.30 (t, J = 1.5 Hz, 1H), 8.13-8.10 (m, 1H), 7.94-7.89 (m, 1H), 7.70 (d, J = 1.2 Hz, 1H), 2.65 (s, 3H).

LCMS (Analytical Method A) Rt=1.08 min, MS (ESIpos): m/z=333.9 (M+H) ⁺ .

Intermediate 4AD: tert-Butyl 3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]azetidine-1-carboxylate

By intermediate 3 (300mg, 1.20mmol), 3- { [(4- methylphenyl) sulfonyl] oxy} azetidine -1- carboxylic acid tert-butyl esters (443mg, 1.56mmol) and cesium carbonate (784mg, 2.04mmol) in MeCN (5mL) merge, and be heated to 100 DEG C, continue 2 hours.After cooling to room temperature, reactant mixture is diluted and filtered with EtOAc (5mL), then concentrated under reduced pressure.By Biotage Isolera ^TM chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 3:2) crude material is purified, 303.7mg (57% yield) title compound is obtained, it is pale solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.13 (t, J = 1.3 Hz, 1H), 7.57-7.55 (m, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.42 (dd, J = 2.4, 1.3 Hz, 1H), 5. 05-4.97(m,1H),4.37(dd,J＝10.0,6.6Hz,2H),4.03(dd,J＝9.8,3.9Hz,2H),3.94(s,3H),2.53(d,J＝0.9Hz,3H),1.45(s,9H).

LCMS (Analytical Method A) Rt=1.37 min, MS (ESIpos): m/z=405.05 (M+H) ⁺ .

Intermediate 5AD: 3-{[1-(tert-Butoxycarbonyl)azetidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4AD (303 mg, 0.68 mmol) was dissolved in MeOH (5 mL) and THF (5 mL). 1 M LiOH (2 mL) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove MeOH/THF, and the residue was dissolved in water (5 mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH 4 with 1 M HCl and the solution was extracted with DCM (3 × 5 mL) to give 205.6 mg (77% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.28 (s, 1H), 7.60-7.58 (m, 1H), 7.58-7.57 (m, 1H), 7.46 (dd, J = 2.4, 1.3Hz, 1H), 5.02 (dd d,J＝10.4,6.3,4.1Hz,1H),4.39(dd,J＝9.9,6.5Hz,2H),4.05(dd,J＝9.8,4.0Hz,2H),2.58-2.49(m,3H),1.46(s,9H).

LCMS (Analytical Method A) Rt=1.19 min, MS (ESIpos): m/z=391.00 (M+H) ⁺ .

Intermediate 4AE: tert-Butyl (3S)-3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]pyrrolidine-1-carboxylate

To intermediate 3 (250mg, 1.0mmol), (3R) -3- hydroxypyrrolidine -1- carboxylic acid tert-butyl ester (375mg, 2mmol) and triphenylphosphine (1.05g, 4mmol) in the solution in THF (5mL) being cooled to 0 DEG C, DIAD (394 μ L, 2mmol) is added dropwise.Solution is stirred at 0 DEG C for 5 minutes, is then warmed to room temperature and stirred for 72 hours.Then the reaction mixture is concentrated under reduced pressure, by Biotage Isolera ^TM chromatography (silica gel, eluted with heptane-EtOAc 20: 1 to 2: 3) purification of crude material, obtain 745mg (88% yield, 50% purity) title compound, is colorless jelly.

¹ H NMR (500 MHz, CHLOROFORM-d) δ [ppm] 8.11 (d, J = 7.2 Hz, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H), 5.04 (s, 1H), 3.94 (s, 3H), 3.68 (s, 3H), 3.30 (s, 1H), 2.53 (s, 3H), 2.26-2.09 (m, 2H), 1.27 (s, 9H).

LCMS (Analytical Method A) Rt=1.37 min, MS (ESIpos): m/z=419.1 (M+H) ⁺ .

Intermediate 5AE: 3-[(3S)-1-tert-Butoxycarbonylpyrrolidin-3-yl]oxy-5-(5-methylthiazol-2-yl)benzoic acid

To a solution of intermediate 4AE (745 mg, 50% purity, 0.89 mmol) dissolved in THF (2 mL) and MeOH (5 mL) was added 1 M LiOH (2.5 mL), and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove the MeOH/THF, and the residue was dissolved in water (5 mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH 4 with 1 M HCl and then extracted with DCM (3 x 10 mL). The combined organics were dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give 296.3 mg (82% yield) of the title compound as a white powder.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]7.99(t,J＝1.4Hz,1H),7.65(d,J＝1.2Hz,1H),7.62-7.59(m,1H),7 .48(dd,J＝2.5,1.3Hz,1H),5.19(s,1H),3.51(dd,J＝39.9,10.7Hz,4H),2.08(s,2H),1.40(s,9H).

LCMS (Analytical Method A) Rt=1.21 min, MS (ESIpos): m/z=405.10 (M+H) ⁺ .

Intermediate 4AF: tert-Butyl 3-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

Intermediate 3 (1.3g, 3.65mmol, 70% purity), 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.47g, 7.3mmol) and triphenylphosphine (3.8g, 14.6mmol) are combined in THF (10mL) and are cooled to 0 DEG C in an ice bath.DIAD (1.43mL, 7.3mmol) is added dropwise, and the reaction mixture is stirred for 10 minutes, then it is warmed to room temperature and stirred for another 16 hours.The reaction mixture is concentrated under reduced pressure, dissolved in DCM (20mL), then washed with salt solution (10mL) and ammonium chloride (10mL).The organic phase is separated, through _MgSO4 drying, filtered and concentrated under reduced pressure.By Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 0:1) crude material is purified, 209mg (15% yield) title compound is obtained, as colorless oil.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.10 (t, J = 1.4Hz, 1H), 7.72-7.63 (m, 1H), 7.62-7.56 (m, 1H), 7.51 (d, J = 1.1Hz, 1H), 4.52-4 .32(m,1H),3.93(s,3H),3.81-3.68(m,1H),3.59-3.25(m,3H),2.52(d,J＝1.1Hz,3H),2.14-1.72(m,4H),1.37(s,9H).

LCMS (Analytical Method A) Rt = 1.60 min, m/z = 433 (M+H) ⁺ .

Intermediate 5AF: 3-{[1-(tert-Butoxycarbonyl)piperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 4AF (367 mg, 0.76 mmol, 90% purity) in THF (2 mL) was added 1 M LiOH (1.1 mL) and the reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was dissolved in water (~1 mL) and basified to pH 4 with 1 M HCl to precipitate a white solid, which was extracted with EtOAc (2 x 5 mL). The combined organics were dried over _MgSO4 , filtered and concentrated under reduced pressure to give a colorless gum which was freeze-dried to give 264 mg (77% yield) of the title compound as a white powder.

LCMS (Analytical Method A) Rt=1.39, MS (ESIpos) m/z=419 (M+H) ⁺ .

Intermediate 4AG: methyl 3-[(1-acetylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

To a solution of intermediate 3 (200 mg, 0.80 mmol), 1-(4-hydroxypiperidin-1-yl)ethanone (126 mg, 0.88 mmol) and triphenylphosphine (630 mg, 2.40 mmol) in THF (2 mL) cooled to 0 ° C was added DIAD (0.3 mL, 1.53 mmol). The resulting solution was allowed to warm to room temperature and stirred for 16 hours. LCMS analysis showed complete conversion to the desired product, so the mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and washed with NH ₄ Cl (5 mL). The organic phase was separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^TM chromatography (silica gel, eluted with heptane-EtOAc 1:4 to 0:1, then with EtOAc-MeOH 1:0 to 20:3) to obtain 182 mg (52% yield) of the title compound as a yellow gum.

¹ H NMR (250MHz, chloroform-d): δ[ppm]8.08(t,1H),7.70(dd,1H),7.58(dd,1H),7.51(d,1H),4.69(tt,1H), 3.93(s,3H),3.77-3.61(m,3H),3.52-3.34(m,1H),2.52(d,3H),2.12(s,3H),2.01-1.79(m,4H).

LCMS (Analytical Method A) Rt=1.28 min, MS (ESIpos): m/z=375.1 (M+H) ⁺ .

Intermediate 5AG: 3-[(1-acetylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 4AG (182 mg, 0.44 mmol, 90% purity) in THF (1 mL) was added 1 M LiOH solution (0.65 mL) and the resulting mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was dissolved in water (4 mL), acidified to pH 4 with 1 M HCl solution, and then extracted with 1:1 IPA/chloroform (2 × 20 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 120 mg (76% yield) of the title compound as a white solid.

1H NMR (500MHz, DMSO): δ[ppm]7.96(t,1H),7.65-7.63(m,2H),7.53(dd,1H),4.85-4.75(m,1H),3.87-3 .77(m,1H),3.72-3.63(m,1H),2.02(s,3H),2.01-1.86(m,2H),1.72-1.61(m,1H),1.61-1.49(m,1H).

LCMS (Analytical Method A) Rt=1.13 min, MS (ESIpos) m/z=361 (M+H) ⁺ .

Intermediate 4AH: tert-Butyl 6-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-2-azaspiro[3.3]heptane-2-carboxylate

Under nitrogen atmosphere, a solution of intermediate 3 (250 mg, 0.702 mmol, 70% purity), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (225 mg, 1.06 mmol) and triphenylphosphine (735 mg, 2.80 mmol) in THF (3 mL) was cooled to 0° C. in an ice bath, and then DIAD (0.2 mL, 1.07 mmol) was added dropwise. The resulting solution was allowed to warm to room temperature and stirred for 16 hours. LCMS (Analytical Method A) showed approximately 50% conversion to product. Another portion of DIAD (0.1 mL, 0.54 mmol) was added, and the mixture was stirred for an additional 24 hours. LCMS (Analytical Method A) still showed incomplete conversion, so another portion of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (40 mg, 0.19 mmol) and DIAD (0.1 mL, 0.54 mmol) were added and stirred for an additional 16 hours. The mixture was then concentrated under reduced pressure, and the residue was triturated with heptane to precipitate triphenylphosphine oxide, which was removed by filtration. The residue was concentrated under reduced pressure and purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 4:1 to 2:3) to give 250 mg (76% yield) of the title compound as a colorless jelly.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.08 (t, J = 1.4Hz, 1H), 7.57-7.49 (m, 2H), 7.44 (dd, J = 2.4, 1.4Hz, 1H), 4.69 (p, J = 6.6Hz ,1H),4.00(s,2H),3.93(d,J＝3.7Hz,5H),2.81-2.73(m,2H),2.52(d,J＝1.0Hz,3H),2.40-2.32(m,2H),1.44(s,9H).

LCMS (Analytical Method A) Rt=1.64 min, MS (ESIpos) 445 (M+H) ⁺ .

Intermediate 5AH: 3-{[2-(tert-Butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 4AH (250 mg, 0.534 mmol, 95% purity) in THF (1 mL) was added 1 M LiOH solution (0.8 mL), and the resulting solution was stirred for 16 hours, then concentrated under reduced pressure. The residue was dissolved in water (1 mL) and acidified to pH 5 with 1 M HCl to precipitate a white solid, which was collected by filtration to give 160 mg (66% yield) of the title compound as a white powder.

¹ H NMR (250MHz, DMSO): δ[ppm]7.96(t,1H),7.64(d,1H),7.54-7.44(m,1H),7.37(dd,1H),4 .78(q,1H),3.93(s,2H),3.83(s,2H),2.81-2.65(m,2H),2.35-2.19(m,2H),1.37(s,9H).

LCMS (MS17, 2min) Rt = 1.42min, MS (ESIpos) m/z = 431 (M+H) ⁺ .

Intermediate 47: Methyl 3-({trans-3-[(tert-butoxycarbonyl)amino]cyclobutyl}oxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

By intermediate 3 (500mg, 2.00mmol), cis- tert-butyl 3-hydroxycyclobutylcarbamate (488.2mg, 2.6mmol) and triphenylphosphine (2104mg, 8.0mmol) in THF (10ml) merge, and be cooled to 0 ℃.DIAD (0.79mL, 4.0mmol) is added dropwise, reaction mixture is stirred 10 minutes, then it is warmed to room temperature, and stirs for 96 hours.Reaction mixture is concentrated under reduced pressure, and by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 9:1 to 3:7) purifying, obtain 1.6mg (74% yield) title compound, be colorless oil.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.09(t,J＝1.4Hz,1H),7.54(dd,J＝2.4,1.6Hz,1H),7.51(d,J＝1.0Hz,1H),7.44(dd,J＝2.5,1.4Hz ,1H),4.94-4.87(m,1H),4.31(s,1H),3.93(s,3H),2.63-2.53(m,2H),2.52(d,J＝1.2Hz,3H),2.48-2.39(m,2H),1.45(s,9H).

LCMS (Analytical Method A) Rt=1.53 min, MS (ESIpos): m/z=419.05 (M+H) ⁺ .

Intermediate 48: Methyl 3-[(trans-3-aminocyclobutyl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 47 (1.6 g, 39% purity, 1.5 mmol) was stirred in hydrochloric acid (4 M in 1,4-dioxane, 1.5 ml, 6.0 mmol) and DCM (10 mL) for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water (15 mL) and washed with EtOAc (2 × 15 mL). The aqueous layer was basified to pH 8 with saturated NaHCO ₃ solution, and the mixture was extracted with DCM (3 × 15 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was loaded in methanol and moved to a pre-washed SCX-2 column, which was washed with additional methanol and then eluted with 2M NH ₃ in MeOH. The substance was further purified by Biotage Isolera ^TM chromatography (silica gel, eluted with heptane-EtOAc 1: 3 to 0: 1) to give 477 mg (80% yield) of the title compound.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.09 (t, J = 1.5 Hz, 1H), 7.55 (dd, J = 2.4, 1.6 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.46 (dd, J = 2.5, 1.4 Hz, 1H), 4.9 8-4.94(m,1H),3.93(s,3H),3.82(tt,J＝7.7,5.2Hz,1H),2.52(d,J＝1.1Hz,3H),2.48(ddt,J＝10.8,7.2,3.4Hz,2H),2.30-2.19(m,2H).

LCMS (Analytical Method A) Rt=0.95 min, MS (ESIpos): m/z=319.0 (M+H) ⁺ .

Intermediate 49: Methyl 3-{[trans-3-(dimethylamino)cyclobutyl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Intermediate 48 (477 mg, 80% purity, 1.19 mmol) was dissolved in methanol (10 mL) and acetic acid (0.5 mL). Formaldehyde (133 μL, 4.79 mmol) was added, followed by STAB (762 mg, 3.60 mmol), and the reaction was stirred for 2 hours. LCMS (Analytical Method A) indicated incomplete conversion, so the reaction was re-treated with formaldehyde (133 μL, 4.79 mmol) followed by STAB (762 mg, 3.60 mmol) and stirred for an additional 4 hours. LCMS (Analytical Method A) still indicated incomplete conversion, so the reaction was re-treated again with formaldehyde (266 μL, 9.58 mmol) followed by STAB (1.53 g, 7.2 mmol) and stirred over the weekend. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in saturated _NaHCO₃ (30 mL), and the solution was extracted with DCM (3×30 mL). The combined organics were dried over _MgSO4 , filtered and concentrated under reduced pressure to give 477.7 mg (92% yield) of the title compound as a colorless gum.

1H NMR (250MHz, chloroform-d): δ[ppm]8.09(t,J＝1.5Hz,1H),7.55(dd,J＝2.5,1.6Hz,1H),7.51(d,J＝1.2Hz,1H),7.46(dd,J＝2.5,1.4H z,1H),4.87(tt,J＝6.7,3.5Hz,1H),3.93(s,3H),3.01-2.89(m,1H),2.52(d,J＝1.1Hz,3H),2.48-2.30(m,4H),2.18(s,7H).

LCMS (Analytical Method A) Rt=1.00 min, MS (ESIpos): m/z=347.1 (M+H) ⁺ .

Intermediate 5AI: 3-{[trans-3-(dimethylamino)cyclobutyl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 49 (477 mg, 80% purity, 1.1 mmol) was dissolved in MeOH (5 mL) and THF (5 mL). 1M LiOH (2 mL) was added, and the reactants were stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove MeOH/THF, and the residue was dissolved in water (5 mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH ₆ with 1M HCl, and the solution was extracted with 1:1 IPA/chloroform (3×5 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was freeze-dried from acetonitrile/water to give 230 mg (57% yield) of the title compound as a white solid.

¹ H NMR (500 MHz, DMSO): δ [ppm] 8.00 (s, 1H), 7.62 (d, J = 1.1 Hz, 1H), 7.40 (s, 2H), 4.85 (s, 1H), 2.88 (p, J = 7.5 Hz, 1H), 2.43-2.33 (m, 2H), 2.24-2.16 (m, 2H), 2.10 (s, 6H). The thiazole methyl group was obscured by the solvent.

LCMS (Analytical Method A) Rt=0.92 min, MS (ESIpos): m/z=333.0 (M+H) ⁺ .

Intermediate 6AJ: tert-Butyl 3-fluoro-4-{[(4-methylphenyl)sulfonyl]oxy}piperidine-1-carboxylate, a mixture of two trans isomers

tert-Butyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (750 mg, 3.42 mmol), trimethylamine (0.72 mL, 5.13 mmol) and trimethylamine hydrochloride (33 mg, 0.34 mmol) were stirred in DCM (15 mL). 4-Methylbenzenesulfonyl chloride (815 mg, 4.28 mmol) was added. The reactants were stirred at room temperature for 4 hours. TLC (50% EtOAc in heptane) showed complete reaction, so the reaction mixture was treated with N, N-dimethylethane-1,2-diamine (225 μL, 2.05 mmol) to consume unreacted TsCl. The reaction mixture was washed with 1M HCl (2 × 5 mL), then dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc 10:1 to 1:1) to afford 606.1 mg (47% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.86-7.78 (m, 2H), 7.35 (d, J = 8.0Hz, 2H), 4.71 (d, J = 10.0Hz, 1H), 4.58 (d, J = 48 .3Hz,1H),3.87(d,J＝52.6Hz,2H),3.34(s,2H),2.45(s,3H),2.08(s,1H),1.76-1.67(m,1H),1.44(s,9H).

Intermediate 4AJ: tert-Butyl 3-fluoro-4-[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate, a mixture of two trans isomers

Intermediate 3 (426 mg, 73% purity, 1.25 mmol), intermediate 6AJ (606 mg, 1.62 mmol) and cesium carbonate (610 mg, 1.87 mmol) are combined in acetonitrile (5 mL) and stirred 3x 30 minutes in a microwave at 120 ° C. The reaction mixture is diluted with EtOAc and filtered, then concentrated under reduced pressure. Purification of crude material by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 2:3) gives 387.6 mg (57% yield) of the title compound as a colorless jelly.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.12 (t, J = 1.4 Hz, 1H), 7.74 (dd, J = 2.4, 1.6 Hz, 1H) ,7.62(dd,J＝2.5,1.3Hz,1H),7.52(d,J＝1.2Hz,1H),4.72-4.52(m,2H),3.95(s ,3H),3.92-3.77(m,1H),3.66(s,1H),3.58(s,1H),3.46(s,1H),2.53(d,J＝1.1 Hz,3H),2.20-2.10(m,1H),1.84-1.75(m,1H),1.70-1.59(m,1H),1.48(s,9H).

LCMS (Analytical Method A) Rt=1.41 min, MS (ESIpos): m/z=451.1 (M+H) ⁺ .

Intermediate 5AJ: 3-{[1-(tert-Butoxycarbonyl)-3-fluoropiperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of stereoisomers

Intermediate 4AJ (387 mg, 83% purity, 0.71 mmol) was dissolved in MeOH (5 mL) and THF (5 mL). 1 M LiOH (2 mL) was added and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove MeOH/THF, and the residue was dissolved in water (5 mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH 4 with 1 M HCl and extracted with DCM (3 × 5 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 2:3) to give 105.2 mg (34% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.27-8.21(m,1H),7.80-7.74(m,1H),7.70-7.64(m,1H),7.56(d,J＝1.2Hz,1H),4.62(d,J＝22.8H z,2H),3.87(d,J＝58.5Hz,1H),3.61(s,2H),3.45(s,1H),2.54(d,J＝1.0Hz,3H),2.20-2.11(m,1H),1.80(s,2H),1.48(s,9H).

LCMS (Analytical Method A) Rt=1.16 min, MS (ESIpos): m/z=437.15 (M+H) ⁺ .

Intermediate 5AK: 3-[(6-methylpyridazin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

A solution of intermediate 3 (130 mg, 0.52 mmol), 3-bromo-6-methyl-pyridazine (135 mg, 0.78 mmol) and cesium carbonate (340 mg, 1.04 mmol) in DMF (2.5 mL) was heated to 120 ° C in a microwave for 45 minutes, then continued for 20 minutes at the same temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (5 mL) and treated with 1 M LiOH (2.5 mL). After 1.5 hours, the reaction was concentrated to remove organic matter, then diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The aqueous layer was acidified to ~ pH 4 with 2 M HCl and extracted with DCM (3 × 10 mL). The combined organic matter was dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain 143 mg (73% yield) of the title compound as a brown jelly.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.48(s,1H),8.06(s,1H),8.00-7.96(m,1H),7.59(s,1H) ), 7.42 (d, J = 9.0Hz, 1H), 7.19 (d, J = 9.0Hz, 1H), 2.70 (d, J = 7.7Hz, 3H), 2.53 (s, 3H).

LCMS (Analytical Method A) Rt=1.01 min, MS (ESIpos): m/z=328.05 (M+H) ⁺ .

Intermediate 4AY: methyl 3-({1-[(tert-butoxycarbonyl)amino]cyclopropyl}methoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

By intermediate 3 (400mg, 1.6mmol), [1- (hydroxymethyl) cyclopropyl] tert-butyl carbamate (390.5mg, 2.01mmol) and triphenylphosphine (1683mg, 6.4mmol) in THF (10mL) merge, and be cooled to 0 DEG C in ice bath.DIAD (0.63mL, 3.2mmol) is dripped, reaction mixture is stirred 10 minutes, then it is warmed to room temperature, stirred for 96 hours.Reaction mixture is concentrated under reduced pressure, and by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 1:1) purifying.By Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 20:3), carry out second purification, obtain 208.9mg (23% yield) title compound, be colorless oil.

LCMS (Analytical Method A) Rt=1.47 min, MS (ESIpos): m/z=419 (M+H) ⁺ .

Intermediate 5AY: 3-({1-[(tert-Butoxycarbonyl)amino]cyclopropyl}methoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4AY (208.9 mg, 0.369 mmol) was stirred in methanol (5 mL) and 1 M LiOH (2.5 mL) for 1 hour. The organics were removed under reduced pressure, and the residue was diluted with water (5 mL) and extracted with EtOAc (5 mL). The aqueous phase was acidified to pH 2 with 2 M HCl and then extracted with DCM (2 x 5 mL). The combined organics were dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give 48.1 mg (32% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.20(s,1H),7.70-7.67(m,1H),7.64(s,1H),7.57-7.53(m,1 H), 5.19 (s, 1H), 4.09 (s, 2H), 2.53 (d, J = 0.9Hz, 3H), 1.43 (s, 9H), 0.94 (d, J = 19.3Hz, 4H).

LCMS (Analytical Method A) Rt=1.31 min, MS (ESIpos): m/z=405 (M+H) ⁺ .

Intermediate 30: 3-Hydroxy-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 3 (500 mg, 2.0 mmol) dissolved in THF (5 mL) and MeOH (5 mL) was added 2 M LiOH (2.5 ml, 5 mmol) and stirred at 50 ° C for 2 hours. The reaction mixture was cooled, concentrated to remove MeOH/THF, and the residue was dissolved in water (5 mL) and washed with EtOAc (5 mL). The aqueous layer was acidified to pH 4 with 1 M HCl, and the precipitate was collected by vacuum filtration and dried in a vacuum oven to give 281.1 mg (59% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 14.89 (s, 1H), 12.60 (t, J = 1.5Hz, 1H), 12.38 (d, J = 1.2Hz, 1H), 12.27-12.22 (m, 1H), 12.14 (dd, J = 2.4, 1.4Hz, 1H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=235.95 (M+H) ⁺ .

Intermediate 32: 3-Hydroxy-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 30 (486 mg, 1.86 mmol), intermediate VI (465.5 mg, 2.05 mmol) and DIPEA (1.30 mL, 7.44 mmol) were combined in DMF (10 mL) and HATU (848.3 mg, 2.23 mmol) was added. The reaction mixture was stirred at room temperature overnight. The crude reaction was quenched by the addition of water (-15 mL). The resulting emulsion was evaporated to a free-flowing oil. Water (-15 mL) was added and the resulting precipitate was filtered off and washed with another portion of water and then dried in air to give 660 mg (82% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] = 10.05 (s, 1H), 9.13-9.09 (m, 3H), 7.79 (t, J = 1.4, 1H), 7.62 (d, J ＝1.2,1H),7.46-7.39(m,1H),7.37-7.29(m,1H),5.28(m,1H),2.49(s,3H),1.59(d,J＝7.1,3H).

LCMS (Analytical Method F) Rt=2.87 min, MS (ESIpos): m/z=409.1 (M+H) ⁺ .

Intermediate 63: 3-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, a mixture of two trans isomers

To a solution of 3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (145 mg, 0.47 mmol), Intermediate VI (129 mg, 0.57 mmol), and DIPEA (0.25 mL, 1.42 mmol) in DCM (2 mL) was added HATU (269 mg, 0.71 mmol). The mixture was stirred at room temperature for 2 hours, then diluted with DCM and washed with water and saturated aqueous ammonium chloride. The organic phase was separated, dried ( _MgSO₄ ), filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 0-7% MeOH in DCM on a pre-packed KP- _SiO₂ column) to afford 222 mg (88% yield) of the title compound.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.79 (s, 1H), 7.55-7.43 (m, 2H), 7.35 (s, 1H), 6.92 (d, J = 6.6Hz, 1H), 5.36 (m ,1H),4.45(dt,J＝6.4,3.4Hz,1H),4.04(s,1H),2.79(s,6H),2.53(s,3H),1.71(d,J＝7.1Hz,4H),1.32-1.23(m,6H).

LCMS (Analytical Method D) Rt=4.22 min, MS (ESIpos) m/z=481 (M+H) ⁺ .

Intermediate 76: 3-(5-chloro-1,3-thiazol-2-yl)-5-{[trans-3-hydroxybutan-2-yl]oxy}benzoic acid as a mixture of trans isomers

To a solution of 3-hydroxy-5-(5-chloro-1,3-thiazol-2-yl)benzoic acid methyl ester (500 mg, 1.67 mmol) and trans-2,3-epoxybutane (0.63 mL, 6.67 mmol) in DMSO (5 mL) was added cesium carbonate (2.17 g, 6.67 mmol). The mixture was heated to 100 ° C for 16 hours, then diluted with water (10 mL) and washed with EtOAc (10 mL). The aqueous layer was acidified with concentrated HCl and extracted into DCM (2×15 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was first passed through Biotage Isolera ^TM chromatography (silica gel, eluted with DCM/MeOH 1: 0 to 4: 1) and then purified by preparative HPLC (method B) to obtain 306 mg (56% yield) of the title compound as an off-white solid.

¹ H NMR (250MHz, DMSO-d6): δ [ppm] 8.00 (s, 1H), 7.94 (t, J = 1.4Hz, 1H), 7.64-7.60 (m, 1H), 7.55 (dd, J = 2.4, 1. 4Hz, 1H), 4.82 (s, 1H), 4.47-4.32 (m, 1H), 3.85-3.69 (m, 1H), 1.24 (d, J = 6.2Hz, 3H), 1.14 (d, J = 6.4Hz, 3H).

LCMS (Analytical Method D) Rt=3.84 min, MS (ESIpos): m/z=327.97 (M+H) ⁺ .

The mixture of trans isomers was separated using chiral purification (Method 1) to give Intermediate 77 (trans isomer 1) and Intermediate 78 (trans isomer 2)

Intermediate 77: Trans Isomer 1; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}benzoic acid

Chiral SFC purification (Method 1) of 296 mg of intermediate 76 gave 98.4 mg of the title compound as an off-white solid.

SFC chiral analysis (method 1): 96.2% e.e. Rt = 2.71 min.

¹ H NMR (250MHz, DMSO-d6) δ [ppm] = 7.99 (s, 1H), 7.94 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 4.8 2(s,1H),4.52-4.28(m,1H),3.75(s,1H),1.23(d,J=6.2Hz,3H),1.13(d,J=6.4Hz,3H).

Intermediate 78: Trans Isomer 2; 3-(5-chloro-1,3-thiazol-2-yl)-5-{[3-hydroxybutan-2-yl]oxy}benzoic acid

Chiral SFC purification (Method 1) of 296 mg of intermediate 76 afforded 93.2 mg of the title compound as an off-white solid.

SFC chiral analysis (method 1): 97.2% e.e. Rt = 3.18 min.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]8.00(s,1H),7.97-7.88(m,1H),7.64-7.59(m,1H),7.56-7.51(m,1H),4. 83(d,J＝5.1Hz,1H),4.49-4.33(m,1H),3.85-3.70(m,1H),1.23(d,J＝6.2Hz,3H),1.13(d,J＝6.4Hz,3H).

Intermediate 87: 3-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of trans isomers

To a solution of intermediate 3 (300 mg, 0.88 mmol) and trans-2,3-butylene oxide (0.32 mL, 3.51 mmol) in DMSO (3 mL) was added cesium carbonate (1145 mg, 3.51 mmol). The mixture was heated to 100°C for 16 hours, then diluted with water (10 mL) and acidified with concentrated HCl to form a white precipitate, which was extracted into _IPA /CHCl₃ (1:3) (2 x 25 mL). The combined organics were dried over _MgSO₄ , filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method B) to give 500 mg (57% yield) of the title compound as an off-white solid.

The mixture of trans isomers was separated using chiral purification (Method 1) to give Intermediate 88 (trans isomer 1) and Intermediate 89 (trans isomer 2).

Intermediate 88: Trans Isomer 1; 3-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Chiral SFC purification (Method 1) of 298.2 mg of intermediate 87 gave 183.6 mg of the title compound as an off-white powder.

SFC chiral analysis (method 1): 100% e.e. Rt = 2.17 min.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]7.96-7.92(m,1H),7.66-7.59(m,2H),7.51-7.47(m,1H ),4.43-4.32(m,2H),3.82-3.71(m,1H),1.24(d,J＝6.2Hz,3H),1.14(d,J＝6.4Hz,3H).

Intermediate 89: trans isomer 2; 3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Chiral purification by SFC (Method 1) of 298.2 mg of intermediate 89 afforded 46.7 mg of the title compound as an off-white powder.

SFC chiral analysis (method 1): 100% e.e. Rt = 2.41 min.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]13.25(s,1H),7.97-7.91(m,1H),7.67-7.58(m,2H),7.53-7.47(m,1H),4 .81(d,J＝5.1Hz,1H),4.43-4.31(m,1H),3.82-3.70(m,1H),1.24(d,J＝6.1Hz,3H),1.14(d,J＝6.4Hz,3H.

Intermediate 92: 3-Hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of cis isomers

To a solution of intermediate 3 (780 mg, 3.13 mmol) and cis-2,3-butylene oxide (1.09 mL, 12.5 mmol) in DMSO (10 mL) was added cesium carbonate (4.08 g, 12.5 mmol). The mixture was heated to 100 ° C for 16 hours, then diluted with water (30 mL) and acidified to pH 4 with 2N HCl to form a white precipitate, which was extracted into IPA/CHCl ₃ (1: 1) (30 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified by Biotage Isolera ^TM chromatography (eluted with 0-80% EtOAc in heptane on a 50 g pre-filled KP-SiO ₂ column) to obtain 565 mg (55% yield) of the title compound as an off-white powder.

Intermediate 25: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

3-Bromo-5-fluorobenzonitrile (30 g, 150 mmol), bis(pinacolato)diborane (41.9 g, 0.15 mol), and potassium acetate (44.2 g, 0.45 mol) were combined in 1,4-dioxane (300 mL) and degassed with _N₂ for 10 minutes. [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (5.5 g, 7.5 mmol) was added, and the mixture was degassed with _N₂ for another 10 minutes, then heated at 100°C under a nitrogen atmosphere for 18 hours. The mixture was filtered through Celite®, and the solid was washed with ethyl acetate. The filtrate was washed with brine, and the organic phase was separated, dried over _MgSO₄ , filtered, and concentrated under reduced pressure. The crude material was purified by filtration through a silica column, eluting with EtOAc, and the resulting filtrate was concentrated under reduced pressure to give 43.7 g (assumed quantitative yield, 84% purity) of the title compound as a brown oil.

1H NMR (500MHz, DMSO-d6): δ [ppm] 1.31 (s, 12H), 7.65-7.72 (m, 1H), 7.79-7.83 (m, 1H), 8.00 (ddd, J = 8.8, 2.7, 1.4Hz, 1H).

LCMS (Analytical Method A) Rt = 0.91 min.

Intermediate 26: 3-Fluoro-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

Intermediate 25 (15 g, 51 mmol), 2-bromo-5-methyl-1,3-thiazole (5.9 mL, 56 mmol) and potassium carbonate (17.6 g, 127.5 mmol) were dissolved in 4:1 dioxane/water (200 mL). The solution was degassed with _N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) was added and the reaction mixture was heated at 80 °C for 16 hours. Thereafter, the reaction mixture was partitioned between water and EtOAc. The organic phase was separated and the aqueous phase was extracted with additional EtOAc. The combined organics were washed with brine, dried ( _MgSO4 ), filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 4:1). The fractions containing the product were combined and triturated with heptane, the precipitate was collected and dried by vacuum filtration. The mother liquor and mixed fractions were combined and concentrated. The residue was further purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc 1:0 to 4:1). The two batches were combined to give 7.06 g (59% yield) of the title compound as a white powder.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 7.96 (t, J = 1.4 Hz, 1H), 7.86 (ddd, J = 9.2, 2.4, 1.6 Hz, 1H), 7.57 (d, J = 1.1 Hz, 1H), 7.35 (ddd, J = 7.7, 2.5, 1.3 Hz, 1H), 2.55 (d, J = 1.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.26 min, MS (ESIpos): m/z=218.85 (M+H)+.

Intermediate 29: 3-(5-ethyl-1,3-thiazol-2-yl)-5-fluorobenzonitrile

Intermediate 26 (5 g, 17 mmol), 2-chloro-5-ethyl-1,3-thiazole (3 g, 20 mmol) and cesium carbonate (14 g, 42.5 mmol) were dissolved in 4:1 dioxane/water (50 mL). The solution was degassed with a stream of nitrogen for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (982 mg, 0.85 mmol) was added and the reaction mixture was stirred at 100 °C overnight. The reactants were diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organics were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 3:1). The fractions containing the product were concentrated and the residue was crystallized from heptane to give 2.5 g (63% yield) of the title compound as a white crystalline solid.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 7.97 (d, J = 1.3 Hz, 1H), 7.91-7.79 (m, 1H), 7.59 (s, 1H), 7.35 (ddd, J = 7.7, 2.4, 1.3 Hz, 1H), 3.01-2.82 (m, 2H), 1.37 (t, J = 7.5 Hz, 3H).

LCMS (Analytical Method A) Rt=1.34 min, MS (ESIpos): m/z=232.9 (M+H) ⁺ .

Intermediate 54: tert-Butyl (3-endo)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of (3-endo)-8-azabicyclo[3.2.1]octan-3-ol (3 g, 23.6 mmol) and triethylamine (5.1 mL, 36.6 mmol) in DCM (30 mL) was added di-tert-butyl dicarbonate (10.3 g, 47.2 mmol) in portions, and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the organic layer was separated and washed with saturated citric acid (aqueous solution), water, and brine. The organic layer was dried over _Na₂SO₄ , _filtered , and concentrated under reduced pressure, then triturated with heptane to afford 4.16 g (77% yield) of the title compound as an off-white crystalline solid.

¹ H NMR (250MHz, DMSO-d6): δ [ppm] 1.38 (s, 9H), 1.61 (d, J = 13.5Hz, 2H), 1.70-1.9 6(m,4H), 2.12(d,J=6.7Hz,2H), 3.94(d,J=19.0Hz,3H), 4.56(d,J=2.3Hz,1H).

Intermediate 27AL: tert-Butyl (3-endo)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-8-azabicyclo[3.2.1]octane-8-carboxylate

To the stirred solution of intermediate 54 (1.56g, 8.86mmol) in anhydrous DMF (10mL) was added NaH (60% dispersion in mineral oil, 274mg, 6.85mmol). After the mixture was stirred for 15 minutes, intermediate 26 (1.0g, 4.58mmol) was added at a time. The resulting mixture was stirred for 18 hours. After this, the reaction mixture was quenched with saline and extracted with EtOAc. The organic phase was separated and washed with salt water, dried with _MgSO4 , filtered and evaporated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 1:1) to obtain 1.25g (58% yield) of the title compound.

¹ H NMR (250MHz, chloroform-d): δ[ppm]7.67(t,J＝1.4Hz,1H),7.67-7.57(m,1H),7.53(d,J＝1.2Hz,1H),7.08(dd,J＝2.4,1 .3Hz, 1H), 4.72 (t, J = 4.7Hz, 1H), 4.22 (s, 2H), 2.54 (d, J = 1.1Hz, 3H), 2.33-1.89 (m, 9H), 1.47 (d, J = 4.7Hz, 9H).

LCMS (Analytical Method A) Rt=1.49 min, MS (ESIpos) m/z=426 (M+H) ⁺ .

Intermediate 28AL: 3-{[(3-endo)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 27AL (1.25 g, 2.64 mmol) in DMSO (5 mL) was added 2 M NaOH (2 mL) and the mixture was stirred at 110° C. for 3 hours. The mixture was slowly acidified with 2 M HCl to pH 5 to precipitate a white solid which was collected by filtration. The solid was dried in a vacuum oven, allowing the compound to melt, to afford 290 mg (53% yield) of the title compound as a colorless gum.

LCMS (Analytical Method A) Rt=1.32 min, MS (ESIpos) m/z=445 (M+H) ⁺ .

Intermediate 63: tert-Butyl (3-exo)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate

To a solution of (3-exo)-8-azabicyclo[3.2.1]octan-3-ol (0.95 g, 7.5 mmol) and triethylamine (1.7 mL, 12.2 mmol) in DCM (10 mL) was added di-tert-butyl dicarbonate (3.27 g, 15.0 mmol) in portions and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water, and the organic layer was separated and washed with saturated citric acid (aqueous solution), water, and brine. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to afford 1.65 g (97% yield) of the title compound as an off-white solid.

1H NMR (250 MHz, chloroform-d): δ [ppm] 4.41-3.95 (m, 3H), 2.00-1.53 (m, 9H), 1.45 (s, 9H).

Intermediate 27AM: tert-Butyl (3-exo)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-8-azabicyclo[3.2.1]octane-8-carboxylate

To the stirred solution of intermediate 63 (0.68g, 2.98mmol) in anhydrous DMF (10mL) was added NaH (60% dispersion in mineral oil, 120mg, 3.00mmol). After the mixture was stirred for 15 minutes, intermediate 26 (0.5g, 2.29mmol) was added at a time. The resulting mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into brine and extracted into EtOAc. The organic layer was washed with brine, separated, dried over _MgSO4 , filtered and concentrated under reduced pressure to give a brown oil. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 0:1) to obtain 531mg (54% yield) of the title compound as off-white powder.

¹ H NMR (250MHz, chloroform-d): δ[ppm]7.71(t,J＝1.4Hz,2H),7.68-7.63(m,1H),7.53(d,J＝1.2Hz,1H),7.13(dd,J＝2.4,1.3Hz,1H ),4.75(tt,J＝10.6,5.9Hz,1H),4.34(s,2H),2.53(d,J＝1.1Hz,3H),2.20-2.00(m,4H),1.93-1.65(m,4H),1.49(s,9H).

LCMS (Analytical Method A) Rt=1.46 min, MS (ESIpos): m/z=426.05 (M+H) ⁺ .

Intermediate 28AM: 3-{[(3-exo)-8-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]oct-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 27AL (1.25 g, 2.64 mmol) in DMSO (5 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 110° C. for 3 hours. The mixture was slowly acidified with 2 M aqueous HCl to pH 5 to precipitate a white solid, which was collected by filtration. The solid was dried in a vacuum oven to give 0.56 g (48% yield) of the title compound as an off-white powder.

LCMS (Analytical Method A) Rt=1.35 min, MS (ESIpos) m/z=445 (M+H) ⁺ .

Intermediate 27AN: 3-[(3-methyloxetan-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a solution of 3-methyloxetane-3-ol (121 mg, 1.37 mmol) in anhydrous DMF (2 mL) was added NaH (60% dispersion in mineral oil, 55 mg, 1.38 mmol), the mixture was stirred at room temperature for 1 hour, and then intermediate 26 (200 mg, 0.92) was added. The resulting mixture was stirred at room temperature for 3 hours, then distributed between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic matter was washed with salt water, dried over MgSO ₄ , filtered and concentrated under reduced pressure. TLC analysis (EtOAc-heptane, 1: 1) showed that SM was not completely consumed. The residue was dissolved in DMF (1 mL) and added to a solution of pre-stirred 3-methyloxetane-3-ol (121 mg, 1.37 mmol) and NaH (60% dispersion in mineral oil, 55 mg, 1.38 mmol). The mixture was stirred at room temperature overnight, and now TLC analysis showed that the raw material was consumed. The mixture was distributed between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic matter was washed with salt water, dried over _MgSO4 , filtered and concentrated under reduced pressure. Purification of crude material by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 2:3) gave 140mg (51% yield) of the title compound as a brown oil.

¹ H NMR (250MHz, chloroform-d): δ[ppm]7.73(t,J＝1.4Hz,1H),7.53(d,J＝1.2Hz,1H),7.40(dd,J＝2.4,1.5Hz,1H),6.8 6(dd,J＝2.4,1.3Hz,1H), 4.94(d,J＝6.6Hz,2H), 4.64(d,J＝7.3Hz,2H), 2.54(d,J＝1.1Hz,3H), 1.79(s,3H).

LCMS (Analytical Method A) Rt=1.18 min, MS (ESIpos) m/z=287 (M+H) ⁺ .

Intermediate 28AN: 3-[(3-methyloxetan-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 27AN (140 mg, 0.46 mmol) was stirred in 2M NaOH (2.3 mL) and DMF (1 mL) in a sealed tube at 110°C for 14 hours. THF was added to aid dissolution, and the resulting solution was heated in a sealed tube at 110°C for 16 hours. Another portion of 2M NaOH solution (2 mL) was added and heated to 110°C for 3 hours. The mixture was acidified with 2M HCl to form a white precipitate, which was extracted into EtOAc. The organic phase was separated, dried over _MgSO4 , filtered and concentrated under reduced pressure to give 118 mg (75% yield) of the title compound as a white powder.

LCMS (Analytical Method A) Rt=1.05 min, MS (ESIpos) m/z=306 (M+H) ⁺ .

Intermediate 27AO: tert-Butyl (3S)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

To a solution of (3S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (415mg, 2.06mmol) in anhydrous DMF (3mL) was added NaH (60% dispersion in mineral oil, 88mg, 2.2mmol), the mixture was stirred at room temperature for 1 hour, and intermediate 26 (300mg, 1.38mmol) was subsequently added. The resulting mixture was stirred at room temperature for 16 hours, then distributed between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic matter was washed with salt water, dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 4:1 to 1:4) to obtain 510mg (93% yield) of the title compound.

¹ H NMR (500MHz, chloroform-d): δ[ppm]7.72-7.68(m,1H),7.68-7.63(m,1H),7.53-7.49(m,1H),7.16-7.12(m,1H),4.36(tt,J＝6.8, 3.3Hz,1H),3.96-3.11(m,4H),2.51(s,3H),2.07-1.96(m,1H),1.91-1.72(m,2H),1.60-1.50(m,1H),1.48-1.26(m,9H).

Intermediate 57: 3-{[(3S)-1-methylpiperidin-3-yl]oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To the solution of intermediate 27AO (510mg, 1.28mmol) in DCM (5mL), TFA (0.5mL, 6.49mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM and poured into a saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic matter was dried over _MgSO4 , filtered and concentrated under reduced pressure. The gained solid was dissolved in DCE (3mL), followed by the addition of formaldehyde (37% aqueous solution) (1mL, 1.08mmol) and acetic acid (0.1mL, 1.04mmol). The solution was stirred at room temperature for 15 minutes, then STAB (540mg, 2.55mmol) was added in batches, and then stirred for 2 hours. The reaction mixture was diluted with DCM and poured into a saturated sodium bicarbonate solution. The organic phase was separated and the aqueous phase was extracted with another DCM. The combined organic matter was dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-TBME 2:3 to 0:1) to afford 172 mg (43% yield) of the title compound.

LCMS (Analytical Method A) Rt=0.85 min, MS (ESIpos) m/z=314 (M+H) ⁺ .

Intermediate 28AO: 3-{[(3S)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

At 110 ℃, intermediate 57 (172 mg, 0.55 mmol) and 2M NaOH (5.5 mL, 11.0 mmol) were heated together in a sealed tube for 6 hours. After cooling to room temperature, the mixture was acidified to pH 11 and extracted with IPA/CHCl (1:4) (3 × 15 mL). The combined organic matter was dried with _MgSO and concentrated under reduced pressure to give 130 mg (71% yield) of the title compound as a white powder.

LCMS (Analytical Method A) Rt=0.80 min, MS (ESIpos) m/z=333 (M+H) ⁺ .

Intermediate 27AP: tert-Butyl (3R)-3-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]piperidine-1-carboxylate

To a solution of (3S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (415mg, 2.06mmol) in anhydrous DMF (3mL) was added NaH (60% dispersion in mineral oil, 88mg, 2.2mmol), the mixture was stirred at room temperature for 1 hour, and intermediate 26 (300mg, 1.38mmol) was subsequently added. The resulting mixture was stirred at room temperature for 16 hours, then distributed between EtOAc and water. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic matter was washed with salt water, dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 4:1 to 1:4) to obtain 452mg (82% yield) title compound.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.72 (t, J = 1.3 Hz, 1H), 7.70-7.65 (m, 1H), 7.55-7.50 (m, 1H), 7.18-7.13 (m, 1H), 4.38 (tt, J ＝6.9,3.4Hz,1H),4.02-3.09(m,4H),2.53(d,J＝0.9Hz,3H),2.11-1.97(m,1H),1.95-1.71(m,2H),1.61-1.30(m,10H).

LCMS (Analytical Method A) Rt=1.38 min, MS (ESIpos) m/z=400 (M+H) ⁺ .

Intermediate 58: 3-{[(3R)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To the intermediate 27AP (452 mg, 1.28 mmol) in DCM (5 mL) was added TFA (0.4 mL, 5.19 mmol), and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM and poured into a saturated sodium bicarbonate aqueous solution. The organic phase was separated and the aqueous phase was extracted with DCM. The combined organic matter was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The resulting solid was dissolved in DCE (3 mL), followed by the addition of formaldehyde (37% aqueous solution) (0.4 mL, 5.33 mmol) and acetic acid (0.1 mL, 1.04 mmol). The solution was stirred at room temperature for 15 minutes, and STAB (480 mg, 2.27 mmol) was then added in portions, which was then stirred for 2 hours. The reaction mixture was diluted with DCM and poured into a saturated sodium bicarbonate aqueous solution. The organic phase was separated and the aqueous phase was extracted with another DCM. The combined organic matter was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-TBME 2:3 to 0:1) to afford 183 mg (52% yield) of the title compound.

LCMS (Analytical Method A) Rt=0.84 min, MS (ESIpos) m/z=314 (M+H) ⁺ .

Intermediate 28AP: 3-{[(3R)-1-methylpiperidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 58 (183 mg, 0.58 mmol) and 2M NaOH (5.8 mL, 11.6 mmol) were heated together in a sealed tube at 110° C. for 6 hours. After cooling to room temperature, the mixture was acidified to pH 11 and extracted with IPA/CHCl ₃ (1:4) (3×15 mL). The combined organics were dried over MgSO ₄ , filtered, and concentrated under reduced pressure to afford 185 mg (95% yield) of the title compound as a white powder.

LCMS (Analytical Method A) Rt=0.81 min, MS (ESIpos) m/z=333 (M+H) ⁺ .

Intermediate 27AR: 3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of (3R)-1-azabicyclo[2.2.2]octan-3-ol hydrochloride (0.29 g, 1.79 mmol) in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil, 137 mg, 3.44 mmol). After the mixture was stirred for 15 minutes, intermediate 26 (0.3 g, 1.38 mmol) was added in one portion. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into brine and extracted with EtOAc. The organic layer was washed with brine, separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^TM chromatography (silica gel, first with heptane-EtOAc 3: 2 to 0: 1, then eluted with EtOAc-MeOH 1: 0 to 4: 1) to obtain 258.8 mg (51% yield) of the title compound as a yellow gum that crystallized on standing.

¹ H NMR (500MHz, chloroform-d): δ[ppm]7.70(t,J＝1.4Hz,1H),7.64(dd,J＝2.4,1.6Hz,1H),7.54( d,J＝1.2Hz,1H),7.11(dd,J＝2.4,1.3Hz,1H),4.55-4.44(m,1H),3.42-3.31(m,1H),3. 07-2.96(m,1H),2.96-2.79(m,4H),2.54(d,J＝1.1Hz,3H),2.23-2.17(m,1H),2.03-1 .95(m,1H),1.80(ddt,J＝14.0,9.3,4.3Hz,1H),1.67-1.58(m,1H),1.50-1.40(m,1H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=326 (M+H) ⁺ .

Intermediate 28AR: 3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid-formic acid

Intermediate 27AR (258 mg, 0.7 mmol) was stirred in 2M NaOH (3.5 mL) and DMSO (3.5 mL) at 110°C for 3 hours. After cooling to room temperature, the mixture was slowly acidified to pH ~2 and then concentrated under reduced pressure to give the crude material in DMSO. The crude material was purified by preparative HPLC (Method A). The product-containing fractions were concentrated, and the residue was freeze-dried from MeCN/water to give 146.4 mg (53% yield) of the title compound as an off-white powder.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]8.21(s,1H),7.96(s,1H),7.64(d,J＝1.2Hz,1H),7.55(d,J＝1.7Hz,1H),7.48(s,1H),4 .71(s,1H),3.44(d,J＝13.1Hz,1H),3.04-2.77(m,4H),2.21(d,J＝11.9Hz,1H),1.94(s,1H),1.74(s,2H),1.51(s,1H).

LCMS (Analytical Method A) Rt=0.91 min, MS (ESIpos): m/z=345 (M+H) ⁺ .

Intermediate 27AS: 3-(1-azabicyclo[2.2.2]oct-4-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of quinuclidine-4-ol (250 mg, 1.97 mmol) in anhydrous DMF (4 mL) was added NaH (60% dispersion in mineral oil, 78 mg, 1.95 mmol). After the mixture was stirred for 15 minutes, intermediate 26 (286 mg, 1.31 mmol) was added at once, and the resulting mixture was stirred at room temperature for 24 hours. Another portion of NaH (78 mg, 1.95 mmol) was added together with DBU (1 mL), and finally intermediate 26 (286 mg, 1.31 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted into EtOAc. The organic phase was separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (method A). The fraction containing the product was concentrated, and the residue was freeze-dried from MeCN/ water to obtain 111 mg (26% yield) of the title compound as a beige powder.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 7.86 (t, J = 1.4 Hz, 1H), 7.72 (t, J = 1.9 Hz, 1H), 7.58-7. 49(m,1H),7.25-7.21(m,1H),3.11-2.97(m,6H),2.53(d,3H),1.90-1.76(m,6H).

LCMS (Analytical Method A) Rt=1.00 min, MS (ESIpos) m/z=326 (M+H) ⁺ .

Intermediate 28AS: 3-(1-azabicyclo[2.2.2]oct-4-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 27AS (111 mg, 0.34 mmol) was suspended in 2M NaOH (2.5 mL) and heated to 120° C. in a sealed tube for 1 hour to give a yellow solution. The mixture was acidified to pH 6 and concentrated under reduced pressure to give 531 mg (>100% yield) of the title compound as a light yellow solid. The crude material was used in the next step without purification.

LCMS (Analytical Method A) Rt=0.90 min, MS (ESIpos) m/z=345 (M+H) ⁺ .

Intermediate 65: tert-Butyl 4-hydroxy-2-(trifluoromethyl)piperidine-1-carboxylate, a mixture of two cis isomers

Sodium borohydride (71 mg, 1.87 mmol) was added to a solution of 1-boc-2-trifluoromethyl-piperidin-4-one (250 mg, 0.94 mmol) in MeOH (8 mL) at -10°C, and the reaction was stirred at -10°C for 1 hour. Saturated aqueous _NH4Cl (3 mL) was added, and the resulting mixture was allowed to warm to room temperature. The MeOH was removed under reduced pressure, and the resulting aqueous layer was extracted with DCM (4 x 5 mL). The combined organics were washed with brine, dried over _MgSO4 , filtered, and concentrated under reduced pressure to afford 247.6 mg (98% yield) of the title compound as a colorless oil.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 4.84-4.62 (m, 1H), 4.15-3.95 (m, 2H), 3.39-3.18 (m, 1H), 2.10-2.00 (m, 1H), 1.91-1.57 (m, 3H), 1.47 (s, 9H).

Intermediate 27AT: tert-Butyl 4-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-2-(trifluoromethyl)piperidine-1-carboxylate, a mixture of two cis isomers

To the stirred solution of intermediate 65 (125 mg, 0.467 mmol) in anhydrous DMF (2 mL) was added NaH (60% dispersion in mineral oil, 19 mg, 0.49 mmol) to obtain a white precipitate. After the mixture was stirred for 15 minutes, intermediate 26 (85 mg, 0.39 mmol) was added at once. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into saline and extracted into EtOAc. The organic layer was washed with salt water, separated, dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 100: 1 to 3: 2) to obtain 111.1 mg (61% yield) of the title compound as a brown jelly.

¹ H NMR (500MHz, chloroform-d): δ[ppm]7.71(t,J＝1.3Hz,1H),7.68-7.65(m,1H),7.54(d,J＝1.2Hz,1H),7.14(dd,J＝2.3,1.3Hz,1H),4.78(s,1H),4.76-4 .72(m,1H),4.15-4.06(m,1H),3.36(s,1H),2.54(d,J＝1.1Hz,3H),2.3 6(d,J＝15.6Hz,1H),2.13-1.97(m,3H),1.90-1.81(m,1H),1.49(s,9H).

LCMS (Analytical Method A) Rt=1.48 min, MS (ESIpos): m/z=468 (M+H) ⁺ .

Intermediate 28AT: 3-{[1-(tert-Butoxycarbonyl)-2-(trifluoromethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, a mixture of two cis isomers

Intermediate 27AT (111 mg, 0.22 mmol) was stirred in 2M NaOH (1.5 mL) and DMSO (1.5 mL) at 130° C. for 3 hours. After cooling to room temperature, the organics were removed under reduced pressure, and the residue was diluted with water (3 mL) and slowly acidified to pH~4 with 1M HCl, then extracted with EtOAc (3×10 mL). The combined organics were dried over MgSO ₄ , filtered, and concentrated under reduced pressure to afford 104.8 mg (83% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, chloroform-d) δ8.19(t,J＝1.3Hz,1H),7.73-7.68(m,1H),7.62-7.59(m,1H),7.56(s,1H),4.85-4.70(m,2H),4.07(d,J＝19.4Hz,1 H),3.38(s,1H),2.53(d,J＝1.0Hz,3H),2.38(d,J＝15.5Hz,1H),2.14-2.07(m,2H),2.06-1.97(m,2H),1.89-1.80(m,1H),1.49(s,9H).

LCMS (Analytical Method A) Rt=1.34 min, MS (ESIpos): m/z=487 (M+H) ⁺ .

Intermediate 27AU: 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

At room temperature and under stirring, (S)-quinuclidine-3-ol (0.758g, 5.96mmol) is dissolved in DMF (15mL). NaH (60% dispersion in mineral oil, 458mg, 11.46mmol) is added, and the mixture is stirred for 15 minutes. Intermediate 26 (1.0g, 4.58mmol) is added and the mixture is stirred overnight. The reactant is quenched with water and then concentrated under reduced pressure. Purification of crude material by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 0:1) gives 386mg (23% yield) title compound as off-white powder.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 7.82 (t, J = 1.3, 1H), 7.67 (d, J = 1.2, 1H), 7.66-7. 64(m,1H),7.50(dd,J＝2.3,1.3,1H),4.65(dd,J＝7.3,3.3,1H),2.85-2.74(m,2H ),2.72-2.60(m,4H),2.52(d,J＝0.9,3H),2.08(q,J＝2.9,1H),1.81(dddt,J＝12. 5,10.0,5.1,2.9,1H),1.70-1.52(m,2H),1.35(dtd,J＝11.4,8.1,7.6,2.9,1H).

LCMS (Analytical Method F) Rt=1.91 min, MS (ESIpos): m/z=326 (M+H) ⁺ .

Intermediate 28AU: 3-[(3S)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid monosodium chloride (1:3)

Intermediate 27AU (386 mg, 1.04 mmol, 88%) was dissolved in EtOH (5 mL) in a sealed tube with stirring at room temperature, and 2M NaOH (1.57 mL, 3.13 mmol) was added. The reaction was stirred at 80° C. for 5 hours and then at 100° C. for 24 hours. The reaction mixture was quenched with 2M HCl (1.57 mL, 3.13 mmol) and then concentrated under reduced pressure to give 449 mg (83% yield) of the title compound.

1H NMR (500MHz, DMSO-d6): δ [ppm] 7.87 (s, 1H), 7.57 (d, J = 1.2, 1H), 7.45-7.42 (m, 1H), 7.33-7.30 (m, 1H), 4.52-4.44 (m, 1H), 3.26-3.18 (m, 1H), 2.8 4-2.59(m,5H),2.49(s,3H),2.05(q,J＝3.0,1H),1.89-1.79(m,1H),1.70 -1.60(m,1H),1.55(dddd,J＝12.5,8.9,6.3,2.8,1H),1.38-1.26(m,1H).

LCMS (Analytical Method A) Rt=0.93 min, MS (ESIpos): m/z=345 (M+H) ⁺ .

Intermediate 27AV: 3-[(3R)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of (3R) -1- azabicyclo [2.2.2] octan-3-ol hydrochloride (0.37 g, 2.24 mmol) in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil, 172 mg, 4.3 mmol). After the mixture was stirred for 15 minutes, intermediate 29 (0.4 g, 1.72 mmol) was added at once. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into brine and extracted into EtOAc. The organic layer was washed with brine, separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^TM chromatography (silica gel, eluted with DCM-MeOH 1: 0 to 4: 1) to obtain 374.9 mg (64% yield) of the title compound as a yellow gum.

1H NMR (500MHz, chloroform-d): δ [ppm] 7.71 (t, J = 1.3 Hz, 1H), 7.64 (dd, J = 2.3, 1.6 Hz, 1H), 7.56 (s, 1H),7.11(dd,J＝2.4,1.3Hz,1H),4.51-4.44(m,1H),3.34(ddd,J＝14.3,7.9,2.0Hz,1H) ,3.04-2.76(m,7H),2.19(q,J＝3.1Hz,1H),2.01-1.93(m,1H),1.79(ddt,J＝14.0,9.6,4 .3Hz,1H),1.60(dtd,J＝13.4,6.1,3.0Hz,1H),1.48-1.40(m,1H),1.37(t,J＝7.5Hz,3H).

LCMS (Analytical Method A) Rt=1.03 min, MS (ESIpos): m/z=340 (M+H) ⁺ .

Intermediate 28AV: 3-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzoic acid monosodium chloride (1:3)

Intermediate 27AV (375 mg, 1.11 mmol) was dissolved in EtOH (5 mL) and 2 M NaOH (1.7 mL) was added. The reaction was stirred at 80° C. in a sealed tube for 8 hours. The reaction was quenched by the addition of HCl (2 M, 1.7 mL) and concentrated under reduced pressure to give 602 mg (quantitative yield) of the title compound.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]7.97(t,J＝1.4Hz,1H),7.65(s,1H),7.53-7.44(m,2H),4.81-4.69(m,1H),3.56-3.38(m,2 H),3.04-2.80(m,6H),2.28-2.15(m,1H),2.13-1.92(m,1H),1.87-1.68(m,2H),1.62-1.42(m,1H),1.28(t,J=7.5Hz,3H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=359 (M+H) ⁺ .

Intermediate 27AW: 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzonitrile

To the stirred solution of (3S) -1- azabicyclo [2.2.2] octan-3-ol (0.29 g, 2.24 mmol) in anhydrous DMF (5 mL) was added NaH (60% dispersion in mineral oil) (103 mg, 2.6 mmol). After the mixture was stirred for 15 minutes, intermediate 29 (0.4 g, 1.72 mmol) was added at a time. The resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into saline and extracted into EtOAc. The organic layer was washed with salt water, separated, dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with DCM-MeOH 1: 0 to 4: 1) to obtain 406 mg (69% yield) of the title compound as a yellow jelly.

1H NMR (500MHz, chloroform-d): δ [ppm] 7.71 (t, J = 1.3Hz, 1H), 7.66-7.63 (m, 1H), 7.56 (s, 1H), 7.11(dd,J＝2.4,1.3Hz,1H),4.46(dd,J＝7.3,3.4Hz,1H),3.33(ddd,J＝14.4,8.0,2 .0Hz,1H),3.03-2.75(m,7H),2.20-2.14(m,1H),2.00-1.92(m,1H),1.77(ddt,J＝1 4.1, 9.9, 4.3Hz, 1H), 1.64-1.55 (m, 1H), 1.46-1.40 (m, 1H), 1.37 (t, J = 7.5Hz, 3H).

LCMS (Analytical Method A) Rt=1.03 min, MS (ESIpos): m/z=340 (M+H) ⁺ .

Intermediate 28AW: 3-[(3S)-1-Azabicyclo[2.2.2]oct-3-yloxy]-5-(5-ethyl-1,3-thiazol-2-yl)benzoic acid monosodium chloride (1:3)

Intermediate 27AW (365 mg, 1.08 mmol) was dissolved in EtOH (5 mL) and 2 M NaOH (1.6 mL) was added. The reaction was stirred at 80 ° C in a sealed tube for 8 hours. The reaction was quenched by the addition of HCl (2 M, 1.6 mL) and concentrated under reduced pressure to give 502 mg (86% yield) of the title compound.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]7.97(t,J＝1.3Hz,1H),7.65(s,1H),7.57-7.44(m,2H),4.82-4.67(m,1H),3.49(dd,J＝13.6,7.8 Hz,1H),3.08-2.79(m,7H),2.28-2.17(m,1H),2.08-1.87(m,1H),1.86-1.70(m,2H),1.61-1.43(m,1H),1.28(t,J＝7.5Hz,3H).

LCMS (Analytical Method A) Rt=0.95 min, MS (ESIpos): m/z=359 (M+H) ⁺ .

Intermediate 6AX: 2-Methyl-2-nitropropyl-4-methylbenzenesulfonate

2-Methyl-2-nitropropan-1-ol (0.5 g, 4.2 mmol), triethylamine (0.878 ml, 6.3 mmol), and trimethylamine hydrochloride (40 mg, 0.42 mmol) were stirred in DCM (10 mL), and 4-methylbenzenesulfonyl chloride (1.2 g, 6.3 mmol) was added. The reaction was stirred at room temperature for 1.5 hours. TLC (70% EtOAc in heptane) indicated complete reaction, so the reaction mixture was treated with N,N-dimethylethane-1,2-diamine (0.28 ml, 2.52 mmol) to consume unreacted TsCl. The reaction mixture was washed with 1 M HCl (10 mL) and then with water (10 mL), then dried over _MgSO₄ , filtered, and concentrated under reduced pressure to afford 1.16 g (99% yield) of the title compound as a yellow crystalline solid.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 7.77 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 4.28 (s, 2H), 2.47 (s, 3H), 1.60 (s, 6H).

Intermediate 27AZ: tert-Butyl 5-[3-cyano-5-(5-methylthiazol-2-yl)phenoxy]-2-azabicyclo[2.2.1]heptane-2-carboxylate

To the stirred solution of 5-hydroxy-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (254mg, 1.19mmol) in anhydrous DMF (4mL) was added NaH (60%, 55mg, 1.37mmol). After the mixture was stirred for 90 minutes, intermediate 26 (200mg, 0.92mmol) was added once to the reactant. The resulting mixture was stirred at room temperature overnight. The reaction was stopped and poured into saline and extracted with ethyl acetate. The organic layer was washed with salt water, separated, dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (basic silica gel, first with heptane-EtOAc 6:2 to 0:1, then eluted with EtOAc-MeOH 1:0 to 4:1) to obtain 388mg (86% yield) of the title compound as a yellow jelly.

1H NMR (500MHz, chloroform-d): δ [ppm] 7.71 (s, 1H), 7.63 (s, 1H), 7.54 (d, J = 1.1Hz, 1H), 7.10 (s, 1H), 4.50 (d, J = 6.1Hz, 1H), 3. 37-3.30(m,1H),3.07-2.98(m,1H),2.54(d,J＝1.1Hz,3H),1.87(d,J＝10.0Hz,1H),1.72-1.59(m,5H),1.47(s,9H).

LCMS (Analytical Method A) Rt=1.47 min, MS (ESIpos): m/z=356 (M+H) ⁺ .

Intermediate 28AZ: 3-[(2-tert-Butoxycarbonyl-2-azabicyclo[2.2.1]hept-5-yl)oxy]-5-(5-methylthiazol-2-yl)benzoic acid

A stirred solution of intermediate 27AZ (388 mg, 0.94 mmol) in 2M NaOH (4.71 mL) and DMSO (4.5 mL) was heated to 110° C. for 3 hours. After cooling to room temperature, the mixture was slowly acidified to pH-2 and then dried over a genevac to afford the crude material in residual DMSO. The crude material was dissolved in a minimum amount of MeOH and the salts removed by filtration. The MeOH was removed and the material was purified by preparative HPLC (Method B) to afford 49 mg (12% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.24(t,J＝1.4Hz,1H),7.65-7.58(m,3H),4.63-4.54(m,1H),4.30(d,J＝62.5Hz,1H),3.36-3.30(m,1H),3.08(d d,J＝54.7,10.4Hz,1H),2.82-2.78(m,1H),2.54(d,J＝1.1Hz,3H),2.42-2.30(m,1H),1.92(d,J＝9.9Hz,1H),1.74-1.66(m,2H),1.48(s,9H).

LCMS (Analytical Method A) Rt=1.36 min, MS (ESIpos): m/z=431 (M+H) ⁺ .

Intermediate 27BA: 3-(5-methylthiazol-2-yl)-5-[2-(1,2,4-triazol-1-yl)ethoxy]benzonitrile

A solution of 2-(1H-1,2,4-triazole-1-yl)ethanol (465mg, 4.11mmol) and anhydrous DMF (3mL) was prepared. NaH (60% in mineral oil, 205mg, 5.14mmol) was added, the solution was stirred for 90 minutes, and then intermediate 26 ₍ 747mg, 3.42mmol) was added. The resulting mixture was stirred at room temperature overnight. Brine was then added to the reactant, and the reaction solution was extracted with ethyl acetate. The solution was washed with water, the organic layer was separated, dried over _Na2SO4 , filtered and concentrated under reduced pressure. Biotage Isolera ^™ chromatography (silica gel, eluted with DCM-MeOH 1:0 to 4:1) was performed to obtain 604mg (48% yield) of the title compound as a waxy solid.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.22 (s, 1H), 7.97 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.56-7.50 (m, 1H), 7.15-7.06 (m, 1H), 4.61 (t, J=5.0 Hz, 2H), 4.44 (t, J=5.0 Hz, 2H), 2.53 (s, 3H).

LCMS (Analytical Method A) Rt=1.09 min, MS (ESIpos): m/z=333.95 (M+H) ⁺ .

Intermediate 28BA: 3-(5-methylthiazol-2-yl)-5-[2-(1,2,4-triazol-1-yl)ethoxy]benzoic acid monosodium chloride (1:3)

Intermediate 27BA (604 mg, 1.94 mmol) was dissolved in EtOH (4 mL) and 2 M NaOH (2.91 mL) was added. The reaction was stirred at 130 ° C for 1 hour in a microwave. After completion, the reaction was quenched with 2 M HCl (2.91 mL) and concentrated under reduced pressure to give 572 mg (58% yield) of the title compound.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 8.60 (s, 1H), 8.41 (s, 2H), 7.98 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 4.60 (t, J = 5.0Hz, 2H), 4.41 (t, J = 5.0Hz, 2H).

LCMS (Analytical Method A) Rt=1.00 min, MS (ESIpos): m/z=333 (M+H) ⁺ .

Intermediate 27BC: (4aS,7R,7aR)-7-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-octahydrocyclopenta[b]morpholine-4-carboxylic acid tert-butyl ester

Under nitrogen, in a three-necked flask dried over a heat gun, to a stirred solution of (4aS, 7R, 7aR) -7-hydroxy- octahydrocyclopenta [b] morpholine -4- carboxylic acid tert-butyl ester (215 mg, 0.88 mmol) in anhydrous DMF (3 mL) was added NaH (60% dispersion in mineral oil) (37 mg, 0.92 mmol), the mixture was stirred for 15 minutes, and then intermediate 26 (161 mg, 0.74 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water and extracted with EtOAc (× 2). The combined organic extracts were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane / EtOAc 1: 0 to 3: 2) to obtain 262 mg (68% yield) of the title compound as a brown oil.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.74 (t, J = 1.3 Hz, 1H), 7.70-7.66 (m, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.19 (dd, J = 2.3, 1.3Hz,1H),4.62(ddd,J＝9.3,7.9,4.6Hz,1H),4.03(ddd,J＝11.6,3.5,1.5Hz,1H),3.89(d,J＝13.1Hz,1H),3. 69(td,J＝11.8,2.9Hz,1H),3.58(dd,J＝10.2,7.8Hz,1H),3.07-2.78(m,2H),2.58-2.54(m,1H),2.53(d,J＝1. 0Hz, 3H), 2.32 (dq, J＝14.3, 9.3Hz, 1H), 2.16-1.94 (m, 1H), 1.79 (ddd, J＝14.3, 10.6, 4.4Hz, 1H), 1.47 (s, 9H).

LCMS (Analytical Method A) Rt=1.43 min, MS (ESIpos): m/z=442.0 (M+H) ⁺ .

Intermediate 28BC: 3-{[(4aS,7R,7aR)-4-[(tert-Butoxy)carbonyl]-octahydrocyclopenta[b]morpholin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 27BC (258 mg, 2.01 mmol) was stirred in 2M NaOH (2.8 mL) and DMSO (2.8 mL) at 110° C. for 3 hours. The mixture was slowly acidified with 2M HCl to pH ˜4, at which point a pink precipitate formed. This was filtered and dried under vacuum filtration to afford 155 mg (58% yield) of the title compound as a light pink solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.31 (s, 1H), 7.69-7.67 (m, 1H), 7.67-7.63 (m, 1H), 7.58 (d, J = 0.9H z,1H),4.68(td,J＝9.0,4.6Hz,1H),4.09-3.99(m,1H),3.90(d,J＝13.3Hz,1H),3.72(td,J＝11. 7,2.8Hz,1H),3.63(dd,J＝10.1,7.9Hz,1H),3.05-2.89(m,2H),2.53(s,3H),2.52-2.49(m,1H) ,2.36(dq,J＝14.2,9.1Hz,1H),2.07(dt,J＝22.4,10.3Hz,1H),1.84-1.74(m,1H),1.47(s,9H).

LCMS (Analytical Method A) Rt=1.28 min, MS (ESIpos): m/z=461.1 (M+H) ⁺ .

Intermediate 27BD: (4aS,7S,7aR)-7-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-octahydrocyclopenta[b]morpholine-4-carboxylic acid tert-butyl ester

Under nitrogen, in a three-necked flask dried over a heat gun, to a stirred solution of (4aS, 7S, 7aR) -7- hydroxy - octahydrocyclopenta [b] morpholine -4- carboxylic acid tert-butyl ester (215 mg, 0.88 mmol) in anhydrous DMF (3 mL) was added NaH (60% dispersion in mineral oil) (37 mg, 0.92 mmol), the mixture was stirred for 15 minutes, and intermediate 26 (161 mg, 0.74 mmol) was then added once. The resulting mixture was stirred at ambient temperature for 3.5 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic extracts were dried over MgSO ₄ , filtered, concentrated under reduced pressure, and purified by Biotage Isolera ^TM chromatography (silica gel, eluted with heptane-EtOAc 1: 0 to 3: 2) to give 338 mg (85% yield) of the title compound as a light pink solid.

¹ H NMR (500MHz, chloroform-d): δ[ppm]7.73(d,J＝1.2Hz,1H),7.69-7.64(m,1H),7.52(d,J＝1.1Hz,1H),7.19(dd,J＝ 2.3,1.3Hz,1H),4.84-4.71(m,1H),4.05(ddd,J＝11.6,3.4,1.6Hz,1H),3.86(d,J＝13.5Hz,1H),3.69(td, J＝11.7,2.8Hz,1H),3.46(td,J＝10.5,6.8Hz,1H),3.33(dd,J＝10.5,4.6Hz,1H),3.00(ddd,J＝13.6,11.9, 3.6Hz,1H),2.61-2.54(m,1H),2.53(d,J＝0.9Hz,3H),2.32-2.20(m,1H),1.88-1.72(m,2H),1.47(s,9H).

LCMS (Analytical Method A) Rt=1.40 min, MS (ESIpos): m/z=442.0 (M+H) ⁺ .

Intermediate 28BD: 3-{[(4aS,7S,7aR)-4-[(tert-Butoxy)carbonyl]-octahydrocyclopenta[b]morpholin-7-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 27BD (333 mg, 0.62 mmol) was dissolved in EtOH (3 mL) and 2 M NaOH (1.2 mL) was added. The reaction was stirred at 80° C. for 24 hours. The reaction was stopped, cooled to ambient temperature, and the ethanol was removed under reduced pressure. The resulting mixture was acidified to pH 4 by the addition of 2 M HCl, at which point a white precipitate formed. This was collected by filtration, washed with water, and dried in a vacuum oven to afford 244 mg (77% yield) of the title compound as an off-white solid.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.24(s,1H),7.84(s,1H),7.74(s,1H),7.63(s,1H),4.93(t ,J＝5.4Hz,1H),4.20-4.08(m,1H),3.88(d,J＝13.4Hz,1H),3.78-3.68(m,1H),3.52(td, J＝10.5,6.8Hz,1H),3.38(dd,J＝10.6,4.8Hz,1H),3.05(td,J＝13.6,3.6Hz,1H),2.55(s ,3H),2.54-2.47(m,1H),2.37(dd,J＝20.9,10.1Hz,1H),1.90-1.70(m,2H),1.47(s,9H).

LCMS (Analytical Method A) Rt=1.26 min, MS (ESIpos): m/z=461.1 (M+H) ⁺ .

Intermediate 83: (2S)-2-[(Benzyloxy)methyl]-1,4-dioxane

To a solution of (2R)-3-(benzyloxy)propane-1,2-diol (2 g, 11 mmol) and tetra-n-butylammonium bromide (0.71 g, 2.2 mmol) in dichloroethane (52 mL) was added an aqueous solution (25 mL) of sodium hydroxide (26.3 g, 0.66 mol). The reaction mixture was then stirred at 50 ° C for 16 hours. Additional dichloroethane (52 mL) and an aqueous solution (25 mL) of sodium hydroxide (26.3 g, 0.66 mol) were added, and the reaction mixture was stirred at 50 ° C for another 48 hours. The reaction mixture was filtered under vacuum and washed with ethyl acetate. The filtrate was diluted with water and the layers were separated. The organic layer was further washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc 1:0 to 1:1) to afford 1.25 g (54% yield) of the title compound as a colorless oil.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 7.40-7.27 (m, 5H), 4.55 (s, 2H), 3.86-3.57 (m, 6H), 3.52-3.37 (m, 3H).

Intermediate 84: (2S)-1,4-dioxane-2-ylmethanol

To the solution of intermediate 83 (1.25g, 4.74mmol) in ethanol (20mL) was added 10% palladium (192mg) supported on carbon, and the reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The reaction mixture was filtered through a plug, washed with EtOAc, and concentrated under reduced pressure to obtain 630mg (89% yield) of the title compound as a light yellow oil.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 3.85-3.67 (m, 5H), 3.66-3.57 (m, 2H), 3.55 (dd, J = 11.7, 5.9Hz, 1H), 3.46 (dd, J = 11.1, 10.0Hz, 1H), 1.75 (s, 1H).

Intermediate 27BE: 3-[(2R)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of intermediate 84 (250mg, 1.76mmol) in anhydrous DMF (7mL) was added NaH (60% dispersion in mineral oil) (88mg, 2.20mmol). After the mixture was stirred for 15 minutes, intermediate 26 (385mg, 1.76mmol) was added at once. The resulting mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was then poured into saline and extracted into EtOAc. The organic layer was washed with salt water, dried over _MgSO4 , filtered and concentrated under reduced pressure. Purification of the crude material by BiotageIsolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 1:0 to 20:9) gave 460mg (82% yield) of the title compound as a pale white solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.75 (s, 1H), 7.71-7.67 (m, 1H), 7.55-7.49 (m, 1H), 7.18 (dd, J = 2.3, 1.2Hz, 1H), 4.11-4.05 (m, 1H), 4.05-3.98 (m, 2H), 3.93-3.85(m,2H),3.82(td,J＝11.7,11.1,2.6Hz,1H),3.78-3.72(m,1H) ,3.68(td,J＝11.5,3.2Hz,1H),3.56(dd,J＝11.4,9.3Hz,1H),2.54(s,3H).

LCMS (Analytical Method A) Rt=1.17 min, MS (ESIpos): m/z=317.0 (M+H) ⁺ .

Intermediate 28BE: 3-[(2R)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 27BE (455 mg, 1.44 mmol) was dissolved in EtOH (7 mL) and 2M NaOH (2.9 mL) was added. The reaction was stirred at 130° C. for 1 hour in a microwave. The reaction was stopped, cooled to ambient temperature, and the ethanol was removed under reduced pressure. The resulting mixture was acidified to pH 4 by the addition of 2M HCl, at which point a white precipitate formed. This was collected by filtration, washed with water, and dried in a vacuum oven overnight to give 480 mg (99% yield) of the title compound as an off-white solid.

¹ H NMR (500MHz, chloroform-d) δ8.33(s,1H),7.69(s,1H),7.67(s,1H),7.59(s,1H),4.17-4.10(m,1H),4.09-4.00(m,2H),3.97-3.86(m,2H ), 3.83 (td, J = 11.7, 11.2, 2.5Hz, 1H), 3.77 (d, J = 11.0Hz, 1H), 3.69 (td, J = 11.3, 3.0Hz, 1H), 3.59 (t, J = 10.7Hz, 1H), 2.54 (s, 3H).

LCMS (Analytical Method A) Rt=1.05 min, MS (ESIpos): m/z=336.0 (M+H) ⁺ .

Intermediate 85: (2R)-2-[(Benzyloxy)methyl]-1,4-dioxane

To a solution of (2S)-3-(benzyloxy)propane-1,2-diol (0.8 g, 4.4 mmol) and tetra-n-butylammonium bromide (283 mg, 0.88 mmol) in dichloroethane (21 mL) was added an aqueous solution (10 mL) of sodium hydroxide (10.5 g, 0.26 mol). The reaction mixture was then stirred at 50 ° C for 16 hours. Additional dichloroethane (21 ml) and an aqueous solution (10 mL) of sodium hydroxide (10.5 g, 0.26 mol) were added, and the reaction mixture was stirred at 50 ° C for another 48 hours. The reaction mixture was filtered under vacuum and washed with ethyl acetate. The filtrate was diluted with water and separated. The organic layer was further washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc 1 :1 to 1 :1) to afford 560 mg (60% yield) of the title compound as a colorless oil.

¹ H NMR (250 MHz, chloroform-d): δ [ppm] 7.40-7.27 (m, 5H), 4.55 (s, 2H), 3.86-3.60 (m, 6H), 3.52-3.38 (m, 3H).

Intermediate 86: (2R)-1,4-dioxane-2-ylmethanol

To a solution of intermediate 85 (560 mg, 2.47 mmol) in ethanol (10 mL) was added 10% palladium (100 mg) supported on carbon, and the reaction mixture was stirred under a hydrogen atmosphere for 18 hours. The solution was filtered through a plug, washed with EtOAc, and concentrated under reduced pressure to give 260 mg (89% yield) of the title compound as a light yellow oil.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 3.87-3.66 (m, 5H), 3.65-3.58 (m, 2H), 3.54 (dd, J = 11.7, 5.9Hz, 1H), 3.46 (t, J = 10.6Hz, 1H), 1.95 (s, 1H).

Intermediate 27BF: 3-[(2S)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a stirred solution of intermediate 86 (250 mg, 2.12 mmol) in anhydrous DMF (7 mL) was added NaH (60% dispersion in mineral oil) (88 mg, 2.20 mmol). After the mixture was stirred for 15 minutes, intermediate 26 (385 mg, 1.76 mmol) was added at once. The resulting mixture was stirred for 2.5 hours at ambient temperature. The reaction mixture was then poured into saline and extracted into ethyl acetate. The organic layer was washed with salt water, separated, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^TM chromatography (silica gel, eluted with heptane-EtOAc 1: 0 to 20: 9) to obtain 400 mg (72% yield) of the title compound as a light yellow solid.

¹ H NMR (500MHz, chloroform-d): δ[ppm]7.75(s,1H),7.69(s,1H),7.54(s,1H),7.18(s,1H),4.11-4.05(m,1H),4.05-3.98(m,2H),3.92-3.86(m,2H ), 3.82(td,J＝11.7,11.2,2.6Hz,1H), 3.76(d,J＝12.1Hz,1H), 3.68(td,J＝11.3,3.2Hz,1H), 3.56(dd,J＝11.4,9.3Hz,1H), 2.54(s,3H).

LCMS (Analytical Method A) Rt=1.17 min, MS (ESIpos): m/z=317.0 (M+H) ⁺ .

Intermediate 28BF: 3-[(2S)-1,4-dioxan-2-ylmethoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 27BF (395 mg, 1.25 mmol) was dissolved in ethanol (6 mL) and 2 M NaOH (2.5 mL) was added. The reaction was stirred at 130 ° C for 2 hours in a microwave. The reaction was stopped, cooled to ambient temperature, and ethanol was removed under reduced pressure. The resulting mixture was acidified to pH 4 by adding 2 M HCl, at which time a white precipitate was formed. It was collected by filtration, washed with water, and dried overnight in a vacuum oven to obtain 380 mg (89% yield) of the title compound as a pale white solid.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]13.32(s,1H),7.98(s,1H),7.65(s,1H),7.61(s,1H),7.49(s,1H),4.15-4.04(m,2H),3 .93-3.86(m,1H),3.84(d,J=11.4Hz,1H),3.80-3.74(m,1H),3.71-3.59(m,2H),3.55-3.47(m,1H),3.47-3.40(m,1H).

LCMS (Analytical Method A) Rt=1.05 min, MS (ESIpos): m/z=336.0 (M+H) ⁺ .

Intermediate 34: tert-Butyl 3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}carbamoyl)phenoxy]azetidine-1-carboxylate

To the solution of intermediate 5AD (185mg, 0.47mmol), intermediate XVIII (130mg, 0.57mmol) and DIPEA (248 μ L, 1.42mmol) in DCM (1mL) was added HATU (270mg, 0.71mmol), and the resulting mixture was stirred at room temperature for 2 hours. DCM (1mL) was added and the crude reaction product was washed with water (1mL). The organic phase was separated, dried over _MgSO4 , filtered and concentrated under reduced pressure. Purification of the crude material by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc 9:1 to 1:9) gave 248mg (63% yield) of the title compound as a yellow oil.

¹ H NMR (250MHz, chloroform-d): δ[ppm]7.91(t,J＝1.4Hz,1H),7.81(s,1H),7.76(s,1H),7.57(d,J＝7.3Hz,1H),7.51(d,J＝1.2Hz,1H),7.42(dd,J＝2.4,1.4Hz,1H) ,5.59(m,1H),5.07-4.92(m,1H),4.35(dd,J＝9.7,6.4Hz,2H),4.01(dd,J＝ 9.5, 3.7Hz, 2H), 2.52 (d, J = 1.1Hz, 3H), 1.75 (d, J = 7.0Hz, 3H), 1.44 (s, 9H).

LCMS (Analytical Method A) Rt=1.49 min, MS (ESIpos): m/z=508.1 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 34 using HATU and the appropriate carboxylic acid and amine starting materials.

Intermediate 33: tert-Butyl 3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]azetidine-1-carboxylate

Intermediate 5AD (205.6 mg, 0.527 mmol), Intermediate VI (121 mg, 0.632 mmol) and DIPEA (367 μL, 2.1 mmol) were combined in DCM (5 mL) and T3P (470 μL, 0.79 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then washed with saturated _NaHCO3 (5 mL). The layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined organics were dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc 4:1 to 1:4) to obtain 226 mg (74% yield) of the title compound as a colorless solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.90 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.22 (s, 1H), 6.69 (d, J = 6.5Hz, 1H), 5.36 (m, 1H), 4.98 ( ddd,J＝10.4,6.4,4.0Hz,1H),4.35(dd,J＝9.6,6.5Hz,2H),4.00(dd,J＝9.7,3.7Hz,2H),2.54(s,3H),1.72(d,J＝7.2Hz,3H),1.45(s,9H).

LCMS (Analytical Method A) Rt=1.33 min, MS (ESIpos): m/z=508 (M-tBu) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 33 using T3P and the appropriate carboxylic acid and amine starting materials.

Intermediate 35: 3-(azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To the solution that intermediate 33 (226mg, 0.40mmol) is dissolved in DCM (5mL), TFA (0.3mL, 4.0mmol) is added, and reactant is stirred at room temperature until gas release stops.Reactant mixture is neutralized with saturated _NaHCO solution, produces precipitation.It is collected by filtering under reduced pressure, and is dried in a vacuum oven to obtain 188.7mg (quantitative yield) title compound, is white powder.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]9.42-9.09(m,3H),7.94(s,1H),7.65(s,1H),7.42(m,2H),5 .30(m,1H),5.17-4.92(m,1H),4.03-3.76(m,2H),3.62-3.51(m,2H),1.62(d,J＝7.1Hz,3H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=464.0 (M+H) ⁺ .

Intermediate 36: 3-(azetidin-3-yloxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of intermediate 34 (248 mg, 0.30 mmol, 68% purity) in DCM (1 mL) was added TFA (0.1 mL) and then stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water and basified to pH ~4 with 10 M NaOH solution to give an off-white precipitate, which was collected by filtration to give 81 mg (53% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]9.35(d,J＝6.9Hz,1H),8.24(d,J＝8.8Hz,1H),8.06(d,J＝8.8Hz,1H),7.99(s,1H),7.65(s,1H),7. 43(d,J＝11.9Hz,2H),5.52-5.45(m,1H),5.17(q,J＝5.8Hz,1H),3.92(t,J＝7.6Hz,2H),3.65-3.61(m,2H),1.66(d,J＝7.1Hz,3H).

LCMS (Analytical Method A) Rt = 0.88 min, MS (ESIpos) m/z 464 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 36 using TFA and the appropriate N-Boc protected amine starting material.

Intermediate 6AY: 1,1-dioxotetrahydro-2H-thiopyran-4-yl 4-methylbenzenesulfonate

A mixture of tetrahydro-2H-thiopyran-4-ol 1,1-dioxide (660 mg, 4.39 mmol), 4-methylbenzenesulfonyl chloride (922 mg, 4.83 mmol), TEA (920 μl, 6.6 mmol), and trimethylamine hydrochloride (42.0 mg, 439 μmol) was stirred in DCM (5.4 mL) at room temperature until complete conversion. DCM and water were added, and the layers were separated. The organic layer was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to obtain 1.03 g (77% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6) δ [ppm] 0.16-0.84 (m, 1H) 1.99-2.18 (m, 4H) 2.43 (s, 3H) 3.01-3.24 (m, 4H) 4.83 (dt, 1H) 7.49 (d, 2H) 7.85 (d, 2H).

Intermediate 4AZ: methyl 3-[(1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of Intermediate 3 (519 mg, 2.08 mmol), Intermediate 6AY (951 mg, 3.13 mmol), and Cs ₂ CO ₃ (1.02 g, 3.13 mmol) was stirred in DMF (15 mL) at 90° C. until complete conversion. The mixture was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane/EE gradient) to give 680 mg (86% yield) of the title compound.

LCMS, method 1, rt: 1.10 min, MS ES+ m/z = 382 (M+H) ⁺ .

Intermediate 5AZ: 3-[(1,1-dioxotetrahydro-2H-thiopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

A mixture of intermediate 4AZ (680 mg, 1.78 mmol), aqueous NaOH solution (356 mg, 8.91 mmol, 2 M) and MeOH (50 mL) was stirred at room temperature until complete conversion. The solvent was evaporated under reduced pressure, and aqueous HCl solution (2 M) was added to adjust the pH to pH 6. The aqueous layer was separated, and the organic layer was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel) to give 288 mg (44% yield) of the title compound.

LCMS, method 1, rt: 0.92 min, MS ES+ m/z = 368 (M+H) ⁺ .

Intermediate 4BA: methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of intermediate 8 (950 mg, 2.73 mmol), 2-bromo-5-ethyl-1,3-thiazole (681 mg, 3.55 mmol), [1,1,-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (334 mg, 409 μmol) and K ₂ CO ₃ (6.5 ml, 1.0 M, 6.5 mmol) was stirred under reflux in THF (45 mL) until complete conversion and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EE/MeOH gradient) to give 265 mg (29% yield) of the title compound.

LCMS, method 1, rt: 1.33 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 5BA: 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid

A solution of intermediate 4BA (265 mg, 94% purity, 780 μmol) in MeOH (5 mL), THF ( ₅ mL), and aqueous NaOH (780 μl, 2.0 M, 1.6 mmol) was stirred at room temperature until complete conversion. Water was added and the pH was adjusted to pH 2. The aqueous phase was extracted with EE, and the combined organic layers were dried over _Na₂SO₄ , filtered, and evaporated to dryness under reduced pressure to afford 252 mg (100% yield) of the title compound, which was used without further purification.

LCMS, Method 1, MS ES+ m/z = 320 (M+H) ⁺ .

Intermediate 4BB: methyl 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of intermediate 8 (870 mg, 2.50 mmol), 2-chloro-5-cyclobutyl-1,3-thiazole (564 mg, 3.25 mmol), [1,1,-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (306 mg, 375 μmol) and K ₂ CO ₃ (6.0 ml, 1.0 M, 6.0 mmol) was stirred under reflux in THF (41 mL) until complete conversion and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EE gradient) to give 390 mg (43% yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z = 360 (M+H) ⁺ .

Intermediate 5BB: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid

A solution of intermediate 4BB (390 mg, 94% purity, 1.02 mmol) in MeOH and aqueous NaOH (1.5 ml, 2.0 M, 3.1 mmol) was stirred at room temperature until complete conversion. Water was added and the pH was adjusted to pH _2. The aqueous phase was extracted with EE, and the combined organic layers were dried over _Na₂SO₄ , filtered, and evaporated to dryness under reduced pressure to yield 334 mg (95%) of the title compound, which was used without further purification.

LCMS, method 1, rt: 1.23 min, MS ES+ m/z = 346 (M+H) ⁺ .

Intermediate 4BC: methyl 3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

A mixture of intermediate 8 (870 mg, 2.50 mmol), 2-bromo-5-(propan-2-yl)-1,3-thiazole (669 mg, 3.25 mmol), [1,1,-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (306 mg, 375 μmol) and K ₂ CO ₃ (6.0 ml, 1.0 M, 6.0 mmol) was stirred in THF (41 ml) under reflux until complete conversion and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EE/MeOH gradient) to give 451 mg (52% yield) of the title compound.

LCMS, method 1, rt: 1.41 min, MS ES+: MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 5BC: 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid

A solution of intermediate 4BC (390 mg, 94% purity, 1.06 mmol) in MeOH and aqueous NaOH (1.6 ml, 2.0 M, 3.2 mmol) was stirred at room temperature until complete conversion. Water was added and the pH was adjusted to pH _2. The aqueous phase was extracted with EE, and the combined organic layers were dried over _Na₂SO₄ , filtered, and evaporated to dryness under reduced pressure to yield 400 mg of the title compound, which was used without further purification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 6AZ: (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

A mixture of (3R)-tetrahydrofuran-3-ol (18 g, 204 mmol), TEA (42.7 ml, 306 mmol) and trimethylamine hydrochloride (1.95 g, 20.4 mmol) was stirred at room temperature in DCM (626 ml) for 20 minutes. 4-Methylbenzenesulfonyl chloride (42.8 g, 225 mmol) was added and the reaction mixture was stirred at room temperature until complete conversion. N,N-dimethylethylenediamine (26.4 ml, 245 mmol) was added to the reaction mixture and stirred for 30 minutes to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added and the mixture was extracted with DCM (3x). The combined organic layers were evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel, hexane/EE/DCM/MeOH gradient) to give 41.0 g (83% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6) δ [ppm] 1.79-1.95 (m, 1H) 2.08 (dtd, 1H) 2.43 (s, 3H) 3.57-3.81 (m, 4H) 5.12 (ddt, 1H) 7.49 (d, 2H) 7.81 (d, 2H).

Intermediate 95: Methyl 3-bromo-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

A mixture of Intermediate 1 (3.00 g, 13.0 mmol), Intermediate 6AZ (4.72 g, 19.5 mmol), and _Cs2CO3 (6.35 g, 19.5 mmol) was stirred in 25 ml _of DMF at 80°C until complete conversion. The reaction mixture was cooled to room temperature, and the solid was filtered through HPLC and washed with DMF. The filtrate was evaporated, and the residue was purified by column chromatography (silica gel, hexane/EE gradient) to give 2.63 g (67% yield) of the title compound.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z = 301 (M+H) ⁺ .

Intermediate 94: Methyl 3-[(3S)-tetrahydrofuran-3-yloxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of intermediate 95 (2.63 g, 8.73 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane (5.54 g, 21.8 mmol), potassium acetate (3.00 g, 30.6 mmol) and [1,1'-bis(diphenylphosphino)-ferrocene]-palladium(II) dichloride (638 mg, 873 μmol) was stirred in 1,4-dioxane (50 ml) at 90°C until complete conversion. The mixture was filtered through Celite®, and the filtrate was evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EE/MeOH gradient) to give 4.36 g of the title compound.

LCMS, method 1, rt: 1.31 min, MS ES+ m/z = 349 (M+H) ⁺ .

Intermediate 4BD: methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

A mixture of intermediate 94 (1.00 g, 2.87 mmol), 2-bromo-5-ethyl-1,3-thiazole (662 mg, 3.45 mmol), [1,1,-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II) (352 mg, 431 μmol) and K ₂ CO ₃ (6.9 ml, 1.0 M, 6.9 mmol) was stirred under reflux in THF (47 ml) until complete conversion and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, hexane/EE gradient) to give 327 mg (34% yield) of the title compound.

LCMS, method 1, rt: 1.33 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 5BD: 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid

A solution of intermediate 4BD (327 mg, 94% purity, 922 μmol) in MeOH (8.5 ml), THF (8.5 ml), and aqueous NaOH (920 μl, 2.0 M, 1.8 mmol) was stirred at room temperature until complete conversion. Water was added and the pH was adjusted to pH 2. The aqueous phase was extracted with EE, and _the combined organic layers were dried over _Na₂SO₄ , filtered, and evaporated to dryness under reduced pressure to yield 299 mg of the title compound, which was used without further purification.

LCMS, method 1, rt: 1.10 min, MS ES+ m/z = 320 (M+H) ⁺ .

Intermediate 4BE: methyl 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 94 (1.00 g, 2.87 mmol) was reacted with 2-chloro-5-cyclobutyl-1,3-thiazole (648 mg, 3.73 mmol) to give 410 mg (39% yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z = 360 (M+H) ⁺ .

Intermediate 5BE: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid

Analogously to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BE (410 mg, 94% purity, 1.07 mmol) was saponified to give 413 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.22 min, MS ES+ m/z = 346 (M+H) ⁺ .

Intermediate 4BF: methyl 3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 94 (1.00 g, 2.87 mmol) was reacted with 2-bromo-5-(propan-2-yl)-1,3-thiazole (710 mg, 3.45 mmol) to give 374 mg (37% yield) of the title compound.

LCMS, method 1, rt: 1.41 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 5BF: 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid

Analogously to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BF (374 mg, 94% purity, 1.01 mmol) was saponified to give 333 mg (99% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 4BG: methyl 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 94 (500 mg, 1.44 mmol) was reacted with 2,5-dichloro-1,3-thiazole (288 mg, 1.87 mmol) to give 347 mg (71% yield) of the title compound.

LCMS, method 1, rt: 1.36 min, MS ES+ m/z = 340 (M+H) ⁺ .

Intermediate 5BG: 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoic acid

Intermediate 4BG (347 mg, 1.02 mmol) was saponified similarly to the conversion of Intermediate 4BD to Intermediate 5BD to give 300 mg (90% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 1.12 min, MS ES+ m/z = 326 (M+H) ⁺ .

Intermediate 4BH: methyl 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoate

Analogously to the conversion of intermediate 8 to intermediate 4BA, intermediate 8 (500 mg, 1.44 mmol) was reacted with 2,5-dichloro-1,3-thiazole (288 mg, 1.87 mmol) to give 249 mg (51% yield) of the title compound.

LCMS, method 1, rt: 1.36 min, MS ES+ m/z = 340 (M+H) ⁺ .

Intermediate 5BH: 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid

Intermediate 4BH (239 mg, 703 μmol) was saponified similarly to the conversion of intermediate 4BA to intermediate 5BA to give 282 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.11 min, MS ES+ m/z = 326 (M+H) ⁺ .

Intermediate 4BI: methyl 3-(5-chloro-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 14W (500 mg, 1.38 mmol) was reacted with 2,5-dichloro-1,3-thiazole (255 mg, 1.66 mmol) to give 380 mg (78% yield) of the title compound.

LCMS, method 1, rt: 1.42 min, MS ES+ m/z = 354 (M+H) ⁺ .

Intermediate 5BI: 3-(5-chloro-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid

Intermediate 4BI (300 mg, 848 μmol) was saponified similarly to the conversion of intermediate 4BD to intermediate 5BD to give 353 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z = 340 (M+H) ⁺ .

Intermediate 6BA: (3R)-tetrahydrofuran-3-ylmethyl 4-methylbenzenesulfonate

Analogously to the synthesis of intermediate 6AZ, (3S)-tetrahydrofuran-3-ylmethanol (5.4 g, 52.87 mmol) was reacted with 4-methylbenzenesulfonyl chloride (11.09 g, 58.16 mmol) to give 12.26 g (90% yield) of the title compound.

LCMS, method 1, rt: 1.02 min, MS ES+ m/z = 257 (M+H) ⁺ .

Intermediate 97: Methyl 3-bromo-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate

Analogously to the reaction of Intermediate 1 and Intermediate 6AZ to give Intermediate 95, Intermediate 1 (2.25 g, 9.75 mmol) was reacted with Intermediate 6BA (3.0 g, 11.7 mmol) to give 3.44 g of the title compound.

LCMS, method 1, rt: 1.25 min, MS ES+ m/z = 317 (M+H) ⁺ .

Intermediate 96: Methyl 3-[(3R)-tetrahydrofuran-3-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Analogously to the conversion of intermediate 95 to intermediate 94, intermediate 97 (4.11 g, 13.0 mmol) was reacted with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane (8.28 g, 32.6 mmol) to give 5.16 g of the title compound.

LCMS, method 1, rt: 1.43 min, MS ES+ m/z = 363 (M+H) ⁺ .

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.26-1.33(m,12H)1.61-1.74(m,1H)1.92-2.11(m,1H)2.56-2.75(m,1H)3.53(d d,1H)3.65(d,1H)3.71-3.82(m,2H)3.85(s,3H)3.96(d,1H)4.00(d,1H)7.38(dd,1H)7.54(dd,1H)7.84(d,1H).

Intermediate 4BJ: methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 96 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) to give 493 mg (51% yield) of the title compound.

LCMS, method 1, rt: 1.38 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 5BJ: 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoic acid

Intermediate 4BJ (490 mg, 94% purity, 1.33 mmol) was saponified similarly to the conversion of Intermediate 4BD to Intermediate 5BD to give 448 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.15 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 4BK: methyl 3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 96 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) to give 445 mg (45% yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z = 362 (M+H) ⁺ .

Intermediate 5BK: 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3R)-tetrahydrofuran-3-ylmethoxy]benzoic acid

Intermediate 4BK (450 mg, 94% purity, 1.17 mmol) was saponified similarly to the conversion of intermediate 4BD to intermediate 5BD to give 400 mg (98% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 1.23 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 6BB: (2R)-tetrahydrofuran-2-ylmethyl 4-methylbenzenesulfonate

Analogously to the synthesis of intermediate 6AZ, (2R)-tetrahydrofuran-2-ylmethanol (4.00 g, 39.2 mmol) was reacted with 4-methylbenzenesulfonyl chloride (8.21 g, 43.1 mmol) to give 10.1 g of the title compound.

LCMS, method 1, rt: 1.05 min, MS ES+ m/z = 257 (M+H) ⁺ .

Intermediate 99: Methyl 3-bromo-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the reaction of Intermediate 1 and Intermediate 6AZ to give Intermediate 95, Intermediate 1 (4.94 g, 21.4 mmol) was reacted with Intermediate 6BB (6.58 g, 25.7 mmol) to give 6.26 g (93% yield) of the title compound.

Intermediate 98: Methyl 3-[(2R)-tetrahydrofuran-2-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Analogously to the conversion of intermediate 95 to intermediate 94, intermediate 99 (6.26 g, 19.9 mmol) was reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis-1,3,2-dioxaborolane (12.6 g, 49.7 mmol) to give 6.26 g (87% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.23-1.39(m,12H)1.66-1.77(m,1H)1.78-1.94(m,2H)1.94-2.04(m,1H)3.62-3.72(m ,1H)3.73-3.82(m,1H)3.86(s,3H)3.94-4.08(m,2H)4.11-4.22(m,1H)7.39(dd,1H)7.55(dd,1H)7.81-7.89(m,1H).

Intermediate 4BL: methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 98 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) to give 182 mg (19% yield) of the title compound.

LCMS, method 1, rt: 1.39 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 5BL: 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoic acid

Analogously to the conversion of intermediate 4BD to intermediate 5BD, intermediate 4BL (188 mg, 94% purity, 509 μmol) was saponified to give 185 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.17 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 4BM: methyl 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 98 (1.00 g, 2.76 mmol) was reacted with 2-chloro-5-cyclobutyl-1,3-thiazole (527 mg, 3.04 mmol) to give 329 mg (32% yield) of the title compound.

LCMS, method 1, rt: 1.52 min, MS ES+ m/z = 374 (M+H) ⁺ .

Intermediate 5BM: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoic acid

Analogously to the conversion of intermediate 4BD to intermediate 5BD, intermediate 4BM (329 mg, 94% purity, 828 μmol) was saponified to give 316 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.30 min, MS ES+ m/z = 360 (M+H) ⁺ .

Intermediate 4BN: methyl 3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 98 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) to give 386 mg (39% yield) of the title compound.

LCMS, method 1, rt: 1.47 min, MS ES+ m/z = 362 (M+H) ⁺ .

Intermediate 5BN: 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoic acid

Analogously to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BN (386 mg, 94% purity, 1.00 mmol) was saponified to give 401 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.26 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 101: Methyl 3-bromo-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Analogously to the reaction of Intermediate 1 and Intermediate 6AZ to give Intermediate 95, Intermediate 1 (4.85 g, 21.0 mmol) was reacted with Intermediate 17A (6.45 g, 25.2 mmol) to give 7.47 g of the title compound.

LCMS, method 1, rt: 1.25 min, MS ES+ m/z = 315 (M+H) ⁺ .

Intermediate 100: Methyl 3-[(3S)-tetrahydrofuran-3-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Analogously to the conversion of intermediate 95 to intermediate 94, intermediate 101 (7.47 g, 23.7 mmol) was reacted with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis-1,3,2-dioxaborolane (15.0 g, 59.3 mmol) to give 9.27 g of the title compound.

LCMS, method 1, rt: 1.36 min, MS ES+ m/z = 363 (M+H) ⁺ .

1H NMR(400MHz,DMSO-d6)δ[ppm]1.27-1.33(m,12H)1.63-1.78(m,1H)1.94-2.07(m,1H)2.56-2.72(m,1H)3.54 (dd,1H)3.66(d,1H)3.73-3.83(m,2H)3.86(s,3H)3.99(dd,2H)7.39(dd,1H)7.55(dd,1H)7.81-7.89(m,1H).

Intermediate 4BO: methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 100 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) to give 538 mg (56% yield) of the title compound.

LCMS, method 1, rt: 1.38 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 5BO: 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoic acid

Analogously to the conversion of intermediate 4BD to intermediate 5BD, intermediate 4BO (538 mg, 94% purity, 1.46 mmol) was saponified to give 525 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.15 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 4BP: methyl 3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 100 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) to give 570 mg (57% yield) of the title compound.

LCMS, method 1, rt: 1.46 min, MS ES+ m/z = 362 (M+H) ⁺ .

Intermediate 5BP: 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoic acid

Analogously to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BP (570 mg, 94% purity, 1.48 mmol) was saponified to give 534 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.22 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 4BQ: methyl 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 100 (100 mg, 276 μmol) was reacted with 2,5-dichloro-1,3-thiazole (51.0 mg, 331 μmol) to give 77.8 mg (80% yield) of the title compound.

LCMS, method 1, rt: 1.42 min, MS ES+ m/z = 354 (M+H) ⁺ .

1H NMR(500MHz,DMSO-d6)δ[ppm]1.71(d,1H)1.98-2.11(m,1H)2.61-2.75(m,1H)3.57(dd,1H)3.67(td,1H)3.7 3-3.85(m,2H)3.89(s,3H)3.98-4.05(m,1H)4.06-4.16(m,1H)7.55(dd,1H)7.64(dd,1H)7.96-8.06(m,2H).

Intermediate 5BQ: 3-(5-chloro-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzoic acid

Intermediate 4BQ (347 mg, 981 μmol) was saponified similarly to the conversion of intermediate 4BD to intermediate 5BD to give 329 mg (99% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 1.18 min, MS ES+ m/z = 340 (M+H) ⁺ .

Intermediate 6BC: (2S)-tetrahydrofuran-2-ylmethyl 4-methylbenzenesulfonate

Analogously to the synthesis of intermediate 6AZ, (2S)-tetrahydrofuran-2-ylmethanol (3.00 g, 29.4 mmol) was reacted with 4-methylbenzenesulfonyl chloride (6.16 g, 32.3 mmol) to give 6.22 g (83% yield) of the title compound.

LCMS, method 1, rt: 1.06 min, MS ES+ m/z = 257 (M+H) ⁺ .

Intermediate 103: Methyl 3-bromo-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the reaction of Intermediate 1 and Intermediate 6AZ to give Intermediate 95, Intermediate 1 (4.94 g, 21.4 mmol) was reacted with Intermediate 6BC (6.58 g, 25.7 mmol) to give 4.08 g (61% yield) of the title compound.

LCMS, method 1, rt: 1.26 min, MS ES+ m/z = 315 (M+H) ⁺ .

Intermediate 102: Methyl 3-[(2S)-tetrahydrofuran-2-ylmethoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Analogously to the conversion of intermediate 95 to intermediate 94, intermediate 103 (4.08 g, 12.9 mmol) was reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis-1,3,2-dioxaborolane (8.22 g, 32.4 mmol) to give 6.62 g (80% yield) of the title compound.

LCMS, method 1, rt: 1.40 min, MS ES-m/z=641 (MH) ⁻ .

Intermediate 4BR: methyl 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 102 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-ethyl-1,3-thiazole (583 mg, 3.04 mmol) to give 480 mg (50% yield) of the title compound.

LCMS, method 1, rt: 1.40 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 5BR: 3-(5-ethyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid

Analogously to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BR (480 mg, 94% purity, 1.30 mmol) was saponified to give 552 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.19 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 4BS: methyl 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 102 (1.00 g, 2.76 mmol) was reacted with 2-chloro-5-cyclobutyl-1,3-thiazole (527 mg, 3.04 mmol) to give 590 mg (58% yield) of the title compound.

LCMS, method 1, rt: 1.52 min, MS ES+ m/z = 374 (M+H) ⁺ .

Intermediate 5BS: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid

Analogously to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BS (594 mg, 94% purity, 1.50 mmol) was saponified to give 634 mg of the title compound which was used without further purification.

LCMS, method 1, rt: 1.31 min, MS ES+ m/z = 360 (M+H) ⁺ .

Intermediate 4BT: methyl 3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoate

Analogously to the conversion of Intermediate 94 to Intermediate 4BD, Intermediate 102 (1.00 g, 2.76 mmol) was reacted with 2-bromo-5-(propan-2-yl)-1,3-thiazole (626 mg, 3.04 mmol) to give 485 mg (49% yield) of the title compound.

LCMS, method 1, rt: 1.47 min, MS ES+ m/z = 362 (M+H) ⁺ .

Intermediate 5BT: 3-[5-(Propan-2-yl)-1,3-thiazol-2-yl]-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid

Similar to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BT (490 mg, 94% purity, 1.27 mmol) was saponified to give 444 mg (100% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 1.25 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 104: 1-(2,2,2-trifluoroethyl)piperidin-4-ol

A mixture of 1-(2,2,2-trifluoroethyl)piperidin-4-one (2.40 g, 13.2 mmol) and NaBH ₄ (1.50 g, 39.7 mmol) was stirred in MeOH at room temperature for 16 hours. Saturated aqueous NaHCO ₃ was added, and the aqueous layer was extracted with DCM (3×). The combined organic layers were reduced to dryness under reduced pressure to give 2.14 g (88% yield) of the title compound, which was used without further purification.

Intermediate 6BD: 1-(2,2,2-trifluoroethyl)piperidin-4-yl 4-methylbenzenesulfonate

Analogously to the synthesis of intermediate 6AZ, intermediate 104 (2.14 g, 11.7 mmol) was reacted with 4-methylbenzenesulfonyl chloride (2.45 g, 12.9 mmol) to give 3.70 g (94% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.59(m,2H)1.65-1.79(m,2H)2.42(s,3H)2.7 0(m,2H)3.14(q,J＝10.31Hz,2H)4.52(dt,1H)7.47(d,2H)7.75-7.86(m,2H).

Intermediate 4BU: methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzoate

Analogously to the reaction of Intermediate 3A with Intermediate 6AY to give Intermediate 4AZ, Intermediate 3 (1.89 g, 7.59 mmol) was reacted with Intermediate 6BD (3.7 g, 90% purity, 9.87 mmol) to give 2.0 g (64% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.69(d,2H)1.93(d,2H)2.58-2.69(m,2H)2.78-2.92(m,2H)3 .13-3.27(m,2H)3.89(s,3H)4.55-4.69(m,1H)7.51(dd,1H)7.61-7.69(m,2H)7.97(t,1H).

Intermediate 5BU: 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy}benzoic acid

Intermediate 4BU (2.0 g, 4.83 mmol) was saponified similarly to the conversion of intermediate 4BD to intermediate 5BD to give 1.9 g (98% yield) of the title compound which was used without further purification.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.58-1.77(m,2H)1.95(dd,2H)2.57-2.69(m,2H)2.76- 2.94(m,2H)3.20(q,2H)4.46-4.67(m,1H)7.50(dd,1H)7.53-7.69(m,2H)7.95(t,1H).

Intermediate 105: 1-(2,2-difluoroethyl)piperidin-4-ol

Analogously to the synthesis of intermediate 104, 1-(2,2-difluoroethyl)piperidin-4-one (2.70 g, 16.5 mmol) was reduced to give 2.20 g (80% yield) of the title compound which was used without further purification.

Intermediate 6BE: 1-(2,2-difluoroethyl)piperidin-4-yl 4-methylbenzenesulfonate

Analogously to the synthesis of intermediate 6AZ, intermediate 105 (2.20 g, 13.3 mmol) was reacted with 4-methylbenzenesulfonyl chloride (2.79 g, 14.7 mmol) to give 4.80 g of the title compound.

LCMS, method 1, rt: 0.86 min, MS ES+ m/z = 320 (M+H) ⁺ .

Intermediate 4BV: Methyl 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Analogously to the reaction of intermediate 3A with intermediate 6AY to give intermediate 4AZ, intermediate 3 (2.25 g, 9.02 mmol) was reacted with intermediate 6BE (4.80 g, 90% purity, 13.5 mmol) to give 2.1 g (59% yield) of the title compound.

LCMS, method 1, rt: 0.94 min, MS ES+ m/z = 397 (M+H) ⁺ .

Intermediate 5BV: 3-{[1-(2,2-difluoroethyl)piperidin-4-yl]oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4BV (2.10 g, 5.30 mmol) was saponified similarly to the conversion of Intermediate 4BD to Intermediate 5BD to give 600 mg (30% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 0.76 and 0.83 min, MS ES+ m/z = 383 (M+H) ⁺ .

Intermediate 6BF: 4-methylbenzenesulfonic acid (3-methyloxetan-3-yl)methyl ester

Analogously to the synthesis of intermediate 6AZ, (3-methyloxetan-3-yl)methanol (630 mg, 6.17 mmol) was reacted with 4-methylbenzenesulfonyl chloride (1.29 g, 6.79 mmol) to give 1.20 g (76% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6) δppm 1.13-1.23(m,3H)2.43(s,3H)4.11(s,2H)4.15-4.20(m,2H)4.22-4.28(m,2H)7.50(d,2H)7.77-7.86(m,2H).

Intermediate 4BW: methyl 3-[(3-methyloxetan-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate

Analogously to the reaction of Intermediate 3A with Intermediate 6AY to give Intermediate 4AZ, Intermediate 3 (200 mg, 802 μmol) was reacted with Intermediate 6BF (308 mg, 1.20 mmol) to give 80.0 mg (30% yield) of the title compound.

LCMS, method 1, rt: 1.24 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 5BW: 3-[(3-methyloxetan-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Similar to the conversion of Intermediate 4BD to Intermediate 5BD, Intermediate 4BW (80.0 mg, 240 μmol) was saponified to give 75.0 mg (98% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 1.03 min, MS ES+ m/z = 320 (M+H) ⁺ .

Intermediate 6BG: (2-methyltetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate, mixture of two enantiomers

Analogously to the synthesis of intermediate 6AZ, racemic (2-methyltetrahydrofuran-2-yl)methanol (944 mg, 8.13 mmol) was reacted with 4-methylbenzenesulfonyl chloride (1.70 g, 8.94 mmol) to give 1.68 g (76% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]0.99-1.12(s,3H)1.47-1.65(m,1H)1.66-1.89(m,3H)2.37-2.4 7(s,3H)3.49-3.63(m,1H)3.63-3.74(m,1H)3.78-3.92(m,2H)7.49(d,2H)7.72-7.96(d,2H).

Intermediate 5BX: 3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, mixture of two enantiomers

A mixture _of Intermediate 3 (400 mg, 1.60 mmol), Intermediate 6BG (650 mg, 2.40 mmol) and _Cs2CO3 (783 mg, 2.40 mmol) was stirred in DMF (12 ml) at 90°C for 3 days. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to give 2.34 g of the title compound which was used without further purification.

LCMS, method 1, rt: 1.18 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 6BH: 4-methylbenzenesulfonic acid (3-methyltetrahydrofuran-3-yl)methyl ester, mixture of two enantiomers

Analogously to the synthesis of intermediate 6AZ, racemic (3-methyltetrahydrofuran-3-yl)methanol (1.00 g, 8.61 mmol) was reacted with 4-methylbenzenesulfonyl chloride (1.81 g, 9.47 mmol) to give 2.00 g (82% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]0.93-1.05(m,3H)1.54(ddd,1H)1.69(ddd,1H)2.37-2.47(m,3H)3.22(d1 H)3.45(d,1H)3.59-3.73(m,2H)3.81-3.92(m,2H)7.50(d,2H)7.80(d,2H).

Intermediate 4BY: Methyl 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate, mixture of two enantiomers

Analogously to the reaction of Intermediate 3A with Intermediate 6AY to give Intermediate 4AZ, Intermediate 3 (1.11 g, 4.44 mmol) was reacted with Intermediate 6BH (2.00 g, 90% purity, 6.66 mmol) to give 1.10 g (75% purity, 53% yield) of the title compound.

LCMS, method 1, rt: 1.37 min, MS ES+ m/z = 348 (M+H) ⁺ .

Intermediate 5BY: 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, mixture of two enantiomers

Intermediate 4BY (1.10 g, 3.17 mmol) was saponified similarly to the conversion of intermediate 4BD to intermediate 5BD to give 700 mg (63% yield) of the title compound which was used without further purification.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.21(s,3H)1.67(ddd,1H)1.86-2.01(m,1H)3.39(d,1H)3. 71(d,1H)3.75-3.88(m,2H)3.90-4.03(m,2H)7.53(dd,1H)7.56-7.67(m,2H)7.98(t,1H).

Intermediate 4BI: 1-methyl-6-oxopiperidin-3-yl 4-methylbenzenesulfonate, mixture of two enantiomers

Analogously to the synthesis of intermediate 6AZ, racemic 5-hydroxy-1-methylpiperidin-2-one (800 mg, 6.19 mmol) was reacted with 4-methylbenzenesulfonyl chloride (1.33 g, 6.81 mmol) to give 1.33 g (76% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]1.74-1.87(m,1H)1.87-2.01(m,1H)2.15-2.25(m,2H)2.43(s,3 H)2.71(s,3H)3.19-3.28(m,1H)3.53(dd,1H)4.88-5.02(m,1H)7.49(d,2H)7.79-7.91(m,2H).

Intermediate 4BZ: methyl 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate, mixture of two enantiomers

Analogously to the reaction of Intermediate 3A with Intermediate 6AY to give Intermediate 4AZ, Intermediate 3 (702 mg, 2.82 mmol) was reacted with Intermediate 4BI (1.33 g, 90% purity, 4.22 mmol) to give 350 mg (34% yield) of the title compound.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]2.06(br.s.,2H)2.20-2.30(m,1H)2.31-2.42(m,1H)2.81(s,3H)3.41 -3.46(m,1H)3.65(m,1H)3.89(s,3H)4.99-5.13(m,1H)7.57(dd,1H)7.63-7.74(m,2H)8.02(t,1H).

Intermediate 5BZ: 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, mixture of two enantiomers

Intermediate 4BZ (350 mg, 971 μmol) was saponified similarly to the conversion of intermediate 4BD to intermediate 5BD to give 330 mg (98% yield) of the title compound which was used without further purification.

¹ H NMR(400MHz,DMSO-d6)δ[ppm]2.01-2.10(m,2H)2.21-2.31(m,1H)2.31-2.42(m,1H)2.79-2.84 (m,3H)3.39-3.45(m,2H)3.66(dd,1H)5.05(m,1H)7.55(dd,1H)7.62-7.71(m,2H)8.00(t,1H).

Intermediate 4CA: Methyl 3-[(2-hydroxycyclopentyl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate, a mixture of two trans stereoisomers

A mixture of intermediate 3 (360 mg, 1.44 mmol), 6-oxabicyclo[3.1.0]hexane (182 mg, 2.17 mmol), and KOtBu (16.2 mg, 144 μmol) was stirred in DMF (11 ml) at 130° C. for 6 hours. Water and DCM were added to the mixture, and the phases were separated. The organic layer was extracted with DCM (3×). The combined organic layers were evaporated to dryness, and the residue was purified by column chromatography to give 800 mg of the title compound, which was used without further purification.

LCMS, method 1, rt: 1.21 min, MS ES+ m/z = 334 (M+H) ⁺ .

Intermediate 5CA: 3-[(2-hydroxycyclopentyl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, a mixture of two trans stereoisomers

Intermediate 4CA (500 mg, 1.50 mmol) was saponified similarly to the conversion of Intermediate 4BD to Intermediate 5BD to give 380 mg (79% yield) of the title compound which was used without further purification.

Intermediate 5CB: 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, a mixture of two trans stereoisomers

Intermediate 3 (600 mg, 2.4 mmol) and cis-2,3-butylene oxide (840 μl, 9.6 mmol) in THF (18.0 ml) were treated with NaOH (14.4 ml, 1.0 M, 14.4 mmol) and heated under reflux for 72 hours. The pH was adjusted to pH 5, the reaction mixture was extracted with ethyl acetate, and the combined organic layers were dried over Na ₂ SO ₄ , filtered and evaporated to dryness under reduced pressure to give 1.30 g of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.97 min, MS ES+ m/z = 308 (M+H) ⁺ .

Intermediate 4CC: methyl 3-(2-hydroxy-2-methylpropoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of intermediate 3 (221 mg, 887 μmol), 2,2-dimethyloxirane (320 mg, 4.43 mmol) and K ₂ CO ₃ (245 mg, 1.77 mmol) was stirred in DMSO (17 ml) at 130° C. for 3 hours. The mixture was evaporated to dryness under reduced pressure and purified by column chromatography (silica gel) to give 230 mg (81% yield) of the title compound.

Intermediate 5CC: 3-(2-hydroxy-2-methylpropoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4CC (230 mg, 716 μmol) was saponified similarly to the conversion of Intermediate 4BD to Intermediate 5BD to give 180 mg (82% yield) of the title compound which was used without further purification.

Intermediate 106: tert-Butyl 9-[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate, a mixture of two stereoisomers (cis/trans)

To a solution of tert-butyl 9-hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate (a mixture of two stereoisomers (cis/trans), 900 mg, 3.70 mmol) in DMF (12 ml) was added NaH (148 mg, 60% purity, 3.70 mmol), and the mixture was stirred at room temperature for 1 hour. Intermediate 26 (621 mg, 2.85 mmol) was added, and the resulting mixture was stirred at room temperature for 17 hours. Water was carefully added, the mixture was stirred for 30 minutes, and extracted with EE. The combined organic layers were washed with water and a saturated aqueous NaCl solution, dried over Na ₂ SO ₄ , filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give 665 mg (53% yield) of the title compound.

LCMS, method 1, rt: 1.40 min, MS ES+ m/z = 442 (M+H) ⁺ .

Intermediate 107: 3-{[7-(tert-Butoxycarbonyl)-3-oxa-7-azabicyclo[3.3.1]non-9-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid, a mixture of two stereoisomers (cis/trans)

To a solution of intermediate 106 (670 mg, 1.52 mmol) in DMSO (5 ml) was added sodium hydroxide (7.6 ml, 2.0 M, 15 mmol), and the mixture was stirred at 110° C. for 3 hours. The mixture was acidified with 2 M aqueous HCl and the pH was adjusted to pH 5. The solution was extracted with EE, and the combined organic layers were dried over Na ₂ SO ₄ , filtered, and evaporated to dryness under reduced pressure to give 808 mg of the title compound, which was used without further purification.

LCMS, method 1, rt: 1.23 min, MS ES+ m/z = 461 (M+H) ⁺ .

Intermediate 108: tert-Butyl 9-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate, a mixture of two stereoisomers (cis/trans)

A mixture of intermediate 107 (1.61 g, 3.50 mmol), intermediate VI (1:1) (1.11 g, 4.89 mmol), HATU (3.19 g, 8.39 mmol) and DIPEA (3.0 ml, 17 mmol) was stirred in DMF (160 ml) at ambient temperature for 12 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel) to give 1.35 g (58% yield) of the title compound.

LCMS, method 1, rt: 1.38 min, MS ES+ m/z = 634 (M+H) ⁺ .

Intermediate 109: 3-(5-methyl-1,3-thiazol-2-yl)-5-(3-oxa-7-azabicyclo[3.3.1]non-9-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, a mixture of two stereoisomers (cis/trans)

A mixture of intermediate 108 (1.32 g, 2.08 mmol) and TFA (3.2 ml, 42 mmol) was stirred in DCM (110 ml) at room temperature for 17 hours. The mixture was evaporated to dryness under reduced pressure and purified by column chromatography to give (818 mg, 73% yield) the title compound.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z = 534 (M+H) ⁺ .

¹ H NMR(500MHz,DMSO-d6)δ[ppm]1.62(d,3H)2.11-2.19(m,1H)2.20-2.30(m,1H)3.38-3.49(m,2H)3.54-3.67(m,1H)3.83- 3.94(m,2H)4.05-4.20(m,2H)4.96-5.13(m,1H)5.18-5.37(m,1H)7.66(m,3H)7.98(s,1H)9.12(d,2H)9.17-9.28(m,1H).

Intermediate 6CD: tert-Butyl (2S)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)morpholine-4-carboxylate

To (2S) -2- (hydroxymethyl) morpholine -4- carboxylic acid tert-butyl ester (5g, 23mmol), TEA (4.8ml, 34.5mmol) and trimethylamine hydrochloride (210mg, 2.2mmol) in DCM (60ml) was added 4- methylbenzenesulfonyl chloride (6.6g, 34.5mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was treated with N, N- dimethylethylene -1,2- diamine (1.5ml, 13.8mmol) to consume unreacted 4- methylbenzenesulfonyl chloride. The reaction mixture was washed with 1M HCl and water. The organic fraction was dried (sodium sulfate), filtered and concentrated under reduced pressure to obtain 10.1g (99% yield) of the title compound as a yellow oil that solidified on standing.

¹ H NMR (250MHz, DMSO-d6): δ[ppm]1.38(s,9H),2.43(s,3H),2.55-2.71(m,1H),2.71-2.89(m,1H),3.24-3.4 1(m,1H),3.52(m,1H),3.59-3.84(m,3H),3.92-4.14(m,2H),7.49(d,J=8.1Hz,2H),7.79(d,J=8.3Hz,2H).

Intermediate 110: (2R)-2-[(benzyloxy)methyl]morpholine

To a stirred mixture of (2R)-2-[(benzyloxy)methyl]oxirane (27.7 g, 0.17 mol) and NaOH (54.0 g, 1.3 mol) in water (130 ml) and MeOH (50 ml) was added 2-aminoethyl hydrogen sulfate (100 g, 0.7 mol) in portions. After the addition was complete, the reaction mixture was stirred at 40° C. for 2 hours. After cooling, the mixture was treated with another portion of NaOH (40.5 g, 1.0 mol) and then with toluene (200 ml) and stirred at 65° C. overnight. The mixture was cooled and diluted with toluene and water. The toluene layer was separated and the aqueous layer was extracted with DCM (2×100 ml). The combined organic layers were concentrated to give the title compound, which was used in the next step without purification.

Intermediate 111: tert-Butyl (2R)-2-[(benzyloxy)methyl]morpholine-4-carboxylate

A solution of intermediate 110 in acetone (400ml) and water (120ml) was cooled to 0°C, potassium carbonate (70g, 0.5mol) was added, followed by di-tert-butyl dicarbonate (44g, 0.2mol). The reaction mixture was allowed to warm to ambient temperature and stirred for 18 hours. Acetone was removed under reduced pressure and the aqueous solution was extracted twice with EtOAc. The combined organic matter was dried (MgSO ₄ ), filtered and concentrated under reduced pressure. Purification of the crude material by Biotage Isolera ^™ chromatography (eluting with 0-25% EtOAc in heptane on a pre-filled 340g silica gel column) gave 19.8g (38% yield) of the title compound as a light yellow oil.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 7.39-7.27 (m, 5H), 4.56 (s, 2H), 4.03-3.73 (m, 3H), 3.69-3.34 (m, 4H), 3.05-2.86 (m, 1H), 2.84-2.65 (m, 1H), 1.46 (s, 9H).

LC-MS (Method A) Rt=1.27 min, MS (ESIpos): m/z=252 (M-tBu) ⁺ .

Intermediate 112: tert-Butyl (2R)-2-(hydroxymethyl)morpholine-4-carboxylate

Intermediate 111 (19.8 g, 64.4 mmol) was stirred under a hydrogen atmosphere in the presence of 10% Pd/C (1.98 g, 1.86 mmol) for 16 hours. The catalyst was removed by vacuum filtration and the filtrate was concentrated under reduced pressure to give 13.98 g (100% yield) of the title compound as a colorless viscous oil which crystallized on standing.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 3.98-3.75 (m, 3H), 3.73-3.41 (m, 4H), 3.03-2.83 (m, 1H), 2.82-2.65 (m, 1H), 2.12 (t, J = 5.9Hz, 1H), 1.45 (s, 9H).

Intermediate 6CE: tert-Butyl (2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)morpholine-4-carboxylate

Intermediate 112 (5.96 g, 27.4 mmol), triethylamine (5.74 ml, 41.1 mmol), and trimethylamine hydrochloride (262 mg, 2.74 mmol) were stirred in dichloromethane (62 ml), followed by the addition of 4-toluenesulfonyl chloride (7.85 g, 41.1 mmol). The reaction was stirred at ambient temperature for 2 hours, then treated with N,N-dimethylethane-1,2-diamine (1.81 ml, 16.5 mmol) to consume unreacted 4-toluenesulfonyl chloride. The reaction mixture was washed with 1M HCl (2 x 100 ml) and water (50 ml). The organic fraction was dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford the title compound (11.4 g, 100% yield) as a yellow oil.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.80 (d, J = 8.3Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 4.02 (qd, J = 10.6, 5.0Hz, 2H), 3.94-3.74 (m, 3H),3.67-3.55(m,1H),3.46(td,J=11.6,2.8Hz,1H),2.98-2.81(m,1H),2.75-2.57(m,1H),2.45(s,3H),1.45(s,9H).

LC-MS (Method A) Rt=1.28 min, MS (ESIpos): m/z=394 (M+Na) ⁺ .

Intermediate 4CF: tert-Butyl 2-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

Intermediate 3 (300 mg, 1.2 mmol), tert-butyl 2-({[(4-methylphenyl)sulfonyl]oxy}methyl)morpholine-4-carboxylate (424.2 mg, 1.14 mmol) and cesium carbonate (439.4 mg, 1.32 mmol) were stirred in acetonitrile (5 ml) at 100 ° C in a sealed tube for 6 hours. The reaction mixture was cooled to room temperature, filtered through HPLC and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by Biotage Isolera ^™ chromatography (eluting with 5-70% EtOAc in heptane on a 25 g pre-packed KP-SiO ₂ column) to give 331.1 mg (70% yield) of the title compound as a colorless gum.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 8.13 (t, J = 1.4 Hz, 1H), 7.72-7.68 (m, 1H), 7.61 (dd, J = 2.5, 1.4 Hz, 1H), 7.52 (d, J = 1.2 Hz, 1H), 4.18-4.05 (m, 2H), 3.93 (s, 5H), 3.88-3.76 (m, 2H), 3.67-3.55 (m, 1H), 3.07-2.80 (m, 2H), 2.52 (d, J = 1.1 Hz, 3H), 1.48 (s, 9H).

Intermediate 4CE: (2R)-tert-Butyl 2-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

Intermediate 3 (23.17 g, 70.6 mmol), intermediate 6CE (28.9 g, 77.7 mmol) and cesium carbonate (34.52 g, 105.9 mmol) were combined in acetonitrile (300 ml) and stirred at 100 ° C under nitrogen for 2.5 hours. The cooled reaction mixture was filtered through 4% paraffin wax and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by Biotage Isolera ^™ chromatography (eluting with 0-50% EtOAc in heptane on a 340 g pre-packed KP-SiO ₂ column) to give 27.22 g (69% yield) of the title compound as a viscous yellow oil.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.13(t,J＝1.4Hz,1H),7.70(s,1H),7.61(dd,J＝2.4,1.3Hz,1H),7.52(d,J =1.1Hz,1H),4.18-3.78(m,11H),3.67-3.54(m,1H),2.95(m,2H),2.52(d,J=1.0Hz,3H),1.48(s,9H).

LCMS (Method A) Rt=1.40 min, MS (ESIpos): m/z=449 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 4CE using the corresponding phenol and tosylate starting materials.

Intermediate 4CG: tert-Butyl 4-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}piperidine-1-carboxylate

Intermediate 3 (300mg, 1.20mmol), 1-Boc-4-bromomethylpiperidine (4.35mg, 1.56mmol) and cesium carbonate (784mg, 2.04mmol) are combined in MeCN (5ml) and are heated to 100 ℃ for 6 hours. After cooling to room temperature, the reaction mixture is diluted with EtOAc (5ml), filtered and the filtrate is concentrated under reduced pressure. Purification of the crude material by Biotage Isolera ^™ chromatography (eluting with 0-40% EtOAc in heptane on a 25g pre-packed KP-SiO ₂ column) gives 272.2mg (49% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.08(s,1H),7.69(s,1H),7.58(s,1H),7.53(s,1H),4.24-4.09(m,2H),3.94(s,3H),3.92(d, J＝6.4Hz,2H),2.84-2.71(m,2H),2.53(s,3H),2.03-1.95(m,1H),1.84(d,J＝11.5Hz,2H),1.47(s,9H),1.36-1.23(m,2H).

LC-MS (Method A) Rt=1.50 min, MS (ESIpos): m/z=447 (M+H) ⁺ .

Intermediate 4CL: tert-Butyl 3-fluoro-3-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}azetidine-1-carboxylate

To a stirred solution of intermediate 3 (300 mg, 1.201 mmol), 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester (321 mg, 1.56 mmol) and triphenylphosphine (1.26 g, 4.81 mmol) in anhydrous THF (3 ml) at 0 ° C was added DIAD (472 μ L, 2.41 mmol). After 10 minutes, the reaction mixture was warmed to room temperature and stirred for 16 hours. Additional DIAD (200 μ L, 1.02 mmol) was added and the reactant was stirred at room temperature for 24 hours. Additional DIAD (200 μ L, 1.02 mmol) was added and the reactant was stirred at room temperature for 70 hours. The reaction mixture was concentrated under reduced pressure and purified by Biotage Isolera ^™ chromatography (eluting with a 0-100% gradient of EtOAc in heptane on a pre-packed KP-SiO ₂ column) to give 1.43 g (41% yield) of the title compound as a colorless oil. This material was used without further purification.

LC-MS (Method A) Rt=1.37 min, MS (ESIpos): m/z=437 (M+H) ⁺ .

Intermediate 6CV: tert-Butyl 3-({[(4-methylphenyl)sulfonyl]oxy}methyl)azetidine-1-carboxylate

By 3- (hydroxymethyl) azetidine -1- carboxylic acid tert-butyl esters (600mg, 3.20mmol), 4- methylbenzenesulfonyl chloride (672mg, 3.52mmol), TEA (670 μ L, 4.8mmol), trimethylammonium chloride (30.6mg, 320 μ mol) mixture in DCM (3.2ml) at room temperature is stirred until complete conversion.Reactant mixture is evaporated to dryness.Crude material is purified by column chromatography (silica gel, hexane/EtOAc gradient), 800mg (73% yield) title compound is obtained.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]1.34(s,9H),2.43(s,3H),2.73-2.87(m,1H),3.46( br.s.,2H),3.74-3.91(m,2H),4.16(d,2H),7.44-7.57(m,2H),7.74-7.85(m,2H).

Intermediate 4CV: tert-Butyl 3-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}azetidine-1-carboxylate

_A mixture of intermediate 3 (389 mg, 1.56 mmol), intermediate 6CV (389 mg, 1.56 mmol) and _CsCO was stirred in DMF (11 ml) at 90°C until complete conversion. The DMF was evaporated under reduced pressure, water and DCM were added, and the aqueous layer was extracted with DCM. The combined organics were evaporated to dryness. The crude material was purified by column chromatography (silica gel, hexane/EtOAc gradient) to give 300 mg (46% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]1.38-1.44(m,9H),2.90-3.05(m,1H),3.66-3.80(m,2H),3 .89(s,3H),3.93-4.04(m,2H),4.26(d,2H),7.52(dd,1H),7.60-7.69(m,2H),8.00(t,1H).

Intermediate 149: N-[(2R)-1-(Benzyloxy)-3-hydroxypropan-2-yl]-2-chloroacetamide

(2R)-2-amino-3-(benzyloxy)propan-1-ol (5.00 g, 27.6 mmol) was dissolved in acetonitrile (87 ml) and MeOH (16 ml) and TEA (4.6 ml, 33 mmol) were added. The mixture was cooled to -10°C and a solution of chloroacetyl chloride (2.4 ml, 30 mmol) in acetonitrile was added dropwise. The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/hexane gradient) to give 5.46 g (77% yield) of the title compound.

¹ H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.57 (br. s., 1H) 3.51-3.71 (m, 3H) 3.81 (dd, 1H) 3.95-4.10 (m, 3H) 4.42-4.52 (m, 2H) 7.16 (d, 1H) 7.21-7.35 (m, 5H).

Intermediate 150: (5S)-5-[(Benzyloxy)methyl]morpholin-3-one

Over 2 hours, to a solution of potassium tert-butoxide (980 mg, 8.73 mmol) in 2-methylbutan-2-ol was added dropwise a solution of intermediate 149 (2.25 g, 8.73 mmol) in 2-methylbutan-2-ol. After 12 hours, another equivalent of potassium tert-butoxide was added, and the reaction mixture was stirred for 12 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/EtOH gradient) to give 1.50 g (78% yield) of the title compound.

¹ H NMR (400MHz, chloroform-d): δ[ppm]3.39-3.48(m,1H)3.56(dd,1H)3.63(dd,1H)3.70-3.8 1(m,1H)3.87(dd,1H)4.16(d,2H)4.55(d,2H)6.33(br.s.,1H)7.29-7.42(m,5H).

Intermediate 151: (5S)-5-[(Benzyloxy)methyl]-4-methylmorpholin-3-one

A solution of intermediate 150 (619 mg, 2.8 mmol) in THF (25 ml) was added dropwise to a suspension of NaH (134 mg, 60%, 3.36 mmol) in THF (70 ml) at 0°C. The mixture was stirred at room temperature for 30 minutes, then cooled to 0°C and MeI (870 μL, 14 mmol) was added. After 15 minutes, the reaction mixture was warmed to room temperature and stirred for 15 hours. Saturated aqueous _NH4Cl solution (50 ml) was added at 0°C, and the solvent was evaporated under reduced pressure. The residue was diluted with water and extracted with EtOAc, and the organic layer was dried over _MgSO4 . The solvent was distilled off under reduced pressure to give 650 mg (99% yield) of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z = 236 (M+H) ⁺ .

Intermediate 152: (5S)-5-(Hydroxymethyl)-4-methylmorpholin-3-one

Intermediate 151 (617 mg, 2.62 mmol) was dissolved in EtOH and Pd(OH) ₂ (92 mg, 20% on carbon, 131 μmol) was added and stirred under a hydrogen atmosphere for 10 hours. Additional Pd(OH) ₂ (0.025 equivalent) was added and the mixture was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was filtered and washed with EtOH. The organic phase was concentrated to dryness under reduced pressure to give 398 mg (100% yield) of the title compound.

¹ H NMR (400 MHz, chloroform-d): δ [ppm] 1.96 (t, 1H) 3.06 (s, 3H) 3.29 (td, 1H) 3.79-3.96 (m, 3H) 4.08-4.28 (m, 3H).

Intermediate 6CX: 4-methylbenzenesulfonic acid [(3R)-4-methyl-5-oxomorpholin-3-yl]methyl ester

A mixture of intermediate 152 (322 mg, 2.22 mmol), TEA (460 μL, 3.3 mmol) and trimethylamine hydrochloride was cooled to 0 ° C in DCM and stirred for 10 minutes. 4-Methylbenzenesulfonyl chloride (465 mg, 2.44 mmol) was added in three portions, and the solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (290 μL, 2.7 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added to the reaction mixture, and the aqueous phase was extracted with DCM. The organic phase was concentrated to dryness to obtain 505 mg (68% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ [ppm] 2.43 (s, 3H) 2.81 (s, 3H) 3.54-3.62 (m, 1H) 3.75 (d, 2H) 3.97 (s, 2H) 4.15-4.25 (m, 2H) 7.50 (d, 2H) 7.82 (d, 2H).

Intermediate 4CX: methyl 3-{[(3R)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of intermediate 3 (280 mg, 1.12 mmol), intermediate 6CX (505 mg, 1.69 mmol) and Cs ₂ CO ₃ (550 mg, 1.69 mmol) was stirred at 90° C. until complete conversion. DMF was evaporated under reduced pressure, water and DCM were added, and the aqueous layer was extracted with DCM (three times). The combined organics were evaporated to dryness and the crude material was purified by column chromatography (silica gel, hexane/EtOAc gradient) to give 530 mg of the title compound.

LCMS, method 1, rt: 1.09 min, MS ES+ m/z = 377 (M+H) ⁺ .

Intermediate 153: (5S)-5-(Hydroxymethyl)morpholin-3-one

Intermediate 150 (650 mg, 2.94 mmol) was dissolved in MeOH (53 ml), and Pd(OH) (103 _mg , 20% on carbon, 147 μmol) was added and stirred under a hydrogen atmosphere for 8 hours. The mixture was filtered through Celite®, washed with EtOH, and the filtrate was concentrated under reduced pressure to give 322 mg (74% yield) of the title compound, which was used without further purification.

¹ H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.88 (br. s., 1H) 3.59-3.79 (m, 4H) 3.82-3.97 (m, 1H) 4.06-4.25 (m, 2H) 7.18 (br. s., 1H).

Intermediate 6CY: 4-methylbenzenesulfonic acid [(3R)-5-oxomorpholin-3-yl]methyl ester

A mixture of intermediate 153 (322 mg, 2.46 mmol), TEA (510 μL, 3.7 mmol) and trimethylamine hydrochloride (23.5 mg, 246 μmol) was cooled to 0 ° C and stirred for 10 minutes in DCM (7.2 ml). 4-Methylbenzenesulfonyl chloride (515 mg, 2.70 mmol) was added in three portions, and the solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (320 μL, 2.9 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added to the crude mixture, and the collected aqueous phase was extracted with DCM (three times). The combined organic layer was concentrated to dryness to obtain 526 mg (42% yield) of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z = 286 (M+H) ⁺ .

Intermediate 4CY: methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3R)-5-oxomorpholin-3-yl]methoxy}benzoate

_A mixture of intermediate 3 (306 mg, 1.23 mmol), intermediate 6CY (526 mg, 1.84 mmol) and _Cs2CO3 (601 mg, 1.84 mmol) was stirred in DMF (120 ml) at 90°C until complete conversion. The DMF was evaporated under reduced pressure, and the residue was partitioned between water and DCM. The aqueous layer was extracted with DCM (three times), and the combined organic layers were evaporated to dryness. Purification by column chromatography (silica gel, EtOAc/hexane gradient) gave 834 mg of the title compound.

LCMS, method 1, rt: 1.03 min, MS ES+ m/z = 363 (M+H) ⁺ .

Intermediate 154: (2S)-3-[Benzyl(methyl)amino]propane-1,2-diol

A solution of (2R)-oxiran-2-ylmethanol (4.71 g, 63.6 mmol) and N-methyl-1-phenylmethanamine (7.9 ml, 61 mmol) in MeOH (350 ml) was heated under reflux for 24 h, cooled to RT and evaporated to dryness under reduced pressure to give 12.6 g of the title compound which was used without further purification.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z = 196 (M+H) ⁺ .

Intermediate 155: (2S)-3-(Methylamino)propane-1,2-diol

A mixture of intermediate 154 (12.6 g, 64.5 mmol) and palladium on carbon (4.12 g, 5%, 1.94 mmol) in MeOH (78 ml) was hydrogenated at 5 bar for 18 h at 23° C. The mixture was filtered, washed with MeOH, and the filtrate was evaporated to dryness under reduced pressure to give 6.07 g (76% yield) of the title compound, which was used without further purification.

¹ H NMR (400 MHz, chloroform-d): δ [ppm] 2.45 (s, 3H) 2.63-2.70 (m, 1H) 2.71-2.77 (m, 1H) 2.89-2.98 (m, 3H) 3.54-3.62 (m, 1H) 3.67-3.74 (m, 1H) 3.79 (ddt, 1H).

Intermediate 156: (5S)-5-(Hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one

To a mixture of intermediate 155 (3.25 g, 30.9 mmol) and diethyl carbonate (22 ml, 190 mmol) was added potassium tert-butoxide (173 mg, 1.55 mmol). The reaction mixture was stirred at 100° C. for 14 hours and evaporated to dryness to give 1.44 g (31% yield) of the title compound which was used without further purification.

¹ H NMR (400MHz, DMSO-d6): δ [ppm] 2.72 (s, 3H) 3.27 (dd, 1H) 3.41-3.49 (m, 1H) 3.53 (t, 2H) 4.46 (ddd, 1H) 5.09 (s, 1H).

Intermediate 6CZ: 4-methylbenzenesulfonic acid [(5S)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methyl ester

A mixture of intermediate 156 (2.24 g, 17.1 mmol), TEA (3.6 ml, 26 mmol) and trimethylamine hydrochloride (163 mg, 1.71 mmol) was stirred in DCM (50 ml) at 0 ° C for 10 minutes and then treated with 3 batches of 4-methylbenzenesulfonyl chloride. The mixture was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (2.2 ml, 20 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added, the aqueous phase was extracted with DCM (three times), and the combined organic layers were concentrated to dryness to give 4.67 g (91% yield) of the title compound.

1H NMR (400 MHz, chloroform-d): δ [ppm] 2.47 (s, 3H) 2.87 (s, 3H) 3.44 (dd, 1H) 3.65 (t, 1H) 4.06-4.21 (m, 2H) 4.61-4.73 (m, 1H) 7.38 (d, 2H) 7.76-7.86 (m, 2H).

Analytical chiral HPLC, method G: retention times: 5.04 min (78.4%) and 5.48 min (21.6%), ee-value: 56.8%.

Intermediate 4CZ: methyl 3-{[(5S)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of intermediate 3 (582 mg, 2.34 mmol), intermediate 6CZ (1.00 g, 3.50 mmol) and Cs ₂ CO ₃ (1.14 g, 3.50 mmol) was stirred in DMF (17 ml) at 90° C. until complete conversion. DMF was evaporated under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to give 844 mg (94% yield) of the title compound.

LCMS, method 1, rt: 1.07 min, MS ES+ m/z = 363 (M+H)+.

Intermediate 157: (2R)-3-[Benzyl(methyl)amino]propane-1,2-diol

A solution of (2S)-oxiran-2-ylmethanol (3.77 g, 50.9 mmol) and N-methyl-1-phenylmethanamine (6.3 ml, 49 mmol) in MeOH (280 ml) was heated under reflux for 24 h, cooled to RT and evaporated to dryness under reduced pressure to give 9.72 g (98% yield) of the title compound which was used without further purification.

LCMS, method 1, rt: 0.86 min, MS ES+ m/z = 196 (M+H) ⁺ .

Intermediate 158: (2R)-3-(Methylamino)propane-1,2-diol

A mixture of intermediate 157 (9.72 g, 49.8 mmol) and palladium on carbon (3.18 g, 5%, 1.49 mmol) in MeOH (60 ml) was hydrogenated at 23 °C under 5 bar for 18 h. The mixture was filtered, washed with MeOH and the filtrate was evaporated to dryness under reduced pressure to give 5.35 g of the title compound which was used without further purification.

¹ H NMR (400 MHz, CHLOROFORM-d): δ [ppm] 2.43-2.47 (m, 3H) 2.64-2.71 (m, 1H) 2.72-2.79 (m, 1H) 2.91 (br. s., 3H) 3.57-3.63 (m, 1H) 3.68-3.75 (m, 1H) 3.76-3.83 (m, 1H).

Intermediate 159: (5R)-5-(Hydroxymethyl)-3-methyl-1,3-oxazolidin-2-one

To a solution of intermediate 158 (2.58 g, 24.5 mmol) in diethyl carbonate (18 ml, 150 mmol) was added potassium tert-butoxide (138 mg, 1.23 mmol). The reaction mixture was stirred at 100 ° C for 24 hours and evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to give 861 mg (27% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ [ppm] 2.72 (s, 3H) 3.27 (dd, 1H) 3.47 (dd, 1H) 3.49-3.58 (m, 2H) 4.40-4.51 (m, 1H) 5.10 (t, 1H).

Intermediate 6DA: 4-methylbenzenesulfonic acid [(5R)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methyl ester

A mixture of intermediate 159 (2.74 g, 20.9 mmol), TEA (4.4 ml, 31 mmol) and trimethylamine hydrochloride (200 mg, 2.09 mmol) was cooled to 0 ° C in DCM (61 ml) and stirred for 10 minutes. 4-Methylbenzenesulfonyl chloride (4.38 g, 23.0 mmol) was added in three portions, and the solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (2.7 ml, 25 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added, the aqueous phase was extracted with DCM (three times), and the combined organic layers were concentrated to dryness to give 5.97 g (94% yield) of the title compound, which was used without further purification.

¹ H NMR (400MHz, DMSO-d6): δppm 2.43(s,3H)2.66-2.73(m,3H)3.17(dd,1H)3.57(t,1H)4.09-4.17(m,1H)4.18-4.25(m,1H)4.69(dt,1H)7.47-7.55(m,2H)7.75-7.85(m,2H).

Analytical chiral HPLC, method G: retention time: 5.46 min (88.0%) and 5.05 min (12.0%), ee-value: 76.0%.

Intermediate 4DA: methyl 3-{[(5R)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of intermediate 6DA (582 mg, 2.34 mmol), intermediate 3 (1.00 g, 3.50 mmol) and _{CsCO (} 1.14 g, 3.50 mmol) was stirred in DMF (17 ml) at 90°C until complete conversion. The DMF was evaporated under reduced pressure, water and DCM were added, and the aqueous layer was extracted with DCM (three times). The combined organic layers were evaporated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to give 609 mg (67% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δppm 2.79(s,3H)3.33(s,2H)3.43(dd,1H)3.70(t,1H)3.89(s,3H)4.22-4.31(m,1 H)4.32-4.40(m,1H)4.82-4.93(m,1H)7.53(dd,1H)7.66(q,2H)8.02(t,1H).

Intermediate 160: 2-Chloro-N-[(2R)-2,3-dihydroxypropyl]-N-methylacetamide

To a solution of intermediate 158 (2.80 g, 26.6 mmol) in acetonitrile (84 ml) and MeOH (16 ml) was added TEA (4.5 ml, 32 mmol) and the mixture was cooled to -10°C. A solution of chloroacetyl chloride (2.3 ml, 29 mmol) in acetonitrile was added dropwise and the mixture was stirred at room temperature for 20 hours. The reaction solvent was distilled off to give 4.53 g (94% yield) of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.45 min, MS ES+ m/z = 183 (M+H) ⁺ .

Intermediate 161: (6R)-6-(Hydroxymethyl)-4-methylmorpholin-3-one

Over 2 hours, to a solution of potassium tert-butoxide (5.60 g, 49.9 mmol) in dimethylbutan-2-ol was added dropwise a solution of intermediate 160 (4.53 g, 24.9 mmol) in 2-methylbutan-2-ol. After 4 hours, the conversion was complete. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/EtOH gradient) to give 4.63 g of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ [ppm] 2.85 (s, 3H) 3.21-3.27 (m, 2H) 3.37-3.54 (m, 2H) 3.78 (dq, 1H) 4.01-4.06 (m, 2H) 4.91 (t, 1H).

Intermediate 6DB: 4-methylbenzenesulfonic acid [(2R)-4-methyl-5-oxomorpholin-2-yl]methyl ester

A mixture of intermediate 161 (4.63 g, 31.9 mmol), TEA (6.7 ml, 48 mmol) and trimethylamine hydrochloride (305 mg, 3.19 mmol) was cooled to 0 ° C in DCM (94 ml) and stirred for 10 minutes. Afterwards, 4-methylbenzenesulfonyl chloride (6.69 g, 35.1 mmol) was added in three portions. The solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N,N-dimethylethylenediamine (4.2 ml, 38 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added, the aqueous phase was extracted with DCM (three times), and the organic layer was concentrated to dryness to give 3.43 g (36% yield) of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z = 300 (M+H) ⁺ .

Intermediate 4DB: methyl 3-{[(2R)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of intermediate 3 (1.90 g, 7.64 mmol), intermediate 6DB (3.43 g, 11.5 mmol) and _Cs2CO3 (3.73 g, 11.5 mmol) was stirred in DMF (56 ml) at 90°C until complete conversion. DMF was evaporated under reduced pressure to give 2.76 g (96% yield) _of the title compound which was used without further purification.

LCMS, method 1, rt: 1.06 min, MS ES+ m/z = 377 (M+H) ⁺ .

Intermediate 162: 2-Chloro-N-[(2S)-2,3-dihydroxypropyl]acetamide

(2S)-3-Aminopropane-1,2-diol (5.00 g, 54.9 mmol) was dissolved in acetonitrile (170 ml), and MeOH (32 ml) and TEA (9.2 ml, 66 mmol) were added. The mixture was cooled to -10°C, and a solution of chloroacetyl chloride (4.8 ml, 60 mmol) in acetonitrile was added dropwise. The mixture was stirred at room temperature for 21 hours. The reaction solvent was distilled off under reduced pressure, and the remaining residue was purified by column chromatography (silica gel, EtOAc/hexane/MeOH gradient) to obtain 10.5 g of the title compound.

Intermediate 163: (6S)-6-(Hydroxymethyl)morpholin-3-one

Potassium tert-butoxide (14.0 g, 125 mmol) was dissolved in 2-methylbutan-2-ol. A solution of intermediate 162 in 2-methylbutan-2-ol was added dropwise over 2 hours, and the reaction mixture was stirred until complete conversion. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to give 7.46 g (27% yield).

Intermediate 6DC: 4-methylbenzenesulfonic acid [(2S)-5-oxomorpholin-2-yl]methyl ester

A mixture of intermediate 163 (7.46 g, 56.9 mmol), TEA (12 ml, 85 mmol) and trimethylamine hydrochloride (544 mg, 5.69 mmol) was cooled to 0 ° C in DCM and stirred for 10 minutes. Afterwards, 4-methylbenzenesulfonyl chloride (11.9 g, 62.6 mmol) was added in 3 portions. The solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (7.5 ml, 68 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added, the aqueous phase was extracted with DCM (three times), and the organic layer was concentrated to dryness under reduced pressure to give 5.23 g of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.86 min, MS ES+ m/z = 286 (M+H) ⁺ .

Intermediate 4DC: methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2S)-5-oxomorpholin-2-yl]methoxy}benzoate

A mixture of intermediate 3 (3.05 g, 12.2 mmol), intermediate 6DC (5.23 g, 18.3 mmol) and Cs ₂ CO ₃ (5.97 g, 18.3 mmol) was stirred in DMF (89 ml) at 90° C. until complete conversion. The DMF was evaporated, and DCM and water were added. The mixture was extracted with DCM (three times), and the combined organic layers were evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/EtOH gradient) to give 2.14 g (48% yield) of the title compound.

LCMS, method 1, rt: 1.00 min, MS ES+ m/z = 363 (M+H) ⁺ .

Intermediate 164: 2-Chloro-N-[(2S)-2,3-dihydroxypropyl]-N-methylacetamide

Intermediate 155 was dissolved in acetonitrile (84 ml), MeOH (16 ml) and TEA (4.5 ml, 32 mmol) were added, and the mixture was cooled to -10°C. A solution of chloroacetyl chloride (2.3 ml, 29 mmol) in acetonitrile was added dropwise, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure to give 8.64 g of the title compound, which was used without further purification.

Intermediate 165: (6S)-6-(Hydroxymethyl)-4-methylmorpholin-3-one

Potassium tert-butoxide (8.01 g, 71.4 mmol) was dissolved in 2-methylbutan-2-ol. A solution of intermediate 164 in 2-methylbutan-2-ol was added dropwise over 2 hours. The mixture was stirred overnight, and then the reaction solvent was distilled off under reduced pressure to give 3.63 g (53% yield) of the title compound, which was used without further purification.

Intermediate 6DD: 4-methylbenzenesulfonic acid [(2S)-4-methyl-5-oxomorpholin-2-yl]methyl ester

A mixture of intermediate 165 (4.00 g, 27.6 mmol), TEA (5.8 ml, 41 mmol) and trimethylamine hydrochloride (263 mg, 2.76 mmol) was cooled to 0 ° C in DCM (81 ml) and stirred for 10 minutes. Afterwards, 4-methylbenzenesulfonyl chloride (5.78 g, 30.3 mmol) was added in three portions. The solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (3.6 ml, 33 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added, the aqueous phase was extracted with DCM (three times), and the combined organic layer was concentrated to dryness. The residue was purified by column chromatography (silica gel, EtOAc/MeOH gradient) to obtain 2.55 g (31% yield) of the title compound.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z = 300 (M+H) ⁺ .

Intermediate 4DD: methyl 3-{[(2S)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of intermediate 3 (1.42 g, 5.68 mmol), intermediate 6DD (2.55 g, 8.52 mmol) and Cs ₂ CO ₃ (2.78 g, 8.52 mmol) was stirred in DMF (41 ml) at 90° C. until complete conversion. DMF was distilled off under reduced pressure and the residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to give 1.57 g (73% yield) of the title compound.

LCMS, method 1, rt: 1.06 min, MS ES+ m/z = 377 (M+H) ⁺ .

Intermediate 166: N-[(2S)-1-(Benzyloxy)-3-hydroxypropan-2-yl]-2-chloroacetamide

(2S)-2-Amino-3-(benzyloxy)propan-1-ol (5.00 g, 27.6 mmol) was dissolved in acetonitrile (87 ml), and MeOH (16 ml) and TEA (4.6 ml, 33 mmol) were added. The mixture was cooled to -10°C, and a solution of chloroacetyl chloride (2.4 ml, 30 mmol) in acetonitrile was added dropwise. The mixture was stirred at room temperature for 20 hours, and the reaction solvent was distilled off to obtain 10.91 g of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z = 258 (M+H) ⁺ .

Intermediate 167: (5R)-5-[(Benzyloxy)methyl]morpholin-3-one

Potassium tert-butoxide (3.96 g, 35.3 mmol) was dissolved in 2-methylbutan-2-ol. A solution of intermediate 166 (5.68 g, 17.6 mmol) in 2-methylbutan-2-ol (160 ml in total) was added dropwise over 2 hours and the mixture was stirred until complete conversion. The reaction solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (EtOAc/EtOH gradient) to give 3.57 g (89% yield) of the title compound.

¹ H NMR (400MHz, chloroform-d): δ[ppm]3.39-3.47(m,1H)3.56(dd,1H)3.63(dd,1H)3.71-3.81(m,1 H)3.87(dd,1H)4.09-4.24(m,2H)4.49-4.60(m,2H)6.39(br.s.,1H)7.29-7.43(m,5H).

Intermediate 168: (5R)-5-[(Benzyloxy)methyl]-4-methylmorpholin-3-one

A solution of intermediate 167 (2.00 g, 9.04 mmol) in THF (25 ml) was added dropwise to a suspension of NaH (434 mg, 60% purity, 10.8 mmol) in THF (70 ml) at 0°C. The mixture was stirred at room temperature for 30 minutes. MeI (2.8 ml, 45 mmol) was added to the mixture at 0°C, and the mixture was stirred at room temperature for 15 hours. Saturated aqueous _NH4Cl solution (50 ml) was added at 0°C, and the solvent was distilled off under reduced pressure. The residue was diluted with water and extracted with EtOAc (three times). The combined organic layers were dried over _MgSO4 , and the solvent was distilled off under reduced pressure to obtain 1.78 g (78% yield) of the title compound.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 3.03 (s, 3H) 3.40 (ddd, 1H) 3.62-3.81 (m, 3H) 4.03-4.24 (m, 3H) 4.51-4.61 (m, 2H) 7.29-7.41 (m, 5H).

Intermediate 169: (5R)-5-(Hydroxymethyl)-4-methylmorpholin-3-one

Intermediate 168 (1.78 g, 7.57 mmol) was dissolved in MeOH (140 ml), Pd(OH)2 (266 mg, 20% on carbon, 378 μmol) was added, and the mixture was stirred under a hydrogen atmosphere for 10 hours. An additional 0.0025 equivalents of catalyst was added, and the mixture was stirred under a hydrogen atmosphere for an additional 3 hours. The reaction mixture was filtered through HPLC and washed with EtOH to give 1.12 g of the title compound from the filtrate under reduced pressure, which was used without further purification.

Intermediate 6DE: 4-methylbenzenesulfonic acid [(3S)-4-methyl-5-oxomorpholin-3-yl]methyl ester

A mixture of intermediate 169, TEA (1.6 ml, 12 mmol) and trimethylamine hydrochloride (73.7 mg, 772 μmol) was cooled to 0 ° C and stirred for 10 minutes in DCM (23 ml). Afterwards, 4-methylbenzenesulfonyl chloride (1.62 g, 8.49 mmol) was added in 3 portions. The solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (1.0 ml, 9.3 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added to the mixture and each phase was separated. The aqueous phase was extracted with DCM (three times) and the combined organic layer was concentrated to dryness. The residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to obtain 917 mg (40% yield) of the title compound.

LCMS, method 1, rt: 0.89 min, MS ES+ m/z = 300 (M+H) ⁺ .

Intermediate 4DE: methyl 3-{[(3S)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate

A mixture of intermediate 3 (312 mg, 1.25 mmol), intermediate 6DE (450 mg, 1.50 mmol) and _{CsCO (} 612 mg, 1.88 mmol) was stirred in DMF (6.3 ml) at 90°C until complete conversion. The DMF was distilled off under reduced pressure, water and DCM were added, and the layers were separated. The aqueous layer was extracted with DCM (three times), and the combined organic layers were evaporated to dryness. The residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to give 294 mg (58% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]3.00(s,3H)3.71-3.79(m,1H)3.83-3.92(m,4H)4.01(d,1H)4 .08(d,2H)4.29(d,1H)4.33-4.42(m,1H)7.57(dd,1H)7.66(d,1H)7.70(dd,1H)8.02(t,1H).

Intermediate 170: (5R)-5-(Hydroxymethyl)morpholin-3-one

Intermediate 167 was dissolved in MeOH (120 ml), Pd(OH)2 (244 mg, 20% on carbon, 348 μmol) was added and stirred under a hydrogen atmosphere for 10 hours. An additional 0.025 equivalent of catalyst was added and the mixture was stirred for an additional 3 hours. The reaction mixture was filtered through HPLC and washed with EtOH. The filtrate was concentrated under reduced pressure to give 1.16 g of the title compound, which was used without further purification.

Intermediate 6DF: 4-methylbenzenesulfonic acid [(3S)-5-oxomorpholin-3-yl]methyl ester

A mixture of intermediate 170 (1.16 g, 8.85 mmol), TEA (1.8 ml, 13 mmol) and trimethylamine hydrochloride (84.5 mg, 885 μmol) was cooled to 0 ° C in DCM (26 ml) and stirred for 10 minutes. Afterwards, 4-methylbenzenesulfonyl chloride (1.86 g, 9.73 mmol) was added in 3 portions. The solution was stirred at room temperature until complete conversion. The reaction mixture was treated with N, N-dimethylethylenediamine (1.2 ml, 11 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added to the mixture, the layers were separated, and the aqueous phase was extracted with DCM (three times). The combined organic layer was concentrated to dryness, and the residue was purified by silica gel column chromatography (hexane/EtOAc/MeOH gradient) to obtain 1.06 g (42% yield) of the title compound.

LCMS, method 1, rt: 0.83 min, MS ES+ m/z = 286 (M+H) ⁺ .

Intermediate 4DF: methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3S)-5-oxomorpholin-3-yl]methoxy}benzoate

A mixture of intermediate 3 (364 mg, 1.46 mmol), intermediate 6DF (500 mg, 1.75 mmol), and _{CsCO (} 714 mg, 2.19 mmol) was stirred at 90°C until complete conversion. DMF was evaporated under reduced pressure, water and DCM were added, and the layers were separated. The aqueous layer was extracted with DCM (three times), and the combined organic layers were evaporated to dryness. The residue was purified by silica gel column chromatography (hexane/EtOAc/MeOH gradient) to give 349 mg (59% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]3.76(d,1H)3.84-3.88(m,2H)3.89(s,3H)4.01(s,2H)4 .08(dd,1H)4.20(dd,1H)7.55(dd,1H)7.63-7.72(m,2H)7.98-8.05(m,1H)8.30(d,1H).

Intermediate 6DJ: tert-Butyl 1-({[(4-methylphenyl)sulfonyl]oxy}methyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate as a mixture of two enantiomers

A mixture of 1-(hydroxymethyl)-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylic acid tert-butyl ester (1.00 g, 4.36 mmol), TEA (910 μL, 6.5 mmol) and trimethylamine hydrochloride (41.7 mg, 436 μmol) was cooled to 0 ° C in DCM (13 ml) and stirred for 10 minutes. Afterwards, 4-methylbenzenesulfonyl chloride (915 mg, 4.80 mmol) was added in three portions, and the solution was stirred at room temperature overnight. The reaction mixture was treated with N, N-dimethylethylenediamine (570 μL, 5.2 mmol) to consume unreacted 4-methylbenzenesulfonyl chloride. Water was added to the mixture, the aqueous phase was extracted with DCM (three times), and the combined organic layers were concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc/MeOH gradient) to obtain 1.41 g (84% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]1.38(d,9H)1.63-1.82(m,2H)2.43(s,3H)3.04-3.24(m,2H)3.66(s,2H)4.37(d,3H)7.49(d,2H)7.75-7.85(m,2H).

Intermediate 4DG: tert-butyl 1-{[3-(methoxycarbonyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate, as a mixture of two enantiomers

A mixture of Intermediate 3 (450 mg, 1.81 mmol), Intermediate 6DJ, _Cs2CO3 (882 mg, 2.71 mmol) _, and DMF (10 ml) was stirred at 90°C until complete conversion. The DMF was evaporated under reduced pressure, and the residue was dissolved in water and DCM, and the phases were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/EtOAc gradient) to give 635 mg (69% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]1.35-1.47(m,9H)1.84-1.96(m,2H)3.35-3.48(m,2H)3.70- 3.79(m,1H)3.81-3.92(m,4H)4.34-4.57(m,3H)7.55(dd,1H)7.64-7.72(m,2H)8.01(t,1H).

Intermediate 171: Methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-(2-oxa-5-azabicyclo[2.2.1]hept-1-ylmethoxy)benzoate as a mixture of two enantiomers

A mixture of intermediate 4DG, TFA (4.4 ml, 57 mmol) and DCM (44 ml) was stirred at room temperature until complete conversion. The mixture was evaporated to dryness under reduced pressure to give 530 mg of the title compound which was used without further purification.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]2.02(m,1H)2.12(m,1H)3.35(t,2H)3.85-3.93(m,4H)3.97- 4.18(m,2H)4.45(br.s.,1H)4.50-4.67(m,2H)7.56(dd,1H)7.64-7.76(m,2H)8.02(t,1H).

Intermediate 173: Methyl 3-[(5-methyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate as a mixture of two enantiomers

A mixture of intermediate 171 (257 mg, 712 μmol), formaldehyde (530 μL, 37%, 7.1 mmol), acetic acid (410 μL, 100%, 7.1 mmol) and 1,2-dichloroethane (6.1 ml) was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (3.0 ml, 2.1 mmol) was then carefully added and the mixture was stirred at room temperature. Additional amounts of formaldehyde, acetic acid and sodium triacetoxyborohydride were added to facilitate completion of the reaction. Saturated aqueous _NaHCO₃ solution was added and the aqueous layer was extracted twice with DCM. The combined organic layers were evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc gradient) to give 100 mg (38% yield) of the title compound.

¹ H NMR (600MHz, DMSO-d6): δ[ppm]1.68-1.75(m,1H)1.84-1.92(m,1H)2.34(s,3H)2.90-2.97(m,1H)3.36-3.41(m,1H) 3.62-3.68(m,1H)3.89(s,3H)3.96-4.01(m,1H)4.37(s,1H)4.41(s,1H)7.48-7.57(m,1H)7.66(d,2H)8.01(s,1H).

Intermediate 174: Methyl 3-[(5-isopropyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate as a mixture of two enantiomers

Intermediate 174 (150 mg, 54%) was synthesized from intermediate 171 (250 mg, 694 μmol) and acetone (200 μL, 2.8 mmol) in analogy to the conversion of intermediate 171 to intermediate 173.

¹ H NMR(500MHz,DMSO-d6)δ[ppm]0.96-1.07(m,6H)1.70-1.85(m,2H)2.61-2.77(m,1H)3.05-3.20(m,1H)3 .60-3.75(m,2H)3.89(s,3H)3.99(d,1H)4.30-4.47(m,2H)7.53(dd,1H)7.63-7.70(m,2H)8.00(t,1H).

Intermediate 5CF: 3-{[4-(tert-Butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of enantiomers

Intermediate 4CF (331 mg, 0.59 mmol) was dissolved in MeOH (5 ml) and THF (5 ml). 1 M LiOH (2 ml) was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness, and the residue was dissolved in water (5 ml) and washed with EtOAc (5 ml). The aqueous layer was acidified to pH 4 with 1 M HCl and extracted with DCM (2 × 5 ml) and 1: ₁ IPA/CHCl₃ (2 × 5 ml). The combined organics were dried ( _MgSO₄ ), filtered, and concentrated under reduced pressure. The residue was dissolved in MeCN/water and lyophilized to give 231.2 mg (85% yield) of the title compound as a white powder.

¹ H NMR (250MHz, DMSO-d): δ[ppm]7.99(s,1H),7.67-7.63(m,1H),7.63-7.59(m,1H),7.53-7.48(m,1H),4.2 4-4.07(m,2H),3.99-3.81(m,2H),3.79-3.65(m,2H),3.53-3.40(m,1H),3.00-2.79(m,2H),1.41(s,9H).

LC-MS (Method A) Rt=1.36 min, MS (ESIpos): m/z=435 (M+H) ⁺ .

Intermediate 5CE: 3-{[(2R)-4-(tert-Butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

Intermediate 4CE (27.2 g, 48.6 mmol) was dissolved in THF (200 ml). 1 M LiOH (100 ml, 100 mmol) was added, and the reaction was stirred at room temperature for 2 hours. THF (50 ml), 1 M LiOH (50 ml, 50 mmol), and methanol (20 ml) were further added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to remove the MeOH/THF, and the aqueous layer was washed with EtOAc. The aqueous layer was acidified to pH 4 with concentrated HCl and extracted with DCM (3 x 100 ml). The combined DCM and EtOAc organics were dried ( _MgSO₄ ), filtered, and concentrated under reduced pressure to afford 28.21 g (94% yield) of the title compound as a yellow, viscous oil.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 8.23 (s, 1H), 7.65 (s, 2H), 7.54 (s, 1H), 4.27-3.48 (m, 7H), 3.11-2.77 (m, 2H), 2.50 (s, 3H), 1.47 (s, 9H).

LCMS (Method A) Rt=1.23 min, MS (ESIpos): m/z=435 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for Intermediate 5CF using the corresponding ester starting material.

Intermediate 5CV: 3-{[1-(tert-Butoxycarbonyl)azetidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

A mixture of intermediate 4CV (100 mg, 239 μmol) and NaOH (600 μL, 2.0 M, 1.2 mmol) was stirred in MeOH (20 ml) at room temperature until complete conversion. The MeOH was evaporated and aqueous HCl (2 N) was added to adjust the pH to pH 4. The aqueous layer was extracted with DCM. The combined organics were evaporated to dryness to give 95 mg (98% yield) of the title compound, which was used without further purification.

LCMS, method 1, rt: 1.28 min, MS ES+ m/z = 405 (M+H) ⁺ .

Intermediate 5CX: 3-{[(3R)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 4CX (530 mg, 1.41 mmol) in MeOH was added an aqueous solution of NaOH (1.8 ml, 2.0 M, 3.5 mmol). The mixture was stirred at room temperature until complete conversion. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to pH: 5. The mixture was extracted three times with EtOAc and the combined organic layers were evaporated to dryness to give 417 mg (82% yield) of the title compound.

LCMS, method 1, rt: 0.90 min, MS ES+ m/z = 363 (M+H) ⁺ .

Intermediate 5CY: 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3R)-5-oxomorpholin-3-yl]methoxy}benzoic acid

To a solution of intermediate 4CY (834 mg, 50% purity, 1.15 mmol) in MeOH was added aqueous NaOH (1.4 ml, 2.0 M, 2.9 mmol). The mixture was stirred at room temperature for 15 hours, followed by the addition of 1 ml of aqueous NaOH (2.0 M), and the mixture was stirred at room temperature until complete conversion. The reaction mixture was concentrated under reduced pressure and the pH was adjusted to pH 5. The mixture was extracted three times with EtOAc, and the combined organic layers were evaporated to dryness to give 466 mg of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.84 min, MS ES+ m/z = 349 (M+H) ⁺ .

Intermediate 5CZ: 3-{[(5S)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a mixture of intermediate 4CZ in MeOH (15 ml) was added aqueous NaOH (2.9 ml, 2.0 M, 5.8 mmol). The mixture was stirred at room temperature until complete conversion. The solvent was evaporated under reduced pressure and the pH was adjusted to pH 5. The mixture was extracted three times with EtOAc and the organic layer was evaporated to dryness to give 617 mg (83% yield) of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.93 min, MS ES+ m/z = 349 (M+H) ⁺ .

Intermediate 5DA: 3-{[(5R)-3-methyl-2-oxo-1,3-oxazolidin-5-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 4DA (609 mg, 1.68 mmol) in MeOH (6.4 ml) and THF (6.4 ml) was added aqueous NaOH (2.1 ml, 2.0 M, 4.2 mmol). The mixture was stirred at room temperature until complete conversion. The mixture was concentrated under reduced pressure and the pH was adjusted to pH: 3. The mixture was then extracted three times with EtOAc, and the organic layer was evaporated to dryness under reduced pressure to give 518 mg (87% yield) of the title compound, which was used without further purification.

¹ H NMR (400MHz, DMSO-d6): δ[ppm]2.79(s,3H)3.43(dd,1H)3.70(t,1H)4.22-4.30(m,1H)4.31-4 .38(m,1H)4.82-4.93(m,1H)7.53(dd,1H)7.60-7.69(m,2H)8.00(t,1H)13.00-13.56(m,1H).

Intermediate 5DB: 3-{[(2R)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a mixture of intermediate 4DB in MeOH (28 ml) and THF (28 ml) was added aqueous NaOH (9.2 ml, 2.0 M, 18 mmol). The mixture was stirred at room temperature until complete conversion. The mixture was concentrated under reduced pressure and the pH was adjusted to pH: 3. The mixture was extracted three times with EtOAc, the combined organic layers were dried under reduced pressure, and the residue was purified by column chromatography (silica gel, EtOAc/hexane gradient) to give 1.65 g (59% yield) of the title compound.

LCMS, method 1, rt: 0.91 min, MS ES+ m/z = 363 (M+H) ⁺ .

Intermediate 5DC: 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(2S)-5-oxomorpholin-2-yl]methoxy}benzoic acid

To a mixture of intermediate 4DC in MeOH (38 ml) and THF (38 ml) was added aqueous NaOH (7.4 ml, 2.0 M, 15 mmol). The mixture was stirred at room temperature until complete conversion. The mixture was extracted with EtOAc and phase separated. The aqueous layer was extracted three times with EtOAc, and the combined organic layers were evaporated to dryness under reduced pressure to obtain 434 mg (21% yield) of the title compound.

LCMS, method 1, rt: 0.77 min, MS ES+ m/z = 349 (M+H) ⁺ .

Intermediate 5DD: 3-{[(2S)-4-methyl-5-oxomorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 4DD (1.57 g, 4.17 mmol) in MeOH (10 ml) and THF (10 ml) was added an aqueous NaOH solution (3.1 ml, 2.0 M, 6.3 mmol). The mixture was stirred at room temperature until complete conversion. The mixture was concentrated under reduced pressure and extracted three times with EtOAc. The combined organic layer was evaporated to dryness under reduced pressure to give 2.24 g of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.87 min, MS ES+ m/z = 363 (M+H) ⁺ .

Intermediate 5DE: 3-{[(3S)-4-methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a mixture of intermediate 4DE in MeOH was added aqueous NaOH (980 μL, 2.0 M, 2.0 mmol). The mixture was stirred at room temperature until complete conversion. The pH was adjusted to pH 5, the reaction mixture was extracted with EtOAc, _and the organic layer was dried over _Na₂SO₄ and evaporated to dryness under reduced pressure to give 315 mg of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.89 min, MS ES+ m/z = 363 (M+H) ⁺ .

Intermediate 5DF: 3-(5-methyl-1,3-thiazol-2-yl)-5-{[(3S)-5-oxomorpholin-3-yl]methoxy}benzoic acid

To a mixture of intermediate 4DF in MeOH was added aqueous NaOH (1.2 ml, 2.0 M, 2.4 mmol). The mixture was stirred at room temperature until complete conversion. The pH was adjusted to pH ₅ , and the reaction mixture was extracted with EtOAc. The combined organic layers were dried over _Na₂SO₄ , filtered, and evaporated to dryness under reduced pressure to afford 330 mg (98% yield) of the title compound, which was used without further purification.

LCMS, method 1, rt: 0.84 min, MS ES+ m/z = 349 (M+H) ⁺ .

Intermediate 172: 3-{[5-(tert-Butoxycarbonyl)-2-oxa-5-azabicyclo[2.2.1]hept-1-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of two enantiomers

A mixture of intermediate 4DG (630 mg, 1.37 mmol), aqueous NaOH solution (3.4 ml, 2.0 M, 6.8 mmol) and MeOH (20 ml) was stirred at room temperature until complete conversion. The MeOH was evaporated under reduced pressure. DCM and water were added, the pH value was adjusted to pH: 7, and the phases were separated. The aqueous layer was extracted twice with DCM, and the combined organic layers were evaporated to dryness to give 600 mg (98% yield) of the title compound, which was used without further purification.

¹ H NMR (600MHz, DMSO-d6): δ[ppm]1.36-1.49(m,9H)1.82-2.01(m,2H)3.32-3.47(m,2H)3.71-3.80(m,1H )3.81-3.92(m,1H)4.36-4.55(m,3H)7.54(dd,1H)7.65(d,2H)7.91-8.05(m,1H)12.94-13.73(m,1H).

Intermediate 175: 3-[(5-methyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of two enantiomers

A mixture of intermediate 173 (100 mg, 267 μmol), aqueous NaOH solution (670 μL, 2.0 M, 1.3 mmol) in MeOH (10 ml) was stirred at room temperature until complete conversion. The solvent was evaporated under reduced pressure, DCM and water were added, and the pH was adjusted to pH 7. The aqueous layer was collected and evaporated to dryness to give 50 mg (52% yield) of the title compound.

LCMS, method 1, rt: 0.68 min, MS ES+ m/z = 361 (M+H) ⁺ .

Intermediate 176: 3-[(5-Isopropyl-2-oxa-5-azabicyclo[2.2.1]hept-1-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of two enantiomers

A mixture of intermediate 174 (150 mg, 373 μmol) and aqueous NaOH (930 μL, 2.0 M, 1.9 mmol) was stirred in MeOH (10 ml) at room temperature until complete conversion. The solvent was evaporated under reduced pressure, DCM and water were added, and the pH was adjusted to pH 7. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organic layers were evaporated to dryness and the residue was purified by column chromatography to give 70.0 mg (48% yield) of the title compound.

LCMS, method 1, rt: 0.73 min, MS ES+ m/z = 389 (M+H) ⁺ .

Intermediate 114: tert-Butyl 2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate as a mixture of diastereoisomers

To a solution of Intermediate 5CF (497 mg, 0.995 mmol), Intermediate VI (228 mg, 1.19 mmol), and DIPEA (693 μL, 3.98 mmol) in DCM (10 ml) was added T3P (889 μL, 1.49 mmol, 50% EtOAc solution), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with saturated _NaHCO3 (5 ml). The organics were dried ( _MgSO4 ), filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 30-80% EtOAc in heptane on a 25 g pre-packed KP- _SiO2 column) to afford 520.4 mg (86% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.89 (t, J = 1.4 Hz, 1H), 7.56 (dd, J ＝2.3,1.4Hz,1H),7.53-7.51(m,1H),7.40(s,1H),6.78-6.71(m,1H),5.41 -5.32(m,1H),4.18-4.02(m,3H),3.99-3.77(m,3H),3.65-3.55(m,1H),3. 13-2.73(m,2H),2.53(d,J＝1.1Hz,3H),1.71(d,J＝7.2Hz,3H),1.48(s,9H).

LC-MS (Method A) Rt=1.32 min, MS (ESIpos): m/z=608 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 114 using T3P and the corresponding carboxylic acid and primary amine starting materials.

Intermediate 123: tert-Butyl (2S)-2-[[3-(5-chlorothiazol-2-yl)-5-[[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]carbamoyl]phenoxy]methyl]morpholine-4-carboxylate

To a solution of Intermediate 5CJ (150 mg, 0.31 mmol) and DIPEA (0.16 ml, 0.94 mmol) in DCM (5 ml) was added Intermediate VI (86 mg, 0.38 mmol) followed by HATU (121 mg, 0.94 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed with water (5 ml), dried ( _MgSO ), filtered and concentrated under reduced pressure to give a crude residue which was purified by Biotage Isolera ^™ chromatography (eluting with 25-100% EtOAc in heptane on a 25 g pre-packed KP-SiO ₂ column) to give 115 mg (56% yield) of the title compound as a solid.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.94(s,2H),7.83(s,1H),7.67(s,1H),7.61-7.49(m,1H),7.42(s,1H),6.62(s,1H),5.36(m,1H),4.20-4.01(m, 3H),4.00-3.83(m,2H),3.86-3.74(m,1H),3.60(t,J＝10.7Hz,1H),3.0 9-2.91(m,1H),2.95-2.72(m,1H),1.73(d,J=7.1Hz,3H),1.48(s,9H).

LC-MS (Method A) Rt=1.47 min, MS (ESIpos): m/z=650 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 123 using HATU and the corresponding carboxylic acid and primary amine starting materials.

Intermediate 148: tert-Butyl 3-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}azetidine-1-carboxylate

A mixture of intermediate 5CV (90.0 mg, 223 μmol), intermediate VI (53.2 mg, 234 μmol), HATU (118 mg, 312 μmol) and DIPEA (150 μL, 890 μmol) was stirred at room temperature in DMF (3 ml) until complete conversion. DMF was evaporated under reduced pressure, water and DCM were added, and the aqueous layer was extracted with DCM. The combined organic matter was evaporated to dryness. The crude material was purified by column chromatography (silica gel, hexane/EtOAc gradient) to obtain 90 mg (70% yield) of the title compound.

LCMS, method 1, rt: 1.39 min, MS ES+ m/z = 578 (M+H) ⁺ .

Intermediate 116: 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of intermediate 115 (206 mg, 0.34 mmol) in DCM (5 ml) was added TFA (0.26 ml, 3.4 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was neutralized with saturated _NaHCO₃ solution. The organic phase was separated, and the aqueous phase was extracted with DCM (2 x 5 ml). The combined organic phases were dried ( _MgSO₄ ), filtered, and concentrated under reduced pressure. The residue was freeze-dried from MeCN/water to afford 173.6 mg (100% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 8.98 (s, 2H), 7.83 (s, 1H), 7.55-7.44 (m, 2H), 7.38 (s, 1H), 5.47-5.31 (m, 1H), 3.99-3.81 (m, 2H), 3.47 (s, 2H), 2.91 (m, 2H), 2.56-2.40 (m, 3H), 2.08-1.90 (m, 3H), 1.73 (m, 5H).

LC-MS (Method A) Rt=0.94 min, MS (ESIpos): m/z=506 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 116 using TFA and the corresponding N-Boc protected starting material.

Intermediate 126: [(3R)-4-Methylmorpholin-3-yl]methanol

At 0 DEG C, under nitrogen, to a solution of tert-butyl 3-hydroxymethyl-morpholine-4-carboxylate (750mg, 3.45mmol) in anhydrous THF (16.5ml) was added _LiAlH4 solution (2.4M in THF, 8.6ml). The reaction mixture was stirred at 0 DEG C for 20 minutes, then warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0 DEG C, quenched by adding water (1ml), 15% NaOH aqueous solution (1ml) and water (3ml). The inorganic by-products were removed by filtration. The filtrate was concentrated under reduced pressure to obtain 475mg (71% yield) of the title compound as a colorless oil, which was used without further purification.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 3.87-3.73 (m, 3H), 3.64-3.51 (m, 2H), 3.40 (dd, J=11.5, 1.7 Hz, 1H), 2.71 (dt, J=11.5, 1.9 Hz, 1H), 2.41 (td, J=11.4, 3.4 Hz, 1H), 2.33 (s, 3H), 2.25-2.15 (m, 1H).

The following intermediates were prepared in a similar manner to that described for intermediate 126 using LiAlH ₄ and the corresponding N-Boc protected starting material.

Intermediate 130: tert-Butyl 3-fluoro-3-(hydroxymethyl)piperidine-1-carboxylate as a mixture of enantiomers

Under nitrogen atmosphere, borane (1M in THF, 9.1ml, 9.10mmol) was added dropwise to a solution of 1-Boc-3-fluoropiperidine-3-carboxylic acid (750mg, 3.03mmol) in anhydrous tetrahydrofuran (30ml) at 0°C, and the resulting reaction mixture was warmed to room temperature and stirred for 18 hours. The reactant was quenched by the careful addition of methanol and evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried ( _MgSO ), filtered and concentrated under reduced pressure. Purified by Biotage Isolera ^TM chromatography (eluting with 0-60% EtOAc in heptane on 25g pre-filled KP-SiO ₂ columns) to obtain 650mg (95% yield) of the title compound, which was a light yellow viscous oil that solidified on standing.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 4.00-2.86 (m, 6H), 1.95-1.85 (m, 1H), 1.84-1.65 (m, 2H), 1.60-1.52 (m, 1H), 1.49 (s, 9H).

Intermediate 27CQ: (2R)-tert-Butyl 2-{[3-cyano-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

To a stirred solution of intermediate 112 (896 mg, 4.12 mmol) in anhydrous DMF (7.5 ml) was added NaH (60% dispersion in mineral oil) (172 mg, 4.30 mmol). After the mixture was stirred for 15 minutes, intermediate 26 (750 mg, 3.44 mmol) was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into brine and extracted into EtOAc. The organic layer was washed with brine, dried ( _MgSO ), filtered and concentrated under reduced pressure to give a brown oil. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 5-60% EtOAc in heptane on a 50 g pre-packed KP-SiO ₂ column) to give 870.9 mg (59% yield) of the title compound as a colorless gum.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 7.75 (t, J = 1.4 Hz, 1H), 7.71-7.68 (m, 1H), 7.54 (d, J = 1.2 Hz, 1H), 7.19 (dd, J = 2.5, 1.3 Hz, 1H), 4.17-3.74 (m, 6H), 3.67-3.54 (m, 1H), 3.10-2.77 (m, 2H), 2.54 (d, J = 1.1 Hz, 3H), 1.48 (s, 9H).

LC-MS (Method A) Rt=1.33 min, MS (ESIpos): m/z=416 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 27CQ using NaH and the corresponding fluoro-benzonitrile and alcohol starting material.

Intermediate 5CE can also be synthesized from intermediate 27CQ as follows.

Intermediate 5CE: 3-{[(2R)-4-(tert-Butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

A stirred solution of Intermediate 27CQ (0.87 g, 2.01 mmol), DMSO (10 ml) and 2M aqueous sodium hydroxide solution (10 ml) was heated at 110°C for 3 hours. After cooling to room temperature, the mixture was slowly acidified to pH ~4, diluted with water (10 ml) and extracted with EtOAc (3 x 20 ml). The combined organics were washed with water (20 ml), brine (20 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure to give 672.1 mg (77% yield) of the title compound as a foam.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.29 (t, J = 1.4 Hz, 1H), 7.70 (s, 1H), 7.67 (dd, J = 2.4 ,1.3Hz,1H),7.57(d,J＝1.1Hz,1H),4.16(dd,J＝9.9,5.5Hz,1H),4.10(dd,J＝9. 9,4.5Hz,1H),3.97(d,J＝10.7Hz,1H),3.94-3.80(m,2H),3.66-3.57(m,1H),3. 10-2.97(m,1H),2.90(s,1H),2.63(s,2H),2.53(d,J＝1.0Hz,3H),1.49(s,9H).

LC-MS (Method A) Rt=1.20 min, MS (ESIpos): m/z=435.55 (M+H) ⁺ .

Intermediate 28CM: 3-{[(3R)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid monosodium chloride (1:3)

To a solution of intermediate 27CM (304 mg, 0.83 mmol) in ethanol (2 ml) was added 2M aqueous sodium hydroxide solution (1.24 ml) and the resulting mixture was heated to 120 ° C by microwave irradiation for 30 minutes. The cooled solution was diluted with water and washed with EtOAc. The aqueous phase was separated, neutralized with 1M HCl (0.88 ml) and concentrated under reduced pressure. The residue was further dried to constant weight in a vacuum oven to obtain 381 mg (88% yield) of the title compound, which was used without further purification.

LC-MS (Method A) Rt=0.80 min, MS (ESIpos) m/z=349 (M+H) ⁺ .

Intermediate 28CN: 3-{[(3S)-4-methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid hydrochloride (1:1)

To a stirred solution of intermediate 27CN (200 mg, 0.53 mmol) in DMSO (3 ml) was added 2 M aqueous sodium hydroxide solution (3.5 ml), and the resulting mixture was heated to 110 ° C for 3 hours. After cooling to room temperature, the mixture was slowly acidified to pH ~ 2 with HCl and concentrated under reduced pressure to give a crude material in DMSO. The residue was distributed between water and chloroform / isopropanol (1: 1). The organic layer was separated and the aqueous layer was extracted twice with chloroform / isopropanol (1: 1). The combined organic fractions were dried (magnesium sulfate), filtered and concentrated under reduced pressure. LC-MS (method A) showed that the product remained in the aqueous phase. The organic layer and the aqueous layer were dried to remove residual DMSO to give 75 mg (36% yield) and 100 mg (49% yield, uncorrected sodium chloride content). The combined fractions were used in the next step without further purification.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]10.76(s,1H),8.03(s,1H),7.74(s,1H),7.72 -7.57(m,2H),7.61(s,1H),4.52(dd,J＝11.1,2.9Hz,1H),4.44(dd,J＝11.3,2. 8Hz,1H),4.15(d,J＝10.2Hz,1H),4.02(d,J＝12.3Hz,1H),3.86-3.79(m,1H),3 .78-3.68(m,2H),3.29(d,J＝11.6Hz,1H),2.92(d,J＝3.1Hz,3H),2.53(s,3H).

LC-MS (Method A) Rt=0.94 min, MS (ESIpos): m/z=349 (M+H) ⁺ .

Intermediate 28CP: 3-{[1-(tert-Butoxycarbonyl)-3-fluoropiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of enantiomers

To a stirred solution of intermediate 27CP (400 mg, 0.83 mmol) in ethanol (5 ml) was added 2 M sodium hydroxide (1.25 ml, 2.50 mmol) and the mixture was heated to 80 ° C in a sealed tube for 18 hours. The reaction mixture was concentrated under reduced pressure and the aqueous residue was washed with ethyl acetate. The aqueous layer was acidified to pH 4 with 2 M HCl to produce a white solid precipitate, which was collected by filtration and dried to give 310 mg (80% yield) of the title compound as a pale solid.

LC-MS (Method A) Rt=1.26 min, MS (ESIpos): m/z=451.6 (M+H) ⁺ .

Intermediate 28CR: 3-{[(2S)-4-(tert-Butoxycarbonyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

A stirred solution of intermediate 27CR (510 mg, 1.191 mmol) in EtOH (5 ml) and 2M NaOH (1.79 ml) was heated to 130° C. under microwave irradiation for 3 hours. The reaction was quenched by the addition of HCl (2 M, 1.79 ml) and concentrated under reduced pressure. The white residue was slurried in chloroform and the inorganic material was removed by filtration. The filtrate was evaporated under reduced pressure to give 571 mg (79% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 8.29-8.25 (m, 1H), 7.68 (s, 2H), 7.56 (d, 1H), 4.17-4.08 (m, 3H), 3.96 (d, J=11.1 Hz, 1H), 3.84 (br. s, 2H), 3.73 (q, J=7.0 Hz, 1H), 3.65-3.58 (m, 2H), 2.52 (s, 3H), 1.48 (s, 9H).

LC-MS (Method A) Rt=1.22 min, MS (ESIpos): m/z=434.95 (M+H) ⁺ .

Intermediate 28CS: 3-{[(2R)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

A stirred solution of intermediate 27CS (0.348 g, 0.76 mmol) in ethanol (2 ml) and 2M aqueous NaOH (1.0 ml, 2 mmol) was heated to 80° C. in a sealed tube for 3 hours. Another portion of 2M aqueous NaOH (1.0 ml, 2 mmol) was added and the mixture was heated to 80° C. in a sealed tube for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and acidified to form a white precipitate which was collected by filtration to give 0.31 g (81% yield) of the title compound.

LC-MS (Method A) Rt=1.34 min, MS (ESIpos) m/z=419 (M+H) ⁺ .

Intermediate 28CT: 3-{[(2S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

A stirred solution of intermediate 27CT (0.318 g, 0.69 mmol) in ethanol (2 ml) and 2M aqueous NaOH (1.0 ml, 2 mmol) was heated to 80° C. in a sealed tube for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and acidified to form a white precipitate which was collected by filtration to give 0.11 g (35% yield) of the title compound.

LC-AAS (Method A) Rt=1.33 min, MS (ESIpos): m/z=419 (M+H) ⁺ .

Intermediate 28CU: 3-{[1-(tert-Butoxycarbonyl)-4,4-difluoropiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid as a mixture of enantiomers

A stirred solution of intermediate 27CU (340 mg, 0.68 mmol) in ethanol (1 ml) and 2M aqueous sodium hydroxide solution (1 ml, 2 mmol) was heated to 120° C. for 1 hour via microwave irradiation. The reaction mixture was acidified with concentrated HCl to give a white precipitate, which was extracted into ethyl acetate. The organic phase was separated, dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to give 199 mg (62% yield) of the title compound.

LC-MS (Method A) Rt=1.31, MS (ESIpos): m/z=469 (M+H) ⁺ .

Intermediate 128: 3-[(3-fluoroazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

To a solution of intermediate 27CO (330 mg, 0.8 mmol) in DCM (10 ml) was added TFA (4 ml). The reaction was stirred at room temperature for 4 hours and then neutralized with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with 1:1 IPA/CHCl (2 x 20 ml). The combined organics were dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to afford 243.7 mg (95% yield) of the title compound as an off-white powder.

¹ H NMR (250 MHz, methanol-d4): δ [ppm] 7.85 (t, J = 1.4 Hz, 1H), 7.83-7.79 (m, 1H), 7.62-7.59 (m, 1H), 7.46 (dd, J = 2.5, 1.3 Hz, 1H), 4.46 (d, J = 19.2 Hz, 2H), 4.16-3.94 (m, 4H), 2.55 (d, J = 1.1 Hz, 3H).

LC-AAS (Method A) Rt=0.90 min, MS (ESIpos): m/z=304 (M+H) ⁺ .

Intermediate 129: 3-[(3-Fluoro-1-methylazetidin-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)benzonitrile

Intermediate 128 (246 mg, 0.77 mmol), 37% aqueous formaldehyde (289 μL, 3.86 mmol) and acetic acid (5 μL) were combined in methanol (10 ml) and sodium triacetoxyborohydride (491 mg, 2.82 mmol) was added. The resulting solution was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue was dissolved in saturated NaHCO₃ ( ₅ ml) and extracted with DCM (3×5 ml). The combined organic phases were dried ( _MgSO₄ ), filtered and concentrated under reduced pressure to give 222.6 mg (83% yield) of the title compound as a brown gum.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.76 (t, J = 1.4 Hz, 1H), 7.73 (dd, J = 2.4, 1.5 Hz, 1H), 7.55-7.53 (m, 1H), 7.21 (dd, J = 2.5, 1. 3Hz, 1H), 4.37 (d, J = 23.0Hz, 2H), 3.70-3.63 (m, 2H), 3.23 (dd, J = 21.6, 9.5Hz, 2H), 2.54 (d, J = 1.1Hz, 3H), 2.45 (s, 3H).

LC-MS (Method A) Rt=0.86 min, MS (ESIpos): m/z=318 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for Intermediate 28CM using NaOH and the corresponding benzonitrile starting material.

Intermediate 131: tert-Butyl 3-fluoro-3-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}piperidine-1-carboxylate as a mixture of diastereoisomers

To a stirred solution of Intermediate 28CP (150 mg, 0.33 mmol), Intermediate VI (91 mg, 0.40 mmol) and DIPEA (0.17 ml, 0.99 mmol) in dichloromethane (4 ml) was added HATU (189 mg, 0.50 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (5 ml), dried ( _MgSO ), filtered, and concentrated under reduced pressure. Purification by Biotage Isolera ^™ chromatography (eluting with 25-90% EtOAc in heptane on a 25 g pre-packed KP-SiO ₂ column) gave 162 mg (74% yield) of the title compound as a white solid.

¹ H NMR (250MHz, DMSO-d6): δ [ppm] 9.09 (s, 2H), 8.94 (d, J = 7.1Hz, 1H), 8.01-7.84 (m, 1H), 7.67-7.57 (m, 2H), 7.57-7.53 (m, 1H), 5.33 (m, 1H),4.35-4.16(m,2H),4.12-3.95(m,1H),3.85-3.64(m,1H),3.46-3.16(m,1H),1.94-1.87(m,1H),1.81-1.49(m,6H),1.40(s,9H).

LC-MS (Method A) Rt=1.44 min, MS (ESIpos) m/z=624 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 131 using HATU and the corresponding carboxylic acid and primary amine starting materials.

Intermediate 139: (2R)-tert-Butyl 2-{[3-({(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl}carbamoyl)-5-(5-methyl-1,3-thiazol-2-yl)phenoxy]methyl}morpholine-4-carboxylate

To a stirred solution of intermediate 5CE (80 mg, 0.18 mmol), intermediate LIV (46 mg, 0.17 mmol) and DIPEA (0.15 ml, 0.88 mmol) in DCM (2 ml) was added T3P (50% EtOAc solution, 0.21 mL, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 hours and then washed with saturated sodium bicarbonate solution (3 ml). The aqueous phase was re-extracted with DCM (3 ml), and the combined organic matter was passed through a phase separator and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with _0-2 % MeOH in DCM on a 25 g pre-filled KP-SiO2 column) to obtain 58 mg (53% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.71 (d, J = 1.7Hz, 1H), 7.89 (s, 1H), 7.86 (dd, J = 8.1, 2.2Hz,1H),7.63(d,J＝8.1Hz,1H),7.58-7.54(m,1H),7.53-7.51(m,1H),7.42(s ,1H),6.81-6.46(m,2H),5.46-5.32(m,1H),4.22-3.75(m,6H),3.69-3.51(m,1H ), 3.07-2.78 (m, 2H), 2.53 (d, J = 1.0Hz, 3H), 1.66 (d, J = 7.1Hz, 3H), 1.48 (s, 9H).

LC-MS (Method A) Rt=1.32 min, MS (ESIpos): m/z=589 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 139 using T3P and the corresponding carboxylic acid and primary amine starting materials.

Intermediate 138: 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

To a solution of intermediate 137 (126 mg, 0.18 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (0.28 ml, 3.66 mmol) and the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was passed through an SCX column (washed with methanol and eluted with 7N ammonia in methanol) to give 85 mg (92% yield) of the title compound as a glassy solid.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.80 (d, J = 1.6 Hz, 1H), 7.97-7.82 (m, 2H), 7.68 (d, J = 8.1 Hz, 1H), 7.61-7.55 (m, 1H), 7.53 (d, 1H), 7.49-7.36 (m, 1H) ), 6.68(d,J＝6.9Hz,1H),5.40(m,1H),4.21-3.82(m,4H),3.73(td,J＝11.0,3.5Hz,1H),3.15-2.64(m,4H),2.55(s,3H),1.69(d,J＝7.1Hz,3H).

LC-MS (Method A) Rt=0.96 min, MS (ESIpos): m/z=507 (M+H) ⁺ .

The following intermediates were prepared in analogy to the procedure described for intermediate 138 using TFA and the corresponding N-Boc protected starting material.

Intermediate 133: 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]benzoic acid trifluoroacetate (1:1)

To a solution of intermediate 5CE (120 mg, 0.276 mmol) in DCM was added trifluoroacetic acid (2 ml, 25.96 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction was stopped and concentrated under reduced pressure to give 200 mg (quantitative yield; residual TFA was present) of the title compound as a light yellow oil.

LC-MS (Method A) Rt=0.85 min, MS (ESIpos): M/Z=335 [M+H] ⁺ .

Intermediate 134: 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid

To a solution of intermediate 133 (200 mg, 0.45 mmol), formaldehyde (37% in water, 167.1 μL, 2.23 mmol) and acetic acid (38.3 μL, 1.05 mmol) in MeOH (2 ml) was added STAB (283.6 mg, 1.34 mmol) and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the resulting residue was basified to pH 8-9 with saturated NaHCO ₃ and extracted with DCM (3×5 ml). The aqueous layer was neutralized to pH 7 with acid and concentrated under reduced pressure to give 859 mg of the title compound (quantitative yield; inorganic salts were present).

¹ H NMR (500MHz, DMSO-d6): δ[ppm]7.92-7.91(m,1H),7.57(d,J＝1.1Hz,1H),7.47(dd,1H),7.36-7.34(m,1H),4.03-4.00(m,2H),3.83- 3.77(m,3H),3.55(td,J＝11.2,8.8Hz,3H),2.81-2.77(m,1H),2.62-2.58(m,1H),2.20(s,3H),2.00(td,1H),1.90(t,J＝10.7Hz,1H).

LC-MS (Method A) Rt=0.93 min, MS (ESIpos): m/z=349 (M+H) ⁺ .

Intermediate 147: 3-{[3-fluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide as a mixture of two diastereoisomers

To a solution of intermediate 132 (55 mg, 0.1 mmol) in methanol (1 ml) was added formaldehyde (37% in water, 16 uL, 0.21 mmol) and acetic acid (6 μL, 0.1 mmol), and the reaction was stirred at room temperature for 15 minutes. STAB (33 mg, 0.16 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction mixture was passed through an SCX column (washed with methanol, eluted with 7N ammonia in methanol) and concentrated under reduced pressure to give 52 mg (91% yield) of the title compound as an off-white glass.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 9.17 (d, J = 7.0Hz, 1H), 9.12 (s, 2H), 7.93 (s, 1 H),7.64(s,1H),7.60(s,1H),7.56(s,1H),5.30(m,1H),4.27(d,J＝22.1Hz,2 H),2.62-2.53(m,2H),2.39-2.31(m,1H),2.29-2.22(m,1H),2.19(s,3H),1. 87-1.77(m,1H),1.75-1.67(m,2H),1.61(d,J＝7.1Hz,3H),1.58-1.48(m,1H).

LC-MS (Analytical Method F) Rt=2.19 min, MS (ESIpos): m/z=538 (M+H) ⁺ .

Intermediate I: Ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate

Note: The reaction was split into two 37.5 g batches and the isolated products were combined into one batch.

To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (37.5 g, 142.9 mmol) in ethanol (750 mL) was added DIPEA (68 mL, 392.3 mmol) and 10% Pd/C (50% moisture, 3 g), and the reaction mixture was stirred under a hydrogen atmosphere for 1 h. The reaction mixture was filtered through glass fiber filter paper, and the filtrate was concentrated under reduced pressure to give a yellow solid. The solid was dissolved in EtOAc (500 mL), washed with water (500 mL), 1 M aqueous HCl (500 mL), saturated aqueous NaHCO ₃ (500 mL), dried (over MgSO ₄ ), filtered, and concentrated under reduced pressure. The pale yellow solid was triturated with heptane and the solid was collected by filtration. The filtrate was concentrated and the trituration with heptane was repeated. The mother liquors of two batches are combined and purified by Biotage Isolera ^™ chromatography (eluting with 1-30% EtOAc in heptane on 100 g KP-SiO ₂ posts). The product containing fractions is concentrated and the residue is ground with heptane. All solids are combined to obtain 56.8 g (90% yield) of the title compound as a yellow solid.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 9.43 (s, 2H), 4.50 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.24 min, MS (ESIpos): m/z=220.9 (M+H) ⁺ .

Intermediate II: 2-(trifluoromethyl)pyrimidine-5-carboxylic acid

To a solution of ethyl 2-(trifluoromethyl)pyrimidine-5-carboxylate (56.8 g, 252.8 mmol) in THF (500 mL) was added 1 M aqueous LiOH (380 mL, 379.3 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated under vacuum to remove the organic solvent, and the remaining aqueous solution was acidified to pH 1 with concentrated HCl. The resulting precipitate was collected by vacuum filtration to provide 44.4 g (91% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, DMSO-d ₆ ): δ [ppm] 9.44 (s, 2H).

LCMS (Analytical Method A) Rt=0.81 min, MS (ESIneg): m/z=190.9 (M) ⁻ .

Intermediate III: N-methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide

2-(Trifluoromethyl)pyrimidine-5-carboxylic acid (44.39 g, 231.1 mmol), methoxymethylamine hydrochloride (33.8 g, 346.6 mmol) and DIPEA (119.5 mL, 924.3 mmol) were combined in DCM (750 mL) and HATU (105.4 g, 277.3 mmol) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was washed with water ( ₃ x 300 mL) and the organic phase was collected, dried (over MgSO ), filtered and concentrated in vacuo to give a viscous yellow oil. The crude material was purified by dry flash chromatography (eluting with 0-40% EtOAc in heptane) to give 54.2 g (95% yield) of the title compound as a free-flowing light yellow oil.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 9.22 (s, 2H), 3.61 (s, 3H), 3.43 (s, 3H).

LCMS (Analytical Method A) Rt=1.03 min, MS (ESIpos): m/z=235.9 (M+H) ⁺ .

Intermediate IV: 1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanone

N-Methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide (54.9 g, 218.9 mmol) was dissolved in anhydrous THF (550 mL) and cooled to 0°C in an ice bath. Methylmagnesium bromide (1.4 M in toluene/THF, 188 mL, 262.7 mmol) was added dropwise over 30 minutes. The reaction was stirred at 0°C for a further 10 minutes, slowly quenched with 1 M HCl (260 mL), stirred for an additional 30 minutes, and then extracted with ethyl acetate (300 mL). The organic phase was separated, dried (over MgSO ₄ ), filtered, and concentrated in vacuo to give a yellow solid. LCMS and ¹ H NMR indicated the presence of ~20 mol% unhydrolyzed intermediate, so the solid was stirred in a mixture of 2 M HCl (200 mL) and DCM (200 mL) for 20 minutes. The layers were separated, and the aqueous layer was extracted with additional DCM (2×100 mL). The combined organics were dried (over _MgSO4 ), filtered and concentrated under reduced pressure to afford 33.57 g (80% yield) of the title compound as a yellow solid.

¹ H NMR (500 MHz, chloroform-d) δ [ppm] 9.36 (s, 2H), 2.72 (s, 3H).

LCMS (Analytical Method A) Rt=0.99 min, MS (ESIpos): m/z=191.0 (M+H) ⁺ .

Intermediate V: (S)-2-Methyl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}propane-2-sulfenamide

To a stirred solution of 1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanone (20.65 g, 107.5 mmol) and tetraethyl titanate (69.4 mL, 215.1 mmol) in Et ₂ O (1 L) was added (S)-2-tert-butylsulfenamide (14.3 g, 118.3 mmol), and the resulting solution was stirred at reflux overnight under a nitrogen atmosphere. The reaction mixture was cooled to -78°C and lithium tri-sec-butylborohydride (118.3 mL, 1 M solution in THF) was added dropwise, maintaining the internal temperature below -70°C. The reaction was stirred at -78°C for an additional 2 h, after which LCMS (Analytical Method A) showed residual imine intermediate. The reaction mixture was further treated with lithium tri-sec-butylborohydride (12 mL, 1 M solution in THF) and stirred for 1 h. LCMS showed complete conversion of the imine. The reaction was quenched by the addition of brine (500 mL) and warmed to RT. The suspension was filtered through a plug of celite and washed with EtOAc. The filtrate was washed with brine (500 mL), and the aqueous layer was re-extracted with EtOAc (2×300 mL). The combined organics were dried (over _MgSO ), filtered, and concentrated under reduced pressure. The residue was triturated with Et ₂ O, and the resulting precipitate was collected by vacuum filtration to give 18.12 g (57% yield) of the title compound as an off-white powder.

¹ H NMR (500 MHz, CHLOROFORM-d) δ [ppm] 8.88 (s, 2H), 4.75 (qd, J = 6.8, 3.1 Hz, 1H), 3.43 (d, J = 2.5 Hz, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.24 (s, 9H).

LCMS (Analytical Method A) Rt=1.14 min, MS (ESIpos): m/z=296.0 (M+H) ⁺ .

Intermediate VI: (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethan-1-amine hydrochloride (1:1)

To a solution of (S)-2-methyl-N-[(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]propane-2-sulfenamide (14.37 g, 48.66 mmol) in methanol (140 mL) was added 4 M HCl in dioxane (120 mL), and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, collected by vacuum filtration, and then diethyl ether was added to precipitate the title compound as an off-white solid, 10.06 g (91% yield).

¹ H NMR (250MHz, DMSO-d6): δ [ppm] 9.28 (s, 2H), 8.96 (s, 2H), 4.67 (q, J = 6.9 Hz, 1H), 1.64 (d, J = 6.9 Hz, 3H).

Analytical HPLC: column: Chiralpak AD-H 25 cm; mobile phase: 90:10 heptane:ethanol; flow rate: 0.3 ml/min; detection: UV 254 nm; run time: 70 min; Rt = 49.44 min; 100% ee.

Intermediate VII: (S)-2-methyl-N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]propane-2-sulfenamide

1-(6-Methylpyridin-3-yl)ethan-1-one (1.6 g, 11.8 mmol) and (S)-tert-butylsulfenamide (1.4 g, 11.8 mmol) were dissolved in THF (20 mL). Tetraethyl titanate (containing 33% _TiO2 ) (6.1 g, 17.8 mmol) was added and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was cooled to -78°C and lithium tri-sec-butylborohydride (1 M solution in THF, 11.8 mL, 11.8 mmol) was added dropwise over 30 minutes, maintaining the internal reaction temperature below -70°C. The reaction mixture was stirred at -78°C for 1 hour and then quenched with MeOH (2 mL). The solution was allowed to warm to room temperature and diluted with water (50 mL). The resulting solid was removed by vacuum filtration, the filtrate was collected, and the solvent was removed in vacuo. The residue was dissolved in brine (40 mL) and extracted with TBME (2 x 60 mL). The combined organics were dried ( _{over Na2SO4} ), filtered and concentrated under reduced pressure.The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 0-20% MeOH in DCM) to give 1.25 g (34% yield) of the title compound.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 8.46 (d, J = 2.2, 1H), 7.53 (dd, J = 8.0, 2.3, 1H), 7.13 (d, J = 8.0, 1H), 4.57 (qd, J = 6.7, 6.7, 6.7, 3.4, 1H), 2.55 (s, 3H), 1.54 (d, J = 6.7, 3H), 1.18 (s, 9H).

Intermediate VIII: (1R)-1-(6-methylpyridin-3-yl)ethylamine hydrochloride

To a solution of (S)-2-methyl-N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]propane-2-sulfinamide (1.25 g, 4.1 mmol) in 2-propanol (5 mL) cooled to 0° C. in an ice bath was added 5M HCl in 2-propanol (4 mL, 20 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. A white precipitate was observed to form. The precipitate was collected by filtration and washed with TBME to give 616 mg (78% yield) of the title compound as a white solid.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]8.98(s,3H),8.85(d,J＝2.0Hz,1H),8.47(dd,J＝8.3,2.0Hz,1H ),7.77(d,J＝8.3Hz,1H),7.53-7.24(m,2H),4.60(s,1H),2.68(s,3H),1.58(d,J＝6.9Hz,3H).

Intermediate IX: 1-(5-methylpyrazin-2-yl)ethanone

5-Methylpyrazine-2-carbonitrile (25.0 g, 210 mmol) was dissolved in ether (500 mL) and cooled to -15 ° C. Methylmagnesium bromide (3 M in THF, 84 mL, 241 mmol) was added dropwise over 1 hour and the internal temperature was maintained below -10 ° C. A cloudy orange precipitate formed during the addition of the reactants. The reaction was terminated by slowly pouring the mixture into a 1 M aqueous solution of HCl (250 mL) and crushed ice. The mixture was warmed to room temperature and basified with a saturated aqueous solution of NaHCO ₃ . TBME (300 mL) was added and the organic layer was collected. The aqueous layer was extracted with TBME (2 × 300 mL) and the combined organic layers were washed with brine (300 mL), dried (over Na ₂ SO ₄ ), filtered and concentrated under reduced pressure to obtain 18.4 g (61% yield) of the title compound as a yellow solid.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 8.97 (d, J = 1.2 Hz, 1H), 8.68 (s, 1H), 2.62 (s, 3H), 2.60 (s, 3H).

Intermediate X: (S)-2-methyl-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]propane-2-sulfenamide

1-(5-methylpyrazine-2-yl)ethanone (27.2 g, 200 mmol), (S)-tert-butylsulfenamide (24.24 g, 200 mmol) and tetraethyl titanate (102 g, 300 mmol, containing 33% TiO ₂ ) were heated at 80° C. for 1 hour in THF (1000 mL) and then cooled to room temperature. TLC (EtOAc/acetone 1:1) indicated that intermediate IX had been consumed. The mixture was cooled to -78° C. and lithium tri-sec-butylborohydride (1 M in THF, 200 mL, 200 mmol) was added dropwise over 60 minutes, maintaining the internal temperature below -70° C. The mixture was stirred at -78° C. for 1 hour and then the reaction was terminated by the dropwise addition of MeOH (50 mL) and allowed to warm to room temperature. A white precipitate was formed by the addition of water (100 mL), which was collected by filtration and washed with TBME (2 L). The aqueous layer of the filtrate was separated and washed with TBME (2 x 200 mL). The combined organics were washed with brine (100 mL), dried ( _{over Na2SO4} ), filtered, and concentrated under reduced pressure. The residue was purified by dry flash chromatography (silica gel, eluting with 0-60% acetone in EtOAc) to give 35.8 g (49% yield) of the title compound as a brown oil.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]8.57(d,J＝1.1Hz,1H),8.45(s,1H),5.56(d,J＝6.4Hz,1H),5. 29(s,1H),4.56-4.44(m,1H),2.47(s,3H),1.51(d,J=6.9Hz,3H),1.11(s,9H),1.08(s,5H).

Intermediate XI: (1R)-1-(5-methylpyrazin-2-yl)ethylamine dihydrochloride

To a solution of (S)-2-methyl-N-[(1R)-1-(5-methylpyrazine-2-yl)ethyl]propane-2-sulfinamide (35 g, 63.7 mmol) in 2-propyl alcohol (200 mL) was added 5M HCl in 2-propyl alcohol (65 mL, 325 mmol) at 0°C. The mixture was warmed to room temperature, resulting in the formation of a precipitate. After stirring for 1 hour, the precipitate was collected by filtration. Recrystallization from hot TBME (200 mL) gave 19.8 g (78% yield) of the title compound as a light brown solid.

¹ H NMR (500MHz, DMSO-d6) δ [ppm]: 8.70 (s, 4H), 8.59 (s, 1H), 4.57 (dq, J = 12.2, 6.1Hz, 1H), 2.52 (s, 3H), 1.53 (d, J = 6.8Hz, 3H).

Intermediate XII: 6-Methylpyridazine-3-carbonitrile

A solution of 3-chloro-6-methylpyridazine (50 g, 389 mmol) in DMA (1250 mL) was degassed under nitrogen for 10 minutes, followed by the addition of zinc (II) cyanide (27.4 g, 233 mmol), zinc powder (1017 mg, 15.6 mmol), and Pd(dppd) _Cl2.DCM (12.7 g, 15.6 mmol). The mixture was heated at 120°C overnight. The reaction mixture was cooled to room temperature, diluted with DCM (1 L), and filtered through celite, washing with additional DCM. The filtrate was concentrated under reduced pressure. The residue was purified by dry flash chromatography (eluting with TBME) to give 34.9 g (75%) of the title compound as an off-white solid.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 7.72 (d, J=8.6 Hz, 1H), 7.48 (d, J=8.6 Hz, 1H), 2.85 (s, 3H).

Intermediate XIII: 1-(6-methylpyridazin-3-yl)ethan-1-one

A solution of 6-methylpyridazine-3-carbonitrile (23.8 g, 200 mmol) in TBME (1.2 L) was stirred under nitrogen and cooled to -15 ° C. Methylmagnesium bromide (3 M in Et2O, 80 mL, 240 mmol) was added in ～20 min, keeping the internal temperature below -15 ° C. The reaction mixture was stirred for 1.5 h and _then terminated by adding 2M HCl (120 mL). The mixture was warmed to room temperature, the organic layer was collected, dried (passed through _Na2SO4 ), filtered and concentrated under reduced pressure to obtain a yellow solid. The aqueous layer was alkalized to pH 8-9 with _NaHCO3 , extracted with DCM (4 × 200 mL) and _the combined organic matter was dried (passed through _Na2SO4 ), filtered and concentrated under reduced pressure. Two batches were merged to obtain 26.2 g (67% yield) of the title compound as a yellow solid.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.02 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 2.87 (s, 3H), 2.81 (s, 3H).

Intermediate XIV: (S)-2-Methyl-N-[(1R)-1-[6-methylpyridazin-3-yl]ethyl]propane-2-sulfenamide

To a stirred solution of 1-(6-methylpyridazin-3-yl)ethan-1-one (26.2 g crude, 19.90 g purity corrected mass, 146.2 mmol) and tetraethyl titanate (61.3 mL, 292.3 mmol) in anhydrous THF (600 mL) was added (S)-2-tert-butylsulfenamide (17.71 g, 146.2 mmol) and the resulting solution was stirred at 80° C. for 60 min. The solution was cooled to −70° C. and lithium tri-sec-butylborohydride was added dropwise while maintaining the internal temperature below −72° C. The reaction mixture was stirred at −78° C. for 30 min, quenched by the slow addition of methanol (30 mL) and allowed to warm to room temperature. Ethyl acetate (800 mL) and water (800 mL) were added to cause precipitation. The solid was collected by filtration and washed with ethyl acetate (3×400 mL). Each 3 x ~400 mL EtOAc filtrate was used to back- _extract the aqueous layer. The combined organics were dried (over _Na2SO4 ), filtered, and concentrated under reduced pressure. The crude material was partially purified by dry flash chromatography (eluting with EtOAc then acetone). Repurification by dry flash chromatography (eluting with 50% acetone in EtOAc) gave 21.4 g (44% yield) of the title compound as a brown, viscous oil.

¹ H NMR (250 MHz, chloroform-d): δ 7.40 [ppm] (d, J = 8.6 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 4.84 (p, J = 6.7 Hz, 1H), 3.97 (d, J = 6.1 Hz, 1H), 3.71 (s, 1.3H), 2.70 (s, 3H), 1.68 (d, J = 6.8 Hz, 3H), 1.22 (s, 6H), 1.20 (s, 9H).

Intermediate XV: (1R)-1-(6-methylpyridazin-3-yl)ethan-1-amine hydrochloride

(S)-2-Methyl-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]propane-2-sulfinamide (21.3 g, 88.3 mmol) was dissolved in methanol (400 mL) and cooled to 0°C before slowly adding 12 M HCl in water (73.6 mL, 883 mmol). The reaction was stirred at room temperature for 1 hour and then evaporated under vacuum. The residue was azeotroped twice with isopropanol (100 mL) and triturated with warm isopropanol (100 mL). After cooling to room temperature, the precipitate was collected by filtration and dried under vacuum to give 11.8 g (55% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]8.90(s,3H),8.02(d,J＝8.7Hz,1H),7.87(d,J＝8.7Hz,1H ),7.58-7.14(m,2H),4.71(dt,J＝12.4,6.1Hz,1H),2.71(s,3H),1.58(d,J＝6.9Hz,3H).

Analytical HPLC: column: Chiralpak AD-H 25 cm; mobile phase: 90:10 heptane:ethanol + 1% DEA; flow rate: 1 ml/min; detection: UV 254 nm; run time: 60 min; Rt = 28.64 min; 100% ee.

Intermediate XVI: 1-[6-(trifluoromethyl)pyridazin-3-yl]ethanone

To a degassed solution of 3-chloro-6-(trifluoromethyl)pyridazine (17.26 g, 94.6 mmol) and tributyl(1-ethoxyvinyl)stannane (38.3 mL, 113.5 mmol) in DMF (400 mL) was added PdCl ( _{pph ) ( 0.66} g, 0.95 mmol) under N. The reaction was stirred at 100°C for 3 h. The cooled reaction mixture was diluted with ether (800 mL) and treated with KF aqueous solution (27 g KF in 800 mL water). The mixture was stirred vigorously for 1 h and then filtered through celite. The filtrate was washed with saturated NaHCO _solution (400 mL) and brine (400 mL). The aqueous phase was re-extracted with EtOAc (500 mL) and the combined organics were dried (over _MgSO ) and concentrated under reduced pressure. The crude material was suspended in THF (400 mL) and 2M HCl (400 mL) was added. The solution was stirred at room temperature overnight, then concentrated to remove THF and extracted with DCM (3×500 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by dry flash chromatography (eluting with DCM) to give 11.2 g (61% yield) of the title compound as a white solid.

¹ H NMR (500MHz, CDCl ₃ ): δ [ppm] 8.32 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 2.95 (s, 3H).

LLCMS (analytical method A): Rt=1.01 min, MS (ESIpos): m/z=190.9 (M+H) ⁺ .

Intermediate XVII: (S)-2-Methyl-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]propane-2-sulfenamide

To a stirred solution of 1-[6-(trifluoromethyl)pyridazine-3-yl]ethanone (1.27 g, 6.68 mmol) and tetraethyl titanate (2.80 mL, 13.36 mmol) in anhydrous THF (27.5 mL) was added (S)-2-tert-butylsulfenamide (0.81 g, 6.68 mmol), and the resulting solution was stirred at 80 ° C for 60 min. The reaction was cooled to below-70 ° C, and lithium tri-sec-butylborohydride (1 M, 6.7 mL) was added dropwise, keeping the internal temperature below-68 ° C. After the addition was complete, the reaction was stirred for another 60 minutes at this temperature, and then EtOAc (40 mL) and water (40 mL) were added dropwise to terminate the reaction by adding methanol (1.4 mL). The organic layer was collected by pouring out, and the solid residue was stirred with EtOAc (30 mL). The organic layer was collected by pouring out, and this process was repeated three times. The combined organics were dried ( _{over Na2SO4} ), filtered, diluted with heptane (20 mL) and evaporated onto silica (5 g).The material was purified by dry flash chromatography (eluting with TBME then EtOAc then acetone) to give 1.09 g (51% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, CDCl ₃ ) δ [ppm] = 7.81 (d, J = 8.7Hz, 1H), 7.75 (d, J = 8.7Hz, 1H), 5.01 (p, J = 6.7Hz, 1H), 3.93 (d, J = 5.8Hz, 1H), 1.75 (d, J = 6.9Hz, 3H), 1.23 (s, 9H).

Intermediate XVIII: (1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethanamine hydrochloride (1:1)

To a solution of (S)-2-methyl-N-[(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl]propane-2-sulfinamide (998 mg, 3.38 mmol) in methanol (12 mL) was added concentrated HCl (12 M, 2.8 mL, 883 mmol) at 0 ° C., and the reactants were stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and azeotroped with isopropanol (2×30 mL). The residue was ground with anhydrous acetone, and the precipitate was collected by vacuum filtration. The mother liquor was concentrated, and the residue was ground with EtOAc. The precipitate was collected by vacuum filtration and the batches were combined to obtain 738 mg (89% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, DMSO-d6) δ [ppm] = 8.95 (s, 3H), 8.42 (d, J = 8.8Hz, 1H), 8.27 (d, J = 8.8Hz, 1H), 4.88 (q, J = 6.8Hz, 1H), 1.63 (d, J = 6.9Hz, 3H).

Intermediate XIX: tert-Butyl [(2R)-1-(2-acetylhydrazinyl)-1-oxopropan-2-yl]carbamate

N-tert-Butoxycarbonyl-D-Alanine (1g, 5.29mmol) is dissolved in DCM (15mL).Once add EEDQ (1.3g, 5.29mmol), then add acetic hydrazide (0.47g, 6.34mmol) and solution is stirred 72h.Reactant mixture is concentrated under reduced pressure, and gained residue is passed through Biotage Isolera ^TM chromatogram (at 25g pre-packed KP-SiO ₂ post upper with 20-100% acetone in heptane elution) purifying to obtain the title compound of 917.7mg (71% yield) white solid.

¹ H NMR (500MHz, CDCl ₃ ): δ [ppm] 8.95 (s, 1H), 8.29 (s, 1H), 5.06 (d, J = 7.2Hz, 1H), 4.30 (s, 1H), 2.06 (s, 3H), 1.45 (s, 9H), 1.40 (d, J = 7.2Hz, 3H).

Intermediate XX: tert-Butyl [(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]carbamate

[(2R)-1-(2-acetylhydrazine)-1-oxopropyl-2-yl] tert-butyl carbamate (917.7mg, 3.74mmol) is dissolved in anhydrous THF (50mL), and Lawesson's reagent (1.66g, 4.12mmol) is added once. The gained suspension is heated under reflux for 2h and allowed to cool to room temperature overnight. The crude residue evaporated is partially purified by Biotage Isolera ^™ chromatography (eluting with 0-50% EtOAc in heptane on the Isolute silica gel column pre-packed with 25g) to obtain yellow glue. Purify by being dissolved in EtOAc (20mL) and stirring 10 minutes with the charcoal (2×4g) of decolorization. The filtrate is concentrated under reduced pressure to obtain the transparent colloid title compound that can crystallize after standing 876.6mg (96% yield).

¹ H NMR (500 MHz, chloroform-d): δ 5.32-5.04 (m, 2H), 2.75 (s, 3H), 1.65 (d, J=6.6 Hz, 3H), 1.45 (s, 9H).

LCMS (Analytical Method A) Rt=1.04 min, MS (ESIpos): m/z=244.0 (M+H) ⁺ .

Intermediate XXI: (1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethylamine hydrochloride

To a solution of tert-butyl [(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]carbamate (876.6 mg, 3.6 mmol) in MeOH (12 mL) at 0° C. was added 4 M HCl in dioxane (9 mL, 36.0 mmol). After stirring at room temperature for 4 h, the solvent was evaporated and the residue was triturated with Et ₂ O. The precipitate was collected by filtration and dried in a vacuum oven to give 565 mg (81% yield) of the title compound as a white solid.

¹ H NMR (250MHz, DMSO-d6): δ7.21 (s, 3H), 4.77-4.63 (m, 1H), 2.71 (s, 3H), 1.51 (d, J = 6.7Hz, 3H).

Analytical HPLC: column: YMC Amy-C (1500 mm×4.6 mm, 5 μm); mobile phase: heptane/ethanol (1:1) (DEA added as a modifier); flow rate: 1 ml/min; detection: UV 254 nm; run time: 10 min; Rt=5.13 min; 92.1% ee.

Intermediate XXII: 2-(trifluoromethyl)pyrimidine-5-carbaldehyde

N-methoxy-N-methyl-2-(trifluoromethyl)pyrimidine-5-carboxamide (1 g, 4.25 mmol) was dissolved in anhydrous THF (25 mL) under _N and cooled to -78°C. Lithium aluminum hydride (1 M in THF, 2.66 mL, 6.34 mmol) was added dropwise and the reaction was stirred for 30 min. The reaction was terminated by adding water (5 mL) and the reaction mixture was allowed to warm to room temperature. EtOAc (10 mL) and 1 M HCl (10 mL) were added and the mixture was stirred for 30 min. The aqueous layer was collected and extracted with EtOAc (10 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure to give 577.2 mg (77% yield) of the title compound as a colorless oil.

¹ H NMR (250MHz, CDCl ₃ ): δ [ppm] 10.26 (s, 1H), 9.35 (s, 2H).

Intermediate XXIII: (R)-2-Methyl-N-{(E)-[2-(trifluoromethyl)pyrimidin-5-yl]methylene-propane-2-sulfenamide

To a solution of 2-(trifluoromethyl)pyrimidine-5-carboxaldehyde (0.58 g, 3.28 mmol) in DCE (10 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (0.44 g, 3.60 mmol) and copper (II) sulfate (1.05 g, 6.55 mmol). The mixture was heated to 50° C. and stirred overnight. The reaction mixture was cooled and filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure to give 697.8 mg (76% yield) of the title compound as a brown gum.

¹ H NMR (250MHz, CDCl ₃ ): δ9.30 (s, 2H), 8.73 (s, 1H), 1.30 (s, 9H).

Intermediate XXIV: (R)-2-Methyl-N-{(1R)-1-(trifluoromethyl)pyrimidin-5-yl}propyl}propane-2-sulfenamide

To a solution of (R)-2-methyl-N-{(E)-[2-(trifluoromethyl)pyrimidin-5-yl]methylene}propane-2-sulfenamide (697.8 mg, 2.5 mmol) in THF (10 mL) was added ethylmagnesium bromide (1 M in THF, 2.75 mL, 2.75 mmol) at 70°C. The mixture was stirred at -70°C for 15 min. The mixture was quenched with saturated _NH4Cl and the reaction was allowed to warm to room temperature. The solution was extracted with EtOAc (3 x 10 mL) and the combined organics were dried (over _MgSO4 ) and concentrated under reduced pressure. The crude material was purified by Biotage Laolera ^™ chromatography (basic silica gel, eluting with 0-60% EtOAc in heptane) to give 445.2 mg (52% yield) of the title compound as a yellow gum.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.87(s,2H),4.42(q,J＝6.2Hz,1H),3.52(d,J＝5.4Hz,1H),2.12(tt,J＝14 .0,7.3Hz,1H),1.89(dp,J＝14.7,7.4Hz,1H),1.24(s,10H),0.93(t,J＝7.4Hz,3H).

LCMS (Analytical Method A) Rt=1.19 min, MS (ESIpos): m/z=310 (M+H) ⁺ .

Intermediate XXV: (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propan-1-amine hydrochloride

To a solution of (R)-2-methyl-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}propane-2-sulfinyl (445.2 mg, 1.31 mmol) in diethyl ether (5 mL) was added hydrochloric acid (2M in _Et2O , 3.3 mL, 6.6 mmol) and the reaction was stirred at room temperature for 1 h. The precipitate was collected by filtration and dried in a vacuum oven to give 283.0 mg (89% yield) of the title compound as a yellow powder.

¹ H NMR (250MHz, DMSO): δ [ppm] 9.26 (s, 2H), 8.81 (s, 3H), 4.45 (dd, J = 8.5, 6.4Hz, 1H), 2.19-1.89 (m, 2H), 0.85 (t, J = 7.4Hz, 3H).

Intermediate XXVI: (R)-2-Methyl-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}propane-2-sulfenamide

To a stirred solution of 1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanone (331 mg, 1.74 mmol) and tetraethyl titanate (0.73 mL, 3.5 mmol) in THF (10 mL) was added (R)-2-tert-butylsulfenamide (211 mg, 1.74 mmol), and the resulting solution was stirred at 80 ° C for 45 min. The reaction mixture was cooled to -78 ° C and lithium tri-sec-butylborohydride (1.74 mL, a 1M solution in THF) was added dropwise, maintaining the internal temperature below -70 ° C. The reaction was stirred for another 30 min at -78 ° C. The reaction was terminated by adding MeOH (1 mL) and warmed to room temperature. Water (50 mL) was added followed by EtOAc (100 mL), and the mixture was filtered through glass fiber filter paper and washed with EtOAc (2 × 50 mL). The filtrate was separated and the aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organics were dried (over _Na2SO4 ), filtered and concentrated under reduced pressure.The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with 0-10% MeOH in EtOAc) followed by trituration with TBME _to afford 170 mg (28% yield) of an off-white powder.

¹ H NMR (500MHz, CDCl ₃ ) δ [ppm] = 8.88 (s, 2H), 4.75 (qd, J = 6.8, 3.6Hz, 1H), 3.48-3.38 (m, 1H), 1.68-1.62 (m, 3H), 1.24 (s, 9H).

Intermediate XXVII: (1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine hydrochloride (1:1)

(R)-2-Methyl-N-[(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl]propane-2-sulfinamide (0.17 g, 0.58 mmol) was dissolved in methanol (5 mL) and cooled to 0°C. Concentrated aqueous HCl (0.55 mL) was added dropwise and the reaction was stirred at room temperature for 1 hour, then concentrated under vacuum. The resulting yellow oil was sonicated with ether to give a white solid, which was collected by filtration to give 0.107 g (82% yield) of the title compound as a white solid.

¹ H NMR (250MHz, DMSO-d6) δ [ppm] = 9.25 (s, 2H), 8.79 (s, 3H), 4.67 (q, J = 6.9Hz, 1H), 1.63 (d, J = 6.9Hz, 3H).

Analytical HPLC: column: Chiralpak AD-H 25 cm; mobile phase: 90:10 heptane:ethanol; flow rate: 0.3 ml/min; detection: UV 254 nm; run time: 70 min; Rt = 37.79 min; 100% ee.

Intermediate XXVIII: (1R)-1-(2-methylpyrimidin-5-yl)ethylamine

Intermediate XXVIII was synthesized as described in WO2008/130481.

Intermediate XXXIX: 2-(Trifluoromethyl)pyrimidine-5-carbonitrile

Intermediate II (1 g, 5.2 mmol), ammonium chloride (0.56 g, 10.4 mmol), and triethylamine (1.45 mL, 10.4 mmol) were suspended in 1,4-dioxane. T3P (50% in EtOAc, 7.3 mL, 12.5 mmol) was added, and the reaction was stirred at 100°C for 24 h. The reaction was further treated with T3P (50% in EtOAc, 3.65 mL, 6.25 mmol) and heated for an additional 6 h. The reaction was further treated with ammonium chloride (0.56 g, 10.4 mmol) and triethylamine (1.45 mL, 10.4 mmol) and stirred at 100°C for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 1:1) to provide 642 mg (71% yield) of the title compound as a colorless oil.

¹ H NMR (250 MHz, chloroform-d): δ [ppm] 9.19 (s, 2H).

LCMS (Analytical Method A) Rt = 0.96 min.

Intermediate XL: 1-[2-(trifluoromethyl)pyrimidin-5-yl]methanamine hydrochloride

To a solution of intermediate XXXIX (500 mg, 2.9 mmol) in ethanol (10 mL) was added 1 M hydrochloric acid (1 mL) and Pd/C (10% wt. 50 mg, 10% weight) and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 h. The catalyst was removed by filtration under reduced pressure, and the solid was washed with MeOH. The filtrate was concentrated under reduced pressure and the residue was triturated with _Et2O to provide 381.3 mg (50% yield) of the title compound as an off-white powder.

1H NMR (250 MHz, DMSO): δ [ppm] 9.22 (s, 2H), 8.71 (s, 3H), 4.22 (s, 2H), containing 19 wt% NH ₄ Cl.

Intermediate XLI: 1-[6-(trifluoromethyl)-3-pyridyl]ethanone

Under nitrogen, 5-bromo-2-(trifluoromethyl)pyridine (10.0 g, 44.3 mmol), water (40 mL), DMF (120 mL), potassium carbonate (12.2 g, 88.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (621 mg, 2 mol%) and tributyl(1-ethoxyvinyl)stannane (19.2 g, 53.1 mmol) were stirred and heated to 110° C. over a period of 1.5 h. The reaction mixture was cooled, diluted with ether (120 mL) and KF (12.8 g in 50 mL of water) was added. The resulting reaction mixture was stirred vigorously for 1 h and then filtered through Celite®. The organic layer was then washed with saturated aqueous NaHCO ₃ solution and then with brine, then dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was dissolved in THF (200 mL) and 2M HCl (60 mL), and the reaction was stirred at ambient temperature for 40 minutes. The organic matter was removed under reduced pressure, and the aqueous layer was extracted with DCM (3×50 mL). The organic layers were combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc, 1:0 to 10:1) to provide 4.90 g (56% yield) of a white crystalline solid.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 9.25 (d, J = 1.3 Hz, 1H), 8.41 (dd, J = 8.2, 1.6 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 2.70 (s, 3H).

LCMS (Analytical Method A) Rt=1.15 min, MS (ESIpos): m/z=190.0 (M+H) ⁺ .

Intermediate XLII: 2-Methyl-N-[(1R)-1-[6-(trifluoromethyl)-3-pyridyl]ethyl]propane-2-sulfenamide

To the stirred solution of intermediate XLI (5.44g, 28.8mmol) and tetraethyl titanate (18.6mL, 57.5mmol) in ether (120mL), (S)-2-tert-butyl sulfenamide (3.85g, 31.6mmol) is added, and the resulting solution is stirred for 3h under nitrogen under reflux. The reaction mixture is cooled to room temperature, then cooled to-78°C, and tri-sec-butyl lithium borohydride (1M in THF, 34.5mL, 34.5mmol) is added dropwise. Reactant is stirred for 30 minutes at-78°C. The reaction is stopped and allowed to warm up to room temperature by adding concentrated brine (20mL), then filtered (washed with ethyl acetate) by plug. The filtrate is washed with concentrated brine (40mL), and the aqueous solution layer is extracted once with ethyl acetate (40mL). The organic layer is merged, and passed through _MgSO4 drying, filtered and concentrated under reduced pressure. The residue was triturated with _Et2O and the solid was collected by vacuum filtration to provide 5.15 g (61% yield) of the title compound as a white solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.71 (d, J = 1.6, 1H), 7.83 (dd, J = 8.1, 2.0, 1H), 7.66 (d, J = 8 .1,1H),4.70(qd,J＝6.7,2.6,1H),3.44-3.39(m,1H),1.58(d,J＝6.8,3H),1.21(s,9H).

LCMS (Analytical Method A) Rt=1.13 min, MS (ESIpos): m/z=295.05 (M+H) ⁺ .

Intermediate XLIII: (1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethanamine hydrochloride

To a solution of intermediate XLII (5.15 g, 17.5 mmol) in 2-propanol (20 mL) cooled to 0 ° C in an ice bath was added concentrated HCl (5 mL, 60 mmol). The mixture was allowed to warm to room temperature and after 20 minutes, methanol (5 mL) was added to increase solubility. The reactant was stirred for 3 hours. The solvent was removed under reduced pressure, and the residue was ground with ether and collected by vacuum filtration to provide 3.28 g (83% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.68 (s, 1H), 7.79 (dd, J = 8.1, 2.1, 1H), 7.64 (d, J = 8.1, 1H), 4.88 (s, 2H), 1.48 (d, J = 6.7, 3H), 1.41 (s, 9H).

Intermediate XLIV: tert-Butyl {(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}carbamate

To a solution of intermediate XLIII in DCM (40 mL) was added di-tert-butyl dicarbonate (2.91 g, 13.3 mmol) and triethylamine (5.1 mL, 36.4 mmol). The reaction mixture was stirred at room temperature for 4 h and then washed with saturated _NH4Cl solution (40 mL). The aqueous phase was re-extracted with DCM (2×40 mL), and the combined organics were dried over _MgSO4 , filtered, and concentrated under reduced pressure to provide 3.7 g (100% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.68 (s, 1H), 7.79 (dd, J = 8.1, 2.1, 1H), 7.64 (d, J = 8.1, 1H), 4.88 (s, 2H), 1.48 (d, J = 6.7, 3H), 1.41 (s, 9H).

LCMS (Analytical Method A) Rt=1.37 min, MS (ESIpos): m/z=290.95 (M+H) ⁺ .

Intermediate XLVII: Ethyl (5-bromopyrimidin-2-yl)(difluoro)acetate

Under _N2 , to a mixture of zinc powder (9.6 g, 147.4 mmol) in triethylene glycol dimethyl ether (100 mL) was added TMSBr (1.9 mL, 14.4 mmol), and the reaction was stirred at reflux for 90 minutes. The reaction was cooled to room temperature, ethyl bromo(difluoro)acetate (15.3 mL, 119.3 mmol) was added dropwise, and the mixture was stirred for 30 minutes and then cooled to ~10°C. 5-Bromo-2-iodo-pyrimidine (10 g, 35.1 mmol) in DMA (100 mL) was added dropwise, and the reaction was then allowed to warm to RT. Copper bromide (21.1 g, 147.4 mmol) was added portionwise over 40 minutes, and the reaction was then stirred at room temperature for another 1 hour. The reaction mixture was slowly poured into a cooled mixture of 10% NaCl (100 mL), 5M HCl (100 mL) and toluene (200 mL) and stirred for 30 minutes. The mixture was filtered, the organic layer was separated and dried over _MgSO4 , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc, 1:0 to 7:3) to provide 10.34 g (82% yield, 78% purity) of the title compound as a colorless oil.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.92 (s, 2H), 4.41 (qd, J=7.1, 3.4 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.10 min, MS (ESIpos): m/z=280.9/282.9 (M+H) ⁺ .

Intermediate XLVIII: Ethyl (5-acetylpyrimidin-2-yl)(difluoro)acetate

To a degassed solution of intermediate XLVII (4.5 g, 12.5 mmol) and tributyl(1-ethoxyvinyl)stannane (5.06 mL, 15.0 mmol) in anhydrous DMF (45 mL) was added _PdCl ( _PPh ) ( ₈₈ mg, 0.13 mmol) _under N₂. The reaction mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with ether (90 mL) and treated with KF aqueous solution (7.26 mg KF in 90 mL water). The mixture was stirred vigorously for 1 h and then filtered through glass fiber filter paper. The filtrate was washed with saturated _NaHCO₃ solution and then with concentrated brine. The aqueous solution was extracted with EtOAc. The combined organics were dried over _MgSO₄ , filtered, and concentrated under reduced pressure. The crude material was suspended in THF (90 mL) and 1 M HCl (90 mL) was added. The solution was stirred at room temperature for 2 h, then concentrated to remove THF and then extracted with DCM (3 x 90 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc, 3:2 to 1:1) to provide 1.37 g (45% yield) of the title compound as a colorless oil.

¹ H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 9.32 (s, 2H), 4.41 (q, J=7.1 Hz, 2H), 2.70 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=1.01 min, MS (ESIpos): m/z=244.95 (M+H) ⁺ .

Intermediate XLIX: 1-[2-(difluoromethyl)pyrimidin-5-yl]ethanone

A mixture of intermediate XLVIII (1.05 g, 4.3 mmol), KF (1.25 g, 21.5 mmol) and water (387.3 μL, 21.5 mmol) was stirred in DMF (20 mL) under _N at 170 ° C for 3 h and then cooled to room temperature. Saturated _NaHCO solution (20 mL) was added and the mixture was extracted with _Et O (3×40 mL). The combined organics were dried over _MgSO , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc, 3:2) to provide 493 mg (67% yield) of the title compound as a yellow oil, which crystallized upon standing.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 9.33 (s, 2H), 6.71 (t, J=54.2 Hz, 1H), 2.70 (s, 3H).

LCMS (Analytical Method A) Rt=0.69 min, MS (ESIpos): m/z=172.90 (M+H) ⁺ .

Intermediate L: (S)-N-[(1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethyl]-2-methylpropane-2-sulfenamide

To a stirred solution of intermediate XLIX (492 mg, 2.86 mmol) and tetraethyl titanate (1.84 mL, 3.14 mmol) in _Et2O (20 mL) was added (S)-2-tert-butylsulfenamide (381 mg, 3.14 mmol), and the resulting solution was stirred at reflux under nitrogen for 2 h. The reaction mixture was cooled to room temperature, then to -78°C, and lithium tri-sec-butylborohydride (3.7 mL, 1 M solution in THF) was added dropwise. The reaction was stirred at -78°C for an additional 45 min, then quenched by the addition of brine (5 mL) and allowed to warm to room temperature. The suspension was filtered through a plug of Celite® and washed with EtOAc. The filtrate was washed with brine (10 mL) and the aqueous layer was re-extracted with EtOAc (2 x 10 mL). The combined organics were dried over _MgSO4 , filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether to provide 365.1 mg (45% yield) of the title compound as a white solid.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 8.84 (s, 2H), 6.67 (t, J = 54.5 Hz, 1H), 4.72 (qd, J = 6.7, 3.1 Hz, 1H), 3.41 (d, J = 2.6 Hz, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.23 (s, 9H).

LCMS (Analytical Method A) Rt=0.90 min, MS (ESIpos): m/z=277.95 (M+H) ⁺ .

Intermediate LI: (1R)-1-[2-(difluoromethyl)pyrimidin-5-yl]ethanamine hydrochloride

Intermediate L (982 mg, 3.54 mmol) was stirred in 1 M HCl in diethyl ether (35 mL) for 4 h to form a white precipitate. The material was collected by filtration and dried in a vacuum oven to provide 780 mg (90% yield) of a yellow glass.

¹ H NMR (250MHz, DMSO-d6): δ [ppm] 9.17 (s, 2H), 8.87 (s, 2H), 7.01 (t, J = 53.9Hz, 1H), 4.68-4.55 (m, 1H), 1.62 (d, J = 6.9Hz, 3H).

Intermediate LII: 1-[6-(difluoromethyl)pyridin-3-yl]ethanone

To a degassed solution of 5-bromo-2-(difluoromethyl)pyridine (1 g, 4.81 mmol) and tributyl(1-ethoxyvinyl)stannane (1.95 mL, 5.77 mmol) in DMF (20 mL) was added PdCl( _{PPh ) ( 34} mg, 0.05 mmol) under N. The reaction mixture was stirred at 100°C for 2.5 h. The reaction mixture was diluted with ether (40 mL) and treated with KF aqueous solution (1.4 g KF in 40 mL water). The mixture was stirred vigorously for 1 h before being filtered through Celite®. The filtrate was diluted with ethyl acetate (50 mL), washed with saturated sodium bicarbonate solution and then with concentrated brine, dried over _MgSO , filtered, and concentrated under reduced pressure. The crude material was suspended in THF (20 mL), and 2M HCl (20 mL) was added. The solution was stirred vigorously at room temperature for 15 minutes, then concentrated to remove THF, and then extracted with DCM (3 x 50 mL). The combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluting with heptane-EtOAc, 1:0 to 4:1) to provide 730 mg (87% yield) of the title compound as a colorless oil.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 9.20 (d, J = 1.6 Hz, 1H), 8.47 (dd, J = 8.1, 2.1 Hz, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.05 (t, J = 54.6 Hz, 1H), 2.67 (s, 3H).

LCMS (Analytical Method A) Rt=0.94 min, MS (ESIpos): m/z=171.9 (M+H) ⁺ .

Intermediate LIII: (S)-N-[(1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethyl]-2-methylpropane-2-sulfenamide

To the stirred solution of intermediate LII (725mg, 4.19mmol) and tetraethyl titanate (2.73mL, 8.47mmol) in diethyl ether (40mL), (S)-2-tert-butylsulfenamide (565mg, 8.47mmol) was added, and the resulting solution was stirred for 20h under nitrogen at reflux. The reaction mixture was cooled to room temperature, then further cooled to -78°C, and tri-sec-butyl lithium borohydride (4.66mL, 1M solution in THF) was added dropwise. The reactant was stirred for another 1h at -78°C, then the reaction was terminated by adding concentrated brine (25mL), and then allowed to warm to room temperature. The suspension was filtered through a plug and washed with ethyl acetate. The filtrate was washed with concentrated brine (20mL), and the aqueous layer was extracted again with EtOAc (30mL). The combined organic matter was dried by _MgSO4 , filtered and concentrated under reduced pressure. The crude yellow solid was triturated with diethyl ether to provide 525 mg (44% yield) of the title compound as a white solid.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 8.67 (d, J = 1.7Hz, 1H), 7.96 (dd, J = 8.1, 2.0Hz, 1H), 7.67 (d, J = 8.1Hz, 1H), 6.93 (t, J = 55.0Hz, 1H), 5.58 (d, J = 5.6Hz, 1H), 4.56 (m, 1H), 1.51 (d, J = 6.8Hz, 3H), 1.11 (s, 9H).

LCMS (Analytical Method A) Rt=0.99 min, MS (ESIpos): m/z=276.95 (M+H) ⁺ .

Intermediate LIV: (1R)-1-[6-(difluoromethyl)pyridin-3-yl]ethanamine hydrochloride

To a solution of intermediate LIII (517 mg, 2.23 mmol) in methanol (2 mL) cooled to 0°C in an ice bath was added 5M HCl in 2-propanol (1.87 mL, 9.35 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. The solvent was removed under reduced pressure and the residue was ground in ether to provide 450 mg (97% yield) of the title compound as a white solid.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 8.84-8.79 (m, 1H), 8.65 (s, 3H), 8.18 (d, J = 8.2Hz, 1H ), 7.79 (d, J = 8.1Hz, 1H), 6.98 (t, J = 54.8Hz, 1H), 4.57 (m, 1H), 1.57 (d, J = 6.9Hz, 3H).

Intermediate LV: (2R)-2-(tert-butoxycarbonylamino)propionic acid

To a solution of D-alanine methyl ester hydrochloride (5 g, 35.8 mmol) and sodium bicarbonate (9.0 g, 107 mmol) in water (100 mL) was added di-tert-butyl dicarbonate (11.7 g, 53.7 mmol), and the resulting solution was stirred at room temperature overnight. The reaction mixture was extracted with DCM (3 × 100 mL), and the combined organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure. Preliminary NMR showed a large amount of unreacted di-tert-butyl dicarbonate, so the material was dissolved in DCM (50 mL) and treated with N, N-dimethylethylenediamine (5 mL) and stirred for 30 min. The solution was washed with 1M HCl (50 mL), dried over MgSO ₄ , filtered and concentrated under reduced pressure to provide 5.35 g (73% yield) of the title compound as a colorless oil.

¹ H NMR (500 MHz, CHLOROFORM-d) δ 5.04 (s, 1H), 4.31 (m, 1H), 3.73 (s, 3H), 1.44 (s, 9H), 1.37 (d, J=7.2 Hz, 3H).

Intermediate LVI: tert-butyl [(2R)-1-hydrazino-1-oxopropan-2-yl]carbamate

To a solution of intermediate LV (5.35 g, 26.3 mmol) in ethanol (140 mL) was added hydrazine hydrate (19.8 mL) and the reaction was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure and the residue was triturated with heptane. The resulting precipitate was collected by filtration and dried in a vacuum oven to provide 5.00 g (93% yield) of the title compound as a crystalline powder.

¹ H NMR (250MHz, DMSO): δ [ppm] 8.96 (s, 1H), 6.81 (d, J = 7.7Hz, 1H), 4.17 (s, 2H), 4.03-3.81 (m, 1H), 1.36 (s, 9H), 1.14 (d, J = 7.1Hz, 3H).

Intermediate LVII: tert-butyl {(2R)-1-oxo-1-[2-(trifluoroacetyl)hydrazinyl]propan-2-yl}carbamate

To a solution of intermediate LVI (3.96 g, 19.5 mmol) and DIPEA (4.07 mL, 23.4 mmol) in MeCN (100 mL) was added trifluoroacetic anhydride (3.03 mL, 21.4 mmol) under _N at -45 °C. The reaction was gradually warmed to room temperature and stirred for a further 30 min. The solvent was removed by evaporation, and the residue was partitioned between H ₂ O (25 mL) and EtOAc (25 mL). The organic phase was separated, and the aqueous phase was re-extracted with EtOAc (25 mL). The combined organic phases were washed with H ₂ O (30 mL), concentrated brine (30 mL), dried over MgSO ₄ and evaporated. The residue was purified by flash column chromatography (silica gel, eluted with heptane-EtOAc, 3:2) to provide 4.30 g (69% yield) of the title compound as a white solid foam.

¹ H NMR (250 NHz, chloroform-d): δ [ppm] 9.16 (s, 1H), 8.89 (s, 1H), 4.93 (s, 1H), 4.39-4.22 (m, 1H), 1.46 (s, 9H), 1.42 (d, J=7.1 Hz, 3H).

LCMS (Analytical Method A) Rt=0.90 min, MS (ESIpos): m/z=321.95 (M+Na) ⁺ .

Intermediate LVIII: tert-butyl {(1R)-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}carbamate

Intermediate LVII (1.25g, 4.18mmol) is dissolved in anhydrous THF (50mL), and once add Lawesson's reagent (1.86g, 4.6mmol).Then gained suspension is heated to reflux 2h, then under reduced pressure concentrated.Resistates is passed through Biotage Isolera ^™ chromatogram (at pre-packed KP-SiO ₂ post upper with 10-25%EtOAc wash-out in heptane) purifying.The product containing fraction is merged, and with～5g activated carbon decolorizing (stirring 1h).Mixture is filtered and under reduced pressure concentrated to obtain 0.63g (51% yield) white powdery title compound.

¹ H NMR (250 MHz, chloroform-d): δ [ppm] 5.30-5.21 (m, 1H), 5.17 (s, 1H), 1.74 (d, J=6.9 Hz, 3H), 1.46 (s, 9H).

LCMS (Analytical Method A) Rt=1.18 min, MS (ESIpos): m/z=241.85 (M+H) ⁺ .

Intermediate LIX: (1R)-1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine hydrochloride

Intermediate LVIII (571 mg, 1.92 mmol) was stirred in 4M hydrochloric acid in 1,4-dioxane (4.5 mL, 16 mmol) for 2 h. The solution was concentrated under reduced pressure and the residue was triturated with _Et20 to afford 384 mg (86% yield) of the title compound as a white powder.

¹ H NMR (250MHz, DMSO-D6): δ [ppm] 9.03 (s, 3H), 5.20 (q, J = 6.8 Hz, 1H), 1.71 (d, J = 6.8 Hz, 3H).

Example 1: 3-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a stirred solution of Intermediate 5A (46 mg, 0.16 mmol), Intermediate VI (40.1 mg, 0.176 mmol), DIPEA (0.111 mL, 0.64 mmol) and DMAP (3.9 mg, 0.032 mmol) was added HATU (73.0 mg, 0.192 mmol) at room temperature. After stirring at room temperature for 2 h, the reaction mixture was washed with water (3 mL) and the aqueous layer was re-extracted with DCM (2×3 mL). The combined organics were dried (over MgSO ₄ ) and evaporated under reduced pressure. The crude material was purified by crystallization from acetonitrile to give 43.4 mg (59% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.84 (s, 1H), 7.55-7.53 (m, 1H), 7.53-7.51 (m, 1H), 7.42-7.35 (m, 1H), 6.62 (d, J = 6.6Hz, 1H), 5.3 6(p,J＝7.1Hz,1H),3.91(d,J＝7.0Hz,2H),2.53(s,3H),1.71(d,J＝7.2Hz,3H),1.36-1.22(m,1H),0.71-0.63(m,2H),0.37(q,J＝4.9Hz,2H).

Analytical LC-MS (Analytical Method D) 99% @ Rt = 4.57, MH+ = 463.

Example 2: 3-(Cyclopropylmethoxy)-N-[(6-methylpyridazin-3-yl)methyl]5-(5-methyl-1,3-thiazol-2-yl)benzamide

Analogously to Example 1, 50 mg of intermediate 5A was reacted with 22 mg (0.18 mmol) of 1-(6-methylpyridazin-3-yl)methanamine and subsequently purified by preparative HPLC (Method A) to give 38.2 mg (59% yield) of the title compound.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.92 (t, J = 1.4Hz, 1H), 7.65 (m, J = 5.3Hz, 1H), 7.62 (d d,J＝2.4,1.5Hz,1H),7.54(d+s,J＝8.6Hz,2H),7.47(dd,J＝2.3,1.5Hz,1H),7.40 (d,J＝8.6Hz,1H),4.95(d,J＝5.3Hz,2H),3.95(d,J＝6.9Hz,2H),2.76(s,3H),2.5 4(d,J＝1.1Hz,3H),1.36-1.28(m,1H),0.72-0.66(m,2H),0.40(q,J＝4.7Hz,2H).

Analytical LC-MS (Analytical Method F): 98.5% @ Rt = 2.90, MH+ = 395.

Example 3: 3-(Cyclopropylmethoxy)-N-[(5-methylpyrazin-2-yl)methyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (50 mg, 0.16 mmol), 1-(5-methylpyrazin-2-yl)methanamine (22 mg, 0.18 mmol), and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA (84 μL, 0.48 mmol) and HATU (73 mg, 0.19 mmol), and the reaction was stirred for 18 h. The reaction mixture was diluted with DCM (4 mL) and washed with saturated aqueous NaHCO ₃ (2×2 mL), brine (2 mL), dried (over MgSO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A) to give 36 mg (55% yield) of the title compound.

¹ H NMR (500MHz, CDCl ₃ ): δ [ppm] = 8.57-8.51 (m, 1H), 8.40 (s, 1H), 7.87 (d, J = 1.3Hz, 1H), 7.58-7. 55(m,1H),7.50(d,J＝1.1Hz,1H),7.44-7.41(m,1H),7.29(s,1H),4.76(d, J＝5.2Hz,2H),3.91(d,J＝6.9Hz,2H),2.57(s,3H),2.51(d,J＝0.9Hz,3H),1 .29(dqt,J＝9.5,7.1,4.8Hz,1H),0.69-0.64(m,2H),0.37(q,J＝4.8Hz,2H).

LCMS (Analytical Method F) Rt=3.19 min, MS (ESIpos) m/z=395 (M+H) ⁺ .

Example 4: 3-(Cyclopropylmethoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (50 mg, 0.16 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (30 mg, 0.18 mmol) and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA (84 μL, 0.48 mmol) and HATU (73 mg, 0.19 mmol), and the reaction was stirred for 18 h. The reaction mixture was diluted with DCM (4 mL) and washed with saturated aqueous NaHCO ₃ (2×2 mL), brine (2 mL), dried (over MgSO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A) to give 43 mg (63% yield) of the title compound.

¹ H NMR (500 MHz, CDCl ₃ ): δ [ppm] = 8.52 (d, J = 1.3Hz, 1H), 8.40 (s, 1H), 7.86 (d, J = 1.3Hz, 1H), 7.58-7.5 3(m,1H),7.50(d,J＝1.1Hz,1H),7.43-7.38(m,1H),7.31(d,J＝7.5Hz,1H),5.42( p,J＝6.9Hz,1H),3.91(d,J＝7.0Hz,2H),2.56(s,3H),2.51(d,J＝0.9Hz,3H),1.5 9(d,J＝6.8Hz,3H),1.34-1.24(m,1H),0.68-0.63(m,2H),0.36(q,J＝4.8Hz,2H).

LCMS (Analytical Method F) Rt=3.42 min, MS (ESIpos) m/z=409 (M+H) ⁺ .

Example 5: N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (47.5 mg, 0.15 mmol), 1-(3-chloro-5-fluoropyridin-2-yl)ethanamine hydrochloride (35 mg, 0.17 mmol), and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA (80 μL, 0.46 mmol) and HATU (70 mg, 0.18 mmol), and the reaction was stirred for 2.5 h. The reaction mixture was diluted with DCM (4 mL) and washed with saturated aqueous NaHCO ₃ (2×2 mL), brine (2 mL), dried (over MgSO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A) and then triturated with diethyl ether to afford 31 mg (59% yield) of the title compound as a mixture of two enantiomers.

¹ H NMR (500MHz, CDCl3): δ [ppm] = 8.39 (d, J = 2.5Hz, 1H), 7.90 (t, J = 1.4Hz, 1H), 7.64 (d, J＝7.6Hz,1H),7.58(dd,J＝2.4,1.5Hz,1H),7.54-7.49(m,2H),7.44(dd,J＝2.4,1.5H z,1H),5.76(p,J＝6.6Hz,1H),3.93(d,J＝7.0Hz,2H),2.53(d,J＝1.1Hz,3H),1.53(d, J=5.6Hz, 3H), 1.30 (td, J=7.9, 4.0Hz, 1H), 0.71-0.64 (m, 2H), 0.38 (q, J= 4.8Hz, 2H).

LCMS (Analytical Method F): Rt=4.18 min, MS (ESIpos) m/z=446 (M+H) ⁺ .

Example 6: N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (47.5 mg, 0.15 mmol), 1-(5-chloro-3-fluoropyridin-2-yl)ethanamine hydrochloride (35 mg, 0.17 mmol), and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA (80 μL, 0.46 mmol) and HATU (70 mg, 0.17 mmol), and the reaction was stirred for 2.5 h. The reaction mixture was diluted with DCM (4 mL) and washed with saturated aqueous NaHCO ₃ (2×2 mL), brine (2 mL), dried (over MgSO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A) and then triturated with acetonitrile to afford 30 mg (43% yield) of the title compound as a mixture of two enantiomers.

¹ H NMR (500 MHz, CDCl ₃ ): δ [ppm] = 8.38 (d, J = 1.8Hz, 1H), 7.89 (t, J = 1.4Hz, 1H), 7.58 (dd, J = 2.4, 1.5Hz, 1 H),7.57-7.51(m,2H),7.47(dd,J＝8.9,2.0Hz,1H),7.43(dd,J＝2.4,1.5Hz,1H),5 .70-5.62(m,1H),3.93(d,J＝7.0Hz,2H),2.53(d,J＝1.1Hz,3H),1.55(d,J＝6.7Hz, 3H), 1.31 (ddd, J＝12.8, 8.0, 5.3Hz, 1H), 0.70-0.64 (m, 2H), 0.38 (q, J＝4.7Hz, 2H).

LCMS (Analytical Method F) Rt = 4.19 min, MS (ESIpos) m/z = 446 (M+H) ⁺ .

Example 7: 3-(Cyclopropylmethoxy)-N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a solution of 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (58 mg, 0.2 mmol), (1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethanamine hydrochloride (43 mg, 0.24 mmol) and DIPEA (0.174 mL, 1.0 mmol) in DCM (2 mL) was added T3P (0.23 mL, 0.4 mmol, 50% solution in EtOAc), and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with 2M NaOH (2 mL) and the aqueous layer was further extracted with DCM (2×2 mL). The combined organic phases were dried (over MgSO ₄ ) and concentrated under reduced pressure. The material was triturated with Et ₂ O to give 46.8 mg (54% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ [ppm] = 7.84 (t, J = 1.4Hz, 1H), 7.57 (dd, J = 2.4, 1.5Hz, 1H), 7.51 (d, J = 1. 2Hz,1H),7.41(dd,J＝2.3,1.6Hz,1H),6.99(d,J＝7.5Hz,1H),5.68(p,J＝7.0 Hz,1H),3.92(d,J＝6.9Hz,2H),2.76(s,3H),2.52(d,J＝1.1Hz,3H),1.79(d, J＝6.9Hz,3H),1.35-1.24(m,1H),0.70-0.63(m,2H),0.37(q,J＝4.7Hz,2H).

LCMS (Analytical Method F) Rt=3.33 min, MS (ESIpos): m/z=415 (M+H) ⁺ .

Example 8: 3-(Cyclopropylmethoxy)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a solution of 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (46 mg, 0.16 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanamine hydrochloride (30.6 mg, 0.18 mmol), DIPEA (0.11 mL, 0.64 mmol), and DMAP (3.9 mg, 0.032 mmol) in DCM (2 mL) was added HATU (73.0 mg, 0.19 mmol), and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with water (3 mL), and the aqueous layer was re-extracted with DCM (2 x 3 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) and then triturated with Et ₂ O to give 29.7 mg (45% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]＝7.90-7.86(m,1H),7.73(d,J＝7.4Hz,1H),7.60-7.57(m,1H),7.5 1(s,1H),7.44-7.42(m,1H),7.40(d,J＝8.5Hz,1H),7.33(d,J＝8.5Hz,1H),5. 46(p,J＝7.2Hz,1H),3.92(d,J＝6.9Hz,2H),2.73(s,3H),2.52(s,3H),1.68(d ,J＝6.8Hz,3H),1.35-1.23(m,1H),0.71-0.61(m,2H),0.37(q,J＝4.8Hz,2H).

LCMS (Analytical Method D) Rt=3.96 min, MS (ESIpos) m/z=409 (M+H) ⁺ .

Example 9: 3-(Cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (60 mg, 0.21 mmol), (1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethanamine hydrochloride (51 mg, 0.22 mmol) and DIPEA (144 μL, 0.83 mmol) in DCM (1 mL) was added HATU (95 mg, 0.25 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (1 mL) and washed with water (2×2 mL). The aqueous phase was re-extracted with DCM (2 mL), and the combined organics were dried (over Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A) to give 61.2 mg (64% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, CDCl ₃ ): δ [ppm] = 7.88 (s, 1H), 7.82 (d, J = 8.7Hz, 1H), 7.74 (d, J = 8.7Hz, 1H), 7.59-7.5 4(m,1H),7.51(d,J＝1.1Hz,1H),7.48-7.38(m,2H),5.60(p,J＝7.0Hz,1H),3.91 (d,J＝6.9Hz,2H),2.52(d,J＝0.9Hz,3H),2.00(s,1H),1.76(d,J＝7.0Hz,3H),1. 29(dtd,J＝14.7,7.4,6.8,4.7Hz,1H),0.70-0.61(m,2H),0.37(q,J＝4.8Hz,2H).

LCMS (Analytical Method F) Rt=3.84 min, MS (ESIpos) m/z=463 (M+H) ⁺ .

Example 10: 3-(Cyclopropylmethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

To a suspension of sodium 3-(cyclopropylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)benzoate (50 mg, 0.16 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine (24 mg, 0.18 mmol) and DMAP (4 mg, 0.03 mmol) in DCM (1 mL) was added DIPEA (85 μL, 0.48 mmol) and HATU (73 mg, 0.19 mmol), and the reaction was stirred for 2 h. The reaction mixture was diluted with DCM (4 mL), washed with saturated aqueous NaHCO ₃ solution (2×2 mL), brine (2 mL), and the organic phase was dried (over MgSO ₄ ) and concentrated in vacuo to give 37.4 mg (56% yield) of the title compound.

¹ H NMR (500MHz, CDCl ₃ )δ[ppm]＝8.69(s,2H),7.85(s,1H),7.56-7.48(m,2H),7.39(dd,J＝2.3,1.6Hz,1H),6.53(d,J＝6.8Hz,1H),5.30(p,J＝7.2Hz,1H),3.91 (d,J＝6.9Hz,2H),2.73(s,3H),2.53(d,J＝1.1Hz,3H),1.66(d,J＝7.1Hz,3H),1.34-1.24(m,1H),0.69-0.62(m,2H),0.39-0.33(m,2H).

LCMS (Analytical Method F) Rt=3.17 min, MS (ESIpos) m/z=409 (M+H) ⁺ .

Example 11: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid, Intermediate 5B (6.8 g, 22.3 mmol), Intermediate VI (6.8 g, 26.7 mmol), and DIPEA (15.5 mL, 89.1 mmol) in DCM (100 mL), T3P (19.5 mL, 33.4 mmol, 50% in EtOAc) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with 1 M NaOH (100 mL), and the aqueous layer was re-extracted with DCM (2×50 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The residue was triturated with Et ₂ O to give 7.51 g (70% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]＝8.93(s,2H),7.85(t,J＝1.4Hz,1H),7.53-7.52(m,1H),7.51(dd,J＝2.4,1 .5Hz,1H),7.36(t,J＝2.4,1.6Hz,1H),6.64(d,J＝6.5Hz,1H),5.36(p,J＝7.1Hz,1H), 5.08-5.03(m,1H),4.05-3.97(m,3H),3.91(td,J＝8.4,4.3Hz,1H),2.54(d,J＝1.1Hz ,3H),2.27(dtd,J＝14.4,8.4,6.1Hz,1H),2.20-2.12(m,1H),1.72(d,J＝7.2Hz,3H).

LCMS (Analytical Method D) Rt=4.16 min, MS (ESIpos) m/z=479 (M+H) ⁺ .

Example 12: N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid (40 mg, 0.13 mmol), 1-(5-methylpyrazin-2-yl)methanamine dihydrochloride (30.8 mg, 0.16 mmol) and DIPEA (91 μL, 0.52 mmol) in DCM (1 mL) was added HATU (74.7 mg, 0.20 mmol), and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (1 mL), washed with water (2×1 mL), dried (through a hydrophobic frit), and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC (Method A) to give 35.1 mg (65% yield) of the title compound as a yellow gum.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]＝8.58(d,J＝1.1Hz,1H),8.44(s,1H),7.94(s,1H),7.58(dd,J＝2.3,1.5Hz ,1H),7.54(d,J＝1.2Hz,1H),7.44(dd,J＝2.2,1.5Hz,1H),7.33(s,1H),5.10(ddt,J＝ 5.9,4.0,2.0Hz,1H),4.79(d,J＝5.1Hz,2H),4.11-3.98(m,3H),3.94(td,J＝8.4,4. 3Hz, 1H), 2.60 (s, 3H), 2.55 (d, J = 1.1Hz, 3H), 2.36-2.26 (m, 1H), 2.24-2.14 (m, 1H).

LCMS (Analytical Method D) Rt=3.66 min, MS (ESIpos) m/z=411 (M+H) ⁺ .

Example 13: N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (70 mg, 0.23 mmol), (+/-) 1-(3-chloro-5-fluoropyridin-2-yl)ethanamine (44 mg, 0.25 mmol), DIPEA (119 mg, 0.92 mmol) and HATU (123 mg, 0.32 mmol) were dissolved in DMF (3.1 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (method 1, rt: 1.27 min) to provide 65 mg (60% yield) of the title compound as a mixture of two diastereomers.

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.49(d,J＝6.84Hz,3H)1.95-2.05(m,1H)2.25(d,J＝7.86Hz,1H)3.73-3.95(m,4H)5.15-5.24(m,1H)5.54(t,J＝6.97Hz,1H)7.51(d .

Example 14: N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (74 mg, 0.24 mmol), (+/-) 1-(5-chloro-3-fluoropyridin-2-yl)ethanamine (47 mg, 0.27 mmol), DIPEA (126 mg, 0.97 mmol) and HATU (130 mg, 0.34 mmol) were dissolved in DMF (3.2 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, rt: 1.27 min) to provide 65 mg (57% yield) of the title compound as a mixture of two diastereomers.

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.51(d,J＝7.10Hz,3H)1.94-2.05(m,1H)2.19-2.31(m,1H)3.73-3.95(m,4H)5.15-5.24(m,1H)5.42(t,J＝6.97Hz,1H)7.47 -7.54(m,2H)7.64(d,J＝1.27Hz,1H)7.90-7.96(m,1H)8.06(dd,J＝10.01,1.90Hz,1H)8.49(d,J＝1.77Hz,1H)9.10(d,J＝7.10Hz,1H).

Example 15: N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (80 mg, 0.26 mmol), (1R)-1-(5-chloropyridin-2-yl)ethanamine hydrochloride (56 mg, 0.29 mmol), DIPEA (135 mg, 1.05 mmol) and HATU (139 mg, 0.37 mmol) were dissolved in DMF (3.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, rt: 1.21 min) to provide the title compound 60 mg (51% yield).

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.52(d,J＝7.16Hz,3H)1.94-2.06(m,1H)2.26(d,J＝7.72Hz,1H)3.75-3.95(m,4H)5.15-5.26(m,2H)7.46(d,J＝8.48Hz,1H)7.53 (d, J=1.13Hz, 2H) 7.65 (d, J= 1.32Hz, 1H) 7.90 (dd, J= 8.48, 2.64Hz, 1H) 7.93-7.98 (m, 1H) 8.58 (d, J= 2.07Hz, 1H) 9.08 (d, J= 7.54Hz, 1H).

Example 16: N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (80 mg, 0.26 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine (40 mg, 0.29 mmol), DIPEA (135 mg, 1.05 mmol) and HATU (139 mg, 0.37 mmol) were dissolved in DMF (3.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, rt: 1.04 min) to provide the title compound 40 mg (35% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.54(d,J＝7.07Hz,3H)1.96-2.05(m,1H)2.20-2.31(m,1H)2.47(s,3H)3.75-3.94(m,4H)5.18-5.26(m,2H)7.52(d,J＝ 1.26Hz, 2H) 7.64 (d, J = 1.26Hz, 1H) 7.94 ( t, J = 1.39Hz, 1H) 8.48 ( d, J = 1.01Hz, 1H) 8.56 ( d, J = 1.26Hz, 1H) 9.08 ( d, J = 7.58Hz, 1H).

Example 17: N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (77 mg, 0.25 mmol), 1-(6-methylpyridazin-3-yl)methanamine (34 mg, 0.28 mmol), DIPEA (130 mg, 1.0 mmol) and HATU (133 mg, 0.35 mmol) were dissolved in DMF (3.3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, rt: 0.91 min) to provide the title compound 50 mg (48% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]2.02(d,J＝6.84Hz,1H)2.26(dd,J＝13.43,6.8Hz,1H)2.60(s,3H)3.73-3.95(m,4H)4.73(d,J＝5.83Hz ,2H)5.14-5.23(m,1H)7.48-7.57(m,4H)7.64(d,J＝1.01Hz,1H)7.98(t,J＝1.39Hz,1H)9.39(t,J＝5.83Hz,1H).

Example 18: N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (69 mg, 0.23 mmol), Intermediate XV (43 mg, 0.25 mmol), DIPEA (117 mg, 0.9 mmol) and HATU (120 mg, 0.32 mmol) were dissolved in DMF (3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, rt: 0.95 min) to provide the title compound 30 mg (31% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.58(d,J＝7.10Hz,3H)2.01(d,J＝6.59Hz,1H)2.20-2.31(m,1H)2.59(s,3H)3.74-3.95(m,4H)5.15-5.25 (m,1H)5.36(t,J＝7.22Hz,1H)7.49-7.56(m,3H)7.56-7.67(m,2H)7.95(t,J＝1.39Hz,1H)9.14(d,J＝7.35Hz,1H).

Example 19: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid (50 mg, 0.16 mmol), (1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethanamine hydrochloride (48 mg, 0.21 mmol) and DIPEA (113 μL, 0.65 mmol) in DCM (1 mL) was added HATU (74 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM (1 mL) and washed with water (2×2 mL). The aqueous phase was re-extracted with DCM (2 mL), and the combined organics were dried (over Na ₂ SO ₄ ) and concentrated in vacuo. The crude product was purified by preparative HPLC (Method A) to give 39.5 mg (51% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 7.88 (t, J = 1.4Hz, 1H), 7.82 (d, J = 8.7Hz, 1H), 7.74 (d, J = 8.7Hz, 1H) ,7.54(dd,J＝2.4,1.5Hz,1H),7.51(d,J＝1.2Hz,2H),7.37(dd,J＝2.3,1.5Hz,1H),5.60(p,J＝7.0 Hz,1H),5.06(ddt,J＝6.1,4.0,1.8Hz,1H),4.06-3.95(m,3H),3.91(td,J＝8.4,4.2Hz,1H),2.52 (d,J＝1.1Hz,3H),2.26(dtd,J＝14.4,8.4,6.1Hz,1H),2.20-2.11(m,1H),1.76(d,J＝7.0Hz,3H).

LCMS (Analytical Method F) Rt=3.32 min, MS (ESIpos) m/z=479 (M+H) ⁺ .

Example 20: N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid (61 mg, 0.2 mmol), (1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethanamine hydrochloride (43 mg, 0.24 mmol) and DIPEA (0.174 mL, 1.0 mmol) in DCM (2 mL) was added T3P (0.23 mL, 0.4 mmol, 50% in EtOAc) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with 2M NaOH (1 mL) and the aqueous layer was further extracted with DCM (2×2 mL). The combined organic phases were dried (over MgSO ₄ ), evaporated and the resulting material was triturated in Et ₂ O to give 42.0 mg (49% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 7.85 (t, J = 1.4Hz, 1H), 7.55 (dd, J = 2.4, 1.5Hz, 1H), 7.52 (d, J = 1.2Hz,1H),7.39(dd,J＝2.4,1.5Hz,1H),7.02(d,J＝7.5Hz,1H),5.69(p,J＝7.0Hz,1H),5.08( td,J＝4.2,2.1Hz,1H),4.07-3.97(m,3H),3.92(td,J＝8.4,4.2Hz,1H),2.76(s,3H),2.53(d, J=1.1Hz, 3H), 2.28 (dtd, J=14.4, 8.4, 6.1Hz, 1H), 2.22-2.14 (m, 1H), 1.80 (d, J= 7.0Hz, 3H).

LCMS (Analytical Method F) Rt=2.72 min, MS (ESIpos): m/z=431 (M+H) ⁺ .

Example 21: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{[6-(trifluoromethyl)pyridazin-3-yl]methyl}benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid (40 mg, 0.13 mmol), 1-[6-(trifluoromethyl)pyridazin-3-yl]methanamine monohydrochloride (31 mg, 0.14 mmol), and DIPEA (68 μL, 0.52 mmol) in DCM (1 mL) was added T3P (50% in EtOAc, 117 μL, 0.20 mmol), and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (1 mL), washed with water (1 mL), dried (over MgSO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A) to give 13 mg (21% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ )δ[ppm]＝7.88(s,1H),7.82(d,J＝2.2Hz,2H),7.76(t,J＝5.3Hz,1H),7.52(s,1H),7.48(s,1H),7.39(s,1H),5.04(d ,J＝5.5Hz,3H),4.04-3.95(m,3H),3.90(td,J＝8.4,4.2Hz,1H),2.50(s,3H),2.30-2.20(m,1H),2.19-2.10(m,1H).

LCMS (Analytical Method D) Rt=4.05, m/z=465 (M+H) ⁺ .

Example 22: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propyl}benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid (61 mg, 0.2 mmol), (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]propan-1-amine hydrochloride (31 mg, 0.14 mmol) and DIPEA (68 μL, 0.52 mmol) in DCM (2 mL) was added T3P (0.23 mL, 0.4 mmol, 50% in EtOAc), and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was washed with saturated _NaHCO3 solution (2 mL), and the aqueous layer was further extracted with DCM (2×2 mL). The combined organics were dried (over _MgSO4 ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) and freeze-dried from acetonitrile/water to give 70.6 mg (72% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]＝8.91(s,2H),7.85(s,1H),7.53(d,J＝1.1Hz,1H),7.51(dd,J＝2.3,1.4H z,1H),7.36-7.34(m,1H),6.62(d,J＝6.8Hz,1H),5.10(q,J＝7.3Hz,1H),5.06(d,J ＝2.4Hz,1H),4.04-3.98(m,3H),3.91(td,J＝8.4,4.3Hz,1H),2.54(d,J＝1.0Hz,3H ),2.32-2.23(m,1H),2.20-2.11(m,1H),2.10-1.96(m,2H),1.08(t,J＝7.4Hz,3H).

LCMS (Analytical Method F) Rt=3.60 min, MS (ESIpos): m/z=493.3 (M+H) ⁺ .

Example 23: N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5B (70 mg, 0.23 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (53 mg, 0.25 mmol), DIPEA (119 mg, 0.92 mmol) and HATU (122 mg, 0.32 mmol) were dissolved in DMF (3.05 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, Rt: 0.97 min) to provide the title compound 45 mg (45% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.54(d,J＝7.07Hz,3H)1.96-2.05(m,1H)2.25(s,1H)2.59(s,3H)3.74-3.95(m,4H)5.12-5.23(m,2H)7.48(dd, J＝2.27,1.52Hz,1H)7.50-7.53(m,1H)7.64(d,J＝1.26Hz,1H)7.91(t,J＝1.52Hz,1H)8.72(s,2H)9.04(d,J＝7.58Hz,1H).

Example 24: N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]benzoic acid (61 mg, 0.2 mmol), (1R)-1-[6-(methylpyridin-3-yl)ethanamine (33 mg, 0.24 mmol) and DIPEA (0.17 mL, 1.0 mmol) in DCM (2 mL) was added T3P (0.23 mL, 0.4 mmol, 50% in EtOAc) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with 2M NaOH (2 mL) and the aqueous layer was further extracted with DCM (2 x 2 mL). The combined organics were dried (over _MgSO4 ) and concentrated under reduced pressure. The material was triturated in _Et2O to give 50.7 mg (60% yield) of the title compound as an off-white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.55 (d, J = 2.3Hz, 1H), 7.81 (t, J = 1.3Hz, 1H), 7.60 (dd, J = 8.0, 2.4Hz, 1H),7.51(d,J＝1.2Hz,1H),7.50(dd,J＝2.4,1.5Hz,1H),7.37(dd,J＝2.3,1.5Hz,1H),6.44(d,J＝7. 4Hz,1H),5.32(p,J＝7.0Hz,1H),5.09–5.03(m,1H),4.06–3.96(m,3H),3.91(td,J＝8.4,4.3Hz,1H) ,2.55(s,3H),2.53(d,J＝1.1Hz,3H),2.32-2.22(m,1H),2.19-2.12(m,1H),1.63(d,J＝7.0Hz,4H).

LCMS (Analytical Method D) Rt=3.06, MS (ESIpos) m/z=424 (M+H) ⁺ .

Example 25: N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (240 mg, 0.79 mmol), Intermediate XV (191 mg, 1.1 mmol), TEA (0.22 mL, 1.57 mmol) and HATU (329 mg, 0.87 mmol) were dissolved in DMF (12 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (system: Labomatic Vario 2000, HPLC pump HD-3000; column: Chromatex C18 10 μm 125×30 mm; flow rate: 150 ml/min; solvent: acetonitrile/water; A=85%, B=15% to A=0%, B=100%; rt: 6.26-6.77 min) to provide the title compound 150 mg (44% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.59(d,J＝7.07Hz,3H)1.96-2.07(m,1H)2.20-2.31(m,1H)2.59(s,3H)3.75-3.95(m,4H)5.17-5.24(m,1H)5.37( t,J＝7.20Hz,1H)7.50-7.56(m,3H)7.57-7.62(m,1H)7.64(d,J＝1.26Hz,1H)7.95(t,J＝1.39Hz,1H)9.13(d,J＝7.58Hz,1H).

Example 26: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5C (230 mg, 0.75 mmol), (1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethan-1-amine dihydrochloride (239 mg, 0.9 mmol), TEA (0.42 ml, 3.01 mmol) and HATU (430 mg, 1.13 mmol) were dissolved in DMF (6.9 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (system: Labomatic Vario 2000, HPLC pump HD-3000; column: Chromatex C18 10 μm 125×30 mm; flow rate: 150 ml/min; solvent: acetonitrile/water; A=70%, B=30% to A=0%, B=100%; rt: 6.46-7.42 min) to provide the title compound 205 mg (57% yield).

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.61(d,J＝7.16Hz,3H)2.02(d,J＝6.03Hz,1H)2.19-2.33(m,1H)3.74-3.96(m,4H) 5.15-5.36(m,2H)7.47-7.55(m,2H)7.65(d,J=1.13Hz,1H)7.93(s,1H)9.09-9.20(m,3H).

Example 27: N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (1R)-1-(5-chloropyridin-2-yl)ethanamine hydrochloride (106 mg, 0.55 mmol), TEA (0.16 mL, 1.18 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF (4.3 mL). The reaction mixture was stirred at 60° C. until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, rt: 1.22 min) to provide the title compound 100 mg (57% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.53(d,J＝7.10Hz,3H)1.97-2.07(m,1H)2.20-2.32(m,1H)3.76-3.95(m,4H)5.14-5.26(m,2H)7.47(d,J＝8.36Hz,1H)7.51-7 .56 (m, 2H) 7.65 (d, J = 1.27Hz, 1H) 7.91 (dd, J = 8.62, 2.53Hz, 1H) 7.96 (t, J = 1.39Hz, 1H) 8.58 (d, J = 2.03Hz, 1H) 9.08 (d, J = 7.60Hz, 1H).

Example 28: N-[(1R)-1-(5-methylpyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (1R)-1-(5-methylpyridin-2-yl)ethanamine hydrochloride (95 mg, 0.55 mmol), TEA (0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF (3.9 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 2, rt: 1.15 min) to provide the title compound 93 mg (56% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.50(d,J＝7.10Hz,3H)1.96-2.07(m,1H)2.20-2.31(m,4H)3.75-3.95(m,4H)5.12-5.24(m,2H)7.30(d,J＝7.86Hz,1H )7.49-7.54(m,2H)7.55-7.60(m,1H)7.64(d,J＝1.27Hz,1H)7.95(t,J＝1.39Hz,1H)8.33-8.40(m,1H)9.00(d,J＝7.86Hz,1H).

Example 29: N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (1R)-1-(5-methylpyridin-2-yl)ethanamine hydrochloride (116 mg, 0.55 mmol), TEA (0.16 mL, 1.18 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF (4.3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 2, rt: 1.04 min) to provide the title compound 50 mg (30% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.54(d,J=7.10Hz,3H)1.97-2.06(m,1H)2.25(s,1H)2.47(s,3H)3.75-3.94(m,4H)5.17-5.28(m,2H)7.49-7.54( m, 2H) 7.64 (d, J = 1.27Hz, 1H) 7.94 (t, J = 1.52Hz, 1H) 8.49 (d, J = 1.01Hz, 1H) 8.56 (d, J = 1.27Hz, 1H) 9.09 (d, J = 7.35Hz, 1H).

The following examples were prepared in a similar manner to the procedure described in Example 7 using the appropriate carboxylic acids and amines as starting materials.

The following examples were prepared in a similar manner to the procedure described in Example 1 using the appropriate carboxylic acids and amines as starting materials.

The following examples were prepared in a similar manner to the procedure described in Example 7 using the appropriate carboxylic acids and amines as starting materials.

Example 42: N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (81 mg, 0.28 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine (44 mg, 0.32 mmol), DIPEA (144 mg, 1.11 mmol) and HATU (148 mg, 0.39 mmol) were dissolved in DMF (3.7 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1: rt: 1.00 min) to provide the title compound 20 mg (18% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.54(d,J＝7.07Hz,3H)2.48(s,3H)4.55-4.63(m,2H)4.95(t,J＝6.95Hz,2H)5.23(s,1H)5.46(s,1H)7.37(t,J＝1.5 2Hz, 2H) 7.65 (d, J = 1.01Hz, 1H) 7.98 ( t, J = 1.39Hz, 1H) 8.49 ( d, J = 0.76Hz, 1H) 8.56 ( d, J = 1.26Hz, 1H) 9.10 ( d, J = 7.33Hz, 1H).

Example 43: N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (73 mg, 0.25 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (58 mg, 0.28 mmol), DIPEA (0.17 mL, 1.0 mmol) and HATU (133 mg, 0.35 mmol) were dissolved in DMF (3.3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1: rt: 0.93 min) to provide the title compound 48 mg (47% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.55(d,J＝7.10Hz,3H)2.59(s,3H)4.55-4.62(m,2H)4.91-4.99(m,2H)5.16(t,J＝7.22Hz,1H)5.41-5 .50(m,1H)7.31-7.40(m,2H)7.65(d,J＝1.01Hz,1H)7.95(t,J＝1.39Hz,1H)8.72(s,2H)9.07(d,J＝7.35Hz,1H).

Example 44: N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (74 mg, 0.25 mmol), (+/-) 1-(5-chloro-3-fluoropyridin-2-yl)ethanamine (49 mg, 0.28 mmol), DIPEA (131 mg, 1.02 mmol) and HATU (136 mg, 0.36 mmol) were dissolved in DMF (3.4 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1: rt: 1.24 min) to provide the title compound 50 mg (43% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.52(d,J＝7.10Hz,3H)4.54-4.62(m,2H)4.95(t,J＝6.59Hz,2H)5.36-5.49(m,2H)7.33-7.39(m,2H)7.64(d ,J＝1.27Hz,1H)7.96(t,J＝1.39Hz,1H)8.07(dd,J＝9.89,2.03Hz,1H)8.50(d,J＝2.03Hz,1H)9.12(d,J＝7.10Hz,1H).

Example 45: N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(5-oxetan-3-yloxy)benzamide

Intermediate 5F (73 mg, 0.25 mmol), 1-(6-methylpyridazin-3-yl)methanamine (34 mg, 0.27 mmol), DIPEA (129 mg, 1.0 mmol) and HATU (133 mg, 0.35 mmol) were dissolved in DMF (3.3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1: rt: 0.87 min) to provide the title compound 40 mg (40% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]2.61(s,3H)4.59(dd,J＝7.86,4.82Hz,2H)4.73(d,J＝5.83Hz,2H)4.96(t,J＝6.84Hz,2H)5.40 -5.50(m,1H)7.36(dd,J＝2.28,1.52Hz,1H)7.41(dd,J＝2.53,1.52Hz,1H)7.57(s,2H)7.65(d,J＝1.27 15Hz, 1H) 8.01 (t, J = 1.39 Hz, 1H) 9.41 ( t, J = 5.96 Hz, 1H).

Example 46: N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (81 mg, 0.28 mmol), (1R)-1-(5-chloropyridin-2-yl)ethanamine hydrochloride (59 mg, 0.31 mmol), DIPEA (144 mg, 1.11 mmol) and HATU (148 mg, 0.39 mmol) were dissolved in DMF (3.7 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 2: rt: 1.17 min) to provide the title compound 20 mg (17% yield).

¹ H NMR (400 MHz, DMSO-d ₆ )δ[ppm]1.52(d,J＝7.10Hz,3H)4.59(ddd,J＝7.16,4.63,2.66Hz,2H)4.96 (t,J＝6.59Hz,2H)5.19(t,J＝7.22Hz,1H)5.42-5.50(m,1H)7.36-7.41(m,2 H) 7.46 (d, J = 8.62Hz, 1H) 7.65 (d, J = 1.27Hz, 1H) 7.90 (dd, J = 8.62, 2.53Hz, 1H) 7.99 (t, J = 1.39Hz, 1H) 8.58 (d, J = 2.03Hz, 1H) 9.09 (d, J = 7.35Hz, 1H).

Example 47: N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (72 mg, 0.25 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanamine hydrochloride (Intermediate XV, 47 mg, 0.27 mmol), DIPEA (128 mg, 0.99 mmol) and HATU (132 mg, 0.35 mmol) were dissolved in DMF (3.3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 2: rt: 0.92 min) to provide the title compound 30 mg (30% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.59(d,J＝7.10Hz,3H)2.60(s,3H)4.59(ddd,J＝7.10,4.44,2.91Hz,2H)4.96(t,J＝6.72Hz,2H)5.36(t,J＝7.35Hz,1H)5.46(t,J＝5 .32Hz, 1H) 7.38 (d, J = 1.52Hz, 2H) 7.51-7.56 (m, 1H) 7.57-7.62 (m, 1H) 7.65 (d, J = 1.01Hz, 1H) 7.99 (t, J = 1.27Hz, 1H) 9.16 (d, J = 7.60Hz, 1H).

Example 48: 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5F (76 mg, 0.26 mmol), intermediate VI (65 mg, 0.29 mmol), DIPEA (135 mg, 1.04 mmol) and HATU (139 mg, 0.36 mmol) were dissolved in DMF (3.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to provide the title compound 80 mg (65% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.61(d,J＝7.10Hz,3H)4.54-4.62(m,2H)4.95(t,J＝6.59Hz,2H)5.29(s,1H)5.46(t,J＝4.94Hz,1H )7.37(d,J＝1.01Hz,2H)7.65(d,J＝1.01Hz,1H)7.96(t,J＝1.39Hz,1H)9.12(s,2H)9.18(d,J＝7.10Hz,1H).

Example 49: N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

Intermediate 5F (79 mg, 0.27 mmol), (+/-) 1-(3-chloro-3-fluoropyridin-2-yl)ethanamine (52 mg, 0.30 mmol), DIPEA (140 mg, 1.08 mmol) and HATU (144 mg, 0.38 mmol) were dissolved in DMF (3.6 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1: rt: 1.24 min) to provide the title compound 60 mg (50% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.49(d,J＝7.07Hz,3H)4.54-4.62(m,2H)4.95(t,J＝6.82Hz,2H)5.41-5.48(m,1H)5.53(t,J＝7.07Hz,1H)7.33-7.39(m ,2H)7.64(d,J＝1.26Hz,1H)7.97(t,J＝1.52Hz,1H)8.09(dd,J＝8.59,2.53Hz,1H)8.58(d,J＝2.78Hz,1H)9.09(d,J＝7.07Hz,1H).

Example 50: N-[(1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoic acid (58.3 mg, 0.2 mmol), (1R)-1-(5-methyl-1,3,4-thiadiazol-2-yl)ethanamine hydrochloride (43 mg, 0.24 mmol), and DIPEA (0.174 mL, 1.0 mmol) were dissolved in DCM (2 mL). T3P (0.23 mL, 0.4 mmol, 50% solution in EtOAc) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with 2M NaOH (2 mL), and the aqueous layer was further extracted with DCM (2 x 2 mL). The crude material was purified by Biotage Isolera ^™ chromatography on silica gel (eluent: heptane-acetone, 0 to 1:1) to give 44.7 mg (54% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 7.87 (t, J = 1.3Hz, 1H), 7.52 (d, J = 1.1Hz, 1H), 7. 40(dd,J＝2.4,1.4Hz,1H),7.22(dd,J＝2.3,1.5Hz,1H),7.08(d,J＝7.5Hz,1H) ,5.68(p,J＝7.0Hz,1H),5.33(p,J＝5.5Hz,1H),5.06-5.01(m,2H),4.78(dd,J =7.4,5.4Hz,2H),2.77(s,3H),2.53(d,J=1.1Hz,3H),1.79(d,J=6.9Hz,3H).

LCMS (Analytical Method D) Rt=3.61 min, MS (ESIpos): m/z=417 (M+H) ⁺ .

Example 51: N-[(1R)-1-(6-methylpyridin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzamide

3-(5-Methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)benzoic acid (210 mg, 0.72 mmol), (1R)-1-(6-methylpyridin-3-yl)ethanamine (37 mg, 0.27 mmol), DIPEA (191 μL, 1.1 mmol) and HATU (125 mg, 0.33 mmol) were dissolved in DCM (1 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (1 mL), washed with water (1 mL), dried (over Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified twice by preparative HPLC (Method A) to give 16.8 mg (6% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.55 (d, J = 2.3Hz, 1H), 7.83 (t, J = 1.3Hz, 1H, 7.59 ( dd,J＝8.0,2.4Hz,1H,7.51(d,J＝1.2Hz,1H,7.36(dd,J＝2.4,1.4Hz,1H),7.21-7 .11(m,2H),6.48(d,J＝7.5Hz,1H),5.36-5.26(m,2H),5.02(t,J＝7.0Hz,2H),4. 76 (t, J = 5.8 Hz, 2H), 2.54 (s, 3H), 2.53 (d, J = 1.1 Hz, 3H), 1.63 (d, J = 7.0 Hz, 3H).

LCMS (Analytical Method F) Rt=1.76 min, MS (ESIpos): m/z=409 (M+H) ⁺ .

The following examples were prepared in a similar manner to the procedure described in Example 1 using the appropriate carboxylic acids and amines as starting materials.

The following examples were prepared in a similar manner to the procedure described in Example 7 using the appropriate carboxylic acids and amines as starting materials.

Example 54: N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

A mixture of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (100 mg, 0.313 mmol), (6-methylpyridazin-3-yl)methanamine (46 mg, 0.376 mmol), HATU (142 mg, 0.376 mmol) and DIPEA (60 mg, 0.47 mmol) was stirred in DCM (4 mL) at room temperature for 4 h. The solvent was removed in vacuo and the residue was purified by Biotage Isolera ^™ chromatography (silica, eluting with 100% EtOAc then 1-6% MeOH in DCM) to give 110 mg (79% yield) of the title compound as an off-white gum.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]7.89(t,J＝1.4Hz,1H),7.76(s,1H),7.63-7.55(m,1H),7.50-7.42(m,3H), 7.31(d,J＝8.6Hz,1H),4.89(d,J＝5.3Hz,2H),4.29(qd,J＝6.8,4.3Hz,1H),4.04(h,J＝ 5.8Hz,2H),3.97-3.88(m,1H),3.87-3.79(m,1H),2.69(s,3H),2.50(d,J＝0.9Hz,3H) ,2.07(dtd,J＝12.4,7.6,5.5Hz,1H),2.1-1.91(m,2H),1.76(dq,J＝12.2,7.0Hz,1H).

LCMS (Analytical Method F) Rt=2.53 min, MS (ESIpos): m/z=424 (M+H) ⁺ .

Example 55: N-[(5-chloro-3-fluoropyridin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

A mixture of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (100 mg, 0.313 mmol), (5-chloro-3-fluoropyridin-2-yl)methanamine hydrochloride (74 mg, 0.376 mmol), HATU (143 mg, 0.376 mmol) and DIPEA (101 mg, 0.783 mmol) was stirred in DCM (4 mL) at room temperature for 3 h. The solvent was removed in vacuo, and the residue was purified by preparative HPLC (Method A) to give 95.2 mg (64% yield) of the title compound as an off-white solid.

¹ H NMR (500 MHz, CDCl ₃ ): δ[ppm]8.39(d,J＝1.7Hz,1H),7.92(t,J＝1.4Hz,1H),7.63(dd,J＝2.4,1.5Hz,1 H),7.56-7.41(m,4H),4.81(dd,J＝4.7,1.7Hz,2H),4.32(qd,J＝7.0,3.9Hz,1H),4 .13-4.04(m,2H),3.95(dt,J＝8.2,6.7Hz,1H),3.89-3.83(m,1H),2.53(d,J＝1.1H z,3H),2.14-2.06(m,1H),2.03-1.91(m,2H),1.77(ddt,J=12.2,8.4,7.1Hz,1H).

LCMS (Analytical Method F) Rt=3.53 min, MS (ESIpos): m/z=461 (M+H) ⁺ .

Example 56: N-[(5-methylpyrazin-2-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

To a stirred solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (49 mg, 0.15 mmol), 1-(5-methylpyrazin-2-yl)methanamine hydrochloride (26.9 mg, 0.169 mmol), DIPEA (0.107 μL, 0.614 mmol) and DMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) was added HATU (70.0 mg, 0.184 mmol) and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water (3 mL) and the aqueous layer was re-extracted with additional DCM (2×3 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) to give 39.8 mg (61% yield) of the title compound as a colorless glass.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.55(d,J＝1.2Hz,1H),8.42(s,1H),7.90(t,J＝1.4Hz,1H),7.61(dd,J＝2.4,1.5Hz,1H),7.51( d,J＝1.2Hz,1H,7.47(dd,J＝2.4,1.5Hz,1H),7.25-7.21(m,1H),4.77(d,J＝5.2Hz,2H),4.31(qd,J＝6.9,3 .9Hz,1H),4.11(dd,J＝9.7,3.9Hz,1H),4.06(dd,J＝9.7,6.5Hz,1H),3.95(dt,J＝8.2,6.7Hz,1H),3.88-3 .82(m,1H),2.58(s,3H),2.52(d,J=1.1Hz,3H),2.15-2.5(m,1H),2.03-1.90(m,2H),1.82-1.72(m,1H).

LCMS (Analytical Method D) Rt=3.79 min, MS (ESIpos): m/z=425.1 (M+H) ⁺ .

Example 57: N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

To a stirred solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (49 mg, 0.15 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (29.3 mg, 0.169 mmol), DIPEA (0.107 μL, 0.614 mmol) and DMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) was added HATU (70.0 mg, 0.184 mmol) and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water (3 mL) and the aqueous layer was re-extracted with additional DCM (2×3 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) to give 29.7 mg (44% yield) of the title compound as an orange glass.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.53(d,J＝1.3Hz,1H),8.41(s,1H),7.90(s,1H),7.60(dd,J＝2.4,1.5Hz,1H),7.5 2(d,J＝1.2Hz,1H),7.45(dd,J＝2.4,1.5Hz,1H),7.31(d,J＝7.4Hz,1H),5.42(p,J＝6.9Hz,1H) ,4.31(qd,J＝7.0,3.9Hz,1H),4.10(dd,J＝9.7,3.8Hz,1H),4.05(dd,J＝9.7,6.6Hz,1H),3.9 5(dt,J＝8.3,6.7Hz,1H),3.88-3.83(m,1H),2.57(s,3H),2.53(d,J＝1.1Hz,3H),2.09(dtd,J 12.4,7.7,7.2,5.5Hz,1H),1.97(tq,J＝15.8,6.0,5.2Hz,2H),1.76(ddd,J＝15.6,12.3,7.1Hz,1H),1.60(d,J＝6.8Hz,3H).

LCMS (Analytical Method F) Rt=3.96 min, MS (ESIpos): m/z=439.1 (M+H) ⁺ .

Example 58: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a stirred solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (49 mg, 0.15 mmol), Intermediate VI (38.4 mg, 0.169 mmol), DIPEA (0.107 μL, 0.614 mmol) and DMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) was added HATU (70.0 mg, 0.184 mmol) and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water (3 mL) and the aqueous layer was re-extracted with additional DCM (2×3 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A). The material was further purified by trituration in acetonitrile to give 17.5 mg (23% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.94(s,2H),7.89(s,1H),7.56(dd,J＝2.4,1.5Hz,1H),7.52(d,J＝1.2Hz,1H),7.41(dd,J＝2.3,1 .5Hz,1H),6.71(d,J＝6.6Hz,1H),5.35(p,J＝7.0Hz,1H),4.30(qd,J＝7.0,3.7Hz,1H),4.09(dd,J＝9.7,3.7 Hz,1H),4.02(dd,J＝9.7,6.6Hz,1H),3.97-3.92(m,1H),3.88-3.82(m,1H),2.53(d,J＝1.1Hz,3H),2.09(d td,J＝12.3,7.6,7.2,5.4Hz,1H),1.97(qt,J＝12.1,5.8Hz,2H),1.79-1.74(m,1H),1.72(d,J＝7.2Hz,3H).

LCMS (Analytical Method F) Rt=3.59 min, MS (ESIpos): m/z=493.1 (M+H) ⁺ .

Example 59: N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzamide

To a stirred solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (49 mg, 0.15 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanamine hydrochloride (29.3 mg, 0.169 mmol), DIPEA (0.107 μL, 0.614 mmol) and DMAP (3.7 mg, 0.03 mmol) in DCM (2 mL) was added HATU (70.0 mg, 0.184 mmol) and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water (3 mL) and the aqueous layer was re-extracted with additional DCM (2×3 mL). The combined organics were dried (over MgSO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A). The material was further purified by trituration in acetonitrile to give 31.9 mg (47% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ [ppm] 7.90 (s, 1H), 7.71 (d, J = 7.2Hz, 1H), 7.63-7.60 (m, 1H), 7.51 (d, J = 1.0Hz, 1H), 7.46-7.4 3(m,1H),7.40(d,J＝8.6Hz,1H),7.33(d,J＝8.6Hz,1H),5.46(p,J＝6.9Hz,1H),4.35-4.26(m,1H), 4.08(qd,J＝9.7,5.2Hz,2H),4.00-3.91(m,1H),3.88-3.79(m,1H),2.72(s,3H),2.52(d,J＝0.8Hz ,3H),2.15-2.05(m,1H),1.97(qt,J＝12.3,6.7Hz,2H),1.85-1.74(m,1H),1.68(d,J＝6.8Hz,3H).

LCMS (Analytical Method F) Rt=2.67 min, MS (ESIpos): m/z=439.1 (M+H) ⁺ .

Example 60: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a stirred solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (50 mg, 0.157 mmol), (1R)-1-[(6-trifluoromethyl)pyridazin-3-yl]ethanamine hydrochloride (39 mg, 0.171 mmol) and DIPEA (109 μL, 0.626 mmol) in DCM (2 mL) was added HATU (71 mg, 0.187 mmol) and the reaction was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (1 mL) and washed with water (2×2 mL). The aqueous phase was re-extracted with DCM (2 mL) and the combined organics were dried (over Na ₂ SO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (Method A) to give 34.7 mg (45% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]7.83(s,1H),7.75(d,J＝8.7Hz,1H),7.67(d,J＝8.7Hz,1H),7.53(dd,J＝2 .4,1.5Hz,1H),7.45(d,J＝1.2Hz,1H),7.42-7.34(m,2H),5.53(p,J＝7.0Hz,1H),4. 23(qd,J＝6.9,4.0Hz,1H),4.05-3.94(m,2H),3.92-3.83(m,1H),3.82-3.74(m,1H ), 2.45 (d, J = 1.1Hz, 3H), 2.07-1.97 (m, 1H), 1.93-1.84 (m, 2H), 1.76-1.65 (m, 4H).

LCMS (Analytical Method F) Rt=3.50 min, MS (ESIpos): m/z=493.1 (M+H) ⁺ .

Example 61: N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2S)-tetrahydrofuran-2-ylmethoxy]benzoic acid (40 mg, 0.125 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanamine hydrochloride (29 mg, 0.167 mmol) and DIPEA (87 μL, 0.499 mmol) in DCM (2 mL) was added HATU (60 mg, 0.158 mmol) and the reaction was stirred at room temperature for 1 h before being diluted with DCM (10 mL) and water (10 mL). The aqueous layer was re-extracted with DCM (10 mL) and the combined organic layers were dried (over Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) to give 45 mg (78% yield) of the title compound as a white foam.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]7.88(s,1H),7.76(d,J＝7.3Hz,1H),7.62-7.57(m,1H),7.48(s,1H),7.45-7. 41(m,1H),7.39(d,J＝8.6Hz,1H),7.31(d,J＝8.6Hz,1H),5.49-5.40(m,1H),4.32-4.24 (m,1H),4.09-4.00(m,2H),3.96-3.89(m,1H),3.86-3.78(m,1H),2.70(s,3H),2.50(s ,3H),2.13-2.03(m,1H),2.02-1.86(m,2H),1.82-1.71(m,1H),1.66(d,J＝6.9Hz,3H).

LCMS (Analytical Method D) Rt=3.66 min, MS (ESIpos): m/z=439.1 (M+H) ⁺ .

Example 62: N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoic acid (40 mg, 0.125 mmol), 1-(6-methylpyridazin-3-yl)methanamine (25 mg, 0.203 mmol), and DIPEA (87 μL, 0.499 mmol) in DCM (2 mL) was added HATU (60 mg, 0.158 mmol). The reaction was stirred at room temperature for 16 h, then diluted with DCM (10 mL) and water (10 mL). The aqueous layer was re-extracted with DCM (10 mL) and the combined organic layers were dried (over Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) to give 44 mg (79% yield) of the title compound as a yellow solid.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]7.89(s,1H),7.71(t,J＝5.0Hz,1H),7.62-7.58(m,1H),7.51-7 .43(m,3H),7.31(d,J＝8.6Hz,1H),4.90(d,J＝5.3Hz,2H),4.34-4.23(m,1 H),4.09-4.01(m,2H),3.96-3.90(m,1H),3.87-3.80(m,1H),2.70(s,3H ),2.50(s,3H),2.13-2.03(m,1H),2.03-1.88(m,2H),1.85-1.72(m,1H).

LCMS (Analytical Method F) Rt=2.55 min, MS (ESIpos): m/z=425.2 (M+H) ⁺ .

Example 63: 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoic acid (40 mg, 0.125 mmol), Intermediate VI (33 mg, 0.190 mmol) and DIPEA (87 μL, 0.499 mmol) in DCM (2 mL) was added HATU (60 mg, 0.158 mmol). The reaction was stirred at room temperature for 1 h then diluted with DCM (10 mL) and water (10 mL). The aqueous layer was re-extracted with DCM (10 mL) and the combined organic layers were dried (over Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) to give 42 mg (65% yield) of the title compound as a white solid.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.93(s,2H),7.81(s,1H),7.48(s,2H),7.30(s,1H),6.95(s,1H),5.40-5.27(m,1H),4.33-4.23(m,1H),4.07 -3.90(m,3H),3.90-3.81(m,1H),2.51(s,3H),2.13-2.03(m,1H),2.03-1.89(m,J=7.3,6.6Hz,2H),1.76-1.64(m,4H).

LCMS (Analytical Method F) Rt=3.60 min, MS (ESIpos): m/z=493.1 (M+H) ⁺ .

Example 64: N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzamide

To a solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-[(2R)-tetrahydrofuran-2-ylmethoxy]benzoic acid (40 mg, 0.125 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (33 mg, 0.190 mmol), and DIPEA (87 μL, 0.499 mmol) in DCM (10 mL) was added HATU (60 mg, 0.158 mmol). The reaction was stirred at room temperature for 1 h and then diluted with DCM (10 mL) and water (10 mL). The aqueous layer was re-extracted with DCM (10 mL), and the combined organic layers were dried (over Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) to give 49 mg (85% yield) of the title compound as a beige solid.

¹ H NMR (500MHz, CDCl ₃ )δ8.52(s,1H),8.40(s,1H),7.90-7.84(m,1H),7.62-7.56(m,1H),7.50(s,1H), 7.46-7.41(m,1H),7.30(d,J＝7.0Hz,1H),5.42(p,J＝Hz,1H),4.38-4.22(m,1H),4 .11-4.01(m,2H),3.98-3.91(m,1H),3.88-3.81(m,1H),2.56(s,3H),2.51(s,3H) ,2.14-2.04(m,1H),2.03-1.88(m,2H),1.81-1.69(m,1H),1.59(d,J＝6.8Hz,3H).

LCMS (Analytical Method F) Rt=3.03 min, MS (ESIpos): m/z=439.1 (M+H) ⁺ .

The following examples were prepared in a similar manner to the procedure described in Example 1 using the appropriate carboxylic acids and amines as starting materials.

The following examples were prepared in a similar manner to the procedure described in Example 7 using the appropriate carboxylic acids and amines as starting materials.

The following examples were prepared in a similar manner to the procedure described in Example 1 using the appropriate carboxylic acids and amines as starting materials.

Example 106: 3-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]benzoic acid

Intermediate 1 (2.3 g, 9.95 mmol), 4-bromo-2-methylpyridine (2.05 g, 11.95 mmol) and Cs ₂ CO ₃ (19.5 g, 59.7 mmol) were stirred in DMF (150 mL) at 120° C. for 48 hours. The reaction mixture was cooled to room temperature, filtered and evaporated to dryness. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to provide the title compound 1.1 g (36% yield).

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]benzoyl amine

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]benzoic acid (273 mg, 0.89 mmol), [(1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (205 mg, 0.97 mmol), DIPEA (0.76 mL, 4.4 mmol) and HATU (371 mg, 0.97 mmol) were dissolved in DMF. The reaction mixture was stirred and filtered at room temperature. Additional [(1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (205 mg, 0.97 mmol), DIPEA (0.76 mL, 4.4 mmol) and HATU (371 mg, 0.97 mmol) were added and the reaction mixture was stirred at 60°C until complete conversion and evaporated to dryness. The crude material was purified by column chromatography (silica gel, hexane/EE gradient) to provide the title compound.

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.52(d,J＝7.07Hz,3H)2.43(s,3H)2.58(s,3H)5.13(s,1H)6.78-6.82(m,1H)6.87(d,J＝2.53Hz,1 H)7.63(t,J＝1.39Hz,2H)7.99(t,J＝1.64Hz,1H)8.36(d,J＝5.56Hz,1H)8.69(s,2H)9.03(d,J＝7.33Hz,1H).

(3-[(2-methylpyridin-4-yl)oxy]-5-{[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]carbamoyl phenyl)boronic acid

3-Bromo-5-[(2-methylpyridin-4-yl)oxy]-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]benzamide (0.97 g, 77% purity, 1.75 mmol), bis(pinacolato)diborane (1.11 g, 4.37 mmol), and potassium acetate (0.58 g, 5.94 mmol) were dissolved in 1,4 _- dioxane. Pd(dppf) _Cl₂ · _CH₂Cl₂ (80 mg, 0.1 mmol) was added, and the reaction mixture was stirred at 100°C for 12 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography (silica gel, hexane/EE gradient) to provide 96 mg (14% yield) of the title compound.

(3-[(2-methylpyridin-4-yl)oxy]-N-{[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methylpyrimidin-5-yl)ethyl]- -1,3-thiazol-2-yl)benzamide

(3-[(2-methylpyridin-4-yl)oxy]-5-{[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]carbamoyl}phenyl)borinous acid (96 mg, 0.24 mmol) and 2-bromo-5-methyl-1,3-thiazole (65 mg, 0.37 mmol) were dissolved in 1M _{aqueous K₂CO₃} (0.59 mL) and THF (4 mL). Pd(dppf) _Cl₂ · _CH₂Cl₂ (30 _mg , 0.04 mmol) was added and the reaction mixture was heated to reflux for 2 hours. The reaction mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method 2, rt: 1.03 min) to provide the title compound 27 mg (25% yield).

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.54(d,J＝7.16Hz,3H)2.43(s,3H)2.59(s,3H)5.17(s,1H)6.84(dd,J＝5.65,2.45Hz,1H)6.91(d,J＝2.26Hz ,1H)7.66(d,J＝1.13Hz,1H)7.71-7.78(m,2H)8.24(s,1H)8.37(d,J＝5.65Hz,1H)8.72(s,2H)9.14(d,J＝7.35Hz,1H).

The following examples were prepared in a similar manner to the procedure described in Example 1 using the appropriate carboxylic acids and amines as starting materials.

Example 108: 3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5N (375 mg, 1.15 mmol), intermediate VI (242 mg, 1.26 mmol), DIPEA (0.8 mL, 4.6 mmol) and HATU (612 mg, 1.61 mmol) were dissolved in DMF (13.3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was extracted three times with EE and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 1, rt: 1.16 min) to provide the title compound 18.5 mg (32% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.61(d,J＝7.10Hz,3H)5.24-5.33(m,1H)7.35(d,J＝8.36Hz,1H)7.51(dd,J＝8.49,2.91Hz,1H)7.60(t,J =1.39Hz, 2H) 7.64 (d, J = 1.27Hz, 1H) 8.12 (t, J = 1.52Hz, 1H) 8.36 (d, J = 2.53Hz, 1H) 9.11 (s, 2H) 9.23-9.29 (m, 1H).

The following examples were prepared in a similar manner to the procedure described in Example 7 using the appropriate carboxylic acids and amines as starting materials.

Example 115: N-[(1R)-1-(5-chloropyridin-2-yl)ethyl]-3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)benzamide

Intermediate 5Q (115 mg, 0.34 mmol), (1R)-1-(5-chloropyridin-2-yl)ethanamine dihydrochloride (77 mg, 0.34 mmol), DIPEA (0.23 mL, 1.35 mmol) and HATU (179 mg, 0.47 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 1, rt: 1.44 min) to provide the title compound 81 mg (50% yield).

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.25(s,6H)1.53(d,J＝6.97Hz,3H)3.18(s,3H)3.99(s,2H)5.19(d,J＝7.16Hz,1H)7.46(d,J＝8.29Hz,1H)7.56-7.61(m,1H )7.62-7.66(m,1H)7.90(dd,J＝8.48,2.45Hz,1H)7.96(t,J＝1.41Hz,1H)8.01(s,1H)8.58(d,J＝2.07Hz,1H)9.10(d,J＝7.54Hz,1H).

Example 116: 3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5Q (115 mg, 0.34 mmol), Intermediate VI (77 mg, 0.34 mmol), DIPEA (0.23 mL, 1.35 mmol) and HATU (179 mg, 0.47 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 1, rt: 1.41 min) to provide the title compound 97 mg (56% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.22-1.25(m,6H)1.61(d,J＝7.10Hz,3H)3.17(s,3H)3.99(s,2H)5.30(s,1H)7 .57-7.63(m,2H)7.93(t,J=1.39Hz,1H)8.1(s,1H)9.12(s,2H)9.18(d,J=7.10Hz,1H).

Example 117: 3-(5-chloro-1,3-thiazol-2-yl)-5-(2-methoxy-2-methylpropoxy)-N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]benzamide

Intermediate 5Q (115 mg, 0.34 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (58 mg, 0.34 mmol), DIPEA (0.23 mL, 1.35 mmol) and HATU (179 mg, 0.47 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 1, rt: 1.28 min) to provide the title compound 38 mg (23% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.23-1.25(m,6H)1.55(d,J＝7.10Hz,3H)2.47(s,3H)3.17(s,3H)3.99(s,2H)5.19-5.28(m,1H)7.56-7.59(m,1H) 7.62(d,J＝1.52Hz,1H)7.95(t,J＝1.39Hz,1H)8.00(s,1H)8.49(d,J＝0.76Hz,1H)8.56(d,J＝1.52Hz,1H)9.08-9.14(m,1H).

Example 118: N-[(6-methylpyridazin-3-yl)methyl]-3-(tetrahydro-2H-pyran-4-ylmethoxy)-5-[5-(trifluoromethyl)-1,3-thiazol-2-yl]benzamide

Intermediate 5R (55% purity, 110 mg, 0.156 mmol), 1-(6-methylpyridazin-3-yl)methanamine (19 mg, 0.156 mmol), DIPEA (0.11 mL, 0.63 mmol) and HATU (83 mg, 0.22 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 1, rt: 1.19 min) to provide the title compound 14 mg (18% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.29-1.43(m,2H)1.70(br.s.,2H)1.97-2.12(m,1H)2.60(s,3H)3.32-3.39(m,2H)3.89(dd,J＝11.12,3.28Hz,2H)4.0 0(d,J＝6.32Hz,2H)4.74(d,J＝5.81Hz,2H)7.54(s,2H)7.62-7.74(m,2H)8.12(t,J＝1.39Hz,1H)8.51-8.64(m,1H)9.43(s,1H).

Example 119: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5S (53 mg, 0.14 mmol), 1-(6-methylpyridazin-3-yl)methanamine (18 mg, 0.14 mmol), DIPEA (0.1 mL, 0.57 mmol) and HATU (76 mg, 0.2 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 1, rt: 1.22 min) to provide the title compound 31 mg (45% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.30-1.43(m,2H)1.66-1.74(m,2H)1.85-1.94(m,1H)1.96-2.07(m,2H)2.14 (d,J＝2.53Hz,2H)2.43(d,J＝8.11Hz,2H)2.60(s,3H)3.35(d,J＝1.77Hz,2H)3.77-3.85 (m,1H)3.86-3.92(m,2H)3.96(d,J＝6.59Hz,2H)4.73(d,J＝5.83Hz,2H)7.50-7.56(m, 3H)7.56-7.59(m,1H)7.68(d,J＝0.76Hz,1H)7.99(t,J＝1.39Hz,1H)9.35-9.42(m,1H).

Example 120: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-ylmethoxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5S (53 mg, 0.14 mmol), intermediate VI (27 mg, 0.14 mmol), DIPEA (0.1 mL, 0.57 mmol) and HATU (76 mg, 0.2 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 1, rt: 1.47 min) to provide the title compound 40 mg (52% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.31-1.44(m,2H)1.61(d,J＝7.07Hz,3H)1.67-1.75(m,2H)1.86-1.96(m,1H)1. 97-2.08(m,2H)2.09-2.20(m,2H)2.39-2.47(m,2H)3.35(d,J＝1.77Hz,2H)3.77-3.85(m ,1H)3.86-3.92(m,2H)3.97(d,J＝6.32Hz,2H)5.25-5.35(m,1H)7.49-7.53(m,1H)7.55- 7.58(m,1H)7.68(d,J＝1.01Hz,1H)7.94(t,J＝1.39Hz,1H)9.12(s,2H)9.13-9.16(m,1H).

Example 121: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(5-methylpyridazin-2-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

Intermediate 5T (150 mg, 0.42 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine dihydrochloride (105 mg, 0.5 mmol), TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) were dissolved in DMSO (4.2 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 2, rt: 1.31 min) to provide the title compound 38 mg (19% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.55(d,J＝7.10Hz,3H)1.66-1.77(m,1H)1.84-1.95(m,1H)2.03(dd,J＝10.65,9.38Hz,2H)2.10 -2.21(m,2H)2.44(dt,J＝8.24,3.11Hz,2H)2.47-2.49(m,3H)2.62-2.76(m,1H)3.58(dd,J＝8.62,5.58Hz ,1H)3.68(d,J＝7.10Hz,1H)3.75-3.88(m,3H)3.98-4.13(m,2H)5.24(s,1H)7.53-7.60(m,2H)7.68(d,J＝ 1.01Hz, 1H) 7.97 (t, J = 1.39Hz, 1H) 8.49 (d, J = 0.76Hz, 1H) 8.57 (d, J = 1.52Hz, 1H) 9.09 (d, J = 7.35Hz, 1H).

Example 122: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(6-methylpyridazin-3-yl)methyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

Intermediate 5T (150 mg, 0.42 mmol), 1-(6-methylpyridazine-3-yl)methylamine hydrochloride (93 mg, 0.58 mmol), TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) were dissolved in DMF (4.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 2, rt: 1.19 min) to provide the title compound 13 mg (6% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.70(dd,J＝13.31,5.96Hz,1H)1.84-1.95(m,1H)1.96-2.07(m,2H)2.0 9-2.20(m,2H)2.38-2.47(m,2H)2.60(s,3H)2.64-2.74(m,1H)3.57(dd,J＝8.62, 5.58Hz,1H)3.67(q,J＝7.69Hz,1H)3.74-3.85(m,3H)3.97-4.12(m,2H)4.73(d, J＝5.83Hz,2H)7.51-7.59(m,4H)7.68(s,1H)7.99(s,1H)9.39(t,J＝5.83Hz,1H).

Example 123: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5T (150 mg, 0.42 mmol), intermediate VI (104 mg, 0.46 mmol), TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) were dissolved in DMSO (4.2 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 2, rt: 1.42 min) to provide the title compound 100 mg (45% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.61(d,J＝7.10Hz,3H)1.66-1.76(m,1H)1.84-1.94(m,1H)2.02(td,J＝9.06,1.90Hz,2H) 2.09-2.21(m,2H)2.38-2.48(m,2H)2.63-2.74(m,1H)3.57(dd,J＝8.62,5.58Hz,1H)3.63-3.71(m ,1H)3.74-3.85(m,3H)3.98-4.12(m,2H)5.30(s,1H)7.53(dd,J＝2.28,1.52Hz,1H)7.57(dd,J＝2. 28,1.52Hz,1H)7.68(d,J＝1.01Hz,1H)7.95(t,J＝1.39Hz,1H)9.12(s,2H)9.16(d,J＝7.10Hz,1H).

Example 124: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5S (53 mg, 0.14 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine (20 mg, 0.14 mmol), DIPEA (0.1 mL, 0.57 mmol) and HATU (76 mg, 0.2 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 1, rt: 1.28 min) to provide the title compound 21 mg (29% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.31-1.44(m,2H)1.55(d,J＝7.33Hz,3H)1.66-1.75(m,2H)1.86-1.96(m,1H)1.96 -2.07(m,2H)2.15(s,2H)2.42(s,2H)2.59(s,3H)3.35(d,J＝1.77Hz,2H)3.77-3.85(m,1H)3 .85-3.92(m,2H)3.96(d,J＝6.32Hz,2H)5.13-5.23(m,1H)7.48-7.51(m,1H)7.55(dd,J＝2. 40,1.64Hz,1H)7.68(d,J＝0.76Hz,1H)7.93(t,J＝1.52Hz,1H)8.72(s,2H)9.01-9.6(m,1H).

Example 125: 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5U (50 mg, 0.14 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine (20 mg, 0.14 mmol), DIPEA (0.1 mL, 0.58 mmol) and HATU (77 mg, 0.2 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 1, rt: 1.16 min) to provide the title compound 23 mg (34% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.29(t,J＝7.48Hz,3H)1.37(dd,J＝12.55,4.18Hz,2H)1.55(d,J＝7.10Hz,3H)1. 65-1.76(m,2H)1.96-2.10(m,1H)2.59(s,3H)2.84-2.95(m,2H)3.33-3.39(m,2H)3.89(d d,J＝11.15,3.04Hz,2H)3.96(d,J＝6.34Hz,2H)5.17(t,J＝7.22Hz,1H)7.47-7.51(m,1H) 7.53-7.56(m,1H)7.67(s,1H)7.91(t,J=1.27Hz,1H)8.72(s,2H)9.04(d,J=7.35Hz,1H).

Example 126: N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-[5-(propan-2-yl)-1,3-thiazol-2-yl]-5-(tetrahydro-2H-pyran-4-ylmethoxy)benzamide

Intermediate 5V (70 mg, 0.19 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine (27 mg, 0.19 mmol), DIPEA (0.14 mL, 0.78 mmol) and HATU (103 mg, 0.27 mmol) were dissolved in DMF (2.5 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 1, rt: 1.23 min) to provide the title compound 11 mg (11% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.33(d,J＝6.84Hz,6H)1.37(d,J＝8.62Hz,2H)1.55(d,J＝7.10Hz,3H)1.70(d,J＝10.65Hz,2H)1.97-2.10(m,1H)2.57-10 2.60(m,3H)3.24-3.30(m,1H)3.34-3.39(m,2H)3.89(dd,J＝11.41,2.28Hz,2H)3.96(d,J＝6.34Hz,2H)5.10 -5.23(m,1H)7.47-7.57(m,2H)7.68(d,J＝1.01Hz,1H)7.92(t,J＝1.27Hz,1H)8.72(s,2H)8.99-9.09(m,1H).

Example 127: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

Intermediate 5W (57 mg, 0.16 mmol), (1R) -1- (6- methylpyridazine -3- bases) ethylamine dihydrochloride (37 mg, 0.17 mmol), TEA (0.03 mL, 0.24 mmol) and HATU (66 mg, 0.17 mmol) were dissolved in DMSO (1.6 mL). The reaction mixture was stirred at room temperature until fully converted and evaporated to dryness. The remaining crude material was purified by column chromatography (silica gel, hexane / EE gradient) to provide the title compound 27 mg (36% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.56-1.69(m,5H)1.85-1.94(m,1H)1.95-2.6(m,3H)2.09-2.21(m,2H)2.38-2.48(m,2H)2.59(s,3H)3.48-3.58(m,2H)3.7 6-3.91(m,3H)4.76(s,1H)5.32-5.41(m,1H)7.50-7.62(m,4H)7.68(d,J＝0.76Hz,1H)7.96(t,J＝1.39Hz,1H)9.12(d,J＝7.33Hz,1H).

Example 128: 3-(5-ethyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yloxy)benzamide

Intermediate 5X (62 mg, 0.19 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethylamine dihydrochloride (43 mg, 0.21 mmol), TEA (0.04 mL, 0.28 mmol) and HATU (78 mg, 0.21 mmol) were dissolved in DMSO (1.9 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by column chromatography (silica gel, hexane/EE gradient) to provide the title compound 12 mg (14% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.29(t,J＝7.48Hz,3H)1.55-1.69(m,5H)2.00(d,J＝11.15Hz,2H)2.59(s,3H)2.85-2.96(m,2H)3.48-3.58(m,2H)3 .81-3.91(m,2H)4.76(s,1H)5.36(t,J＝7.22Hz,1H)7.50-7.62(m,4H)7.67(s,1H)7.92-7.97(m,1H)9.13(d,J＝7.60Hz,1H).

Example 129: 3-(5-ethyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5X (62 mg, 0.19 mmol), intermediate VI (47 mg, 0.21 mmol), TEA (0.04 mL, 0.28 mmol) and HATU (78 mg, 0.21 mmol) were dissolved in DMSO (1.9 mL). The reaction mixture was stirred at room temperature until fully converted and evaporated to dryness. The remaining crude material was purified by column chromatography (silica gel, hexane/EE gradient) to provide the title compound 15 mg (16% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.29(t,J＝7.48Hz,3H)1.57-1.68(m,5H)2.00(dd,J＝12.42,2.53Hz,2H )2.90(qd,J＝7.48,0.89Hz,2H)3.47-3.57(m,2H)3.81-3.90(m,2H)4.71-4.81( m,1H)5.29(t,J＝7.10Hz,1H)7.54(dd,J＝2.28,1.52Hz,1H)7.57-7.61(m,1H)7. 68(t,J=1.01Hz,1H)7.93(t,J=1.39Hz,1H)9.12(s,2H)9.15(d,J=7.10Hz,1H).

Example 130: N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine hydrochloride (96 mg, 0.55 mmol), TEA (0.08 mL, 0.59 mmol) and HATU (1.79 g, 4.72 mmol) were dissolved in DMF (4.3 mL). The reaction mixture was stirred at 60° C. until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (Method 1, rt: 0.98 min) to provide the title compound 87 mg (52% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.54(d,J＝7.10Hz,3H)1.95-2.05(m,1H)2.25(s,1H)2.59(s,3H)3.77-3.93(m,4H)5.12-5.23(m,2H)7.48(dd, J＝2.28,1.52Hz,1H)7.50-7.53(m,1H)7.65(d,J＝1.01Hz,1H)7.91(t,J＝1.39Hz,1H)8.72(s,2H)9.05(d,J＝7.60Hz,1H).

Example 131: N-[(1R)-1-(5-methylpyrazin-2-yl)ethyl]-3-[(6-methylpyridin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

Intermediate 5N (375 mg, 1.15 mmol), (1R)-1-(5-methylpyrazin-2-yl)ethanamine hydrochloride (219 mg, 1.26 mmol), DIPEA (0.8 mL, 4.6 mmol) and HATU (612 mg, 1.61 mmol) were dissolved in DMF (13.3 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The crude material was extracted three times with EE and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 1, rt: 0.97 min) to provide the title compound 13 mg (2.5% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.53(d,J＝7.07Hz,3H)2.47(s,3H)5.22(s,1H)7.37(d,J＝8.34Hz,1H)7.54(d,J＝2.78Hz,1H)7.58-7.65 (m, 3H) 8.13 (t, J = 1.39Hz, 1H) 8.38 (d, J = 2.78Hz, 1H) 8.48 (s, 1H) 8.55 (d, J = 1.26Hz, 1H) 9.17 (d, J = 7.58Hz, 1H).

Example 132: N-[1-(3-chloro-5-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (+/-) 1-(3-chloro-fluoropyridin-2-yl)ethanamine (96 mg, 0.55 mmol), TEA (0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF (3.9 mL). The reaction mixture was stirred at 60° C. until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (method 1, rt: 1.28 min) to provide 95 mg (52% yield) of the title compound as a mixture of two diastereomers.

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.49(d,J＝6.84Hz,3H)1.95-2.05(m,1H)2.18-2.31(m,1H)3.75-3.94(m,4H)5.20(d,J＝1.52Hz,1H)5.54(t,J＝6.97Hz,1H)7.51(d .

Example 133: N-[(6-methylpyridazin-3-yl)methyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), 1-(6-methylpyridazin-3-yl)ethanamine hydrochloride (88 mg, 0.55 mmol), TEA (0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF (4.3 mL). The reaction mixture was stirred at 60° C. until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (Method 1, rt: 0.91 min) to provide the title compound 70 mg (42% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]2.03(br.s.,1H)2.21-2.31(m,1H)2.61(s,3H)3.77-3.94(m,4H)4.73(d,J＝5.83Hz,2H)5.16-5.23(m,1H )7.53(dt,J＝6.72,2.09Hz,2H)7.57(s,2H)7.64(d,J＝1.27Hz,1H)7.98(t,J＝1.39Hz,1H)9.40(t,J＝5.83Hz,1H).

Example 134: N-[1-(5-chloro-3-fluoropyridin-2-yl)ethyl]-3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide

Intermediate 5C (120 mg, 0.39 mmol), (+/-) 1-(5-chloro-fluoropyridin-2-yl)ethanamine (96 mg, 0.55 mmol), TEA (0.08 mL, 0.59 mmol) and HATU (164 mg, 0.43 mmol) were dissolved in DMF (4.3 mL). The reaction mixture was stirred at 60° C. until complete conversion and evaporated to dryness. The crude material was purified by preparative HPLC (method 1, rt: 1.28 min) to provide 75 mg (41% yield) of the title compound as a mixture of two diastereomers.

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.51(d,J＝7.10Hz,3H)1.94-2.05(m,1H)2.24(s,1H)3.77-3.93(m,4H)5.19(d,J＝1.52Hz,1H)5.42(s,1H)7.49-7.53(m ,2H)7.64(d,J＝1.27Hz,1H)7.93(q,J＝1.27Hz,1H)8.06(dd,J＝9.89,2.03Hz,1H)8.49(d,J＝1.52Hz,1H)9.10(d,J＝7.10Hz,1H).

Example 135: 3-(5-cyclobutyl-1,3-thiazol-2-yl)-N-[(1R)-1-(6-methylpyridazin-3-yl)ethyl]-5-[(3S)-tetrahydrofuran-3-ylmethoxy]benzamide

Intermediate 5T (150 mg, 0.42 mmol), (1R)-1-(6-methylpyridazin-3-yl)ethanamine dihydrochloride (96 mg, 0.46 mmol), TEA (0.09 mL, 0.63 mmol) and HATU (175 mg, 0.46 mmol) were dissolved in DMSO (4.2 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by preparative HPLC (method 2, rt: 1.24 min) to provide the title compound 57 mg (29% yield).

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.59(d,J＝7.10Hz,3H)1.71(d,J＝7.60Hz,1H)1.91(d,J＝0.76Hz,1H)1.96-2.07(m ,2H)2.09-2.20(m,2H)2.38-2.48(m,2H)2.59(s,3H)2.68(d,J＝6.84Hz,1H)3.58(dd,J＝8. 62,5.58Hz,1H)3.63-3.72(m,1H)3.74-3.88(m,3H)3.98-4.12(m,2H)5.37(t,J＝7.22Hz,1 H)7.50-7.62(m,4H)7.68(d,J＝0.76Hz,1H)7.97(t,J＝1.39Hz,1H)9.14(d,J＝7.60Hz,1H).

Example 136: 3-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazol-2-yl)benzamide

3-Bromo-5-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]benzamide

Intermediate 5Y (5.12 g, 18.6 mmol), (1R)-1-(2-methylpyrimidin-5-yl)ethanamine dihydrochloride (5.08 g, 24.2 mmol), DIPEA (16.2 mL, 93 mmol) and HATU (7.78 g, 20.5 mmol) were dissolved in DMF (25 mL) at 60° C. Water and EE were added, the phases were separated, and the organic phase was washed with water, dried (over Na ₂ SO ₄ ) and evaporated to dryness. The crude material was purified by column chromatography (silica gel, heptane/EE gradient) to provide the title compound 5.45 g (74% yield).

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.51(d,J＝7.16Hz,3H)2.59(s,3H)3.30(s,310H)3.61-3.69(m,2H)4.13-4.20(m ,2H)5.12(s,1H)7.34(s,1H)7.43(s,1H)7.61(s,1H)8.69(s,2H)8.95(d,J=7.16Hz,1H).

3-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)benzamide

3-Bromo-5-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidinyl)-5-yl)ethyl]benzamide (5.3 g, 13.4 mmol), bis(pinacolato)diborane (6.83 g, 26.9 mmol) and potassium acetate (4.62 g, 47 mmol) were dissolved in 1,4-dioxaborolane and the mixture was degassed with nitrogen at room temperature for 20 minutes. Pd(dppf) _Cl₂ (984 mg, 1.34 mmol) was added and the reaction mixture was degassed for another 5 minutes and stirred at 90°C for 16 hours. The reaction mixture was partitioned between EE and water. The aqueous phase was extracted with EE, and _the combined organics were dried ( _Na₂SO₄ ) and concentrated in vacuo. Purification by column chromatography (silica gel, hexane/EE gradient) provided the title compound 2.51 g (42% yield).

3-(2-methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(5-methyl-1,3-thiazolyl)- oxazol-2-yl)benzamide

3-(2-Methoxyethoxy)-N-[(1R)-1-(2-methylpyrimidin-5-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (150 mg, 0.34 mmol) and 2-bromo-5-methyl-1,3-thiazole (91 mg, 0.51 mmol) were dissolved in 1M _K2CO3 aqueous solution (0.84 mL) and THF. _{Pd (} dppf) _Cl2 · _CH2Cl2 (42 mg, 0.05 mmol) was added and the reaction mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method 1) to provide 80 mg (57% yield) of the title compound.

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.54(d,J＝7.16Hz,3H)2.59(s,3H)3.32(s,3H)3.69(dd,J＝5.18,3.67Hz,2H)4.19-4.25(m,2H)5.1 7(t,J＝7.16Hz,1H)7.50-7.56(m,2H)7.64(d,J＝1.32Hz,1H)7.91(s,1H)8.72(s,2H)9.05(d,J＝7.54Hz,1H).

Example 137: tert-Butyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

To a solution of 3-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid (682 mg, 1.63 mmol), intermediate VI (408 mg, 1.79 mmol) and DIPEA (1.14 mL, 6.52 mmol) in DCM (6 mL) was added T3P (1.43 mL, 2.44 mmol) and the reaction solution was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (6 mL) and washed with sodium ^bicarbonate . The organic phase was separated, dried (over _MgSO4 ) and concentrated in vacuo. The crude material was chromatographed on a pre-packed _SiO2 column eluted with EtOAc to give 130 mg (46% yield) of the title compound as a colorless oil.

¹ H NMR (250MHz, CDC1 ₃ ): δ[ppm]＝8.93(s,2H),7.83(s,1H),7.58-7.47(m,2H),7.44-7.34(m,1H),6.83(d,J＝6.7Hz,1H),5.35(p,J＝8.0,7.6Hz,1H),4.59(d t,J＝7.2,3.6Hz,1H),3.76-3.61(m,2H)3.41-3.25(m,2H),2.53(d,J＝0.9Hz,3H),2.01-1.85(m,2H),1.82-1.70(m,5H),1.46(s,9H).

LCMS (Analytical Method D) Rt=5.13, MS (ESIpos) m/z=592 (M+H) ⁺ .

Example 138: 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of tert-butyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate (100 mg, 0.169 mmol) in DCM (1 mL) was added TFA (0.13 mL, 1.69 mmol) and the reaction was stirred at room temperature until gas evolution ceased. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM and neutralized with saturated _NaHCO₃ solution. The organic phase was separated, dried (over _MgSO₄ ) and concentrated in vacuo to afford 72 mg (85% yield) of the title compound as a white solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.95 (s, 2H), 7.89 (s, 1H), 7.57-7.53 (m, 2H), 7. 52(d,J＝1.1Hz,1H),7.42(d,J＝1.5Hz,1H),7.00(d,J＝6.7Hz,1H),5.37(p,J＝ 7.1Hz,1H),4.73-4.69(m,1H),3.34-3.26(m,2H),3.10-3.03(m,2H),2.53(d ,J＝0.9Hz,3H),2.19-2.12(m,4H),2.03-1.97(m,2H),1.72(d,J＝7.1Hz,3H).

LCMS (Analytical Method D) Rt=3.14, MS (ESIpos) m/z=491 (M+H) ⁺ .

Example 139: 3-[(1-methylpiperidin-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-20 1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide hydrochloride (80 mg, 0.15 mmol) suspended in DCE (1 mL) was added a 37% formaldehyde solution in water (0.045 mL, 0.61 mmol), and the resulting mixture was stirred for 30 min. Sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added, and the reaction mixture was stirred for 16 h. LCMS (method A) indicated unreacted starting material. The reaction was further treated with 37% formaldehyde solution (1 mL) and 3 drops of acetic acid and stirred for 30 min. Sodium triacetoxyborohydride (38 mg, 0.18 mmol) was added and the reaction mixture was stirred for 8 h. LCMS (method A) indicated complete conversion to product. The organic solvent was removed under reduced pressure and the remaining aqueous solution was basified to pH 8-9 and extracted into EtOAc (2 mL).The organic phase was separated, dried (over MgSO ₄ ), concentrated and purified by preparative HPLC (Method A) to give the title compound as a white powder 39.6 mg (52% yield).

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.93 (s, 2H), 7.83 (s, 1H), 7.54-7.49 (m, 2H), 7.41-7.37 (m, 1H), 6.70 (d, J = 6.5Hz, 1H), 5.35 (p, J = 7.0Hz, 1H), 4.48-4 .43(m,1H),2.74-2.63(m,2H),2.53(d,J＝0.9Hz,3H),2.34-2.25(m,5H), 2.6-2.01(m,2H),2.00(s,0H),1.90-1.81(m,2H),1.71(d,J=7.2Hz,3H).

LCMS (analytical method) Rt=3.23, MS (ESIpos) m/z=506 (M+H) ⁺ .

Example 140: 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a stirred solution of 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide hydrochloride (80 mg, 50% purity, 0.076 mmol) in DCE (1 mL) was added acetone (1 mL). After stirring at room temperature for 30 min, STAB (20 mg, 0.094 mmol) was added and the reaction mixture was stirred for another 4 h. LCMS (method A) indicated ~20% conversion. Another batch of acetone (1 mL) and STAB (20 mg, 0.094 mmol) was added and the reaction mixture was stirred at 40 ° C for 16 h. LCMS (method A) indicated ~50% conversion. The reaction mixture was concentrated in vacuo and basified with 10 M NaOH to form a white precipitate, which was extracted into EtOAc. The organic phase was concentrated in vacuo and purified by preparative HPLC (Method A) to give the title compound as a tan powder, 20 mg (49% yield).

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.93 (s, 2H), 7.82 (t, J = 1.4Hz, 1H), 7.53-7.49 (m, 2H ),7.41-7.36(m,1H),6.76(d,J＝6.6Hz,1H),5.35(t,J＝7.0Hz,1H),4.42(dt,J＝7. 9,4.0Hz,1H),2.81-2.70(m,3H),2.52(d,J＝1.1Hz,3H),2.39(t,J＝8.9Hz,2H),2. 07-2.00(m,2H),1.87-1.77(m,2H),1.70(d,J＝7.2Hz,3H),1.05(d,J＝6.6Hz,6H).

LCMS (Analytical Method D) Rt=3.36, MS (ESIpos) m/z=534 (M+H) ⁺ .

Example 141: 3-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of methyl 3-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoate (143 mg, 0.32 mmol) in THF (1 mL) was added 1 M lithium hydroxide (0.48 mL) and stirred at room temperature for 16 h. The organic solvent was removed under reduced pressure and the aqueous phase was acidified to pH 4 and then concentrated to dryness. The reaction residue, [Intermediate VI (88 mg, 0.39 mmol)] and DIPEA (0.23 mL, 1.29 mmol) were combined in DCM (1 mL), T3P (50% in EtOAc, 0.14 mL, 0.48 mmol) was added and the resulting solution was stirred at room temperature for 16 h. The mixture was diluted with DCM (1 mL), washed with brine (1 mL), dried ( _{over Na2SO4} ) and concentrated in vacuo to give a yellow oil. The crude material was purified by preparative HPLC (Method A) to give the title compound as a white powder 42 mg (26%).

¹ H NMR (500MHz, chloroform-d): δ [ppm] = 8.95 (s, 2H), 7.86 (t, J = 1.4Hz, 1H), 7.53 (d, J = 1.2Hz, 1H) ,7.51(dd,J＝2.4,1.5Hz,1H),7.37-7.34(m,1H),7.28(s,1H),6.74(d,J＝6.5Hz,1H),5 .37(p,J＝7.0Hz,1H),5.00-4.91(m,1H),2.94-2.88(m,2H),2.77(dd,J＝10.7,5.7Hz,1 H), 2.55 (d, J = 1.1Hz, 3H), 2.45-2.35 (m, 5H), 2.07-1.98 (m, 1H), 1.72 (d, J = 7.2Hz, 3H).

LCMS (Analytical Method D) Rt=3.16, MS (ESIpos) m/z=492 (M+H) ⁺ .

Example 142: 3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

1M lithium hydroxide (0.3mL) was added to 3-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)benzoic acid methyl ester (64mg, 0.19mmol) in THF, and the resulting solution was stirred at room temperature for 4h. The reaction mixture was concentrated in vacuo, and the residue was acidified with 2M HCl and concentrated to dryness. The residue was dissolved in DCM, intermediate VI (48mg, 0.21mmol), DIPEA (0.13mL, 0.77mmol) and HATU (110mg, 0.29mmol) were added, and the mixture was stirred at room temperature for 2h. The reaction mixture was diluted with DCM (1mL), washed with water (1mL), dried (passed through MgSO ₄ ) and concentrated in vacuo. The crude material was purified by preparative HPLC (method A) to obtain 23.9mg (25% yield) of the title compound as an off-white solid.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] = 8.93 (s, 2H), 7.86 (t, J = 1.4 Hz, 1H), 7.51 (d, J = 1.2 Hz, 1H), 7.49 (dd, J = 2.3, 1.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.75 (d, J = 6.6 Hz, 1H), 5.35 (p, J＝7.0Hz,1H),4.97-4.90(m,1H),2.93-2.84(m,2H),2.75(dd,J＝10.8,5.7Hz,1H), 2.53(d,J＝1.1Hz,3H),2.43-2.32(m,5H),2.06-1.96(m,1H),1.70(d,J＝7.2Hz,3H).

LCMS (Analytical Method D) Rt=3.18 min, MS (ESIpos) m/z=492 (M+H) ⁺ .

Example 143: 3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To methyl 3-[(1-methylazetidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)benzoate (80 mg, 0.25 mmol) in THF (1 mL) was added 1 M lithium hydroxide solution (0.37 mL) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo, and the residue was acidified to pH 5 with 1 M HCl and then concentrated to dryness. The residue was dissolved in DCM (1 mL), the intermediate (67 mg, 0.29 mmol), DIPEA (0.17 mL, 0.99 mmol) and HATU (140 mg, 0.37 mmol) were added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM (1 mL), washed with water (1 mL), dried (passed over MgSO ₄ ) and concentrated in vacuo. The residue was purified by preparative HPLC (Method A) to obtain 41.3 mg (35% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]=1.69(d,3H),2.39(s,3H),2.52(d,3H),3.11-3.18(m,2H),3.78-3.85(m,2H),4.82(p,1H) ,5.34(p,1H),6.87(d,1H),7.20-7.25(m,1H),7.37(dd,1H),7.49(d,1H),7.85(s,1H),8.92(s,2H).

LCMS (Analytical Method F) Rt=2.03 min, MS (ESIpos) m/z=478 (M+H) ⁺ .

Example 144: 3-(5-methyl-1,3-thiazol-2-yl)-5-(prop-2-yn-1-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5D (540 mg, 1.98 mmol), (1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (415 mg, 2.17 mmol), TEA (0.41 mL, 2.96 mmol) and HATU (826 mg, 2.17 mmol) were dissolved in DMSO (20 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by column chromatography (silica gel, hexane/EE gradient) to provide the title compound 600 mg (68% yield).

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.61(d,J＝7.16Hz,3H)3.64(t,J＝2.35Hz,1H)4.95(d,J＝2.26Hz,2H)5.30(t,J＝7.06Hz,1H)7.5 3-7.58(m,1H)7.61-7.64(m,1H)7.66(d,J＝1.13Hz,1H)7.97(s,1H)9.12(s,2H)9.19(d,J＝7.16Hz,1H).

Example 145: 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{(1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 5K (530 mg, 1.66 mmol), (1S)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethanamine (349 mg, 1.83 mmol), TEA (0.35 mL, 2.49 mmol) and HATU (694 mg, 1.83 mmol) were dissolved in DMSO (17 mL). The reaction mixture was stirred at room temperature until complete conversion and evaporated to dryness. The remaining crude material was purified by column chromatography (silica gel, hexane/EE gradient) to provide the title compound 600 mg (73% yield).

¹ H NMR (300MHz, DMSO-d ₆ )δ[ppm]1.54-1.70(m,5H)1.93-2.07(m,2H)3.46-3.59(m,2H)3.80-3.91(m,2H)4.69-4.82(m,1H)5.29(t,J＝7.06Hz,1 H)7.51-7.55(m,1H)7.56-7.61(m,1H)7.64(d,J＝1.13Hz,1H)7.91(t,J＝1.32Hz,1H)9.12(s,2H)9.16(d,J＝7.16Hz,1H).

The following examples were prepared by a procedure analogous to that described in Example 1 using HATU and the appropriate carboxylic acid and amine starting materials.

Intermediate 63 was formed as a mixture of two trans isomers. Chiral purification (Method 2) provided Example 162 (trans isomer 1) and Example 163 (trans isomer 2).

Example 162: Trans Isomer 1; 3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral purification of 189 mg of intermediate 63 afforded 72 mg of the title compound.

SFC chiral analysis (method 2): 100% e.e., Rt = 1.25 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.76 (s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 7.31 (s, 1H), 6.95 (d, J = 6.4Hz, 1H), 5.35 (m, 1H), 4.43(qd,J＝6.2,3.3Hz,1H),4.02(qd,J＝6.4,3.3Hz,1H),2.52(s,3H),1.72(s,3H),1.27(d,J＝6.3Hz,3H),1.25(d,J＝6.5Hz,3H).

LCMS (Analytical Method D) Rt=4.14 min, MS (ESIpos) m/z=481 (M+H) ⁺ .

Example 163: Trans Isomer 2; 3-{[3-hydroxybutan-2-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral purification of 189 mg of intermediate 63 afforded 77.2 mg of the title compound.

SFC chiral analysis (method 2): 99.4% e.e., Rt = 1.42 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.80 (s, 1H), 7.54-7.49 (m, 1H), 7.47 (s, 1H), 7.38-7.33 (m, 1H), 6.82 (d, J = 6.5Hz, 1H), 5.35 (m, 1H), 4.4 7(qd,J＝6.3,3.3Hz,1H), 4.03(qd,J＝6.4,3.3Hz,1H), 2.53(d,J＝0.9Hz,3H), 1.71(d,J＝7.2Hz,3H), 1.29(d,J＝6.3Hz,3H), 1.27(d,J＝6.5Hz,3H).

LCMS (Analytical Method D) Rt=4.15 min, MS (ESIpos) m/z=481 (M+H) ⁺ .

The following examples were prepared by a procedure analogous to that described in Example 7 using T3P and the appropriate carboxylic acid and amine starting materials.

Example 190: tert-Butyl (3R)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate as a mixture of enantiomers

To a solution of Intermediate 5AF (200 mg, 0.44 mmol), Intermediate VI (121 mg, 0.53 mmol) and DIPEA (0.231 mL, 1.33 mmol) in DCM (1 mL) was added T3P (50% solution in EtOAc, 0.198 mL, 0.66 mmol), and the resulting solution was stirred at room temperature for 16 h. LCMS analysis indicated that the starting material was not completely consumed. HATU (50 mg, 0.13 mmol) was added and the mixture was stirred at room temperature for 2 h, then diluted with DCM (1 mL) and washed with water (1 mL). The organic phase was dried ( _MgSO4 ), filtered, and concentrated under reduced pressure. Purification by Biotage Isolera ^™ chromatography (eluting with 0-80% EtOAc in heptane on a pre-packed KP- _SiO2 column) gave a colorless oil, which was lyophilized to afford 195 mg (71% yield) of the title compound as a white powder.

¹ H NMR (250MHz, DMSO-d6): δ [ppm] 9.08 (s, 2H), 8.92 (d, J = 7.1Hz, 1H), 7.94 (t, J = 1.4Hz, 1H), 7.65-7.47 (m, 3H), 5.3 3(m,1H),4.53(d,J＝3.1Hz,1H),3.68-3.23(m,4H),2.07-1.59(m,6H),1.60-1.41(m,1H),1.30(d,J＝2.4Hz,9H).

LCMS (Analytical Method F) Rt=4.27 min, MS (ESIpos): m/z=592 (M+H) ⁺ .

The following examples were prepared by a procedure analogous to that described for Example 190 using both T3P and HATU and the appropriate carboxylic acid and amine starting materials.

Examples 193 to 200 were prepared using T3P and the appropriate carboxylic acid and amine starting materials. The isomeric mixtures were separated into the individual isomers by the methods given.

Example 193 (Enantiomer 1) and Example 194 (Enantiomer 2): 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide, formed as a mixture of 2 enantiomers

Intermediate 5F (40 mg, 0.14 mmol), 1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (38 mg, 0.17 mmol), and DIPEA (0.12 mL, 0.69 mmol) were dissolved in DCM (2 mL). T3P (0.16 mL, 0.28 mmol, 50% in EtOAc) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated _NaHCO3 (3 mL), and the aqueous layer was further extracted with DCM (2 x 2 mL). The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 10-70% EtOAc in heptane on a 10 g pre-packed KP- _SiO2 column) to give 31 mg (48% yield) of the title compound as a colorless gum.

¹ H NMR (500MHz, CDC13): δ [ppm] 7.88 (t, J = 1.4Hz, 1H), 7.53 (d, J = 1.2Hz, 1H), 7.40 (dd, J = 2.4, 1.4Hz, 1H), 7.22 (dd, J = 2.4, 1.5Hz, 1H), 6.93 (d, J＝7.4Hz,1H),5.74(m,1H),5.34(m,1H),5.07-5.02(m,2H),4.78(ddd,J＝7.4,5.0,2.8Hz,2H),2.54(d,J＝1.1Hz,3H),1.91(d,J＝7.0Hz,3H).

LCMS (Analytical Method F) Rt=3.37 min, MS (ESIpos): m/z=471.1 (M+H) ⁺ .

Example 193: Enantiomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

28.7 mg of a mixture of enantiomer 1 (Example 193) and enantiomer 2 (Example 194) were subjected to SFC chiral purification (Method 3) to give 8.9 mg of the title compound.

SFC chiral analysis (Method 3): 100% e.e. Rt = 2.21 min.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]7.87(s,1H),7.53(d,J＝1.1Hz,1H),7.42-7.39(m,1H),7.23-7.21(m,1H),6.87(d,J＝7.5Hz,1H),5.78-5.71(m ,1H),5.34(t,J＝5.4Hz,1H),5.04(t,J＝6.7Hz,2H),4.78(t,J＝7.6Hz,2H),2.54(d,J＝1.1Hz,3H),1.91(d,J＝7.0Hz,3H).

LCMS (Analytical Method D) Rt=4.39 min, MS (ESIpos): m/z=471.1 (M+H) ⁺ .

Example 194: Enantiomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-(oxetan-3-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

28.7 mg of a mixture of enantiomer 1 (Example 193) and enantiomer 2 (Example 194) were subjected to SFC chiral purification (Method 3) to give 11.7 mg of the title compound.

SFC chiral analysis (method 3): 99.2% e.e. Rt = 2.53 min.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]7.88(s,1H),7.53(s,1H),7.40(s,1H),7.22(s,1H),6.91-6.85(m,1H),5.78-5.71(m,1H ),5.37-5.31(m,1H),5.04(t,J＝6.7Hz,2H),4.81-4.76(m,2H),2.54(s,3H),1.91(d,J＝7.1Hz,3H).

LCMS (Analytical Method D) Rt=4.40 min, MS (ESIpos): m/z=471.0 (M+H) ⁺ .

Example 195 (Enantiomer 1) and Example 196 (Enantiomer 2): 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide, formed as a mixture of 2 enantiomers

Intermediate 5K (96 mg, 0.3 mmol), 1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (84 mg, 0.36 mmol), and DIPEA (0.261 mL, 1.5 mmol) were dissolved in DCM (3 mL). T3P (0.35 mL, 0.6 mmol, 50% in EtOAc) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated _NaHCO3 (3 mL), and the aqueous layer was further extracted with DCM (2 x 2 mL). The combined organics were dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude material was triturated with _Et2O to give 112 mg (75% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, CDCl ₃ ): δ[ppm]7.84(d,J＝1.4Hz,1H),7.60-7.57(m,1H),7.53(d,J＝1.1Hz,1H),7.4 5-7.42(m,1H),6.89(d,J＝7.4Hz,1H),5.74(m,1H),4.65(dq,J＝7.7,3.8Hz,1H) ,4.03-3.96(m,2H),3.61(ddd,J＝11.6,8.3,3.2Hz,2H),2.54(d,J＝1.0Hz,3H) ,2.11-2.03(m,2H),1.91(d,J＝7.0Hz,3H),1.82(dtd,J＝12.4,8.1,3.6Hz,2H).

LCMS (Analytical Method F) Rt=3.64 min, MS (ESIpos): m/z=499.1 (M+H) ⁺ .

Example 195: Enantiomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

112 mg of a mixture of enantiomer 1 (Example 195) and enantiomer 2 (Example 196) were subjected to SFC chiral purification (Method 3) to give 47.8 mg of the title compound.

SFC chiral analysis (Method 3): 100% e.e. Rt = 2.21 min.

^1H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 7.84 (s, 1H), 7.60-7.57 (m, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.45-7.41 (m, 1H), 6.87 (d, J = 7.1 Hz, 1H), 5.74 (m, 1H), 4.70-4.61 (m, 1H), 4.03-3.96 (m, 2H), 3.61 (ddd, J = 11.6, 8.3, 3.2 Hz, 2H), 2.54 (d, J = 1.1 Hz, 3H), 2.12-2.03 (m, 2H), 1.91 (d, J = 7.0 Hz, 3H), 1.86-1.77 (m, 2H).

LCMS (Analytical Method D) Rt=4.62 min, MS (ESIpos): m/z=499.1 (M+H) ⁺ .

Example 196: Enantiomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-(tetrahydro-2H-pyran-4-yloxy)-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

112 mg of a mixture of enantiomer 1 (Example 195) and enantiomer 2 (Example 196) were subjected to SFC chiral purification (Method 3) to give 49.6 mg of the title compound.

SFC chiral analysis (Method 3): 100% e.e. Rt = 2.70 min.

^1H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 7.85 (s, 1H), 7.59-7.57 (m, 1H), 7.53 (d, J = 1.2 Hz, 1H), 7.45-7.42 (m, 1H), 6.89 (d, J = 7.0 Hz, 1H), 5.74 (m, 1H), 4.71-4.62 (m, 1H), 4.04-3.94 (m, 2H), 3.61 (ddd, J = 11.7, 8.4, 3.2 Hz, 2H), 2.54 (d, J = 1.1 Hz, 3H), 2.11-2.03 (m, 2H), 1.91 (d, J = 7.0 Hz, 3H), 1.87-1.78 (m, 2H).

LCMS (Analytical Method D) Rt=4.62 min, MS (ESIpos): m/z=499.2 (M+H) ⁺ .

Example 197 (Diastereomer 1) and Example 198 (Diastereomer 2): 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide, formed as a mixture of 2 diastereomers

Intermediate 5B (92 mg, 0.3 mmol), 1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (84 mg, 0.36 mmol), and DIPEA (0.261 mL, 1.5 mmol) were dissolved in DCM (3 mL). T3P (0.35 mL, 0.6 mmol, 50% in EtOAc) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated _NaHCO3 (3 mL), and the aqueous layer was further extracted with DCM (2 x 2 mL). The combined organics were dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 10-70% EtOAc in heptane on a 10 g pre-packed KP-SiO2 _column ) to give 86.1 mg (59% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]7.86(s,1H),7.54(dd,J＝2.3,1.5Hz,1H),7.52(d,J＝1.1Hz,1H),7.39(q,J＝2.2Hz,1H),6.91(d,J＝7.3Hz,1H),5.74(m,1H),5.13-5. 03(m,1H),4.07-3.97(m,3H),3.92(td,J＝8.4,4.2Hz,1H),2.54(d,J＝1 .0Hz,3H),2.34-2.23(m,1H),2.23-2.14(m,1H),1.91(d,J＝7.0Hz,3H).

LCMS (Analytical Method F) Rt=3.49 min, MS (ESIpos): m/z=485 (M+H) ⁺ .

Example 197: Diastereomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

86 mg of a mixture of diastereomer 1 (Example 197) and diastereomer 2 (Example 198) were subjected to SFC chiral purification (Method 3) to give 34.6 mg of the title compound.

SFC chiral analysis (Method 3): 100% e.e. Rt = 2.39 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.87 (s, 1H), 7.60-7.50 (m, 2H), 7.40 (s, 1H), 6.88 (d, J = 6.6Hz, 1H), 5.78-5.70 (m, 1H), 5.10-5.06 (m, 1H) ,4.06-3.98(m,3H),3.93(td,J＝8.4,4.3Hz,1H),2.54(s,3H),2.29(td,J＝14.4,8.4Hz,1H),2.21-2.14(m,1H),1.91(d,J＝7.0Hz,3H).

LCMS (Analytical Method D) Rt=4.49 min, MS (ESIpos): m/z=485 (M+H) ⁺ .

Example 198: Diastereomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

86 mg of a mixture of diastereomer 1 (Example 197) and diastereomer 2 (Example 198) were subjected to SFC chiral purification (Method 3) to give 36.9 mg of the title compound.

SFC chiral analysis (method 3): 99.8% e.e. Rt = 2.75 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.87 (s, 1H), 7.58-7.51 (m, 2H), 7.40 (s, 1H), 6.88 (d, J = 6.6Hz, 1H), 5.81-5.69 (m, 1H), 5.08 (d, J = 1.9 Hz,1H),4.07-3.99(m,2H),3.93(td,J＝8.3,4.2Hz,1H),2.54(s,3H),2.37-2.23(m,1H),2.23-2.09(m,1H),1.91(d,J＝7.0Hz,3H).

LCMS (Analytical Method D) Rt=4.49 min, MS (ESIpos): m/z=485 (M+H) ⁺ .

Example 199 (Diastereomer 1) and Example 200 (Diastereomer 2): 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide, formed as a mixture of 2 diastereomers

Intermediate 5C (61 mg, 0.2 mmol), 1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethanamine (56 mg, 0.24 mmol), and DIPEA (0.174 mL, 1 mmol) were dissolved in DCM (3 mL). T3P (0.234 mL, 0.4 mmol, 50% in EtOAc) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was washed with saturated _NaHCO3 (3 mL), and the aqueous layer was further extracted with DCM (2 x 2 mL). The combined organics were dried over _MgSO4 , filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 20-80% EtOAc in heptane on a 10 g pre-packed KP-SiO2 _column ) to give 41.1 mg (42% yield) of the title compound as an off-white solid.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.00(s,1H),7.56(s,1H),7.53(s,1H),7.43(s,1H),7.05(s,1H),5.75(m,1H),5.08(d,J＝1.9Hz,1H),4.09-3.97(m,3 H), 3.93 (td, J = 8.4, 4.3Hz, 1H), 2.55 (d, J = 0.9Hz, 3H), 2.30 (td, J = 14.3, 8.3Hz, 1H), 2.24-2.13 (m, 1H), 1.92 (d, J = 7.0Hz, 3H).

LCMS (Analytical Method D) Rt=4.43 min, MS (ESIpos): m/z=485.95 (M+H) ⁺ .

Example 199: Diastereomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

41 mg of the mixture of diastereomer 1 (Example 199) and diastereomer 2 (Example 200) were subjected to SFC chiral purification (Method 3) to give 13.1 mg of the title compound.

SFC chiral analysis (Method 3): 100% e.e. Rt = 1.74 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.86 (s, 1H), 7.56-7.53 (m, 1H), 7.53-7.52 (m, 1H), 7.41-7.38 (m, 1H), 6.90 (d, J = 7.2Hz, 1H), 5.74 (m, 1H), 5. 10-5.5(m,1H),4.07-3.98(m,3H),3.93(td,J＝8.4,4.3Hz,1H),2.54(s,3H),2.33-2.24(m,1H),2.21-2.14(m,1H),1.91(d,J＝7.0Hz,3H).

LCMS (Analytical Method D) Rt=4.45 min, MS (ESIpos): m/z=485.05 (M+H) ⁺ .

Example 200: Diastereomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{1-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]ethyl}benzamide

41 mg of the mixture of diastereomer 1 (Example 199) and diastereomer 2 (Example 200) were subjected to SFC chiral purification (Method 3) to give 16.1 mg of the title compound.

SFC chiral analysis (Method 3): 100% e.e. Rt = 2.81 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.86 (s, 1H), 7.54 (s, 1H), 7.53 (s, 1H), 7.42-7.38 (m, 1H), 6.89 (d, J = 7.1Hz, 1H), 5.74 (m, 1H), 5.11-5. 03(m,1H),4.6-3.99(m,3H),3.93(td,J＝8.4,4.3Hz,1H),2.54(s,3H),2.35-2.24(m,1H),2.22-2.14(m,1H),1.91(d,J＝7.0Hz,3H).

LCMS (Analytical Method D) Rt=4.45 min, MS (ESIpos): m/z=485.0 (M+H) ⁺ .

Example 201: 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-4-yloxy)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

To a solution of intermediate 41 (178 mg, 0.30 mmol) in DCM (5 mL) was added TFA (0.23 mL, 3.0 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction was terminated with 1 M NaOH (5 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 × 5 mL), and the combined organic matter was dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (silica gel, eluted with heptane-EtOAc, 1: 4 to 0: 1 and then with EtOAc-MeOH, 1: 0 to 4: 1). The fraction containing the product was concentrated, and the residue was freeze-dried in MeCN/water to obtain 101.3 mg (69% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 7.86 (t, J = 1.4Hz, 1H), 7.82 (d, J = 8.7Hz, 1H), 7.74 (d, J = 8.7 Hz,1H),7.58(dd,J＝2.3,1.5Hz,1H),7.52(d,J＝1.2Hz,1H),7.46(d,J＝7.4Hz,1H),7.43- 7.40(m,1H),5.60(m,1H),4.53(tt,J＝8.0,3.8Hz,1H),3.19-3.10(m,2H),2.80-2.71(m, 2H), 2.53 (d, J = 1.1 Hz, 3H), 2.09-1.99 (m, 2H), 1.76 (d, J = 7.0 Hz, 3H), 1.74-1.65 (m, 2H).

LCMS (Analytical Method F) Rt=2.02 min, MS (ESIpos): m/z=492.2 (M+H) ⁺ .

The following examples were prepared by procedures analogous to those described for Example 201 using TFA and the appropriate N-Boc protected amine starting material.

Example 205 (Diastereomer 1) and Example 206 (Diastereomer 2): 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, formed as a mixture of 2 diastereomers

To a solution of Example 190 (189 mg, 0.32 mmol) in DCM (1 mL) was added TFA (0.25 mL, 3.19 mmol), and the resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in water (1 mL) and basified to pH 12 with 10 M NaOH solution to obtain a white precipitate. The precipitate was dissolved and extracted with EtOAc (2 × 5 mL). The combined organic matter was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to obtain 160 mg (quantitative yield) of the title compound as a white powder.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]9.17(d,J＝7.1Hz,1H),9.11(s,2H),7.91(s,1H),7.64(d, J＝1.2Hz,1H),7.59-7.55(m,1H),7.54-7.50(m,1H),5.29(m,1H),4.48(dt,J＝7.5,3.9Hz, 1H),3.15(d,J＝12.2Hz,1H),2.82(dt,J＝11.8,4.4Hz,1H),2.62(dt,J＝30.0,8.9Hz,2H),2 .02(s,1H),1.77-1.67(m,1H),1.61(d,J＝7.1Hz,3H),1.49(ddt,J＝13.1,9.3,5.1Hz,1H).

Example 205: Diastereomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

60 mg of a mixture of diastereomer 1 (Example 205) and diastereomer 2 (Example 206) were subjected to HPLC chiral purification (Method 4) to give 24.6 mg of the title compound.

HPLC chiral analysis (Method 4): 100% e.e. Rt = 10.2 min.

¹ H NMR (500MHz, DMSO): δ[ppm]9.18(d,1H),9.12(s,2H),7.91(t,1H),7.64(d,1H),7.58-7.55(m,1H),7.55-7.51(m,1H),5.30(m,1H) ,4.48(tt,1H),3.18-3.11(m,1H),2.85-2.77(m,1H),2.67-2.54(m,2H),2.06-1.99(m,1H),1.75-1.69(m,1H),1.64-1.44(m,5H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=492 (MH) ⁺ .

Example 206: Diastereomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-(piperidin-3-yloxy)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

60 mg of a mixture of diastereomer 1 (Example 205) and diastereomer 2 (Example 206) were subjected to HPLC chiral purification (Method 4) to give 24.6 mg of the title compound.

HPLC chiral analysis (Method 4): 96% e.e. Rt = 12.4 min.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]9.17(d,J＝7.1Hz,1H),9.11(s,2H),7.90(s,1H),7.64(d,J＝1.1Hz,1H),7.57-7.54(m,2H),7.54-7.50(m,1H),5.29(m ,1H),4.42(dt,J＝8.2,4.2Hz,1H),3.16-3.07(m,1H),2.85-2.74(m,1H),2 .60-2.52(m,2H),2.08-2.00(m,1H),1.74-1.65(m,1H),1.64-1.41(m,5H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=492 (MH) ⁺ .

Intermediate 67 was formed as a mixture of two cis isomers. SFC purification (Method 5) afforded Example 207 (cis isomer 1) and Example 208 (cis isomer 2).

Example 207: Cis Isomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

46.9 mg of intermediate 67 were subjected to SFC chiral purification (Method 5) to give 15.3 mg of the title compound.

SFC chiral analysis (method 2): 99.6% e.e., Rt = 1.66 min.

^1H NMR (500 MHz, CHLOROFORM-d): δ [ppm] 8.96 (s, 2H), 7.88 (s, 1H), 7.59-7.53 (m, 2H), 7.45-7.41 (m, 1H), 6.63 (d, J = 6.5 Hz, 1H), 5.38 (m, 1H), 4.47 (ddd, J = 15.5, 11.0, 4.4 Hz, 1H), 3.36-3.23 (m, 2H), 2.80 (td, J = 12.6, 2.4 Hz, 1H), 2.57 (d, J = 1.0 Hz, 3H), 2.41-2.33 (m, 1H), 2.27-2.18 (m, 1H), 1.75 (d, J = 7.2 Hz, 3H), 1.68-1.60 (m, 3H).

LCMS (Analytical Method D) Rt=3.69 min, MS (ESIpos): m/z=560 (M+H) ⁺ .

Example 208: Cis Isomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

46.9 mg of intermediate 67 were chirally purified (Method 5) to give 14.1 mg of the title compound.

SFC chiral analysis (Method 5): 99.6% e.e., Rt = 1.87 min.

¹ H NMR (500MHz, chloroform-d): δ[ppm]8.94(s,2H),7.85(s,1H),7.55-7.51(m,2H),7 .44-7.38(m,1H),6.61(d,J＝6.4Hz,1H),5.35(m,1H),4.48-4.38(m,1H),3. 32-3.19(m,2H),2.78(td,J＝12.6,2.3Hz,1H),2.54(d,J＝0.9Hz,3H),2.35 -2.29(m,1H),2.23-2.15(m,1H),1.72(d,J=7.2Hz,3H),1.67-1.59(m,3H).

LCMS (Analytical Method D) Rt=3.70 min, MS (ESIpos): m/z=560 (M+H) ⁺ .

Example 209: 3-{[2-methyl-2-azabicyclo[2.2.1]hept-5-yl]oxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Intermediate 74 (30 mg, 0.06 mmol), formaldehyde (37% in water) (22.32 μL, 0.3 mmol) and acetic acid (5.12 μL, 0.09 mmol) were combined in MeOH (2 mL) and STAB (37.88 mg, 0.18 mmol) was added. The resulting solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The resulting residue was dissolved in saturated NaHCO₃ ( ₅ mL) and extracted with DCM (3×5 mL). The combined organics were washed with water and dried over _MgSO₄ , filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method A) and freeze-dried in MeCN/water to give 13.7 mg (44% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.82 (t, J = 1.3Hz, 1H), 7.52 (d, J = 1.2Hz, 1H), 7.49-7 .47(m,1H),7.37-7.35(m,1H),6.60(d,J＝6.0Hz,1H),5.36(m,1H),4.38(d,J＝6.1Hz,1H),3.21 (s,1H),2.84(m,1H),2.60(d,J＝3.4Hz,1H),2.53(d,J＝1.1Hz,3H),2.43-2.37(m,1H),2.33(s ,3H),2.15-2.9(m,1H),1.77(d,J＝10.0Hz,1H),1.71(d,J＝7.2Hz,3H),1.48(d,J＝13.8Hz,1H).

LCMS (Analytical Method F) Rt=2.21 min, MS (ESIpos): m/z=518.1 (M+H) ⁺ .

The following examples were prepared similarly to the procedures described in Example 220/Example 221 using STAB and the appropriate amine starting material.

Example 220 (Diastereomer 1) and Example 221 (Diastereomer 2): 3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, formed as a mixture of 2 diastereomers

Intermediate 40 (93 mg, 0.189 mmol), 37% aqueous formaldehyde (0.07 mL, 0.946 mmol) and acetic acid (0.02 mL, 0.378 mmol) were combined in methanol (1 mL) and STAB (60 mg, 0.28 mmol) was added dropwise. The resulting solution was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in water (1 mL) and basified to pH 5 with 10 M sodium hydroxide solution and extracted with EtOAc. The organic phase was separated, dried ( _MgSO ), filtered, evaporated under reduced pressure and freeze-dried to give 59 mg (62% yield) of the title compound as a white solid.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]9.17(d,J＝7.1Hz,1H),9.11(s,2H),7.91(s,1H),7.64(d, J＝1.2Hz,1H),7.59-7.55(m,1H),7.54-7.50(m,1H),5.29(m,1H),4.48(dt,J＝7.5,3.9Hz, 1H),3.15(d,J＝12.2Hz,1H),2.82(dt,J＝11.8,4.4Hz,1H),2.62(dt,J＝30.0,8.9Hz,2H),2 .02(s,1H),1.77-1.67(m,1H),1.61(d,J＝7.1Hz,3H),1.49(ddt,J＝13.1,9.3,5.1Hz,1H).

Example 220: Diastereomer 1; 3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

56 mg of the mixture of diastereomer 1 (Example 220) and diastereomer 2 (Example 221) were subjected to SFC chiral purification (Method 6) to give 29 mg of the title compound.

SFC chiral analysis (Method 6): 99.8% e.e., Rt = 2.01 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.86 (t, J = 1.4Hz, 1H), 7.57 (dd, J = 2.3, 1.5H z,1H),7.50(d,J＝1.2Hz,1H),7.45-7.40(m,1H),6.80(d,J＝6.6Hz,1H),5.35(m,1H),4 .54(dt,J＝7.2,3.7Hz,1H),2.78(d,J＝10.4Hz,1H),2.52(d,J＝1.1Hz,4H),2.39(s,1H) ,2.29(s,4H),1.95-1.83(m,2H),1.70(d,J＝7.2Hz,3H),1.63(dd,J＝10.6,5.5Hz,2H).

LCMS (Analytical Method D) Rt=3.16 min, MS (ESIpos): m/z=506 (M+H) ⁺ .

Example 221: Diastereomer 2; 3-[(1-methylpiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

56 mg of the mixture of diastereomer 1 (Example 220) and diastereomer 2 (Example 221) were subjected to SFC chiral purification (Method 6) to give 20.1 mg of the title compound.

SFC chiral analysis (Method 6): 95.1% e.e., Rt = 2.19 min.

¹ H NMR (250MHz, MeOD): δ[ppm]9.01(s,2H),7.91(t,1H),7.67-7.59(m,1H),7.54(d,1H),7.51-7.45(m,1H) ,5.34(q,1H),4.64-4.53(m,1H),2.90(d,1H),2.67-2.29(m,9H),2.06-1.82(m,2H),1.75-1.57(m,5H).

LCMS (Analytical Method D) Rt=3.15 min, MS (ESIpos): m/z=506 (M+H) ⁺ .

Example 222 (cis Isomer 1) and Example 223 (cis Isomer 2): 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, formed as a mixture of cis isomers

Intermediate 67 (50 mg, 0.09 mmol), 37% aqueous formaldehyde (33 μL, 0.45 mmol) and acetic acid (5 μL) were combined in methanol (3 mL), STAB (57 mg, 0.27 mmol) was added and the reaction was stirred for 2 h. LCMS showed incomplete conversion. The reaction mixture was further treated with 37% aqueous formaldehyde (33 μL, 0.45 mmol) and STAB (57 mg, 0.27 mmol) and stirred for another 1 h. The reaction required five additional treatments to complete. The crude reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in saturated NaHCO₃ ( ₂ mL) solution and extracted with DCM (3×2 mL). The combined organic phases were dried ( _MgSO₄ ), filtered, concentrated under reduced pressure and freeze-dried in MeCN/water to give 46.6 mg (86% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, chloroform-d): 5 [ppm] 8.93 (s, 2H), 7.85 (d, J = 1.3 Hz, 1H), 7.55-7.49 (m, 2H), 7.39 (s, 1H), 6.61 (d, J = 4.7 Hz, 1H), 5.35 (m, 1H), 4.39 (dq, J = 9.9, 4.8, 4.2 Hz, 1H), 3.03 (dt, J＝12.2,3.5Hz,1H),2.80-2.71(m,1H),2.56-2.50(m,3H),2.45(s,3H),2.41(d,J＝12.6 Hz, 1H), 2.36-2.28 (m, 1H), 2.17-2.08 (m, 1H), 1.88-1.74 (m, 2H), 1.72 (d, J = 7.2Hz, 3H).

LCMS (Analytical Method F) Rt=3.31 min, MS (ESIpos): m/z=574.1 (M+H) ⁺ .

Example 222: Cis Isomer 1; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

43.9 mg of a mixture of cis-isomer 1 (Example 222) and cis-isomer 2 (Example 223) were subjected to SFC chiral purification (Method 7) to give 11.7 mg of the title compound.

SFC chiral analysis (Method 7): 98.2% e.e., Rt = 1.51 min.

¹ H NMR (500MHz, chloroform-d): 5[ppm]8.96(s,2H),7.88(s,1H),7.58-7.52(m,2H),7.46-7 .37(m,1H),6.63(d,J＝6.3Hz,1H),5.38(m,1H),4.49-4.35(m,1H),3.09-3.02(m, 1H),2.78(s,1H),2.56(d,J＝0.9Hz,3H),2.47(s,3H),2.46-2.40(m,1H),2.35(d, J＝11.0Hz,1H),2.14(d,J＝12.3Hz,1H),1.89-1.76(m,2H),1.75(d,J＝7.2Hz,3H).

LCMS (Analytical Method D) Rt=4.26 min, MS (ESIpos): m/z=574 (M+H) ⁺ .

Example 223: Cis Isomer 2; 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-methyl-2-(trifluoromethyl)piperidin-4-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

43.9 mg of a mixture of cis-isomer 1 (Example 222) and cis-isomer 2 (Example 223) were subjected to SFC chiral purification (Method 7) to give 9.5 mg of the title compound.

SFC chiral analysis (Method 7): 98.6% e.e., Rt = 1.76 min.

¹ H NMR (500 MHz, chloroform-d): 5 [ppm] 8.94 (s, 2H), 7.85 (s, 1H), 7.55-7.51 (m, 2H), 7.39 (s, 1H), 6.61 (d, J = 6.4 Hz, 1H), 5.35 (m, 1H), 4.40 (dt, J = 10.5, 5.9 Hz, 1H), 3.06-3.00 (m, 1 H),2.82-2.68(m,1H),2.54(s,3H),2.45(s,3H),2.41(d,J＝11.7Hz,1H),2.31(d,J＝ 12.5Hz, 1H), 2.13 (d, J = 13.4Hz, 1H), 1.80 (p, J = 12.4Hz, 2H), 1.72 (d, J = 7.2Hz, 3H).

LCMS (Analytical Method D) Rt=4.27 min, MS (ESIpos): m/z=574 (M+H) ⁺ .

Example 224: 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)piperidin-4-yl]oxy}-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

Example 201 (50 mg, 0.1 mmol), acetone (1 mL) and acetic acid (50 μL) were stirred in DCE (1 mL) at room temperature for 30 min. STAB (65 mg, 0.3 mmol) was added and the reaction was stirred overnight. The reaction mixture was further treated with acetone (1 mL) and STAB (65 mg, 0.3 mmol) and stirred overnight. The reaction was further treated with acetone (3 mL) and STAB (130 mg, 0.6 mmol) and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in saturated NaHCO₃ ( ₅ mL) and extracted with DCM (3×5 mL). The combined organics were dried over _MgSO₄ , filtered and concentrated under reduced pressure. The compound was freeze-dried in acetonitrile/water to give 48.0 mg (88% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, chloroform-d): 5 [ppm] 7.87-7.84 (m, 1H), 7.82 (d, J = 8.7, 1H), 7.74 (d, J = 8.7, 1H), 7.57 (dd, J = 2.3, 1.5, 1H), 7.53-7.51 (m, 1H), 7.44 (d, J = 7.2, 1H), 7.41 (dd, J = 2.3, 1.6, 1H ),5.64-5.55(m,1H),4.51-4.42(m,1H),2.84-2.72(m,3H),2.53(d,J＝1.1,3H),2.50-2. 38(m,2H),2.11-1.99(m,2H),1.91-1.80(m,2H),1.76(d,J=7.0,3H),1.07(d,J=6.5,6H).

LCMS (Analytical Method D) Rt=3.22 min, MS (ESIpos): m/z=534.2 (M+H) ⁺ .

The following examples were prepared in analogy to the procedure described for Example 224 using STAB and the appropriate ketone and amine starting materials.

Example 226: Methyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

To a solution of Example 138 (60 mg, 0.12 mmol) and DIPEA (0.11 mL, 0.61 mmol) in DCM (1 mL) was added methyl chloroformate (0.028 mL, 0.37 mmol), and the resulting solution was stirred at room temperature for 3 h. The solution was diluted with DCM (5 mL) and washed with water (2 mL). The organic phase was dried ( _MgSO ), filtered and concentrated under reduced pressure, and the crude material was purified by Biotage Isolera ^™ chromatography (on a pre-packed KP-SiO ₂ column, eluted with heptane-EtOAc). The purified material was freeze-dried in MeCN/water to give 53 mg (79% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.82 (s, 1H), 7.55-7.49 (m, 2H), 7.39 (s, 1H), 6.75 (d, J = 6.6Hz, 1H), 5.36 (m, 1H), 4.62 (tt, J＝6.9,3.4Hz,1H),3.76-3.68(m,5H),3.45-3.38(m,2H),2.53(s,3H),1.99-1.90(m,2H),1.81-1.73(m,2H),1.71(d,J＝7.2Hz,3H).

LCMS (Analytical Method D) Rt=4.53, MS (ESIpos) m/z=550 (M+H) ⁺ .

Example 227: Ethyl 4-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

To a solution of Example 138 (60 mg, 0.12 mmol) and DIPEA (0.11 mL, 0.61 mmol) in DCM (1 mL) was added ethyl chloroformate (0.035 mL, 0.37 mmol), and the resulting solution was stirred at room temperature for 3 h. The solution was diluted with DCM (5 mL) and washed with water (2 mL). The organic phase was dried ( _MgSO ), filtered and concentrated under reduced pressure, and the crude material was purified by Biotage Isolera ^™ chromatography (on a pre-packed KP-SiO ₂ column, eluting with heptane-EtOAc). The purified material was freeze-dried in MeCN/water to give 53 mg (79% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.82 (t, J = 1.3Hz, 1H), 7.53 (dd, J = 2.3, 1.5Hz, 1 H),7.52d,J＝1.1Hz,1H),7.42-7.37(m,1H),6.74(d,20J＝6.6Hz,1H),5.36(m,1H),4.66-4 .58(m,1H),4.14(q,J＝7.1Hz,2H),3.77-3.68(m,2H),3.45-3.36(m,2H),2.53(d,J＝1.0Hz ,3H),1.99-1.90(m,2H),1.81-1.73(m,2H),1.71(d,J＝7.2Hz,3H),1.27(t,J＝7.1Hz,3H).

LCMS (Analytical Method D) Rt=4.70, MS (ESIpos) m/z=564 (M+H) ⁺ .

Example 228: Ethyl (3S)-3-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]piperidine-1-carboxylate

To a solution of Example 203 (40 mg, 0.08 mmol) and DIPEA (73 μL, 0.42 mmol) in DCM (1 mL) was added ethyl chloroformate (24 μL, 0.25 mmol), and the resulting solution was stirred at room temperature for 3 h. The solution was diluted with DCM (5 mL) and washed with water (2 mL). The organic phase was dried ( _MgSO ), filtered and concentrated under reduced pressure, and the crude material was purified by Biotage Isolera ^™ chromatography (on a pre-packed KP-SiO ₂ column, eluted with heptane-EtOAc, 3: 2 to 0: 1). The purified material was freeze-dried in MeCN/water to obtain 32.5 mg (71% yield) of the title compound as a white powder.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.95 (s, 2H), 7.91 (s, 1H), 7.54 (s, 1H), 7.52-7.48 (m, 1H), 7.37 (s, 1H), 6.75 (d, J = 6.8Hz, 1H), 5. 44-5.25(m,1H),5.03(m,1H),4.23-4.07(m,2H),3.65(s,4H),2.54(s,3H),2.21(m,2H),1.73(d,J＝7.1Hz,3H),1.26(m,3H).

LCMS (Analytical Method D) Rt=4.52 min, MS (ESIpos): m/z=550.15 (M+H) ⁺ .

Example 229: 3-(5-methyl-1,3-thiazol-2-yl)-5-{[1-(propan-2-yl)azetidin-3-yl]oxy}-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A solution of intermediate 35 (20 mg, 0.043 mmol), 2-bromopropane (6.1 μL, 0.065 mmol) and potassium carbonate (11.9 mg, 0.086 mmol) in acetonitrile (0.5 mL) was heated at 60 ° C in a microwave oven for 10 min and then at 100 ° C for 30 min. The reaction was treated with excess 2-bromopropane (~50 μL) and heated at 100 ° C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by prep-TLC, eluting with 1% NH3 in 5% MeOH in DCM. The material was then freeze-dried in MeCN/water to give 12.9 mg (59% yield) of the title compound as a white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.95 (s, 2H), 7.88 (s, 1H), 7.52 (d, J = 1.1 5Hz,1H),7.46-7.40(m,1H),7.31(s,1H),6.81(s,1H),5.37(m,1H),5.02-4.89(m,1H),3.99(s,2 H), 3.29 (s, 2H), 2.58 (s, 1H), 2.53 (d, J = 1.0Hz, 3H), 1.72 (d, J = 7.2Hz, 3H), 1.05 (d, J = 6.2Hz, 6H).

LCMS (Analytical Method D) Rt=3.34 min, MS (ESIpos): m/z=506.1 (M+H) ⁺ .

Intermediate 93 was formed as a mixture of cis isomers. Chiral purification by SFC (Method 10) afforded Example 230 (cis isomer 1) and Example 231 (cis isomer 2).

Example 230: Cis Isomer 1; 3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

243 mg of intermediate 93 were subjected to chiral SFC purification (Method 10) to give 45.8 mg of the title compound as a white powder.

SFC chiral analysis (Method 10): 100% e.e., Rt = 1.59 min.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 9.27 (d, J = 7.0, 1H), 8.24 ( d, J = 8.8, 1H), 8.03 (d,J＝8.8,1H),7.96-7.89(m,1H),7.64(d,J＝1.2,1H),7.59-7.52(m,2H),5.5 4-5.41(m,1H),4.85(d,J＝4.7,1H),4.50-4.36(m,1H),3.84-3.71(m,1H),2. 54-2.51(m,3H),1.65(d,J=7.2,3H),1.21(d,J=6.2,3H),1.12(d,J=6.4,3H).

LCMS (Analytical Method F) Rt=3.11 min, MS (ESIpos): m/z=481.1 (M+H) ⁺ .

Example 231: Cis Isomer 2; 3-[(-3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide

243 mg of intermediate 93 were subjected to chiral SFC purification (Method 10) to give 43.8 mg of the title compound as a white powder.

SFC chiral analysis (Method 10): 100% e.e., Rt = 2.51 min.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 9.27 (d, J = 7.0, 1H), 8.24 ( d, J = 8.8, 1H), 8.03 (d,J＝8.8,1H),7.95-7.90(m,1H),7.64(d,J＝1.2,1H),7.59-7.52(m,2H),5.5 2-5.45(m,1H),4.84(d,J＝4.8,1H),4.47-4.39(m,1H),3.83-3.75(m,1H),2. 54-2.51(m,3H),1.65(d,J=7.2,3H),1.22(d,J=6.2,3H),1.11(d,J=6.4,3H).

LCMS (Analytical Method F) Rt=3.10 min, MS (ESIpos): m/z=481.1 (M+H) ⁺ .

Example 232: 3-[(1,1-dioxotetrahydro-2H-thioxopyran-4-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A mixture of intermediate 5AZ (158 mg, 430 μmol), intermediate VI (103 mg, 451 μmol), HATU (229 mg, 602 μmol) and DIPEA (602 μL, 1.7 mmol) was stirred in DMF (3.0 mL) at room temperature until complete conversion. The reaction mixture was evaporated to dryness under reduced pressure and the remaining material was purified by preparative HPLC (Method 1) to give 90 mg (39% yield) of the title compound.

LCMS (Method 1): rt: 1.14 min, MS ES+ m/z = 541 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.62(d,3H)2.25(d,4H)3.08-3.32(m,4H)4.93(br.s.,1H)5.30( t,1H)7.55-7.61(m,1H)7.63-7.74(m,2H)7.95(s,1H)9.05-9.25(m,3H).

In analogy to the procedure described for the preparation of Example 232, the following derivatives were prepared.

Example 329 : 3-[(2-Methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide as a mixture of two diastereomers

Example 329 (69 mg) was prepared in a similar manner to that described for Example 232 from Intermediate 5BX.

LCMS (Method 1): rt: 1.30 min, MS ES+ m/z = 507 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.24-1.32(s,3H)1.61(d,3H)1.65-1.74(m,1H)1.93(m,3H)3.70-3.84(m,2H)3. 95(s,2H)5.20-5.40(m,1H)7.49-7.59(m,2H)7.64(d,1H)7.92(t,1H)9.06-9.23(m,3H).

Example 329 (54.5 mg, 108 μmol) was separated into two diastereomers by preparative chiral HPLC (Method A, 54.5 mg in 2.5 mL ethanol) to give Example 330 (Diastereomer 1, 16 mg, rt: 5.6-7.4 min) and Example 331 (Diastereomer 2, 16 mg, rt: 8.0-10.1 min).

Example 330 Diastereomer 1; 3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method A, rt: 2.61 min

¹ H NMR (500MHz, DMSO-d ₆ )δ[ppm]1.28(s,3H)1.61(d,3H)1.65-1.75(m,1(m,3H)3.70-3.85(m,2H)3. 95(d,2H)5.30(m,1H)7.55(m,2H)7.64(d,1H)7.92(t,1H)9.07-9.23(m,3H).

Example 331 Diastereomer 2; 3-[(2-methyltetrahydrofuran-2-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method A, rt: 3.16 min

¹ H NMR (500MHz, DMSO-d ₆ )δ[ppm]1.28(s,3H)1.61(d,3H)1.65-1.77(m,1H)1.93(m,3H)3.70-3.86(m,2H )3.95(s,2H)5.30(m,1H)7.55(m,2H)7.64(d,1H)7.92(t,1H)9.05-9.24(m,3H).

Example 332 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide as a mixture of two diastereomers

Example 332 (1070 mg) was prepared in a similar manner to that described for Example 232 from Intermediate 5BY.

LCMS (Method 1): rt: 1.32 min, MS ES+ m/z = 507 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.21(s,3H)1.55-1.74(m,4H)1.93(m,1H)3.39(d,1H)3.71(d,1H)3.74-3. 88(m,2H)3.96(s,2H)5.30(m,1H)7.47-7.71(m,3H)7.92(t,1H)9.07-9.25(m,3H).

Example 332 (1000 mg, 1 mmol) was separated into two diastereomers by preparative chiral HPLC (Method B, 1000 mg in 7 mL DCM/methanol (1:1)) to give Example 333 (Diastereomer 1, 294 mg, rt: 6.0-8.0 min) and Example 334 (Diastereomer 2, 276 mg, rt: 9.0-10.0 min).

Example 333 Diastereomer 1; 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method B, rt: 2.89 min

¹ H NMR (500MHz, DMSO-d ₆ )δ[ppm]1.21(s,3H)1.61(m,4H)1.88-2.03(m,1H)3.39(d,1H)3.71(d,1H)3.81(td,2H )3.96(s,2H)5.30(m,1H)7.48-7.60(m,2H)7.64(d,1H)7.92(t,1H)9.04-9.24(m,3H).

Example 334 Diastereomer 2; 3-[(3-methyltetrahydrofuran-3-yl)methoxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method B, rt: 4.26 min

¹ H NMR (500MHz, DMSO-d ₆ )δ[ppm]1.21(s,3H)1.51-1.74(m,4H)1.86-2.01(m,1H)3.39(d,1H)3.71(d,1H)3.80(td ,2H)3.96(s,2H)5.30(m,1H)7.46-7.59(m,2H)7.64(d,1H)7.92(t,1H)9.06-9.25(m,3H).

Example 335 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide as a mixture of two diastereomers

Example 335 (760 mg) was prepared in a similar manner to that described for Example 232 from intermediate 5BZ.

LCMS (Method 1): rt: 1.09 min, MS ES+ m/z = 520 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.60(d,3H)2.07(m,2H)2.18-2.43(m,2H)2.82(s,3H)3.37-3.51(m,1H)3.60-3.75 (m,1H)4.96-5.13(m,1H)5.20-5.36(m,1H)7.52-7.70(m,3H)7.94(t,1H)9.04-9.23(m,3H).

Example 335 (700 mg, 1.35 mmol) was separated into two diastereomers by preparative chiral HPLC (Method E, 700 mg in 6 mL DCM/methanol (1:1)) to give Example 336 (Diastereomer 1, 150 mg, rt: 7.00-9.00 min) and Example 337 (Diastereomer 2, 140 mg, rt: 10.00-12.60 min).

Example 336 Diastereomer 1; 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method E, rt: 2.11 min

¹ H NMR (600MHz, DMSO-d ₆ )δ[ppm]1.61(d,3H)2.07(m,2H)2.21-2.32(m,1H)2.33-2.43(m,1H)2.82(s,3H)3.39-3.50(m, 1H)3.64-3.75(m,1H)5.05(m,1H)5.30(m,1H)7.56-7.72(m,3H)7.94(s,1H)9.06-9.23(m,3H).

Example 337 Diastereomer 2; 3-[(1-methyl-6-oxopiperidin-3-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method E, rt: 2.88 min

¹ H NMR (600MHz, DMSO-d ₆ )δ[ppm]1.61(d,3H)2.01-2.14(m,2H)2.21-2.30(m,1H)2.33-2.42(m,1H)2.82(s,3H)3.37-3.49(m, 1H)3.63-3.74(m,1H)4.95-5.12(m,1H)5.22-5.37(m,1H)7.55-7.71(m,3H)7.94(t,1H)9.12(s,3H).

Example 338 3-[(3-Hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide as a mixture of cis isomers

Example 338 (154 mg) was prepared in a similar manner to that described for Example 232 from Intermediate 5CB.

LCMS (Method 1): rt: 1.18 min, MS ES+ m/z = 481 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.11(d,3H)1.21(dd,3H)1.61(d,3H)3.68-3.86(m,1H)4.34-4.48(m,1H)4. 87(dd,1H)5.20-5.38(m,1H)7.53(m,2H)7.64(d,1H)7.89(s,1H)9.06-9.22(m,3H).

Example 338 (646 mg, 1.34 mmol) was separated into two diastereomers by preparative chiral HPLC (Method D, 646 mg in 5 mL DCM/methanol (1:1)) to give Example 339 (cis isomer 1, 197 mg, rt: 9.7-10.8 min) and Example 340 (cis isomer 2, 198 mg, rt: 11.7-13.4 min).

Example 339 cis-isomer 1; 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method D, rt: 5.73 min

¹ H NMR (400MHz, DMSO-d ₆ )d[ppm]1.09-1.12(m,6H)1.21(d,3H)1.61(d,J＝7.35Hz,3H)3.69-3.85(m,1H)4.43(m, 1H)4.86(d,1H)5.29(m,1H)7.47-7.58(m,2H)7.64(d,1H)7.89(t,1H)9.05-9.22(m,3H).

Example 339 cis-isomer 2; 3-[(3-hydroxybutan-2-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical chiral HPLC, method D, rt: 6.97 min

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.09-1.14(m,3H)1.20(d,3H)1.61(d,3H)3.64-3.87(m,1H)4.33-4.50(m,1H )4.87(d,1H)5.18-5.38(m,1H)7.53(m,2H)7.64(d,1H)7.89(t1H)9.05-9.24(m,3H).

Example 341

3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A mixture of intermediate 109 (100 mg, 187 μmol), formaldehyde (140 μL, 37% solution, 1.9 mmol), and acetic acid (107 μL, 100%, 1.9 mmol) was stirred in 1,2-dichloroethane (1.5 mL) at room temperature for 30 min. Sodium triacetoxyborohydride (113 mg, 1.9 mmol) was added and the mixture was stirred at room temperature for 17 h. Saturated aqueous _NaHCO₃ solution was added and the aqueous layer was extracted twice with DCM. The combined organic layers were evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to give 57 mg (55% yield) of the title compound.

LCMS (Method 1): rt: 0.92 min, MS ES+ m/z = 548 (M+H) ⁺ .

¹ H NMR(400MHz, DMSO-d6)δ[ppm]1.61(d,6H)1.91(br.s.,2H)1.96-2.05(m,2H)2 .16(s,6H)2.55-2.64(m,2H)2.71-2.86(m,2H)2.96-3.09(m,2H)3.58-3.70(m ,2H)3.72-3.86(m,2H)3.90-4.05(m,4H)4.58-4.69(m,1H)4.71-4.85(m,1H)5 .20-5.37(m,2H)7.51-7.69(m,6H)7.94(s,2H)9.12(s,4H)9.17-9.25(m,2H).

Example 341 (281 mg, 0.51 mmol) was separated into two enantiomers by preparative HPLC (Method F, 281 mg in 4 mL DMSO) to give Example 342 (Enantiomer 1, 125 mg, rt: 7.0-8.0 min) and Example 343 (Enantiomer 2, 100 mg, rt: 9.0-11.0 min).

Example 342 Enantiomer 1; 3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical HPLC, method F, rt: 2.38 min

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.61(d,3H)1.91(br.s.,2H)2.17(s,3H)3.5(d,2H)3.65(d,2H)3.98(d,2H) 4.63(br.s.,1H)5.29(m,1H)7.51-7.70(m,3H)7.94(t,1H)9.12(s,2H)9.19(d,1H).

Example 343 Enantiomer 2; 3-[(7-methyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Analytical HPLC, Method F, rt: 2.89 min

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.62(d,3H)2.00(br.s.,2H)2.14(s,3H)2.54-2.64(m,2H)2.69-2.82(m,2H)3.80(m,2H)3.95 (m,2H)4.77(br.s.,1H)5.21-5.38(m,1H)7.49-7.72(m,3H)7.94(t,1H)9.13(s,2H)9.17-9.26(m,1H).

Example 344 3-[(7-Isopropyl-3-oxa-7-azabicyclo[3.3.1]non-9-yl)oxy]-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, as a mixture of two enantiomers

Example 344 (66.7 mg) was prepared in a similar manner to the procedure described for Example 341 from Intermediate 109 (100 mg, 187 μmol).

LCMS (Method 1): rt: 0.95 min, MS ES+ m/z = 576 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]0.99(m,12H)1.61(d,6H)1.92(br.s.,2H)1.96-2.05(m,2H)2.60-2.78(m,6H)2.93-3.08(m,2H)3.62(m,2H)3.80(m, 2H)3.91(m,4H)4.54-4.67(m,1H)4.71-4.84(m,1H)5.29(m,2H)7.50-7.67(m,6H)7.93(s,2H)9.12(s,4H)9.17-9.30(m,2H).

Example 345 Methyl 9-[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate, as a mixture of two enantiomers

To a mixture of intermediate 109 (100 mg, 187 μmol) and DIPEA (160 μL, 940 μmol) in DCM ( _4.6 mL) was added methyl chloroformate (43 μL, 560 μmmol), and the mixture was stirred at room temperature for 17 h. Water and DCM were added, the phases were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over _Na₂SO₄ , filtered, and evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give 75 mg (68% yield) of the title compound.

LCMS (Method 1): rt: 1.20 min, MS ES+ m/z = 592 (M+H) ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ )δ[ppm]1.61(d,6H)1.81-1.95(m,2H)1.99(m,2H)3.21-3.32(m,2H)3.35-3.46(m,2H)3.58(d,6H)3.64-3. 81(m,4H)3.97(m,6H)4.16-4.43(m,2H)4.84-4.99(m,2H)5.21-5.37(m,2H)7.54-7.72(m,6H)7.95(d,2H).

Example 346: (2R)-tert-Butyl 2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate

To a solution of Intermediate 5CE (28.21 g, 45.4 mmol), Intermediate VI (11.4 g, 50.0 mmol), and DIPEA (31.6 mL, 181.8 mmol) in ethyl acetate (400 mL) was added T3P (32 mL, 54.5 mmol). The reaction mixture was stirred at room temperature for 15 h. Additional Intermediate VI (1 g, 4.55 mmol), DIPEA (3 mL, 17.7 mmol), and T3P (4 mL, 6.82 mmol) were added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was washed with saturated _NaHCO3 , brine, and the organic layer was dried ( _MgSO4 ), filtered, and concentrated under reduced pressure. The crude product was purified by Biotage Isolera ^™ chromatography (eluting with 0-100% EtOAc in heptane on a pre-packed KP- _SiO2 column) to give 14.8 g (49% yield) of the title compound as a white foam.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.96-7.88 (m, 1H), 7.58-7.53 (m, 1H), 7.54-7.52 (m, 1H), 7.42-7.39 (m, 1H), 6.79 (br s,1H),5.43-5.31(m,1H),4.15-3.76(m,6H),3.64-3.54(m,1H),3.07-2.77(m,2H),2.53(d,J＝1.1Hz,3H),1.72(d,J＝7.2Hz,3H),1.48(s,9H).

LCMS (Analytical Method F) Rt=4.02 min, MS (ESIpos): m/z=608 (M+H) ⁺ .

Example 347: 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To the solution of embodiment 346 (14.7g, 22.3mmol) in DCM (100mL), TFA (17.1mL) is added. The resulting solution is stirred at room temperature for 16h. The reaction mixture is acidified with 2M sodium hydroxide (100mL) and then adjusted to pH 8 with saturated sodium bicarbonate aqueous solution. The organic layer is separated and the aqueous solution layer is extracted with other DCM. The organic matter merged is washed with strong brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to obtain the title compound of 10.5g (93% yield) light yellow solid. Most of the samples are used for the preparation of embodiment 348 without further purification.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.96 (s, 2H), 7.83-7.79 (m, 1H), 7.47 (dd, J = 2.3, 1.5Hz, 1H), 7.46-7.45 (m, 1H), 7.40-7.37 (m, 1H), 7.33-7.28 (m, 1H) ),5.42-5.32(m,1H),4.14-3.53(m,6H),3.21-3.13(m,1H),3.02-2.93( m, 2H), 2.86-2.74 (m, 1H), 2.49 (d, J = 1.0Hz, 3H), 1.70 (d, J = 7.2Hz, 3H).

LCMS (Method A) Rt=1.04 min, MS (ESIpos): m/z=508 (M+H) ⁺ .

An aliquot of Example 347 (150 mg) was further purified by SCX chromatography eluting with methanol then 7N ammonia in methanol. The relevant fractions were concentrated under reduced pressure then lyophilized from acetonitrile/water to give 145 mg of the title compound for characterization and chiral analysis.

HPLC chiral analysis (Method 11): 99.3% e.e. Rt = 10.51 min.

¹ H NMR (250MHz, chloroform-d): δ[ppm]8.94(s,2H),7.94-7.80(m,1H),7.55(dd,J＝2.4,1.5Hz,1H),7.52-7.49(m,1H),7.41(dd,J＝2.3,1.5Hz ,1H),6.78(d,J＝6.6Hz,1H),5.47-5.27(m,1H),4.16-3.64(m,5H),3.13-2.69(m,4H),2.52(d,J＝1.1Hz,3H),1.71(d,J＝7.1Hz,3H).

LCMS (Analytical Method F) Rt=2.16 min, MS (ESIpos): m/z=508 (M+H) ⁺ .

Example 348: 3-{[(2R)-4-Methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Example 347 (10.3 g, 19.3 mmol), formaldehyde (7.2 mL, 37% aqueous solution, 96.4 mmol) and acetic acid (1.10 mL) were combined in methanol (250 mL) and STAB (12.3 g, 57.8 mmol) was added dropwise. The resulting solution was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in saturated _NaHCO₃ (100 mL) solution and extracted with DCM (3×100 mL). The combined organic phases were dried ( _MgSO₄ ), filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 0-10% MeOH in DCM on a 340 g pre-packed KP- _SiO₂ column). The relevant fractions were concentrated and then lyophilized in acetonitrile/water to give 6.75 g (67% yield) of the title compound as a white solid.

HPLC chiral analysis (Method 12): 100% e.e. Rt = 5.09 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87-7.85 (m, 1H), 7.57 (dd, J = 2.4, 1.4Hz, 1H), 7.52-7.50 (m ,1H),7.40(dd,J＝2.3,1.6Hz,1H),6.67(d,J＝6.5Hz,1H),5.42-5.29(m,1H),4.12(dd,J＝9.9,6.1Hz,1 H),4.04(dd,J＝9.9,4.1Hz,1H),4.00-3.93(m,2H),3.79-3.72(m,1H),2.85-2.80(m,1H),2.72-2.65( m,1H),2.53(d,J＝1.1Hz,3H),2.33(s,3H),2.24-2.15(m,1H),2.08-2.0(m,1H),1.71(d,J＝7.2Hz,3H).

LCMS (Analytical Method F) Rt=2.15 min, MS (ESIpos) m/z=522 (M+H) ⁺ .

Example 349: (2S)-tert-Butyl 2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate

Intermediate 5CD (800 mg, 1.84 mmol), intermediate VI (460 mg, 2.02 mmol) and DIPEA (0.96 mL, 5.51 mmol) were combined in DCM (7 mL) and HATU (1050 mg, 2.76 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with water. The aqueous phase was extracted with additional DCM and the combined organics were dried ( _MgSO ), filtered and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 0-10% MeOH in DCM on a 50 g pre-packed KP-SiO ₂ column) to obtain 1.6 g (100% yield) of the title compound as a colorless, viscous oil.

¹ H NMR (250 MHz, CHLOROFORM-d): δ [ppm] 8.94 (s, 2H), 7.88 (s, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 1.1 Hz, 1H), 7.37 (s, 1H), 7.11 (d, J = 6.1 Hz, 1H), 5.45-5.30 (m, 1H), 4.21-3.49 (m, 10H), 2.51 (d, J = 0.9 Hz, 3H), 1.71 (d, J = 7.1 Hz, 3H), 1.47 (s, 9H).

LC-MS (Method A) Rt=1.32 min, MS (ESIpos) m/z=608 (M+H) ⁺ .

Example 350: 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

To a solution of Example 349 (1.6 g, 1.98 mmol) in DCM (16 mL) was added TFA (3 mL). The resulting solution was stirred at room temperature for 4 h and then neutralized with saturated aqueous sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with additional DCM. The combined organics were dried ( _MgSO ), filtered, and concentrated under reduced pressure to afford 0.87 g (87% yield) of the title compound as a pale yellow solid.

HPLC chiral analysis (Method 11): 100% e.e. Rt = 9.04 min.

¹ H NMR (500 MHz, chloroform-d): δ8.93 (s, 2H), 7.86 (s, 1H), 7.56-7.53 (m, 2H), 7.52-7.48 (m, 1H), 7.42-7.37 (m, 1H), 6.81 (d, J = 6.6 Hz, 1H), 5.40-5.31 (m, 1H), 4.07 (dd, J = 9.9, 6.0 Hz, 1H), 4.01 (d d,J＝9.9,4.2Hz,2H),3.98-3.86(m,2H),3.75-3.66(m,1H),3.06-2.99(m,1H),2.98-2.90(m ,1H),2.90-2.84(m,1H),2.78(dd,J＝11.9,10.4Hz,1H),2.52(s,3H),1.71(d,J＝7.2Hz,3H).

LCMS (Analytical Method F) Rt=2.14 min, MS (ESIpos) m/z=508 (M+H) ⁺ .

Example 351: 3-{[(2S)-4-Methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Example 350 (238 mg, 0.47 mmol), formaldehyde (37% aqueous solution, 0.07 mL, 0.94 mmol), and acetic acid (0.03 mL, 0.47 mmol) were stirred in DCE (3 mL) for 15 min before STAB (149 mg, 0.70 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 h, then diluted with DCM and washed with saturated aqueous sodium bicarbonate. The organic phase was separated, dried ( _MgSO₄ ), filtered, and concentrated under reduced pressure. The crude material was purified by high pH preparative HPLC (Method A) to give 144 mg (59% yield) of the title compound, which was lyophilized to a white powder.

HPLC chiral analysis (Method 12): 92.4% e.e. Rt = 4.5 min.

¹ H NMR (250MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.86 (s, 1H), 7.56 (d, J = 1.4Hz, 1H), 7.51 (d, J = 1.2Hz, 1H), 7.41 (s, 1H), 6.71 (d, J = 6.1H z,1H),5.43-5.30(m,1H),4.17-3.90(m,4H),3.80-3.65(m,1H),3.10-2.75(m,4H),2.53(d,J＝1.0Hz,3H),1.72(d,J＝7.1Hz,3H).

LC-MS (Analytical Method F) Rt=2.06 min, MS (ESIpos) 522 (M+H) ⁺ .

Example 347 and Example 350 could also be prepared as a mixture of diastereomers (Example 352) and subsequently separated by HPLC chiral purification (Method 11).

Example 352: 3-(5-methyl-1,3-thiazol-2-yl)-5-[morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, formed as a mixture of Example 347 (Diastereomer 1) and Example 350 (Diastereomer 2)

To a solution of intermediate 114 (197 mg, 0.30 mmol) in DCM (5 mL) was added TFA (0.5 mL, 6.0 mmol), and the reaction was stirred at room temperature overnight. The reaction mixture was neutralized with saturated NaHCO ₃ solution. The organic phases were collected and the aqueous phase was extracted with DCM (2×5 mL). The combined organic phases were dried (MgSO ₄ ), filtered, and concentrated under reduced pressure to afford 177.0 mg (100% yield) of the title compound as a foam.

¹ H NMR (500MHz, CDCl ₃ ): δ [ppm] 8.91-8.87 (m, 2H),

7.74-7.69(m,1H),7.40-7.31(m,3H),7.26-7.22(m,1H),5.34-5.26(m,1H),4.13-3.97(m,3H),3.96-3.8 0(m,2H),3.36-3.26(m,1H),3.19-3.01(m,2H),3.00-2.90(m,1H),2.44-2.40(m,3H),1.66-1.62(m,3H).

LC-MS (Method A) Rt=0.98 min, MS (ESIpos): m/z=508 (M+H) ⁺ .

Example 347: 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(2R)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

60 mg of the diastereomeric mixture of Example 352 were subjected to chiral HPLC purification (Method 11) to give 22 mg of the title compound.

HPLC chiral analysis (Method 11): 95.4% e.e. Rt = 10.81 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.92 (s, 2H), 7.85 (t, J = 1.3Hz, 1H), 7.53 (dd, J = 2.3, 1.5Hz, 2H), 7.50-7. 48(m,1H),7.40-7.35(m,1H),6.90(d,J＝6.6Hz,1H),5.39–5.29(m,1H),4.06(dd,J＝9.9,6.1Hz,1H), 3.98(dd,J＝9.9,4.2Hz,3H),3.96–3.91(m,1H),3.91–3.85(m,1H),3.73–3.64(m,1H),3.04–2.97(m, 1H), 2.96-2.82 (m, 2H), 2.76 (dd, J = 12.0, 10.4Hz, 1H), 2.51 (d, J = 1.0Hz, 3H), 1.68 (d, J = 7.2Hz, 3H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=508 (M+H) ⁺ .

Example 350: 3-(5-Methyl-1,3-thiazol-2-yl)-5-[(2S)-morpholin-2-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

60 mg of the diastereomeric mixture of Example 352 were subjected to chiral HPLC purification (Method 11) to give 13.8 mg of the title compound.

HPLC chiral analysis (Method 11): 100% e.e. Rt = 9.39 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87-7.83 (m, 1H), 7.52 (dd, J = 2.3, 1.5Hz, 2H), 7.50-7.48 (m,1H),7.40-7.35(m,1H),6.93(d,J＝6.7Hz,1H),5.39-5.30(m,1H),4.06(dd,J＝9.9,6.0Hz,4H),4 .00(dd,J＝9.9,4.2Hz,1H),3.97-3.92(m,1H),3.92-3.86(m,1H),3.74-3.65(m,1H),3.05-2.98(m, 1H), 2.97-2.83 (m, 2H), 2.77 (dd, J＝11.9, 10.5Hz, 1H), 2.51 (d, J＝1.0Hz, 3H), 1.69 (d, J＝7.2Hz, 3H).

LCMS (Analytical Method F) Rt=2.08 min, MS (ESIpos): m/z=508 (M+H) ⁺ .

Example 348 and Example 351 could also be prepared as a mixture of diastereomers (Example 353) and subsequently separated by HPLC chiral purification (Method 12).

Example 353: 3-{[4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide, formed as a mixture of Example 348 (Diastereomer 2) and Example 351 (Diastereomer 1)

A mixture of Example 347 and Example 350 (94.4 mg, 0.19 mmol), formaldehyde (37% in water, 70 μL, 0.93 mmol), and acetic acid (100 μL) were combined in methanol (2 mL), and STAB (118 mg, 0.56 mmol) was added. The resulting solution was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was dissolved in saturated NaHCO₃ ( ₅ mL) and extracted with DCM (3×5 mL). The combined organic phases were dried ( _MgSO₄ ), filtered, and concentrated under reduced pressure. The compound was freeze-dried from acetonitrile/water to give 78.7 mg (81% yield) of the title compound as a white powder.

¹ H NMR (500MHz, CDCl ₃ ): δ[ppm]8.93(s,2H),7.88-7.84(m,1H),7.57(dd,J＝2.41.4Hz,1H),7.54–7.50(m,1H),7 .42–7.38(m,1H),6.62(d,J＝6.4Hz,1H),5.40–5.31(m,1H),4.16–4.08(m,1H),4.08–4.01( m,1H),4.00–3.92(m,2H),3.80-3.71(m,1H),2.86-2.79(m,1H),2.71-2.65(m,1H),2.53( d,J＝1.1Hz,3H),2.33(s,3H),2.24-2.15(m,1H),2.09-2.00(m,1H),1.71(d,J＝7.2Hz,3H).

LC-MS (Analytical Method D) Rt=3.17 min, MS (ESIpos): m/z=522 (M+H) ⁺ .

Example 348: 3-{[(2R)-4-Methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

52.4 mg of the diastereomeric mixture of Example 353 were subjected to chiral HPLC purification (Method 12) to give 22.9 mg (44% yield) of the title compound.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.87 (s, 1H), 7.58 (dd, J = 2.4, 1.4 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.41 (s, 1H), 6.71 (s, 1H), 5.36 (m, 1H), 4.17-4.10 (m, 1H), 4.09-4.02 (m, 2H), 3 .97(dd,J＝11.6,1.6Hz,1H),3.82(t,J＝11.0Hz,1H),2.91(d,J＝10.9Hz,1H),2.76(d,J＝10.7 Hz, 1H), 2.53 (d, J = 1.1Hz, 3H), 2.39 (s, 3H), 2.28 (s, 1H), 2.14 (s, 1H), 1.72 (d, J = 7.2Hz, 3H).

LCMS (Analytical Method F) Rt=2.11 min, MS (ESIpos): m/z=522 (M+H) ⁺ .

Example 351: 3-{[(2S)-4-Methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

52.4 mg of the diastereomeric mixture of Example 353 were subjected to chiral HPLC purification (Method 12) to give 21.6 mg (41% yield) of the title compound.

HPLC chiral analysis (Method 11): 100% e.e. Rt = 4.58 min.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.87 (s, 1H), 7.58 (dd, J = 2.3, 1.4 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.41 (s, 1H), 6.71 (s, 1H), 5.36 (m, 1H), 4.16-4.01 (m, 3H), 4.00- 3.93(m,1H),3.81(t,J＝11.0Hz,1H),2.91(d,J＝11.0Hz,1H),2.76(d,J＝10.5Hz,1H), 2.53(d,J＝1.0Hz,3H),2.39(s,3H),2.28(s,1H),2.15(s,1H),1.72(d,J＝7.2Hz,3H).

LCMS (Analytical Method D) Rt=3.31 min, MS (ESIpos): m/z=522 (M+H) ⁺ .

Intermediate 132 was formed as a mixture of two diastereomers. Chiral purification by SFC (Method 13) afforded diastereomer 1 (Example 354) and diastereomer 2 (Example 355).

Example 354: Diastereomer 1; 3-(Fluoropiperidin-3-yl)methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral purification by SFC (Method 13) of 55.2 mg of intermediate 132 followed by purification on an SCX-2 column gave 14 mg of the title compound.

SFC chiral analysis (Method 13): 100% e.e. Rt = 2.17 min.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.97 (s, 2H), 7.84 (s, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 7.02 (s, 1H), 5.36 (q, J = 7.0 Hz, 1H), 4.23-3.99 (m, 2H), 3.43-3.22 (m, 1 H),3.09(d,J＝12.8Hz,1H),2.95(dd,J＝29.1,13.9Hz,1H),2.73(s,1H),2.52(s,3H ),2.09-2.02(m,1H),1.94-1.78(m,3H),1.73(d,J=7.1Hz,3H),1.67-1.60(m,1H).

LCMS (Analytical Method F) Rt=2.14 min, MS (ESIpos): m/z=524.4 (M+H) ⁺ .

Example 355: Diastereomer 2; 3-(Fluoropiperidin-3-yl)methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral purification by SFC (Method 13) of 55.2 mg of intermediate 132 followed by purification on an SCX-2 column gave 15 mg of the title compound.

SFC chiral analysis (Method 13): 98.2% e.e. Rt = 3.26 min.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.90 (s, 2H), 7.74 (s, 1H), 7.42 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 6.97 (s, 1H), 5.40-5.20 (m, 1H), 4.15-3.90 (m, 2H), 3.38-3.19 (m, 1H), 3.0 6(d,J＝11.3Hz,1H),2.88(dd,J＝29.9,13.7Hz,1H),2.68(t,J＝11.1Hz,1H),2.43(s, 3H), 2.05-1.90 (m, 2H), 1.87-1.73 (m, 2H), 1.65 (d, J = 7.0Hz, 3H), 1.60-1.55 (m, 1H).

LCMS (Analytical Method F) Rt = 2.12 min, MS (ESIpos): m/z = 524.4 (M+H) ⁺ .

Intermediate 147 was formed as a mixture of two diastereomers. Chiral purification by SFC (Method 14) afforded diastereomer 1 (Example 356) and diastereomer 2 (Example 357).

Example 356: Diastereomer 1; 3-{[3-fluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral SFC purification (Method 14) of 46 mg of intermediate 147 gave 11 mg of the title compound.

SFC chiral analysis (Method 14): 100% e.e. Rt = 2.56 min.

¹ H NMR (500MHz, Methanol-d4): δ[ppm]9.02(s,2H),7.95(s,1H),7.66(s,1H),7.57(s,1H) ,7.53(s,1H),5.34(q,J＝7.1Hz,1H),4.31-4.11(m,2H),3.03-2.88(m,1H),2.70(d,J＝11 .0Hz,1H),2.54(s,3H),2.43(dd,J＝26.8,12.3Hz,1H),2.31(s,3H),2.22(t,J＝10.6Hz,1 H), 2.00-1.86 (m, 2H), 1.77 (d, J = 11.8Hz, 1H), 1.70 (d, J = 7.1Hz, 3H), 1.68-1.63 (m, 1H).

LCMS (Analytical Method F) Rt=2.18 min, MS (ESIpos): m/z=538 (M+H) ⁺ .

Example 357: Diastereomer 2; 3-{[3-fluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral purification by SFC (Method 14) of 46 mg of intermediate 147 followed by purification on an SCX-2 column gave 10 mg of the title compound.

SFC chiral analysis (Method 14): 97.6% e.e. Rt = 3.06 min.

¹ H NMR (500MHz, Methanol-d4): δ [ppm] 9.02 (s, 2H), 7.96 (s, 1H), 7.69-7.63 (m, 1H), 7.57 (d, J = 1.1Hz, 1H), 7.55-7.50 (m, 1H), 5.34 (q, J = 7.1Hz, 1H), 4 .34-4.6(m,2H),3.09(s,1H),2.80(d,J＝10.2Hz,1H),2.61-2.47(m,4H),2 .39(s,3H),2.32(t,J＝10.1Hz,1H),2.05-1.88(m,2H),1.83-1.66(m,5H).

LCMS (Analytical Method F) Rt=2.15 min, MS (ESIpos): m/z=538.4 (M+H) ⁺ .

The following examples were prepared in analogy to the procedure described in Example 346 using TFA and the corresponding N-Boc protected amine starting material.

Example 360: 3-{[(3R)-4-Methylmorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

At room temperature, to a stirred solution of intermediate 28CM (129 mg, 0.37 mmol), intermediate VI (92.7 mg, 0.41 mmol) and DIPEA (128.98 μL, 0.74 mmol) in N,N-dimethylformamide (1 mL) was added HATU (211.17 mg, 0.56 mmol), and the reaction was stirred at room temperature for 16 h. The material was dissolved in MeCN, water and DMSO and purified by preparative HPLC (Method A). The pure fractions were evaporated and then freeze-dried to obtain 107 mg (54.9% yield) of the title compound as a white flocculent solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.86 (t, J = 1.3Hz, 1H), 7.56 (dd, J = 2.4, 1.4Hz, 1H), 7.52 (d, J = 1.2Hz ,1H),7.41-7.39(m,1H),6.60(d,J＝6.5Hz,1H),5.36(m,1H),4.14-4.10(m,2H),3.93(dd,J＝11.2,3.0Hz,1H) ,3.83(dt,J＝11.4,2.8Hz,1H),3.71(td,J＝10.9,2.5Hz,1H),3.60(dd,J＝11.3,9.4Hz,1H),2.77(dt,J＝11.8, 2.5Hz,1H),2.61-2.55(m,1H),2.54(d,J＝1.1Hz,3H),2.46-2.42(m,1H),2.41(s,3H),1.72(d,J＝7.2Hz,3H).

LCMS (Analytical Method F) Rt=2.09 min, MS (ESIpos): m/z=522.1 (M+H) ⁺ .

The following examples were prepared in a manner analogous to that described in Example 360 using HATU and the corresponding carboxylic acid and primary amine starting materials.

Example 366: 3-{[(2R)-4-methylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

To the solution of intermediate 138 (82mg, 0.16mmol) in methanol (2mL), formaldehyde (37% aqueous solution, 0.02mL, 0.32mmol) and acetic acid (0.009mL, 0.16mmol) were added, and the reactant was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (51mg, 0.24mmol) was added, and the reactant was stirred for 1.5 hours. The reaction mixture was passed through SCX posts (washed with methanol, eluted with the 7N ammonia in methanol) and concentrated under reduced pressure. The gained residue was ground with water, filtered and dried in a high vacuum oven to obtain the title compound of 37mg (44% yield) beige solid.

¹ H NMR (500MHz, DMSO-d6): δ [ppm] 9.13 (d, J = 7.3Hz, 1H), 8.83 (s, 1H), 8.12-8.5 (m, 1H), 7.94 (s,1H),7.90(d,J＝8.1Hz,1H),7.65(s,1H),7.55(s,2H),5.29(m,1H),4.12(d,J＝4.9Hz,2 H),3.83(d,J＝10.4Hz,2H),3.64-3.45(m,1H),2.80(d,J＝11.0Hz,1H),2.67-2.57(m,1H), 2.21 (s, 3H), 2.02 (td, J = 11.2, 3.0Hz, 1H), 1.94 (t, J = 10.6Hz, 1H), 1.57 (d, J = 7.1Hz, 3H).

LCMS (Analytical Method F) Rt=2.18 min, MS (ESIpos): m/z=521.2 (M+H) ⁺ .

The following examples were prepared in analogy to the procedure described in Example 366 using STAB and the corresponding amine and aldehyde or ketone starting materials.

Example 383 was formed as a mixture of two diastereomers. Chiral purification by SFC (Method 15) afforded diastereomer 1 (Example 384) and diastereomer 2 (Example 385).

Example 384: Diastereomer 1; 3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral SFC purification (Method 15) on 90.3 mg of Example 383 gave 32.9 mg of the title compound as a white solid.

SFC chiral analysis (Method 15): 99.2% e.e. Rt = 1.71 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.84 (t, J = 1.4Hz, 1H), 7.54 (dd, J = 2.4, 1.4Hz, 1H), 7.54- 7.52(m,1H),7.39(dd,J＝2.3,1.6Hz,1H),6.58(d,J＝6.4Hz,1H),5.37(m,1H),4.39(dd,J＝9.4,3.8 Hz,1H),4.06(t,J＝9.2Hz,1H),3.03(d,J＝10.4Hz,1H),2.79-2.72(m,1H),2.65-2.56(m,1H),2.54 (d,J＝1.1Hz,3H),2.41-2.31(m,4H),2.31-2.20(m,1H),2.14-2.00(m,2H),1.72(d,J＝7.2Hz,3H).

LC-MS (Analytical Method F) Rt=2.32 min, MS (ESIpos): m/z=556 (M+H) ⁺ .

Example 385: Diastereomer 2; 3-{[4,4-difluoro-1-methylpiperidin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Chiral purification by SFC (Method 15) was performed on 90.3 mg of Example 383 to give 27 mg of the title compound.

SFC chiral analysis (Method 15): 99.9% e.e. Rt = 2.06 min.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.84 (t, J = 1.4Hz, 1H), 7.54 (dd, J = 2.4, 1.4Hz, 1H), 7.53 (d ,J＝1.2Hz,1H),7.39(dd,J＝2.3,1.6Hz,1H),6.57(d,J＝6.5Hz,1H),5.37(m,1H),4.40(dd,J＝9.4,3.8 Hz,1H),4.06(t,J＝9.2Hz,1H),3.02(d,J＝10.4Hz,1H),2.75(d,J＝11.2Hz,1H),2.65-2.55(m,1H),2 .54(d,J＝1.1Hz,3H),2.39-2.31(m,4H),2.26(t,J＝10.1Hz,1H),2.07(m,2H),1.72(d,J＝7.2Hz,3H).

LC-MS (Analytical Method F) Rt=2.32 min, MS (ESIpos): m/z=556 (M+H) ⁺ .

The following examples were prepared in a manner analogous to that described in Example 346 using T3P and the corresponding carboxylic acid and primary amine starting materials.

Example 390: 3-{[(2R)-4-Ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Embodiment 347 (80mg, 0.15mmol), iodoethane (14.5 μ L, 0.18mmol) and potassium carbonate (31mg, 0.23mmol) are stirred at room temperature for 1h in acetonitrile (2mL).Then the reaction mixture is heated to 80 ℃ by microwave radiation for 20min.Reactant is treated with iodoethane (14.5 μ L, 0.18mmol) again and heated to 80 ℃ by microwave radiation for 20min.Reaction mixture is filtered and concentrated under reduced pressure.Crude material is purified by preparative HPLC (method A) and freeze-dried in MeCN/ water to provide the title compound of 40.4mg (50% yield) white powder.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87 (t, J = 1.4Hz, 1H), 7.57 (dd, J = 2.4, 1.5Hz, 1H), 7.52 (d, J = 1.2Hz, 1 H),7.41(dd,J＝2.3,1.6Hz,1H),6.63(d,J＝6.5Hz,1H),5.36(m,1H),4.12(dd,J＝9.9,6.0Hz,1H),4.05(dd,J＝9.9 ,4.1Hz,1H),4.01-3.94(m,2H),3.76(td,J＝11.4,2.4Hz,1H),2.91(d,J＝11.1Hz,1H),2.77(d,J＝11.5Hz,1H),2 .53(d,J＝1.1Hz,3H),2.46(q,J＝7.2Hz,2H),2.17(td,J＝11.4,3.3Hz,1H),2.03(t,J＝10.7Hz,1H),1.71(d,J＝7.2 20Hz, 3H), 1.11 (t, J = 7.2Hz, 3H).

LCMS (Analytical Method F) Rt=2.17 min, MS (ESIpos): m/z=536 (M+H) ⁺ .

Example 391: 3-{[(2R)-4-(2,2-difluoroethyl)morpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A stirred mixture of Example 347 (100 mg, 0.19 mmol), 1,1-difluoro-2-iodoethane (20 μL, 0.21 mmol) and potassium carbonate (40 mg, 0.29 mmol) in anhydrous acetonitrile (3 mL) was heated to 80° C. by microwave irradiation for 20 min. Additional 1,1-difluoro-2-iodoethane (40 μL, 0.42 mmol) and potassium carbonate (40 mg, 0.29 mmol) were added, and the reaction mixture was heated to 100° C. by microwave irradiation for 20 min. An additional amount of 1,1-difluoro-2-iodoethane (100 μL, 2.1 mmol) was added, and the reaction mixture was heated to 100° C. by microwave irradiation for 3 h. 1,1-difluoro-2-iodoethane (100 μL, 2.1 mmol) was added, and the reaction mixture was heated to 100° C. by microwave irradiation for 2 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by preparative HPLC (Method B), then freeze-dried from acetonitrile/water to give 64 mg (58% yield) of the title compound as a white solid.

¹ H NMR (500MHz, chloroform-d): δ [ppm] 8.93 (s, 2H), 7.87 (s, 1H), 7.56 (dd, J = 2.3, 1.4Hz, 1H), 7.52 (d, J = 1.1Hz, 1H), 7.43 -7.35(m,1H),6.62(d,J＝6.3Hz,1H),5.92(t,J＝55.9Hz,1H),5.36(m,1H),4.11(dd,J＝9.8,5.7Hz,1H),4.04(d d,J＝9.8,4.4Hz,1H),4.01-3.96(m,1H),3.96-3.92(m,1H),3.81-3.72(m,1H),2.94(d,J＝11.1Hz,1H),2.84-2 .74(m,3H),2.53(d,J＝0.9Hz,3H),2.48(td,J＝11.3,2.7Hz,1H),2.35(t,J＝10.6Hz,1H),1.71(d,J＝7.2Hz,3H).

LC-MS (Analytical Method F) Rt=3.24 min, MS (ESIpos): m/z=572 (M+H) ⁺ .

Example 392: Methyl (2R)-2-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}morpholine-4-carboxylate

To a solution of Example 347 (35 mg, 69.0 μmmol) in DCM (1 mL) was added DIPEA (24 μL, 138 μmmol) and methyl chloroformate (8.0 μL, 103 μmmol) at room temperature. The reaction was stirred for 1 h, then diluted with DCM (3 mL) and washed with saturated _NaHCO₃ (3 mL). The aqueous layer was extracted with DCM (2×3 mL). The combined DCM layers were dried ( _MgSO₄ ), filtered, and concentrated under reduced pressure. The crude material was purified by Biotage Isolera ^™ chromatography (eluting with 0-20% MeOH in DCM on a ₁₀ g pre-packed KP-SiO₂ column) and the product was lyophilized in MeCN/water to give 31.8 mg (82% yield) of the title compound as a white powder.

¹ H NMR (500 MHz, chloroform-d): δ [ppm] 8.94 (s, 2H), 7.88 (s, 1H), 7.57 (dd, J = 2.3, 1.4 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.42-7.39 (m, 1H), 6.64 (d, J = 5.8 Hz, 1H), 5.36 (m, 1H), 4.21-4.09 (m, 2H ),4.07(dd,J＝9.9,4.7Hz,1H),4.02-3.87(m,2H),3.86-3.78(m,1H),3.74(s,3H),3.61( t,J＝11.6Hz,1H),3.07(s,1H),2.93(s,1H),2.54(d,J＝1.1Hz,3H),1.72(d,J＝7.2Hz,3H).

LCMS (Analytical Method D) Rt=4.31 min, MS (ESIpos): m/z=566 (M+H) ⁺ .

The following examples were prepared in a manner analogous to that described for Example 392 from the corresponding secondary amine and chloroformate starting materials.

Example 394: 3-(azetidin-3-ylmethoxy)-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A mixture of intermediate 148 (90.0 mg, 156 μmmol) and TFA (60 μL, 780 μmmol) was stirred in DCM at room temperature for 18 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC (Method 1, LCMS, Rt: 0.85 min) to give 15.0 mg (18% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ ): δ[ppm]1.61(d,3H)3.10-3.21(m,1H)3.63-3.78(m,2H)3.93(s,2H)4.27(d,2H)5 .19-5.39(m,1H)7.49-7.70(m,3H)7.88-7.99(m,1H)9.12(s,2H)9.20-9.33(m,1H).

LCMS, method 1, rt: 0.85 min, MS ES+ m/z = 478 (M+H) ⁺ .

Example 395: 3-{[(3R)-4-Methyl-5-oxomorpholin-3-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

A mixture of intermediate 5CX (417 mg, 1.15 mmol), intermediate VI (367 mg, 1.61 mmol), HATU (1.05 g, 2.76 mmol) and DIPEA (980 μL, 5.8 mmol) was stirred for 12 h at 60° C. The mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography (silica gel, heptane/EE gradient) to give 313 mg (49% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ ): δ [ppm] 1.61 (d, 3H) 3.01 (s, 3H) 3.70-3.81 (m, 1 3.89(d,1H)3.96-4.12(m,3H)4.22-4.41(m,2H)5.30(s,1H)7.50-7.70(m,3H)7.96(t,1H)9.06-9.27(m,3H).

LCMS, method 1, rt: 1.15 min, MS ES+ m/z = 536 (M+H) ⁺ .

The following examples were prepared from the starting materials using a synthetic procedure similar to that described in Example 395:

Example 407: 3-(5-Methyl-1,3-thiazol-2-yl)-5-[2-oxa-5-azabicyclo[2.2.1]hept-1-ylmethoxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide as a mixture of 2 diastereomers

A mixture of Example 404 (610 mg, 984 μmmol) and TFA (5.0 mL, 65 mmol) in DCM (50 mL) was stirred until complete conversion. The mixture was evaporated to dryness under reduced pressure. Water, saturated NaHCO ₃ aqueous solution and DCM were added and the phases were separated. The aqueous layer was extracted twice with DCM. The combined organic layers were evaporated to dryness and purified by preparative HPLC (Method 1, LCMS, Rt: 0.90 min) to obtain 480.0 mg (94% yield) of the title compound.

¹ H NMR (500MHz, DMSO-d ₆ ): δ[ppm]1.61(d,3H)1.67-1.80(m,2H)2.92-3.03(m,2H)3.62-3.84(m,3H)4.36-4.53(m,2H)5.30(t,1H)7.52-7.67(m,3H)15 7.93(t,1H)9.08-9.24(m,3H).

LCMS, method 1, rt: 0.88 min, MS ES+ m/z = 520 (M+H) ⁺ .

The following examples were prepared in analogy to the synthetic procedure described in Example 366 using STAB and the corresponding amine and aldehyde or ketone starting materials and purification by preparative HPLC (Method 1):

Example 409: Methyl 1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate

To a mixture of Example 407 (105 mg, 202 μmmol) and DIPEA (180 μL, 1.0 mmol) in DCM (5 mL) was added methyl chloroformate (47 μL, 610 μmmol) and the mixture was stirred until complete conversion. Water and DCM were added and the layers were evaporated. The aqueous layer was extracted with DCM and the combined organic layers were evaporated to dryness. The residue was purified by preparative HPLC (method 1, LCMS, Rt: 1.19 min) to obtain 70.0 mg (60% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ ): δ[ppm]1.61(d,3H)1.92(s,2H)3.34-3.54(m,2h)3.61(d,3H)3.73-3.93(m,2H )4.39-4.61(m,3H)5.30(s,1H)7.53-7.70(m,3H)7.94(t,1H)9.07-9.26(m,3H).

LCMS, method 1, rt: 1.19 min, MS ES+ m/z = 578 (M+H) ⁺ .

Example 410: Ethyl 1-{[3-(5-methyl-1,3-thiazol-2-yl)-5-({(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}carbamoyl)phenoxy]methyl}-2-oxa-5-azabicyclo[2.2.1]heptane-5-carboxylate

To a mixture of Example 407 (50.0 mg, 96.2 μmmol) and DIPEA (84 μL, 480 μmmol) in DCM (2.4 mL) was added ethyl chloroformate (31.3 mg, 289 μmmol) and the mixture was stirred until complete conversion. Water and DCM were added and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers were evaporated to dryness. The residue was purified by preparative HPLC (Method 1, LCMS, Rt: 1.25 min) to give 40.0 mg (70% yield) of the title compound.

¹ H NMR (400MHz, DMSO-d ₆ ): δ[ppm]1.19(q,3H)1.61(d,3H)1.91(br.s.,2H)3.35-3.57(m,2H)3.71-3.91(m,2H)3.99 -4.14(m,2H)4.38-4.58(m,3H)5.30(s,1H)7.51-7.71(m,3H)7.94(t,1H)9.07-9.24(m,3H).

LCMS, method 1, rt: 1.25 min, MS ES+ m/z = 592 (M+H) ⁺ .

Example 411: 3-{[(2S)-4-ethylmorpholin-2-yl]methoxy}-5-(5-methyl-1,3-thiazol-2-yl)-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide

Example 350 (50 mg, 0.10 mmol) was dissolved in DCE (1 mL) at room temperature. Acetaldehyde (55 μL) and acetic acid (5 μL) were added and the reaction mixture was stirred at room temperature for 30 minutes. STAB (63 mg, 0.30 mmol) was added and the reaction was stirred overnight. The reaction mixture was neutralized with saturated _NaHCO₃ (2 mL) and extracted with DCM (2×2 mL). The combined organics were dried over magnesium sulfate, filtered, and evaporated to give the crude product. Purification by preparative HPLC (Method A) in two injections gave 11 mg (20% yield) of the title compound.

¹ H NMR (500MHz, DMSO-d6): δ[ppm]1.01(t,J＝7.2,3H),1.61(d,J＝7.1,3H),1.93(t,J＝10.6,1H) ,2.01(td,J＝11.3,3.2,1H),2.35(q,J＝7.2,2H),2.51(s,3H),2.66-2.74(m,1H),2.85-2.92( m,1H),3.55(td,J＝11.2,2.4,1H),3.77-3.86(m,2H),4.7-4.15(m,2H),5.25-5.34(m,1H),7 .54(d,J＝1.3,2H),7.64(d,J＝1.2,1H),7.92(t,J＝1.4,1H),9.12(s,2H),9.15(d,J＝7.1,1H).

LC-MS (Analytical Method A) Rt=2.17 min, MS (ESIpos): m/z=536.1 (M+H) ⁺ .

The following examples were prepared in a manner similar to that described in Example 346 using T3P and the corresponding carboxylic acid and primary amine starting materials:

The following examples were prepared in a manner similar to that described in Example 347 using TFA and the corresponding N-Boc protected amine starting materials:

The following examples were prepared in a manner similar to that described in Example 366 using STAB and the corresponding amine and aldehyde or ketone starting materials:

Pharmaceutical compositions of the compounds of the present invention

The present invention also relates to pharmaceutical compositions comprising one or more compounds of the present invention. These compositions can be used to administer to patients in need thereof to exert the desired pharmacological effect. For the purposes of the present invention, a patient is a mammal, including a human, who is in need of treatment for a specific condition or disease. Therefore, the present invention includes a pharmaceutical composition consisting of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the present invention or a salt thereof. The pharmaceutically acceptable carrier is preferably a relatively non-toxic and harmless carrier to the patient at a concentration consistent with the effective activity of the active ingredient, so that any side effects caused by the carrier do not weaken the beneficial effects of the active ingredient. The pharmaceutically effective amount of the compound is preferably an amount that produces an effect or exerts an influence on the specific condition being treated. The compounds of the present invention can be administered together with pharmaceutically acceptable carriers well known in the art using any effective conventional dosage unit form, including immediate release, sustained release and timed release formulations, and can be administered orally, parenterally, topically, nasally, ophthalmically, ocularly, sublingually, rectally, vaginally, and the like.

For oral administration, the compound can be prepared into solid or liquid preparations, such as capsules, pills, tablets, lozenges, troches, melts, powders, solutions, suspensions or emulsions, and can be prepared according to methods known in the art for preparing pharmaceutical compositions. Solid unit dosage forms can be conventional hard or soft shell gelatin type capsules containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate and corn starch.

In another embodiment, conventional tablet bases such as lactose, sucrose, and corn starch, along with binders such as gum arabic, corn starch, or gelatin, disintegrants that aid disintegration and dissolution of the tablet after administration, such as potato starch, alginic acid, corn starch, and guar gum, tragacanth gum, and gum arabic, lubricants that improve the flowability of the tablet particles and prevent the tablet material from adhering to the surface of the tableting die and the punch, such as talc, stearic acid or magnesium stearate, calcium stearate, or zinc stearate, and dyes, colorants, and flavorings such as mint, wintergreen oil, or cherry flavoring to enhance the aesthetics of the tablets and make them more acceptable to patients, can be tableted together with the compounds of the present invention. Excipients suitable for oral liquid dosage forms include calcium hydrogen phosphate and diluents such as water and alcohols such as ethanol, benzyl alcohol, and polyvinyl alcohol, with or without pharmaceutically acceptable surfactants, suspending agents, or emulsifiers. Various other materials can be present as coating materials or used to modify the physical form of the dosage unit. For example, tablets, pills, or capsules can be coated with shellac, sugar, or both.

Dispersible powders and granules are suitable for preparing aqueous suspensions. They provide the active ingredient in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents have been mentioned above. Other excipients such as those sweeteners, flavorings, and coloring agents described above may also be present.

The pharmaceutical composition of the present invention may also be an oil-in-water emulsion. The oil phase may be a vegetable oil such as liquid paraffin, or a mixture of vegetable oils. Suitable emulsifiers may be (1) naturally occurring gums such as gum arabic and gum tragacanth, (2) naturally occurring phospholipids such as soybean lecithin and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and (4) condensation products of the partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol. The suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben; one or more coloring agents; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin.

Syrups or elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent and preservative such as methyl or propylparaben and flavoring and coloring agents.

The compounds of the present invention can also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as an injectable formulation of the compound, preferably in a physiologically acceptable diluent containing a pharmaceutical carrier, which can be a sterile liquid or a mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, alcohols such as ethanol, isopropanol or hexadecanol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or fatty acid glycerides or acetylated fatty acid glycerides, with or without the addition of pharmaceutically acceptable surfactants such as soaps or detergents, suspending agents such as pectin, carbomer, methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose, or emulsifiers and other pharmaceutical adjuvants.

Examples of oils that can be used for parenteral formulations of the present invention are derived from petroleum, animal, plant or synthetic oils, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. For example, suitable fatty acid esters are ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metals, ammonium and triethanolamine salts, and suitable detergents include cationic detergents such as dimethyldialkylammonium halides, alkylpyridinium halides and alkylamine acetates; anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfate and sulfosuccinate; nonionic detergents such as fatty amine oxides, fatty acid alkanolamides and poly (ethylene oxide-propylene oxide) or ethylene oxide or propylene oxide copolymers; amphoteric detergents such as alkyl-β-aminopropionic acid esters and 2-alkylimidazoline quaternary ammonium salts and mixtures.

The parenteral compositions of the present invention typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be advantageously used. To minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant, preferably one having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The surfactant content of such formulations is preferably in the range of from about 5% to about 15% by weight. The surfactant may be a single component having the aforementioned HLB, or it may be a mixture of two or more components having the target HLB.

Examples of surfactants used in parenteral formulations are polyethylene sorbitan fatty acid esters, such as sorbitan monooleate, and the high molecular weight adducts of ethylene oxide with hydrophobic bases formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical composition can be in the form of a sterile injectable aqueous suspension. Such suspensions can be prepared according to known methods using appropriate dispersants or wetting agents and suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents can be naturally occurring phospholipids such as lecithin, condensation products of alkylene oxides and fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide and long-chain fatty alcohols such as heptadecanol, condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides such as polyoxyethylene sorbitan monooleate.

Sterile injection preparations can also be sterile injection solutions or suspensions in nontoxic, parenteral diluents or solvents. For example, operable diluents and solvents are water, Ringer's solution, isotonic sodium chloride solution, and isotonic glucose solution. In addition, sterile fixed oils are typically used as solvents or suspension media. For this reason, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used to prepare injections.

The compositions of the present invention can also be administered rectally in the form of suppositories. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at normal temperatures but liquid at rectal temperature and thus gradually disappears in the rectum to release the drug. Examples of such substances are cocoa butter and polyethylene glycol.

Another preparation used in the method for the present invention uses a transdermal delivery device ("patch"). This transdermal patch can be used to provide the compounds of this invention that continuously or non-continuously injects a controlled amount. The structure and usage of the transdermal patch for delivering medicament are well known in the art (for example, referring to United States Patent (USP) 5,023,252, authorized on June 11, 1991, which is included herein by reference). This patch can be constructed to be applicable to a medicament that is continuous, pulsating, or can be delivered on demand.

Controlled-release formulations for parenteral administration include liposomes, polymeric microspheres, and polymeric gel formulations known in the art.

It may be desirable or necessary to introduce a pharmaceutical composition to a patient via a mechanical delivery device. The construction and use of mechanical delivery devices for delivering pharmaceutical agents are well known in the art. For example, direct techniques for administering drugs directly to the brain typically involve placing a drug delivery catheter within the patient's ventricular system to cross the blood-brain barrier. U.S. Patent No. 5,011,472, issued April 30, 1991, describes one such implantable delivery system for delivering agents to specific anatomical sites in the body.

If necessary or desired, the compositions of the present invention may also contain other conventional pharmaceutically acceptable combination ingredients, commonly referred to as carriers or diluents. Conventional methods for preparing such compositions in appropriate dosage forms may be used. Such ingredients and methods include those described in the following documents, all of which are incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R.G. "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171.

In formulating the composition for the desired route of administration, common pharmaceutical ingredients that may be used as appropriate include:

Acidifying agents (examples include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid);

Alkalizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine);

Adsorbents (examples include, but are not limited to, powdered cellulose and activated carbon);

Aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl ₂ F ₂ , F ₂ ClC-CClF ₂ , and CClF ₃ );

Air displacers (examples include, but are not limited to, nitrogen and argon);

antifungal preservatives (examples include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);

antimicrobial preservatives (examples include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate, and thimerosal);

Antioxidants (examples include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

Adhesive materials (examples include, but are not limited to, block polymers, natural and synthetic rubbers, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

buffering agents (examples include, but are not limited to, potassium metaphosphate, dipotassium hydrogen phosphate, sodium acetate, anhydrous sodium citrate, and sodium citrate dihydrate);

carrier agents (examples include, but are not limited to, acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection, and bacteriostatic water for injection);

Chelating agents (examples include, but are not limited to, disodium EDTA and EDTA);

Coloring agents (examples include, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel, and red iron oxide);

Clarifying agents (examples include, but are not limited to, bentonite);

emulsifiers (examples include, but are not limited to, gum arabic, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include, but are not limited to, gelatin and cellulose acetate phthalate);

Flavoring agents (examples include, but are not limited to, anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil, and vanillin);

humectants (examples include, but are not limited to, glycerin, propylene glycol, and sorbitol);

abrasives (examples include, but are not limited to, mineral oil and glycerin);

Oils (examples include, but are not limited to, arachis oil, mineral oil, olive oil, peanut oil, sesame oil, and vegetable oil);

ointment bases (examples include, but are not limited to, lanolin, hydrophilic ointments, polyethylene glycol ointments, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment);

Penetration enhancers (transdermal delivery) (examples include, but are not limited to, mono- or polyhydric alcohols, mono- or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalins, terpenes, amides, ethers, ketones, and ureas);

Plasticizers (examples include, but are not limited to, diethyl phthalate and glycerin);

Solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerol, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for irrigation);

Hardening agents (examples include, but are not limited to, cetyl alcohol, cetyl ester wax, microcrystalline wax, paraffin wax, stearyl alcohol, white wax, and yellow wax);

suppository bases (examples include, but are not limited to, cocoa butter and polyethylene glycol (mixture));

Surfactants (examples include, but are not limited to, benzalkonium chloride, nonoxynol 10, nonoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar-agar, bentonite, carbomer, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, gum tragacanth, and magnesium aluminum silicate);

sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerin, mannitol, propylene glycol, sodium saccharin, sorbitol, and sucrose);

Tablet anti-adherents (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sucrose, ethylcellulose, gelatin, liquid dextrose, methylcellulose, non-cross-linked polyvinyl pyrrolidone, and pregelatinized starch);

Tablet and capsule diluents (examples include, but are not limited to, dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol, and starch);

tablet coatings (examples include, but are not limited to, liquid dextrose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate, and shellac);

Tablet direct compression excipients (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrants (examples include, but are not limited to, alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, potassium ion exchange resin, cross-linked polyvinyl pyrrolidone, sodium alginate, sodium starch glycolate, and starch);

Tablet glidants (examples include, but are not limited to, colloidal silicon dioxide, corn starch, and talc);

Tablet lubricants (examples include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, and zinc stearate);

Tablet/capsule opacifiers (examples include, but are not limited to, titanium dioxide);

Tablet polishing agents (examples include, but are not limited to, carnauba wax and white wax);

thickeners (examples include, but are not limited to, beeswax, cetyl alcohol, and paraffin);

Tonicity agents (examples include, but are not limited to, dextrose and sodium chloride);

viscosity-increasing agents (examples include, but are not limited to, alginic acid, bentonite, carbomer, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth); and

Wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitan monooleate, polyoxyethylene sorbitan monooleate, and polyoxyethylene stearate).

Combination therapy

The term "combination" in the present invention is known to those skilled in the art, and can exist in the form of a fixed combination, a non-fixed combination or a "kit-of-parts".

A "fixed combination" as used herein is known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present together in one unit dosage form or in a single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in a mixture, such as a formulation, for simultaneous administration. Another example of a "fixed combination" is a pharmaceutical conjugate in which the first active ingredient and the second active ingredient are present in one unit rather than in a mixture.

A non-fixed combination or "kit of parts" as used herein is known to those skilled in the art and is defined as a combination in which the first active ingredient and the second active ingredient are present in more than one unit. An example of a non-fixed combination or kit of parts is a combination in which the first active ingredient and the second active ingredient are present separately. The components of the non-fixed combination or kit of parts may be administered separately, sequentially, simultaneously, concurrently or staggered in time.

The compounds of the present invention may be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents, provided that the combination does not cause unacceptable adverse effects. The present invention also relates to such combinations.

For example, the compounds of the present invention may be combined with known hormonal therapeutic agents.

In particular, the compounds of the present invention may be administered in combination with hormonal contraceptives or as a combination. Hormonal contraceptives may be administered orally, subcutaneously, transdermally, intrauterinely or intravaginally, for example as a combined oral contraceptive (COC) or a progestogen-only pill (POP) or a hormonal device such as an implant, patch or intravaginal ring.

COCs include, but are not limited to, birth control pills or methods of contraception that include a combination of an estrogen (estradiol) and a progestin (progesterone). The estrogen portion of most COCs is ethinyl estradiol. Some COCs contain estradiol or estradiol valerate.

The COC contains the progestogen norethindrone, norethindrone, norethindrone acetate, norethindrone acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest or nomegestrol acetate.

Contraceptive pills include, for example, but are not limited to, Yasmin, Yaz, both of which contain ethinyl estradiol and drospirenone; Microgynon or Miranova, which contain levonorgestrel and ethinyl estradiol; Marvelon, which contains ethinyl estradiol and desogestrel; Valette, which contains ethinyl estradiol and dienogest; Belara and Enriqa, which contain ethinyl estradiol and chlormadinone acetate; Qlaira, which contains estradiol valerate and dienogest as active ingredients; and Zoely, which contains estradiol and nomegestrol.

POPs are birth control pills that contain only a synthetic progestogen (progesterone) and no estrogen. They are commonly known as the mini-pill.

POPs include, but are not limited to, Cerazette, which contains desogestrel; Microlut, which contains levonorgestrel; and Micronor, which contains norethindrone.

Other progestin-only forms are intrauterine devices (IUDs), such as Mirena, which contains levonorgestrel, or intravenous injectables, such as Depo-Provera, which contains medroxyprogesterone acetate, or implants, such as Implanon, which contains etonogestrel.

Other hormone-containing devices having contraceptive effects and suitable for use in combination with the compounds of the present invention are vaginal rings such as Nuvaring, which contains ethinyl estradiol and etonogestrel, or transdermal systems such as contraceptive patches, for example Ortho-Evra or Apleek (Lisvy), which contain ethinyl estradiol and gestodene.

A preferred embodiment of the present invention is the administration of the compound of formula (I) in combination with the COC or POP or other progestogen-only forms as described above, as well as a vaginal ring or a contraceptive patch.

The compounds of the present invention can be combined with therapeutic agents or active ingredients that are already approved or are still under development for the treatment and/or prevention of diseases associated with or mediated by P2X3 receptors.

For the treatment and/or prevention of urinary tract diseases, the compounds of the present invention may be combined or administered as a combination with any substance which can be used as a therapeutic agent in the following indications:

Urinary tract conditions associated with bladder outlet obstruction; urinary incontinence symptoms such as reduced bladder capacity, increased frequency of urination, urge incontinence, stress incontinence or bladder hypersensitivity; benign prostatic hypertrophy; prostatic hypertrophy; prostatitis; detrusor reflex resistance; overactive bladder and symptoms associated with overactive bladder, wherein the symptoms are particularly increased frequency of urination, nocturia, urgency or urge incontinence; pelvic irritability; urethritis; prostatitis; prostatodynia; cystitis, particularly interstitial cystitis; primary irritable bladder.

For the treatment and/or prevention of overactive bladder and symptoms associated with overactive bladder, the compounds of the present invention may be combined or administered as a combination with an anticholinergic (e.g., oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium chloride, fesoterodine); a beta-3 agonist (e.g., mirabegron); a neurotoxin (e.g., onabutoumtoxin A); or an antidepressant (e.g., imipramine, duloxetine), either alone or in addition to behavioral therapy (e.g., diet, lifestyle, or bladder training).

For the treatment and/or prevention of interstitial cystitis, the compounds of the present invention may be combined or administered as a combination with pentosans (e.g., pentosan sodium sulfate); NSAIDS (nonsteroidal anti-inflammatory drugs) or non-selective NSAIDS (e.g., ibuprofen, diclofenac, aspirin, naproxen, ketoprofen, indomethacin); and Cox-2 selective NSAIDS (e.g., parecoxib, etoricoxib, celecoxib); antidepressants (e.g., amitriptyline, imipramine) or antihistamines (e.g., loratadine), either independently or in addition to behavioral therapy (e.g., diet, lifestyle, or bladder training).

For the treatment and/or prevention of gynecological diseases, the compounds of the present invention may be combined or administered as a combination with any substance which can be used as a therapeutic agent in the following indications:

Dysmenorrhea, including primary and secondary dysmenorrhea; dyspareunia; endometriosis; endometriosis-related pain; symptoms associated with endometriosis, wherein the symptoms are particularly dysmenorrhea, dyspareunia, dysuria or dysuria.

For the treatment and/or prevention of dysmenorrhea (including primary and secondary dysmenorrhea); dyspareunia; endometriosis and endometriosis-associated pain, the compounds of the present invention can be combined or administered as a combination with pain medications, particularly NSAIDs (such as ibuprofen, diclofenac, aspirin, naproxen, ketoprofen, indomethacin); and Cox-2 selective NSAIDs (such as parecoxib, etoricoxib, celecoxib); or with ovulation suppression therapy, particularly COCs as described above or contraceptive patches such as Ortho-Evra or Apleek (Lisvy); or with progestins such as dienogest (Visanne); or with GnRH analogs, particularly GnRH agonists and antagonists (e.g., leuprolide, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix); or with the androgen: danazol.

For the treatment and/or prevention of diseases associated with pain or pain syndromes, the compounds of the present invention can be combined or administered as a combination with any substance that can be used as a therapeutic agent in the following indications:

Hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, traumatic nerve injury, traumatic nerve injury, post-traumatic injury (including fractures and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgia, HIV and HIV treatment-induced neuropathy.

The compounds of the present invention may be combined with other pharmacological agents and compounds intended for the treatment of inflammatory diseases, inflammatory pain, or pain conditions in general.

In addition to known drugs that have already been approved and marketed, the compounds of the present invention can be administered in combination with inhibitors of PTGES (prostaglandin E synthase), inhibitors of IRAK4 (interleukin-1 receptor-associated kinase 4), and antagonists of the prostaglandin EP4 receptor (prostaglandin E2 receptor 4).

In particular, the compounds of the present invention can be administered in combination with pharmacological endometriosis drugs intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfere with endometriotic hyperplasia and endometriosis-related symptoms, namely functional blocking antibodies of Aldo-ketoreductase 1C3 (AKR1C3) and prolactin receptors.

For the treatment and/or prevention of chronic cough and syndromes associated with chronic cough, the compounds of the present invention may be combined or administered as a combination with the following agents: antitussives (e.g., dextromethorphan, benzonatate, codeine, or hydrocodone); inhalers for the treatment of eosinophilic bronchitis, COPD, or asthma (e.g., budesonide, beclomethasone, fluticasone, theophylline, ipratropium bromide, montelukast, or albuterol); proton pump inhibitors for the treatment of gastric acid reflux (e.g., omeprazole, esomeprazole, lansoprazole, ranitidine, famotidine, cimetidine); and enhancers (e.g., metoclopramide); nasal or topical glucocorticoids (e.g., fluticasone or mometasone or triamcinolone acetonide); or oral antihistamines (e.g., loratadine, fexofenadine, or cetirizine).

The compounds of the present invention may be combined with other pharmacological agents and compounds intended to treat, prevent or manage cancer.

In particular, the compounds of the present invention can be administered in combination with the following agents: 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, alenclavulanic acid, alitretinoin, hexamethylmelamine, amifostine, aminoglutethimide, aminolevulinate, amrubicin, amsacrine, anastrozole, ancilastin, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, acitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, ceritinib, brentuximab vedotin), busulfan, cabazitaxel, cabozantinib, leucovorin, leucovorin, capecitabine, caprotinib, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, cimoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone acetate, nitrogen mustard, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone acetate, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa alfa), dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin, denosumab, depo-opeptide, deslorelin, dexrazoxane, dibromospironium chloride, vesconol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptonium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, cyclothiocarbamate, epoetin alpha, epoetin beta, epoetin zeta, epoetin platinum, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, epoetin Simestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadobutric acid meglumine, gadoversetamide, gadoxetine, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, carboxypeptidase (Glucarpidase), oxidized glutathione (glutoxim), GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxyurea, I-125 particles, lansoprazole, Ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indesitron, incadronic acid, ingenol methylbutyrate, interferon alpha, interferon beta, interferon gamma, iobitrone, iobenzylguanidine (1231), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, lanreotide, lapatinib, lasochoe, lenalidomide, levograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoropil, medroxyprogesterone acetate , megestrol acetate, melarsoprol, melphalan, melastrone, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, methyltyrosine, mifatide, miltefosine, miplatin, dibromomannitol, propionamide, dibromodulanol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molastin, mopidarol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentozocin, naltrexone, naltograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpe Ntetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitrocorin, nivolumab, obinutuzumab, octreotide, ofatumumab, homoharringtonine, omeprazole, ondansetron, oprelvekin, octreotide, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronate, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epilepsy Epoetin beta (methoxy-PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peclomycin, perfluorobutane, perfosfamide, pertuzumab, sapelylin, pilocarpine, pirarubicin, pixentron, plerixafor, plicamycin, polyglucosamine, estradiol polyphosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab , radium-223 chloride, radotinib, raloxifene, raltitrexed, ramucitron, ramucirumab, ranimustine, rasburicase, aprotinimide, refametinib, regorafenib, risedronic acid, etidronate rhenium-186, rituximab, romidepsin, romiplostim, romotide, roniciclib, samarium (153Sm), sargramostim, satumomab, secretin, Provenge (sipuleucel-T), sizolan, sobuzosane, glycopyrrolate sodium, sorafenib, stanozolol, streptozotocin, sunitinib, talaporfin, tadalafil, tadalafil Mibarotene, tamoxifen, tapentadol, tasonamine, tesileukin, technetium (99mTc) nofetumomab, nomotumomab, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymosin, thyrotropin-alpha, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab Emtansine, thiosulfate, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, trolofosamide, thrombopoietin, tryptophan, ubenimex, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorizole, yttrium-90 glass beads, statin, statinostatin, zoledronic acid, zorubicin.

In addition, the compounds of the present invention can be combined with known active ingredients for the treatment of cancer-related pain and chronic pain. Such combinations include, but are not limited to, NSAIDS (non-selective NSAIDS such as ibuprofen, diclofenac, aspirin, naproxen, ketoprofen, and indomethacin; and Cox-2 selective NSAIDS such as parecoxib, etoricoxib, and celecoxib), step II opioids such as codeine phosphate, dextropropoxyphene, dihydrocodeine, tramadol, step III opioids such as morphine, fentanyl, buprenorphine, oxymorphone, oxycodone, and hydromorphone; and for the treatment of cancer pain. Other medications that may be used include steroids such as dexamethasone and methylprednisolone; bisphosphonates such as etidronate, clodronate, alendronate, risedronate, and zoledronate; tricyclic antidepressants such as amitriptyline, clomipramine, desipramine, imipramine, and doxepin; class I antiarrhythmics such as mexiletine and lidocaine; anticonvulsants such as carbamazepine; gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital, and phenobarbital.

Treatment

The present invention relates to a method for inhibiting P2X3 receptors using the compounds and compositions of the present invention.

The present invention also provides a method of using the compounds of the present invention and compositions thereof to selectively inhibit the P2X3 receptor over the P2X2/3 receptor, meaning at least 3-fold selectivity over the P2X2/3 receptor.

The present invention also provides a method of using the preferred compounds of the present invention and compositions thereof to selectively inhibit P2X3 receptors over P2X2/3 receptors (at least 10-fold selectivity for P2X2/3 receptors). In addition, the present invention also provides a method of treating mammalian conditions, including human conditions, using the more preferred compounds of the present invention, which exhibit other advantageous properties that are beneficial for their use as drugs, such as desired pharmacokinetic characteristics, which provide suitable metabolic stability and oral bioavailability. In addition, there is also provided a method of treating mammalian conditions, including human conditions, using even more preferred compounds of the present invention, which exhibit other advantageous properties that are beneficial for their use as drugs, such as desired pharmacokinetic characteristics, which provide suitable metabolic stability and oral bioavailability, and at least one other advantageous property selected from favorable cardiovascular characteristics and suitable CYP inhibition characteristics.

The present invention relates to a method of using the compounds of the present invention and compositions thereof to treat mammalian, including human, conditions and diseases, including but not limited to:

genitourinary, gastrointestinal, respiratory or pain-related diseases, conditions or disorders;

Gynecological disorders, including dysmenorrhea (primary and secondary), dyspareunia, and endometriosis and adenomyosis; pain associated with endometriosis; symptoms associated with endometriosis, particularly dysmenorrhea, dyspareunia, dysuria, or dysfecia; endometriosis-related hyperplasia; and pelvic irritation.

Urinary tract conditions associated with bladder outlet obstruction; urinary incontinence symptoms such as reduced bladder capacity, increased frequency of urination, urge incontinence, stress incontinence, or bladder hypersensitivity; benign prostatic hypertrophy; prostatic hypertrophy; prostatitis; detrusor reflex resistance; overactive bladder and symptoms associated with overactive bladder, particularly increased frequency of urination, nocturia, urgency, or urge incontinence; pelvic irritability; urethritis; prostatitis; prostatodynia; cystitis, particularly interstitial cystitis; primary irritable bladder;

Cancer-related pain;

Epilepsy; partial and generalized seizures;

Respiratory disorders, including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, acute cough, chronic cough including chronic primary and chronic refractory cough, and bronchospasm;

Gastrointestinal diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary tract diseases, renal colic, diarrhea-predominant IBS, gastroesophageal reflux, gastrointestinal bloating, Crohn's disease, etc.

Neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, cerebral ischemia, and traumatic brain injury;

Itching.

The present invention relates to a method of using the compounds of the present invention and compositions thereof to treat pain-related conditions and diseases in mammals (including humans), including but not limited to:

a pain-related disease or condition selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injury (including fractures and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgia, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and skeletal diseases such as joint degeneration.

The present invention relates to a method of using the compounds of the present invention and compositions thereof to treat mammalian (including human) conditions and diseases associated with pain or pain syndromes, particularly:

Pain syndromes (including acute, chronic, inflammatory and neuropathic pain), preferably inflammatory pain, low back pain, surgical pain, visceral pain, toothache, periodontitis, premenstrual pain, endometriosis-related pain, pain associated with fibrotic diseases, central pain, pain caused by burning mouth syndrome, pain caused by burns, pain caused by migraine, cluster headache, pain caused by nerve damage, pain caused by neuritis, neuralgia, pain caused by poisoning, pain caused by ischemic injury, pain caused by interstitial cystitis, cancer pain, pain caused by viruses, parasitic or bacterial infections, pain caused by traumatic nerve damage, pain caused by post-traumatic injuries (including fractures and sports injuries) pain, pain caused by trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic low back pain, neck pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, pain associated with gastrointestinal distension, chronic arthritis pain and related neuralgia, cancer-related pain, morphine-resistant pain, chemotherapy-related pain, HIV and HIV treatment-induced neuropathy; pain associated with a disease or condition selected from the group consisting of: hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis).

The present invention relates to a method for treating inflammation, particularly neurological inflammation, using the compounds of the present invention and compositions thereof. The term "inflammation" is also understood to include any inflammatory disease, disorder, or condition per se, any condition with an associated inflammatory component, and/or any condition characterized by inflammation, including, in particular, acute, chronic, ulcerative, atopic, allergic, pathogenic, immune response due to hypersensitivity, foreign body intrusion, bodily injury, and necrotizing inflammation, as well as other forms of inflammation known to those skilled in the art. Therefore, for the purposes of the present invention, the term also includes inflammatory pain, general pain, and/or fever. The present invention relates to a method of treating the following conditions using the compounds of the present invention and compositions thereof: fibromyalgia, myofascial disorders, viral infections (e.g., flu, colds, shingles, hepatitis C, and AIDS), bacterial infections, fungal infections, surgical or dental procedures, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, stroke, autoimmune diseases, allergic diseases, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary artery disease, sarcoidosis, and any other disease with an inflammatory component. The present invention relates to a method of treating conditions and diseases in mammals (including humans) that are not associated with an inflammatory mechanism using the compounds of the present invention and compositions thereof, such as to reduce bone loss in a subject. Diseases which may be mentioned in this context include osteoporosis, osteoarthritis, Paget's disease and/or periodontal disease.

Based on the P2X3 receptor inhibitory activity of the compounds of the present invention, the present invention relates to a method of using the compounds of the present invention and their compositions to treat the following diseases: pain, fever and inflammation of various symptoms, including rheumatic fever, symptoms associated with influenza or other viral infections, colds, back and neck pain, dysmenorrhea, headache, migraine (acute and preventive treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint disease (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injury and postoperative pain (postoperative pain) and dental surgery and preemptive treatment of surgical pain. The pain can be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as visceral pain including acute visceral pain, neuropathy, acute trauma, chemotherapy-induced mononeuropathy pain states, polyneuropathy pain states (e.g., diabetic peripheral neuropathy and/or chemotherapy-induced neuropathy), autonomic neuropathy pain states, cranial nervous system (PNS) lesions or central nervous system (CNS) lesions or disease-related pain states, polyradiculopathies of the cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriceps pain, sciatica, spondylosis ... Acroparesis, pain associated with various infections, chemical injuries, radiation exposure, various polyneuritis conditions associated with diseases or deficiencies (e.g., beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune diseases) such as multiple sclerosis and spinal cord injury, fibromyalgia, nerve damage, ischemia, neurodegeneration, stroke, post-stroke pain, inflammatory diseases, esophagitis, gastroesophageal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, overactive bladder, pelvic irritability, urinary incontinence, cystitis, gastric and duodenal ulcers, muscle pain, hernia pain, and referred pain. The present invention relates to a method of treating hemophilic arthropathy and Parkinson's disease using the compounds of the present invention and compositions thereof.

A preferred embodiment of the present invention relates to a method for treating gynecological diseases using the compounds and compositions of the present invention, wherein the gynecological diseases are preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-related pain, or other endometriosis-related symptoms, wherein the symptoms are particularly dysmenorrhea, dyspareunia, dysuria or dyspnea.

Another preferred embodiment of the present invention relates to a method of using the compounds of the present invention and compositions thereof to treat urinary tract diseases, in particular overactive bladder or cystitis, preferably interstitial cystitis.

Another preferred embodiment of the present invention relates to a method of treating respiratory diseases, preferably cough, especially chronic cough, using the compounds and compositions of the present invention.

Another preferred embodiment of the present invention relates to a method of treating respiratory arthritis, particularly rheumatoid arthritis and ankylosing spondylitis, using the compounds and compositions of the present invention.

These disorders are well characterized in humans, but have similar etiologies in other mammals and can be treated by administering the pharmaceutical compositions of the present invention.

The terms "treating" or "treatment" used herein refer to the conventional usage thereof, such as treating or caring for a subject to combat, alleviate, reduce, lessen or improve symptoms, diseases or conditions such as gynecological diseases, urinary tract diseases, respiratory diseases or arthritis.

Dosage and administration

Compounds useful for treating conditions and/or diseases mediated by P2X3 receptors are evaluated according to known standard experimental techniques. The effective dose of the compounds of the present invention for treating each target indication can be readily determined by conducting standard toxicity and pharmacology tests for the treatment of the aforementioned conditions in mammals and comparing these results with the results of known drugs used to treat these conditions. In treating any of these conditions, the amount of active ingredient administered can vary widely depending on factors such as the specific compound and dosage unit used, the route of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and severity of the condition being treated.

The total amount of active ingredient to be administered is generally about 0.001 mg/kg to about 200 mg/kg body weight per day, preferably about 0.01 mg/kg to about 20 mg/kg body weight per day. Preferred administration of the compounds of the present invention includes, but is not limited to, 0.1 mg/kg to about 10 mg/kg body weight per day. Clinically available dosing regimens range from one to three times a day to once every four weeks. In addition, a "drug holiday" in which the patient is not given the drug for a period of time may be beneficial to the overall balance between pharmacological effect and tolerability. The unit dose may contain about 0.5 mg to about 1500 mg of active ingredient and may be administered once or more times per day or less than once a day. Preferred oral unit doses for administering the compounds of the present invention include, but are not limited to, 0.1 mg/kg body weight to about 10 mg/kg body weight once to three times per day to once a week. The average daily dose administered by injection, including intravenous, intramuscular, subcutaneous, and parenteral injections, and using infusion techniques is preferably about 0.01 to 200 mg/kg of total body weight. The average daily dose for the rectal administration regimen is preferably about 0.01 to 200 mg/kg of total body weight. The average daily dose for vaginal administration is preferably about 0.01 to 200 mg/kg of total body weight. The average daily dose for topical administration is preferably about 0.1 to 200 mg, 1 to 4 times daily. Transdermal concentrates are preferably in an amount sufficient to maintain a daily dose of 0.01 to 200 mg/kg. The average daily dose for inhalation administration is preferably 0.01 to 100 mg/kg of total body weight.

Of course, the specific initial and subsequent dosing regimen for each patient will vary depending on the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of excretion of the drug, drug combinations, etc. The required treatment regimen and frequency of administration of a compound of the present invention, or a pharmaceutically acceptable salt or ester thereof, or composition can be determined by one skilled in the art using routine therapeutic trials.

Preferably, the disease treated by the method is a gynecological disease, more preferably dysmenorrhea, dyspareunia, or endometriosis, endometriosis-related pain, or other endometriosis-related symptoms, wherein the symptoms are particularly dysmenorrhea, dyspareunia, dysuria, or dysfecation. Other diseases that can be treated with the method are osteoarthritis, diabetic neuropathy, burning mouth syndrome, gastroesophageal reflux, migraine, chronic cough, asthma, pruritus, irritable bowel syndrome, overactive bladder, benign prostatic hyperplasia, and interstitial cystitis.

Preferably, the above method for treating a disease is not limited to the treatment of the disease but also includes the treatment of pain associated with or related to the disease.

The compounds of the present invention are particularly useful in the treatment and suppression (ie, prevention) of genitourinary, gastrointestinal, respiratory or pain-related diseases, symptoms or conditions.

Methods of testing for specific pharmacological or pharmaceutical properties are well known to those skilled in the art.

The exemplary test experiments described herein are intended to illustrate the present invention, and the present invention is not limited to the examples given.

Biological tests

The examples were tested in one or more selected biological assays. Unless otherwise stated, when more than one assay was performed, the data reported are the mean or median values, where

The mean, also called the arithmetic mean, represents the total number of values obtained divided by the number of trials, and

The median represents the middle value of a set of values when arranged in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

When synthesized more than once, the data for the biological assays represent the mean or median calculated from the data sets obtained from one or more synthetic batches.

Intracellular calcium measurements to assess antagonist activity of human P2X3 and human P2X2/3 receptors

Intracellular calcium levels were monitored using a fluorescent imaging plate reader (FLEX/FLIPR station; Molecular Devices) using the calcium chelating dye Ruo-4 (Molecular Probes). The excitation and emission wavelengths used to monitor fluorescence were 470-495 nm and 515-575 nm, respectively. Approximately 20 hours before the start of the assay, cells expressing the purinergic receptor P2X3 (human) or P2X2/3 (human) were plated at a density of approximately 15,000 cells/well in collagen-coated 384-well plates. On the day of the assay, 20 μl of loading buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl ₂ , 0.5 mM MgCl ₂ , 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, 2 μM Fluo-4, and 5 units/mL hexokinase, pH = 7.4) was added and the cells were immersed in the dye for 90 min at 37°C. The staining supernatant was removed and replaced with 45 μl of probenecid buffer (Hank's balanced salt solution, 20 mM HEPES, 0.5 mM CaCl ₂ , 0.5 mM MgCl ₂ , 0.1% BSA, 5 mM probenecid, 10 mM D-glucose monohydrate, pH = 7.4). The test compound was added in a volume of 5 μl and incubated at 37°C for 30 min. The final assay DMSO concentration was 1%. The agonist α,β-Me-ATP was added in a volume of 20 μl at a concentration representing the _EC80 value.

Fluorescence was measured at 2 second intervals for 90 seconds and analyzed based on the increase in peak relative fluorescence units (RFU) compared to basal fluorescence. Peak fluorescence was used to determine the response to agonist obtained at each concentration of test compound as follows:

% response = 100 x (RFU _{(test compound)} - RFU _(control) ) / (RFU _(DMSO) - RFU _(control) )

Examples were tested in triplicate and the averages plotted in Excel XLFit to determine _IC50 values, percent maximal inhibition and HH1 coefficients for human P2X3 and human P2X2/3 receptors.

Solubility test

Aqueous solubility of drugs is a crucial physicochemical parameter that plays an important role in various physical and biological processes. In the body, insufficient solubility of the desired dose leads to incomplete absorption of orally administered drugs and low oral bioavailability. Solubility data is used to assess absorption, distribution, metabolism, and elimination parameters and is utilized in the development of safety screening formulations for preclinical and early clinical use.

High-throughput determination of aqueous test compound solubility (100 mM in DMSO)

The assay was performed in a 96-well plate format, with each well filled with a separate compound.

All pipetting steps were performed using a robotic platform.

A 100 mM solution of the test compound in 100 μL of DMSO was concentrated by vacuum evaporation and dissolved in 10 μL of DMSO to obtain a 100 mM DMSO solution. 990 μL of 0.1 M pH 6.5 phosphate buffer was added. The DMSO content was 1%. The multi-well titration plate was placed on a vibrator and mixed at room temperature for 24 hours. 150 μL of the suspension was transferred to a filter plate. After filtering using a vacuum manifold, the filtrate was diluted 1:400 and 1:8000. A second microtiter plate containing 20 μL of a 10 mM test compound solution in DMSO was used for calibration. Two concentrates (0.005 μM and 0.0025 μM) were prepared by diluting in DMSO/water 1:1 and used for calibration. The filtrate and calibration plate were quantified by HPLC-MS/MS.

Chemicals:

Preparation of 0.1 M pH 6.5 phosphate buffer:

61.86 g of NaCl and 39.54 mg of KH ₂ PO ₄ were dissolved in water and made up to 1 L. The mixture was diluted 1:10 with water and the pH was adjusted to 6.5 with NaOH.

Material: Millipore MultiScreen _HTS -HV Plate 0.45μm.

The chromatographic conditions are as follows:

HPLC column: Ascentis Express C18 2.7μm 4.6×30mm

Injection volume: 1 μL

Flow rate: 1.5 mL/min

Mobile phase: acidic gradient

A: Water/0.05%HCOOH

0 min → 95% A 5% B

0.75 min → 5% A 95% B

2.75 min → 5% A 95% B

2.76 min → 95% A 5% B

3 min → 95% A 5% B

The areas of the sample and calibration injections were determined using mass spectrometry (AB Sciex Triple Quad 6500) software (ABSCIEX: Discovery Quant 2.1.3. and Analyst 1.6.1).Solubility values (in mg/L) were calculated from the sample and calibration curves.

Equilibrium shake flask solubility test

Thermodynamic solubility was determined by the equilibrium shake flask method [Literature: Edward H. Kerns and Li Di (2008) Solubility Methods in: Drug-like Properties: Concepts, Structure Design and Methods, 276-286. Burgton, MA: Academic Press].

A saturated solution of the test compound in 0.1 M phosphate buffer (pH 6.5) was prepared and the solution was mixed for 24 h to ensure equilibrium was reached. The solution was centrifuged to remove the insoluble fraction and the concentration of the compound in the solution was determined by HPLC-UV using a standard calibration curve.

To prepare the sample, weigh 1.5 mg of solid compound into a 4 mL glass vial. Add 1 mL of 0.1 M phosphate buffer (pH 6.5). Place the suspension on a stirrer and mix at room temperature for 24 hours. Then centrifuge the solution. To prepare the sample for standard calibration, dissolve 0.6 mg of solid sample in 19 mL of acetonitrile/water (1:1). After sonication, make up the solution to 20 mL with acetonitrile/water (1:1).

Samples and standards were quantified by HPLC with UV detection. For each sample, two injection volumes (5 and 50 μL) were performed in triplicate. Three injection volumes (5 μL, 10 μL, and 20 μL) were prepared for standards.

Chemicals:

Preparation of 0.1 M pH 6.5 phosphate buffer:

61.86 g of NaCl and 39.54 mg of KH ₂ PO ₄ were dissolved in water and made up to 1 L. The mixture was diluted 1:10 with water and the pH was adjusted to 6.5 with NaOH.

The chromatographic conditions are as follows:

HPLC column: Xterra MS C18 2.5 μm 4.6 × 30 mm

Injection volume: Sample: 3 x 5 μL and 3 x 50 μL

Standard: 5μL, 10μL, 20μL

Flow rate: 1.5 mL/min

Mobile phase: acidic gradient

A: Water/0.01% TFA

B: Acetonitrile

0 min → 95% A 5% B

0-3 min → 35% A 65% B, linear gradient

3-5 min → 35% A 65% B, isocratic

5-6 min → 95% A 5% B, isocratic

UV detector: wavelength close to the absorption maximum (200 to 400 nm)

The areas of the sample and calibration injections and the calculation of solubility values (in mg/L) were determined using HPLC software (Waters Empower 2FR).

Bidirectional Caco-2 cell permeability assay

Caco-2 cells (purchased from DSMZ Braunschweig, Germany) were seeded on 24-well inserts with a pore size of 0.4 μm at a density of 4.5 × ¹⁰ cells per well and grown for 15 days in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 1% GlutaMAX (100×, purchased from GIBCO), 100 U/mL penicillin, 100 μg/mL streptomycin (purchased from GIBCO) and 1% non-essential amino acids (100×). The cells were maintained at 37°C and in a humidified 5% _CO atmosphere. The culture medium was replaced every 2-3 days. Before the permeation test, the culture medium was replaced with serum-free hepes-carbonate transport buffer (pH 7.2). The test compound was dissolved in DMSO and added to the donor chamber representing the apical or basolateral chamber at a final concentration of 2 μM. Samples were taken from both chambers (donor and receptor chambers) before and after incubation for 2 hours at 37°C. After precipitation with methanol, the compound concentration was analyzed. Analysis was performed using an Agilent 1200 liquid chromatography system and an AB Sciex API4000 triple quadrupole mass spectrometer by high pressure liquid chromatography and tandem mass spectrometry detector, using parameters optimized to achieve maximum signal intensity for the corresponding test compound. Permeability (Papp) was calculated in the apical to basolateral (A→B) and basolateral to apical (B→A) directions. The apparent permeability was calculated using the following equation: Papp = ( _Vr / _P0 ) (l/S) ( _P2 /t). Wherein _Vr is the volume of the culture medium in the receiving chamber; _P0 is the peak area of the test compound in the donor chamber measured at t=0; S is the surface area of the monolayer; _P2 is the peak area of the test compound in the receiving chamber measured after 2 hours of incubation; t is the incubation time. The efflux rate from the basolateral (B) to the apical (A) was calculated by dividing _PappBA by _PappAB .

The bidirectional Caco-2 cell permeation assay is an established method for predicting in vivo absorption of drugs across the intestinal wall by measuring the transport rate of a compound through the Caco-2 monolayer. Because differentiated Caco-2 cells express functional efflux transporters such as P-gp, they are also used to identify compounds with an efflux load. By affecting intestinal absorption of a compound, intestinal efflux can reduce the systemic plasma concentration of an orally administered compound. Preferred embodiments of the present invention exhibit permeabilities Papp A-B > 50 nm/s and efflux ratios < 5. More preferred embodiments of the present invention exhibit permeabilities Papp A-B > 80 nm/s and efflux ratios < 2.

Table 1: Bidirectional Caco-2 cell permeation assay of test compounds

Example Ejection rate 11 155 216 1.4 19 249 163 0.65 48 180 212 1.2 185 102 181 1.8 339 153 214 1.4 348 135 190 1.4 347 5.8 209 36 419 104 175 1.7

In vitro metabolic stability test

Determination of in vitro metabolic stability in microsomes (including calculation of hepatic blood clearance (CL) and maximum oral bioavailability (F _max ))

The in vitro metabolic stability of test compounds was determined by incubating the _test compounds in suspended liver microsomes in 100 mM phosphate buffer (pH 7.4) ( _NaH2PO4 x _{H2O + Na2HPO4} x _2H2O ) at 1 μM and a protein concentration of 0.5 mg/mL at 37°C. The microsomes were activated by adding a cofactor mixture containing 8 mM glucose-6-phosphate, 4 mM MgCl2, 0.5 mM NADP in phosphate buffer, pH 7.4, and 1 IU/mL G-6-P dehydrogenase. Shortly after the metabolic assay was initiated, the test compounds were added to the incubations in a final volume of ₁ mL. Organic solvents in the incubations were limited to ≤0.01% dimethyl sulfoxide (DMSO) and ≤1% acetonitrile. During the incubation period, the microsomal suspension was continuously shaken at 580 rpm, and aliquots were taken at 2, 8, 16, 30, 45, and 60 minutes, to which an equal volume of cold methanol was immediately added. The samples were frozen at -20°C overnight, subsequently centrifuged at 3000 rpm for 15 minutes and the supernatant analyzed with LCMS/MS detection using an Agilent 1200 HPLC-system.

The half-life of the test compound was determined from the concentration-time plot. Intrinsic clearance was calculated from the half-life (kel: slope of the concentration-time curve; half-life = ln2/kel). In combination with the additional parameters liver blood flow, specific liver weight, and microsomal protein content, in vivo blood clearance (CL) and maximum oral bioavailability (Fmax) were calculated for the livers of different species.

The liver clearance from blood (CLblood) and the maximum oral bioavailability (Fmax) were calculated using the following formulas: CL'intrinsic [ml/(min*kg)] = kel[1/min]/((mg protein/incubation volume [ml])*fu,inc)*(mg protein/liver weight [g])*(specific liver weight [g liver/kg body weight]); CLBlood well stirred [L/(h*kg)] = (QH[L/(h*kg)]*fu, blood*CL'intrinsic [L/(h *kg)])/(QH[L/(h*kg)]+fu,blood*CL'intrinsic[L/(h*kg)]); Fmax＝1-CLblood/QH, using the following parameter values: hepatic blood flow (QH)-1.32L/h/kg (human), 2.1L/h/kg (dog), 4.2L/h/kg (rat); specific liver weight-21g/kg (human), 39g/kg (dog), 32g/kg (rat); microsomal protein content-40mg/g; fu,inc and fu,blood are 1.

Determination of in vitro metabolic stability of rat hepatocytes (including calculation of in vivo serum clearance (CL) of the liver)

Hepatocytes from Han Wistar rats were isolated by a 2-step perfusion method. After perfusion, the liver was carefully removed from the rat: the liver capsule was opened and the hepatocytes were gently shaken into a culture dish with ice-cold Williams medium (WME). The resulting cell suspension was filtered through a sterile gaze in a 50 mL falcon tube and centrifuged at 50 × g for 3 minutes at room temperature. The cell pellet was resuspended in 30 mL WME and centrifuged twice at 100 × g through a gradient. The hepatocytes were washed again with WME and resuspended in culture medium containing 5% FCS. Cell viability was determined by trypan blue exclusion.

For the metabolic stability assay, hepatocytes were plated into glass vials at a density of 1.0 × 10 ⁶ viral cells/mL in WME containing 5% FCS. Test compounds were added to a final concentration of 1 μM. During the incubation period, the hepatocyte suspension was continuously shaken at 580 rpm, and aliquots were taken at 2, 8, 16, 30, 45, and 90 minutes, to which an equal volume of cold methanol was immediately added. The samples were frozen at -20°C overnight, then centrifuged at 3000 rpm for 15 minutes, and the supernatant analyzed using an Agilent 1200 HPLC system with LCMS/MS detection.

The half-life of the test compound is determined from the concentration-time plot. Intrinsic clearance is calculated from the half-life (kel: slope of the concentration-time curve; half-life = ln2/kel), in combination with additional parameters such as liver blood flow and the number of hepatocytes in vivo and in vitro. The hepatic blood clearance (CLblood) and the maximum oral bioavailability (Fmax) in vivo were calculated using the following formulas: CL'int[ml/(min*kg)]=kel[1/min]/((number of cells/incubation volume [ml])*fu,inc)*(number of cells/liver weight [g])*(specific liver weight [g liver/kg body weight]); CLBlood well stirred [L/(h*kg)]=(QH[L/(h*kg)]*fu,blood*CL'int[L/(h*kg)])/(QH[L/(h*kg)]+fu,blood*CL'int[L/(h*kg)]); Fmax=1-CLblood/QH, using the following parameter values: hepatic blood flow (QH) - 4.2 L/h/kg rat; specific liver weight - 32 g/kg rat body weight; hepatocytes in vivo - 1.1×10 ⁸ cells/g liver, hepatocytes in vitro - 1.0×10 ⁶ /ml; fu, inc and fu, blood is 1.

In vitro metabolic stability studies of cryopreserved human hepatocytes (including calculation of hepatic blood clearance (CL) in vivo)

Cryopreserved hepatocytes (e.g., from Celsis InVitro Technologies) were briefly thawed, washed with 45 mL of pre-warmed in vitro GRO HT medium, and centrifuged at 50 × g for 5 minutes. The cell pellet was resuspended in 5 mL of Krebs-Henseleit Butter (KHB). Cell viability was determined by trypan blue exclusion.

For the metabolic stability assay, hepatocytes were distributed into glass vials at a density of 0.5×10 ⁶ viral cells/mL in Lillians Medium E (WME) containing 5% FCS. Test compounds were added to a final concentration of 1 μM. During the incubation period, the hepatocyte suspension was continuously shaken at 580 rpm, and aliquots were taken at 2, 8, 16, 30, 45, and 90 minutes, to which an equal volume of cold methanol was immediately added. The samples were frozen at -20°C overnight, then centrifuged at 3000 rpm for 15 minutes, and the supernatant was analyzed using an Agilent 1200 HPLC system with LCMS/MS detection.

The half-life of the test compound is determined from the concentration-time plot. Intrinsic clearance is calculated from the half-life (kel: slope of the concentration-time curve; half-life = ln2/kel). In combination with the additional parameters liver blood flow and the number of hepatocytes in vivo and in vitro, the in vivo hepatic blood clearance (CL) and the maximum oral bioavailability (Fmax) are calculated. The liver blood clearance in vivo (CLblood) and the maximum oral bioavailability (Fmax) were calculated using the following formulas: CL'intrinsic [ml/(min*kg)] = kel[1/min]/((number of cells/incubation volume [ml])*fu,inc)*(number of cells/liver weight [g])*(specific liver weight [g liver/kg body weight]); CLblood well stirred [L/(h*kg)] = (QH [L/(h*kg)]*fu,blood*CL'intrinsic [L/(h*kg)])/(QH [L/(h*kg)] + L/(h*kg)]); Fmax = 1-CLblood/QH, using the following parameter values: liver blood flow - 1.32 L/h/kg human; specific liver weight - 21 g/kg rat body weight; hepatocytes in vivo - 1.1×10 ⁸ cells/g liver, hepatocytes in vitro - 1.0×10 ⁶ /ml; fu, inc and fu, blood is 1.

Liver microsome and hepatocyte stability assays

Metabolic instability is often the primary clearance mechanism for xenobiotics, leading to high CL and low bioavailability, which can ultimately result in a short half-life and low exposure after oral administration. Therefore, reducing susceptibility to metabolic degradation generally leads to more favorable pharmacokinetic profiles. When using liver microsomes as an incubation matrix, the main phase I metabolic reactions are generally described, with redox reactions by cytochrome P450 enzymes and flavin monooxygenases (FMOs) and hydrolysis reactions by esterases/amidases/epoxide hydrolases. When incubating the test compound in a hepatocyte matrix, all potential hepatic metabolic processes (phase I and phase II) are covered. Preferred embodiments of the present invention show a metabolic stability (expressed as Fmax) of ≥40% Fmax in human liver microsomes and human and rat hepatocyte preparations. More preferred embodiments of the present invention show a metabolic stability (expressed as Fmax) of ≥50% Fmax in human liver microsomes and human and rat hepatocyte preparations.

Table 2: In vitro metabolic stability values of test compounds

Human liver cytosol stability test

The metabolic stability of new drug candidates was evaluated using human liver cytosol to show sensitivity to non-CYP-mediated oxidative biotransformation. If the compound is a strong substrate for aldehyde oxidase or xanthine oxidase, metabolic clearance through this pathway can lead to low bioavailability in humans. Since both enzymes are active in human liver cytosol, the sensitivity of the test compound to aldehyde or xanthine oxidase-mediated metabolism can be predicted and compared by the amount of the test compound (turnover) and the formation of the corresponding oxidative metabolites after incubation in human liver cytosol. More preferred embodiments of the present invention have an amount of <15% after 4 hours of incubation in human liver cytosol preparations.

Description of the method: Human liver cytosol (pooled, >30 male and female donors) was incubated with individual test compounds to compare the extent of test compound consumption and the formation of corresponding oxidative metabolites. The culture medium consisted of 50 mM potassium phosphate buffer (pH 7.4) and 1 mg/mL human liver cytoplasmic protein. A 1000 μL incubation volume was used. Test compounds were added to the incubation at a concentration of 1 or 10 μM from a stock solution in acetonitrile. The incubation was carried out at 37°C. After incubation, 100 μL of acetonitrile was added to 250 μL of the incubation mixture and the reaction was stopped at 0h and 4h. The precipitated protein was removed by centrifugation at approximately 3000 rpm. The supernatant was stored at approximately -20°C until analysis. Consumption of test compounds and formation of metabolites were determined by chromatographic separation (Aquity BEH300 C4 50×2.1 mm, 1.7 μm, gradient: 10 mM ammonium acetate/acetonitrile) with simultaneous UV and mass spectrometric detection using an Accela UPLC pump and a UV detector coupled to a LTQ-FT mass spectrometer (Thermo Fisher Scientific, Bremen, Germany).

Data Analysis: Consumption of test compound and formation of corresponding metabolites were determined at 4 hours post-incubation compared to 0 hours post-incubation by decrease or increase in corresponding peak area in the chromatogram after UV detection at approximately 300 nm. The identity of the analytes underlying the peaks was confirmed by LC-MS/MS.

Table 3: Stability of test compounds in human liver cytosol

CYP inhibition and pre-incubation CYP inhibition assays

The use of in vitro assays to assess the inhibitory potency of new drug candidates against CYP-mediated metabolism has been shown to be effective as part of a strategy to minimize the chance of drug interactions with other drugs. The inhibitory potency of the test compounds against five human cytochrome P450 isoforms (CYP1A2, 2C8, 2C9, 2D6, and 3A4) was determined. More preferred embodiments of the present invention have a CYP inhibition _IC50 ≥10 μM.

For CYP3A4, time-dependent inhibition potency is also tested by administering the test compound in a metabolically active incubation system with a 30-minute preincubation period. If time-dependent inhibition of CYP3A4 is observed, this suggests that the test compound inhibits CYP3A4 activity through an irreversible mechanism. More preferred embodiments of the present invention have a preincubation CYP inhibition _IC50 ≥ 20 μM.

Method Description CYP Inhibition Assay

Human liver microsomes (pooled, >30 male and female donors) were incubated with individual CYP isoform-selective standard probes (phenacetin for CYP1A2, ubiquinone for CYP2C8, diclofenac for CYP2C9, dextromethorphan for CYP2D6, and midazolam for CYP3A4) in the absence and presence of increasing concentrations of the test compound to compare the extent of metabolite formation. Additionally, a set of incubations in the absence of the test compound served as a negative control. Furthermore, the inhibitory potency of standard inhibitors was included as positive controls (fluvoxamine for CYP1A2, montelukast for CYP2C8, sulfaphenazole for CYP2C9, fluoxetine for CYP2D6, ketoconazole for CYP3A4, and mifepristone for CYP3A4 preincubation). Incubation conditions (protein and probe substrate concentrations, incubation time) were optimized for linearity and metabolite abundance. The incubation medium consisted of 50 mM potassium phosphate buffer (pH 7.4) containing 1 mM EDTA, an NADPH regeneration system (1 mM NADP, 5 mM glucose-6-phosphate, glucose-6-phosphate dehydrogenase (1.5 U/mL)). Serial dilutions and incubations were performed in 96-well plates at 37° C. on a Genesis Workstation (Tecan, Crailsheim, FRG). A final incubation volume of 200 μL was used. The reaction was terminated by adding 100 μL of acetonitrile containing each internal standard. The precipitated protein was removed by centrifugation of the well plate, and the supernatants were combined and separated by LC-MS/MS. LC-MS/MS quantification of the metabolites acetaminophen (CYP1A2), desacetaminoquin (CYP2C8), 4-hydroxydiclofenac (CYP2C9), dextrorphan (CYP2D6), and 1-hydroxymidazolam (CYP3A4) was performed using a PE SCIEX API 3000 LC/MS/MS system (Applied Biosystems, MDS Sciex, Concord, Ontario, Canada).

Data Analysis: CYP-mediated activities in the presence of inhibitors are expressed as a percentage of the corresponding control value. Data were fitted using a sigmoid curve and enzyme inhibition parameters _IC50 were calculated using nonlinear least squares regression analysis of the plots of percentage control activity versus test inhibitor concentration.

Table 4: Inhibitory effects of test compounds on CYP enzymes

Patch clamp hERG channel electrophysiological assay

In certain circumstances, dysfunction of cardiac ion channels can lead to arrhythmias. Consequently, safety pharmacology guidelines recommend or mandate studies of compounds’ effects on cardiac ion channels (hERG) ^.1 The hERG potassium channel is the most prominent target of drug-induced QT prolongation, ^2,3 an unwanted side effect that can lead to the life-threatening torsade de pointes ventricular arrhythmia.

The purpose of this assay is to evaluate whether test compounds have intrinsic effects on hERG K ⁺ currents in stably transfected HEK293 cells.Test compounds are evaluated in vitro at concentrations of 0.1, 1 and 10 μmol/L (approximately 5-6 minutes per concentration).

A whole-cell voltage-clamp technique (automated 8-channel system: Patcher, Nanion, Germany) was used using PatchControlHT software (Nanion) to control the Patcher system and handle data acquisition and analysis. Voltage-clamp control was provided by two EPC-10 quad amplifiers at room temperature under the control of PatchMasterPro software (both from HEKA Elektronik, Lambrecht, Germany) and an NPC-16 medium-resistance (~2 MW) chip (Nanion) as a planar substrate. hERG-mediated inward tail currents were evoked by hyperpolarizing voltage steps from +20 mV to -120 mV (500 ms duration); the holding potential was -80 mV and the activation potential was +20 mV (1000 ms duration), with the clamping protocol repeated every 12 s. The composition of the extracellular solution (in mmol/L): NaCl 140, KCl 4, CaCl ₂ 2, MgCl ₂ 1, glucose 5, HEPES 10, pH 7.4 (NaOH); the composition of the intracellular solution (in mmol/L): NaCl 10, KCl 50, KF 60, EGTA 20, HEPES 10, pH 7.2 (KOH). The effects of the test compounds were compared with those induced by the prodrug control values (i.e., no test compound present) and by the positive control E-4031 (a potent and selective hERG K + channel blocker (Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K ⁺ current. Differential sensitivity to block by class III antirrhythmic agents. J Gen Physiol 1990; 96: 195-215).

Exposure of HEK293 cells stably transfected with hERG K+ channels to test compounds is associated with a concentration-dependent inhibition of the hERG-mediated tail current amplitude. The concentration (μM) of test compound that achieves a half-maximal inhibitory concentration ( _IC50 ) is used to assess whether the test compound has an intrinsic effect on hERG K+ current. More preferred embodiments of the present invention have a hERG _IC50 > 5μM.

Rat CFA in vivo model

Male Sprague Dawley rats were used. Mechanical hyperalgesia was induced by injecting 25 μL of complete Freund's adjuvant (CFA) into the plantar surface of one hind paw. Mechanical hyperalgesia was measured using a pressure application measurement device (Ugo Basile, Gemonio, Italy). Briefly, a linearly increasing pressure was applied to an area of 50 ^mm2 on the plantar side of the hind paw until a behavioral response (paw withdrawal) was observed or until the pressure reached 1000 gf. The pressure at which the behavioral response occurred was recorded as the "paw withdrawal threshold" (PWT). The CFA injection and contralateral PWT of each rat were determined for each treatment group and at each time point of the study. Mechanical hyperalgesia was tested before CFA injection, 22 hours after CFA treatment (pre-drug baseline), and 2, 4, and 6 hours after compound administration. Compounds were administered 24 hours after CFA injection. Data are presented as the average PWT for each treatment group and each time point. Data were analyzed by repeated measures two-way ANOVA (time × treatment). Comparisons of planned means (each vs. vehicle) were performed using Dunnett's post hoc test, provided that a main effect was detected. Results were considered statistically significant for p values less than 0.05.

Preclinical in vivo efficacy models, such as the rat CFA in vivo model, are used in drug discovery to assess efficacy responses and demonstrate the desired duration of new drug candidates. A more preferred embodiment of the present invention demonstrates in vivo efficacy in rat CFA as measured by the "paw withdrawal threshold 6 hours post-drug" when administered at a 3 mg/kg p.o. dose.

Table 5: PWT data of the rat CFA in vivo model for the test compounds

*p<0.05, ***p<0.0001, Dunnett's post hoc test, different from the vehicle group, ns: not significant

Table 6: PWT data of rat CFA in vivo model at lower doses of Example 348

*p<0.05, **p<0.01, Dunnett's post hoc test, different from the vehicle group, ns: not significant

Mouse CFA in vivo model

Female C57BL/6 mice were used to evaluate the effect of P2X3 receptor antagonists on CFA-induced mechanical hyperalgesia. 30 μL of complete Freund's adjuvant (CFA, 1 mg/mL) was injected into the plantar surface of one hind paw. Mechanical hyperalgesia was measured using von Frey filaments. Briefly, von Frey filaments were used to stimulate the animal's hind paw, and behavioral responses were measured based on the strength of the von Frey filaments used. The strength of the filaments was expressed in [g], and the threshold was recorded when the animal's response was observed. 72 hours after CFA injection, CFA injection and contralateral response thresholds were determined for each mouse and each treatment group. Compound administration was performed p.o.b.i.d., starting one hour before CFA injection. Data are expressed as the mean threshold for each treatment group. Data were analyzed by one-way ANOVA for different dose groups. Planned means (each vs. vehicle) were compared using Dunnett's post hoc test, provided that a main effect was detected. Results were considered statistically significant for p values less than 0.05.

Example dose Efficacy Mouse CFA Model carrier 0.179g±0.044 11 25mg/kg,p.o. 0.682g±0.122(*)

*p＜0.05, different from the vehicle group

Rat dyspareunia model

Dyspareunia was surgically induced in female Sprague Dawley rats by autologous transplantation of small pieces of the uterine horn onto the abdominal artery, which grew into vascularized cysts.The visceromotor response (VMR) to vaginal distension was used in conscious animals as an objective measure of vaginal sensitivity.

Briefly, biopsies of the left uterine horn (3×3 mm) were surgically implanted around the alternating cascade of mesenteric arteries supplying the small intestine (4 pieces) and on the distal colon wall (2 pieces) of estrus animals. To measure VMR responses, two Teflon-coated electrode threads were sutured in the external oblique abdominal muscles and penetrated subcutaneously at the base of the neck for future access. On the day of VMR assessment, a small lubricated balloon (1 cm long) was inserted into the vaginal cavity. The balloon catheter was fixed to the base of the tail and connected to a volume controller/timing device (infusion pump) for balloon inflation. The vaginal balloon was inflated to increase the inflation intensity (0.05 ml increments every 20 seconds) to a maximum volume of 0.8 ml. The electrodes were connected to an amplifier (Animal Bio Amp, ADInstruments) and a data acquisition system (PowerLab, ADInstruments) was used to record abdominal muscle electromyographic signals for offline analysis using LabChart version 7. The amount of abdominal muscle contraction was manually counted for each 0.1 ml inflation step as an indicator of vaginal pain.

From the 4th to the 5th week after uterine horn implantation, Example 11 or vehicle was administered orally twice daily (b.i.d.) for 2 consecutive weeks. Example 11 was administered at 15 mg/kg b.i.d., and vehicle (0.5% carboxymethylcellulose in Tween 80/water (5/95, v/v)) was administered at 5 ml/kg b.i.d. When the animals were in estrus, VMR/vaginal dilation tests were performed 5 times (with drug) and 6 times (without drug).

Statistical analysis

All data are expressed as mean ± standard deviation (s.d.) for the number of rats measured in each group (n). Analyses were performed by running GraphPad Prism 6.03 software. Two (2) parameters were analyzed for each animal: 1) the cumulative number of abdominal contractions was calculated and plotted against the vaginal expansion volume; 2) the corresponding area under the curve (AUC) was calculated using GraphPad Prism version 6.03. Individual AUC values were subjected to a Grubbs test to reveal potential outliers. A repeated measures two-way analysis of variance (ANOVA) was used to analyze the cumulative number of contractions (expansion volume × treatment). Comparisons of planned means (matched volume vs. vehicle) were performed using the Bonferroni post hoc test, provided that a main effect was detected. The non-parametric Mann-Whitney t-test was used to compare the AUC means to the vehicle. Results were considered statistically significant for p values less than 0.05.

result

In vehicle-treated animals (5 ml/kg orally, b.i.d.), the cumulative number of abdominal contractions increased with increasing vaginal expansion volume, confirming the presence of vaginal hyperalgesia at 5 and 6 weeks after implantation of the uterine horn patch. Animals treated with Example 11 (15 mg/kg orally, b.i.d., within two weeks) presented with a reduction in vaginal hyperalgesia compared to vehicle-treated animals. Indeed, a reduction in the cumulative number of abdominal contractions in response to matching expansion volumes was observed, associated with a significant reduction in the corresponding AUC (see table below). A reduction in vaginal hyperalgesia was observed 5 weeks after implantation (p<0.05), while the animals were still on drug treatment, and 6 weeks after implantation (p<0.01), while the animals were not on drug treatment.

Effect of Example 11 on the area under the curve (AUC, a plot of cumulative number of abdominal contractions versus vaginal distension volume) at weeks 5 and 6 after uterine horn implantation. Data represent mean ± s.d. (n per group). *p < 0.05, **p < 0.01, different from the vehicle group.

In vivo pharmacokinetics in rats, dogs, and monkeys

For in vivo pharmacokinetic studies, test compounds are administered intravenously to male Wistar rats, Beagle dogs, or cynomolgus monkeys at doses of 0.3 to 1 mg/kg and formulated as solutions using well-tolerated solubilizers such as PEG400 for oral gavage at doses of 0.5 to 10 mg/kg.

In rats, box dosing of up to 3 compounds together at low doses was performed.

For pharmacokinetics after intravenous administration, test compounds were administered as i.v. boluses in male rats and as short-term infusions (15 minutes) in dogs and monkeys. Blood samples were taken, for example, at 2 min, 8 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration from the jugular vein (rats) or saphenous vein (dogs, monkeys). For pharmacokinetics after intragastric administration, compounds were administered to the stomach of fasted rats, dogs, and monkeys. Blood samples were taken, for example, at 5 min, 15 min, 30 min, 45 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. Blood was collected into lithium-intravascular (Sarstedt) tubes and centrifuged at 3000 rpm for 15 minutes. 100 μL aliquots were taken from the supernatant (plasma), 400 μL of cold acetonitrile was added for precipitation, and the mixture was frozen overnight at -20°C. The samples were then thawed and centrifuged at 3000 rpm, 4°C for 20 minutes. Aliquots of the supernatant were used for analytical testing using an Agilent HPLC system with LCMS/MS detection. PK parameters were calculated by non-partition analysis using PK calculation software (e.g., Phoenix Certara USA, Inc.).

PK parameters obtained from the concentration-time curve after i.v.: CLplasma (L/kg/h): total plasma clearance of the test compound calculated by dividing the dose (μg/kg) by the area under the concentration-time curve from t=0 h to infinity (extrapolated) (AUCinf, μg*h/L); CLblood: total blood clearance of the test compound: the ratios of the test compound concentrations in plasma and blood are Clplasma*Cp/Cb (L/kg/h) and Cp/Cb. PK parameters obtained directly from or calculated from the concentration-time curve after i.g. administration: Cmax: maximum plasma concentration (directly from the curve, mg/L); Cmaxnorm: Cmax divided by the administered dose (kg/L); Tmax: time point (h) at which Cmax is observed. Parameters calculated from the i.v. and i.g. concentration-time curves: AUCnorm: the area under the concentration-time curve from t = 0 h to infinity (extrapolated) divided by the administered dose (kg*h/L); AUC(0-tlast)norm: the area under the concentration-time curve from t = 0 h to the last time point at which plasma concentration could be measured divided by the administered dose (kg*h/L); t1/2: terminal half-life (h); F: oral bioavailability: AUCnorm after intragastric administration divided by AUCnorm after intravenous administration (%).

Pharmacokinetics describes the relationship between dose and unbound drug concentration at the site of action, as well as the time course of drug concentration in the body. Drug disposition is a broad term encompassing all the processes by which the body handles foreign chemicals, including drugs. These are absorption, distribution, metabolism, and excretion (ADME).

The terminal half-life (t1/2) after oral and intravenous administration and bioavailability (BA) are important pharmacokinetic properties of drugs. Preferred embodiments of the present invention show an elimination half-life of ≥6 hours and a bioavailability of ≥50% in dogs. More preferred embodiments of the present invention have an elimination half-life of ≥7 hours and a bioavailability of ≥70% in dogs.

Table 7: Pharmacokinetic characteristics of test compounds in dogs

Cyclophosphamide-induced overactive bladder (rat)/Cyclophosphamide-induced cystitis (rat)

The aim of this study was to test the efficacy of a P2X3 receptor antagonist against overactive bladder and cystitis in cyclophosphamide-treated rats.

The experimental setup was in accordance with a previously described protocol (Lecci A et al., Br J Pharmacol 130:331-38, 2000).

Briefly, female Sprague Daley rats (~200 g) were housed under normal conditions with a 12:12-hour light:dark cycle. Test compound (30 mg/kg) was administered by oral gavage 1 hour prior to intravenous administration of cyclophosphamide (100 mg/kg). Additionally, 1.5 hours after cyclophosphamide administration, each rat was transferred to a metabolic cage, and urination frequency was recorded for the following 15 hours. Urinating/hourly was recorded, and the AUC during the urination plateau (4-10 hours after transfer to the metabolic cage) was calculated for each animal using GraphPad Prism 6.

Claims (37)

1. Compounds of general formula (I) or salts thereof, or mixtures thereof: in ^R1 represents a _C1 - _C4 -alkyl group optionally substituted with 1-5 identical or different halogen atoms; ^R2 represents tetrahydrofuran-3-yl; ^R3 represents a _C1 - _C4 -alkyl group optionally substituted with 1-5 identical or different halogen atoms; A represents pyrimidinyl, pyridazinyl, pyridinyl, or pyrazinyl, which is optionally substituted by one or more identical or different substituents selected from halogen atoms and _C1 - _C3 -alkyl, wherein the _C1 - _C3 -alkyl is optionally substituted by 1 to 5 identical or different halogen atoms. 2. The compound according to claim 1, having the general formula (Ia): 3. The compound according to claim 2, wherein... ^R1 represents methyl or ethyl. 4. The compound according to claim 2, wherein... R ³ represents methyl. 5. The compound according to any one of claims 1 to 4, wherein A represents pyrimidinyl, pyridazinyl, pyridinyl, or pyrazinyl, which is optionally substituted 1 or 2 times with the same or different substituents, said substituents being selected from: fluorine or chlorine atoms, or _C1 - _C2 -alkyl groups optionally substituted with 1 to 5 fluorine atoms; ^R1 represents methyl; ^R2 represents tetrahydrofuran-3-yl; and R ³ represents methyl. 6. The compound according to any one of claims 1 to 4, wherein A represents _CF3 -pyrimidinyl. 7. The compound according to claim 6, wherein A represents 2- _CF3 -pyrimidin-5-yl. 8. The compound according to claim 1 or 2, i.e. 3-(5-methyl-1,3-thiazolyl-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; 3-(5-methyl-1,3-thiazolyl-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; 3-(5-methyl-1,3-thiazolyl-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazine-3-yl]ethyl}benzamide; 3-(5-methyl-1,3-thiazolyl-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[6-(trifluoromethyl)pyridazin-3-yl]ethyl}benzamide. 9. The compound according to claim 8, namely 3-(5-methyl-1,3-thiazolyl-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide; 3-(5-methyl-1,3-thiazolyl-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide. 10. The compound according to claim 9, namely 3-(5-methyl-1,3-thiazolyl-2-yl)-5-[(3R)-tetrahydrofuran-3-yloxy]-N-{(1R)-1-[2-(trifluoromethyl)pyrimidin-5-yl]ethyl}benzamide. 11. A pharmaceutical composition comprising a compound of any one of claims 1 to 10 or a salt thereof, or a mixture thereof, and a pharmaceutically acceptable diluent or carrier. 12. The pharmaceutical composition according to claim 11, wherein the salt is a pharmaceutically acceptable salt. 13. The use of any compound or salt thereof, or a mixture thereof, according to any one of claims 1 to 10, for the preparation of a medicament for the prevention or treatment of a disease, wherein the disease is selected from diseases, symptoms or disorders of the genitourinary, gastrointestinal, respiratory or pain-related systems; epilepsy; Parkinson's disease; Alzheimer's disease; myocardial infarction; lipid disorders. 14. The use according to claim 13, wherein the salt is a pharmaceutically acceptable salt. 15. The use according to claim 13, wherein the epilepsy is a focal or generalized seizure. 16. The use according to claim 13, wherein the disease is a disease of the urogenital system. 17. The use according to claim 16, wherein the urogenital disease is a urinary tract disease state associated with bladder outlet obstruction; urinary incontinence symptoms; benign prostatic hyperplasia; detrusor reflex resistance; overactive bladder and symptoms associated with overactive bladder; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis; or primary bladder hypersensitivity. 18. The use according to claim 17, wherein the cystitis is interstitial cystitis. 19. The use according to claim 16, wherein the disease of the urogenital tract is a gynecological disease. 20. The use according to claim 19, wherein the gynecological disease is dysmenorrhea, dyspareunia, or endometriosis, pelvic allergy, endometriosis-related pain, or other endometriosis-related symptoms. 21. The use according to claim 20, wherein the symptoms associated with endometriosis are dysmenorrhea, dyspareunia, dysuria, or dyscontinence. 22. The use according to claim 17, wherein the urinary incontinence symptoms are selected from decreased bladder capacity, increased urination frequency, urge incontinence, stress incontinence, or bladder hypersensitivity. 23. The use according to claim 17, wherein the prostate enlargement is benign prostatic hyperplasia. 24. The use according to claim 17, wherein the symptoms associated with overactive bladder are increased urinary frequency, nocturia, urinary urgency, or urge incontinence. 25. The use according to claim 13, wherein the disease is a gastrointestinal disease. 26. The use according to claim 25, wherein the gastrointestinal disease is selected from inflammatory bowel disease (IBD), biliary colic and other biliary tract diseases, renal colic, gastroesophageal reflux, gastrointestinal distension, Crohn's disease, and functional bowel disorders. 27. The use according to claim 13, wherein the disease is a respiratory disorder. 28. The use according to claim 27, wherein the respiratory disorder is selected from chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, and chronic cough. 29. The use according to claim 13, wherein the disease is related to pain syndrome. 30. The use according to claim 29, wherein the pain syndrome is selected from acute, chronic, inflammatory, and neuropathic pain. 31. The use according to claim 29, wherein the pain syndrome is selected from inflammatory pain, surgical pain, visceral pain, toothache, premenstrual pain, endometriosis-related pain, central pain, pain caused by oral burning syndrome, burn-related pain, migraine-related pain, cluster headache, neuralgia, poisoning-related pain, ischemic injury-related pain, interstitial cystitis-related pain, cancer pain, viral pain, parasitic or bacterial infection, traumatic nerve injury-related pain, post-traumatic injury-related pain, small fiber neuropathy-related pain, diabetic neuropathy-related pain, chronic lower back pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, gastrointestinal distension-related pain, chronic arthritis pain and related neuralgia, cancer-related pain, chemotherapy-related pain, HIV and HIV treatment-induced neuropathy; pain associated with diseases or conditions selected from: hyperalgesia, atypical pain, functional bowel disorder and arthritis. 32. The use according to claim 31, wherein the arthritis is selected from osteoarthritis and rheumatoid arthritis. 33. The use according to claim 31, wherein the post-traumatic injury is selected from fractures and sports injuries. 34. The use according to claim 26 or 31, wherein the functional bowel disorder is irritable bowel syndrome (IBS). 35. The use according to claim 34, wherein the functional bowel disorder is diarrhea-predominant IBS. 36. The use according to claim 29, wherein the pain syndrome is selected from pain caused by nerve damage and pain caused by neuritis. 37. The use according to claim 31, wherein the pain syndrome is pain caused by trigeminal neuralgia.