N-PROP-2-YNYL CARBOXAMIDE DERIVATIVES AND THEIR USE AS TRPA1

ANTAGONISTS

TECHNICAL FIELD

The present disclosure relates to pharmacologically active arylamide derivatives, or pharmaceutically acceptable salts and esters thereof, as well as to pharmaceutical compositions comprising them and to their use in the treatment of diseases linked to the activation of the TRPAl (Transient Receptor Potential subfamily A, member 1) receptors.

BACKGROUND OF THE INVENTION

Human TRPAl was first cloned from lung fibroblasts. TRPAl was functionally

characterized as a calcium permeable nonselective cation channel that is selectively localized to pain sensing peptidergic unmyelinated sensory neurons, which coexpress TRPV1, substance P and CGRP. TRPAl exists in both peripheral and central terminals of sensory neurons.; Amino acid sequence comparison revealed that TRPAl is a member of the transient receptor potential ion channel superfamily. A recent study finds a somewhat broader expression of TRPA 1 even in myelinated fibers.

Studies in healthy animals suggest that TRPAl is not activated under physiological conditions. Acute administration of TRPAl agonists such as mustard oil and

cinnamaldehyde to the skin causes acute pain and nocifensive behavior in healthy animals and man. Several pathophysiological conditions such as acute and chronic neuropathic pain, diabetes, cancer, inflammation, asthma, arthritis, migraine, osteoarthritis, sleep deprivation, and bladder dysfunction are known to have increased production of endogenous reactive compounds such as 4-hydroxynonenal, acetaldehyde, hydrogen peroxide, prostaglandin J2, prostaglandin A2, methylglyoxal, which are known to act as TRPAl agonists. Interestingly, several TRPAl agonists also can be produced through an oxidative stress-related non-enzymatic route.

TRPAl is a nonselective cation channel with substantial calcium permeability, TRPAl is activated through an unusual mechanism in which reactive compounds bind covalently to cysteine and lysine amino acid residues in the N-terminus of the channel protein.

Pathophysiological sustained TRPAl activation by reactive agonists in sensory neurons may result in axoplasmic calcium dysregulation which causes peripheral axonopathy.

Axonopathy is a common diagnostic finding in chronic pain patients and patients suffering from work-related exposure to neurotoxic compounds. Axonopathy of sensory neurons is often diagnosed in diabetic patients, who suffer from chronic pain, mechanical

hypersensitivity, erectile dysfunction, impaired wound healing, numbness, and at later stage, from leg amputations.

Activation of presynaptic TRPAl facilitates glutamate release from axon terminals of sensory neurons in the spinal cord. Enhanced glutamate release is shown to cause central pain and secondary mechanical hypersensitivity. Spontaneous pain, secondary mechanical hypersensitivity, and mechanical hyperalgesia are common symptoms of neuropathic pain patients. Recently, human TRPAl gain-of-f unction mutation carriers were discovered and shown to have enhanced secondary hyperalgesia to peripheral TRPAl stimulation, which confirms the role of spinal TRPAl in processing of secondary hyperalgesia. A recent study revealed that spinal TRPA 1 plays a key role in neurogenic inflammation reflex, which is evoked by' peripheral injury. Neurogenic inflammation is enhanced in several diseases such as fibromyalgia, migraine, complex regional pain syndromes, pain in and around the eye, and urticaria.

TRPAl activation in the gastrointestihal tract has been shown to release serotonin from enterochromaffin cells. Increased serotonin release induces hypermotility of the gut.

Treatment of cancer with reactive compounds increases plasma serotonin level, which is well known to induce nausea and vomiting. TRPAl activation in airways has been shown to contribute to sensory neuronal hypersensitivity in several airway diseases such as chronic cough, asthma, and chronic obstructive pulmonary disease. TRPAl activation has been shown to release noradrenaline from superior cervical ganglion sympathetic neurons.

Several cardiovascular disorders such as cardiac dysrhythmias and high blood pressure, are well known to be caused by increased plasma noradrenaline level. TRPAl has been shown to play a critical role in histamine-independent itch transduction. TRPAl activation has been shown to result in cold hypersensitivity. Cold pain is a common symptom present in several disease conditions such as dental pain, fibromyalgia, complex regional pain syndrome, cancer pain, and neuropathic pain. Selective TRPAl modulators can be used for treatment of a large number of acute and chronic TRPAl activation-dependent diseases and symptoms,

Various TRPAl modulators have been described earlier, for example, in the international publications WO 2009/118596, WO 2009/144548, WO 2009/147079, WO 20107004390,

WO 2010/075353, WO 2010/109287, WO 2010/109329, WO 2010/109328, WO

2010/109334, WO 2010/125469, WO 2010/132838, WO 2010/138879, WO 2010/141805, WO 2011/043954, WO2011/132017, WO2011/114184 and WO2012/085662.

WO2004/060286 discloses certain benzamide derivatives for the treatment of pain and traumatic injury.

SUMMARY OF THE INVENTION

An object of the present disclosure is to provide novel TRPAl modulators that can be used for the treatment of disorders, conditions, or diseases mediated by TRPAl, activity.

Accordingly, an object of the present disclosure is to pro vide, further compounds, to be used as TRPAl modulators in the treatment of mammals. Furthermore,, pharmaceutical compositions comprising the presently disclosed compounds are also provided.. , . . , , , ,

The TRPA l modulators of the present disclosure have an enhanced potency and/or improved metabolic stability and/or improved solubility.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to novel TRPAl modulators having the general formula I,

(I)

wherein

A and B form, together' with the atoms to which they are attached,

wherein the atoms marked with * and *' are bonded to the parent molecular moiety;

X is C s or N;

Y is CR6 or N;

Z is CR4 or N, provided that when Y or X is N, then Z is not N;

Ri is (Ci-C6)alkyl, cyclo(C3-C6)alkyl, halo(C C6)alkyl, (C C6)alkoxy(C1-C6)alkyl, halo(C C6)alkoxy(C C6)alkyl, (CrC6)alkyl-S-(CrC6)alkyl, heterocyclyl, heterocyclyl(C1-C3)alkyl, phenyl, phenyl(C1-C3)alkyl, or phenoxy(CrC6)alkyl, wherein said cyclo(C3-C6)alkyl, heterocyclyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (CrC )alkyl, halo(C!-C5)alkyl, (Ci-C5)alkoxy, cyclo(C3-C6)alkyl, CN, haloCQ-Qialkoxy, (C1-C5)alkyl-S-, (C C5)alkyl-(S=0)-, (d-C5)alkyl-(0=S=0)-, (CrC3)alkylamino or di(C C3)alkylamino;

R2 is (C,-C6)alkyl; ;

R3 is (d-C6)alkyl;

R4 is H, halogen, (CrC6)alkyl, (C1-C6)alkoxy, halo(C C6)alkyl, halo(CrC6)alkoxy, (Q-C6)alkoxy(C1-C6)alkoxy, (Cj-C6)alkyl-S-, (C1-C6)alkylamino, hal (C1-C6)alkylamino, (Q-C6)alkyl(C=0), CN, or heterocyclyl;

R5 is H, halogen, (Ci-C6)alkyl, cyclo(C3-C6)alkyl, (C C6)alkoxy, haloCQ-C^alkyl, (C C6)alkoxy(Ci-C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (Ct-Ce^alkyl-S-, (C C6)alkyl-(S=0)-, (C1-C6)alkyl-(0=S=0)-, halo(C1-C6)alkyl-S-, halp(C C6)alkylamino, (C1-C6)alkyl-(C=0), or CN; and

R6 is H, halogen, (Q- alkyl, or halo(C!-C6)alkyl;

or Ri and R6 form, together with the atoms to which they are attached, a condensed 5 or 6 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom to which Ri is attached, 0 or 1 further heteroatom selected from N, O, and S, wherein said heterocyclic ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being (Ci-C2)alkyl or halogen;

or R4 and R5 form, together with the carbon ring atoms to which they are attached, a condensed 5, 6, or 7 membered saturated or unsaturated carbocyclic ring or a condensed 5, 6, or 7 membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatom(s) selected from N, O, arid S, wherein said carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being (Ci-C2)alkyl or halogen; or a pharmaceutically acceptable salt or ester thereof;

with the proviso that the compound is not 2-(methylamino)-N-(2-methylbut-3-yn-2-

yl)benzamide or N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzarnide.

In at least one embodiment,

A and B form together with the atoms to which they are attached,

wherein,

X is CR5 or N;

Z is CR4 or N;

Ri is (CrC6)alkyl, cyclo(C3-C6)alkyl, halo(Ci-C6)alkyl, (CrC6)alkoxy(Ci-C6)alkyl, halo(C C6)alkoxy(C1-C6)alkyl, heterocyclyl, heterocyclyl(C1-C3)alkyl, phenyl, phenyl(CrC3)alkyl, or phenoxy(CrC6)alkyl, wherein said cyclo(C3-C6)alkyl, heterocyclyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen,

( i-C3)alkyl, halo(C1÷C3)alkyl, (C C3)alkoxy, cyclo(C3-C6)alkyl, or CN;

R2 is (C,-C6)alkyl;

R3 is (Q-Q alkyl;

R.4 is H, halogen, (Ci-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, CN, or heterocyclyl;

R5 is H, halogen, (C C6)alkyl, (CrC6)alkoxy, halo(C C6)alkyl, halo(CrC6)alkoxy, (Cr

C6)alkyl-S-, or CN; and

R6 is H or halogen;

or R and R6 form, together with the atoms to which they are attached, a condensed 5 or 6 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom to which Ri is attached, 0 further heteroatoms, wherein said heterocyclic ring is unsubstituted or substituted with 2 substituent(s) each independently being (Q-C^alkyl; or R4 and R5 form, together with the carbon ring atoms to which they are attached, a condensed 5, 6, or 7 membered saturated heterocyclic ring containing 1 or 2 heteroatom(s) which are O, wherein said heterocyclic ring is unsubstituted.

In another embodiment, A arid B form, together with the atoms to which they are attached,

wherein,

X is CR5 or N;

Y is CRe or N;

Z is CR4 or N;

Ri is (C,-C6)alkyl, cyclo(C3-C6)alkyl, halo(d-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halo(C C6)alkoxy(Ci-C6)alkyl, heterocyclyl, heterocyclyl(C1-C3)alkyl, phenyl, phenyl(C1-C3)alkyl, or phenoxy(Ci-C6)alkyl, wherein said cyclo(C3-C6)alkyl, heterocyclyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (CrC3)alkyl, halo(C C3)alkyl, (CrC3)alkoxy, or cyclo(C3-C6)alkyl;

R2 is (Q-Q alkyl;

R3 is (Ci-C6)alkyl;

R4 is H, halogen, (Q-C^alkyl, (Ci-C6)alkoxy, halo(CrC6)alkyl, CN or heterocyclyl;

R5 is H, halogen, (C C6)alkyl, (C C6)alkoxy, haloCQ-Q alkyl, halo(C C6)alkoxy, (C C6)alkyl-S-, or CN; and

R6 is H or halogen;

or Ri and R6 form, together with the atoms to which they are attached, a condensed 5 or 6 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom to which R\ is attached, 0 further heteroatoms, wherein said heterocyclic ring is unsubstituted or substituted with 2 substituent(s) each independently being (C1-C2)alkyl; or R4 and R5 form, together with the carbon ring atoms to which they are attached, a condensed 5, 6 or 7 membered saturated heterocyclic ring containing 1 or 2 heteroatom(s) which are O, wherein said heterocyclic ring is unsubstituted.

In another embodiment,

X is CR5 or N;

Y is CR6 or N;; '

Z is CR4; " '■ - · '■■ " :

Ri is (C,-C6)alkyl, cyclo(C3-Q,)alkyl, halo(C C6)alkyl, (C , -C6)alkoxy(C , -C6)alkyl, halo(C , - C6)alkoxy(C1-C6)aikyl, or phenyl, Wherein said cyclo(C -C6)alkyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (C1-C3)alkyl, or (C C3)alkoxy;

R2 is (C,-C3)alkyl;

R3 is (CrC3)alkyl;

R4 is H, halogen, (CrC)alkoxy, or halo(CrC4)alkyl;

R5 is H, halogen, (C C4)alkyl, (Q-G alkoxy, halo(C1-C4)alkyl, halo(d-C4)alkoxy or (C C4)alkyl-S-; and

R6 is H or halogen;

In another embodiment,

Xis CR5 orN;

YisCR6 orN; ' ·: ^;·--- ·; " v

Z is CR4;

Ri is, (CrC^alkyl, cyclo(C3-C6)alkyl, halo(C!-C6)alkyl, or phenyl, wherein said cycIo(C3-C )alkyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (C1-C3)alkyl, or (Ci-C )alkoxy;

R2 is (C,-C3)alkyl; "; ;- R3 is (Ci-C3)alkyl;

R4 is H, halogen, (C1-C4)alkoxy or halo(Ci-C4)alkyl;

R5 is H, halogen, (C C4)alkyl, (C C4)alkoxy, halo(C C4)alkyl, halo(Ci-C4)alkoxy or (C C4)alkyl-S-; and

R6 is H or halogen.

In another embodiment,

X is CR5; !:'-- Y is CR6; V",:'"'"; ' ; ''--"Γί -■

ZisCR4: ·■ " '': ''' ' ' -;

Ri is, (Ci-C6)alkyl, cyclo(C3-C )alkyl, halo(C1-C6)alkyl, or phenyl, wherein said cyclo(C3- C6)alkyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (Q-C^alkyl, or (CrC2)alkoxy;

R2 is (C C2)alkyl; ,

R3 is (C C2)alkyl;

R4 is H, halogen, (Ci-C2)alkoxy or halo(Ci-C2)alkyl;

R5 is H, halogen, (Cr-C2)alkyl, (CrC2)alkoxy, halo(C1-C2)alkyl, halo(CrC2)alkoxy or (Q-C2)alkyl-S-; and

R6 is H or halogen.

In another embodiment,

X is CR5;

Y is N;

Z is CR4;

Ri is, (CrC6)alkyl, cyclo(C3-C6)alkyl, halo(CrC6)alkyl, Or phenyl, wherein said cyclo(C3-C6)alkyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each

independently being halogen, (CrC2)alkyl, or (Ci-C2)alkoxy;

R2 is (C,-C2)alkyl; :

R3 is (C1-C2)alkyl;

R is H, halogen, (C i -C2)alkoxy or halo(C i -C2)alkyl ; and

R5 is H, halogen, (Ci-C2)alkyl, (C C2)alkoxy, halo(CrC2)alkyl, halo(C(-C2)alkoxy or (Q-C2)alkyl-S-.

In another embodiment,

X is CR5 or N;

Ϋ is CR6 or N; ' ! ' · : ' - ' - "; '■' ■'■■''·■'■'' ' '

Z is CR4;

Ri is phenyl; wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (C!-C3)alkyl or (C1-C3)alkoxy;

R2 is (C-Oalkyl;

R3 is (C1-C3)alkyl;

R4 is H, halogen, (C|-C4)aIkoxy, or halo(Ci-C4)alkyl;

R5 is H, halogen, (C C4)alkyl, (C C4)alkoxy, haloiC C^alkyl, halo(Ci-C4)alkoxy, or (Ct-C4)alkyl-S-; and

R6 is H or halogen.

In yet another embodiment,

X is CR5;

Y is N; ■ ■ ; - --- .■

Z is CR4;

Ri is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (Q-C^alkyl or (Q-C^alkoxy;

R2 is (C1-C2)alkyl;

R3 is (C C2)alkyl;

R4 is H, halogen, (CrC2)alkoxy or halo(C1-C2)alkyl; and

R5 is H, halogen, (C1-C2)alkyl, (C C2)alkoxy, halo(Ci-C2)alkyl, halo(C1-C2)alkoxy or (Q-C2)alkyl-S-.

In a further embodiment, X is CR5, Y is N, and Z is CR4.

In another embodiment, X is CR5, Y is CR6, and Z is CR4.

In yet another embodiment, the compound of formula I is 5-fluoro-iV-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamiho)nicotinamide, N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)-2-(3 ,3 ,3-trifluoropropylamino)nicotinamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzamide, 5-chloro-2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, 5-chlOro-2-(2,2-difluo oethylarmno)-N-(2-methylbut-3-yn-2-yl)benzarnide, N-(2-methyibut-3-yn-2-ylj-7-(3,3,3-trifluoropropylaniino)-2^

6-carboxamide, 6-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)benzo[d][l,3]dioxole-5-carboxamide, 8-(isobutylamino)-iV-(2-methylbut-3-yn-2-yl)-3,4-dihydro-2H-benzo[b][l ,4]dioxepine-7-carboxamide, 7-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)-2,3-dihydrobenzo[bj[ l ,4]dioxine-6-carboxamide, 2-(2,2-difluoroethylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)berizan^

(3,3,3-trifluoropropylamino)pyrimidine-5-carboxamide, N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)-2-(3,3,3-trifluoropropylamino)benzamide, 4-chloro-N-(2-methylbut-3-yn-2-yl)-2-(propyiamino)benzamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylarnino)benzamide, 3-fluoro-N-(2-methylbut-3 -yn-2-yl)-2-(3 ,3 ,3 -trifluoropropylarnino)benzamide, 3-fluoro-N-(2-methylbut-3-yn-2-yl)^2-(propylamino)-benzamide, 2-(cyclobutylarnino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzamide, N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropylarnino)-5-(trifluoro methyl)benzamide, N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropylamino)benzamide, 2-(2,2-difluoroethylamino)-5-fluoro-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2-

(cyclobutylamino)-3-fluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 5-fluoro-/V-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)benzamide, 2-(cyclobutylamino)-iV-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)benzamide, 2-(cyclobutylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 2-(cyclobutylannno)-5-fluoro-N-(2-methylbut-3-yn-2-yl)nic0tinamide, 5-chloro-2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-chloro-2-(cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)nicotinamide, 5-fluoro-iV-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropylan ino)nicotinamide, 5-methyl-N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropylamino)benzamide, 5-fluoro-N-(2-methylbut-3-yn-2-yi)-2 (2,2,3 ,3 ,3-pentafluoropropylamino)benzamide, 5-chloro-2-(2,2-difluoroethyiamino)JN-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2:

trifluoroethylamino)nicotinamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluorOethylainino)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)-5-(trifluoromethyl)nicotinamide, 5-cyano-2-(cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, 4-cyano-2-(cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, 4,5-difluoro-N-(2-methylbut-3-yn-2-yl ^

methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylaniino)-5-(trifluoromethyl)be 5-m.ethyl-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)benzamide, 5-chlpro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)nicotinamide, 2-(butylamino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 5-bromo-N-(3-ethylpent-l-yn-3-yl)-2-(2-methoxyethylamino)benzamide, 5-chloro-N-(3-ethylpent- 1 -yn-3-yl)-2-(2-methoxyethylamino)benzamide, 7V-(3-ethylpent- 1 -yn-3-yl)-4,5-difluoro-2-(2-methoxyethylamino)benzamide^ N-(3-ethylpent- 1 -yn-3-yl)-2-(2-methoxyethylaminb)-5-(trifluoromethyl)berizamide, N-(3-cthylpcnt- 1 -yn-3-yl)-5-iodo-2-(2-methoxyethylamino)-benzamide, 2-(2-methoxyethylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)-benzamide, 2-(butylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 5-iodo-2-(2-methoxyethyIan ino)-N-(2-methylbut-3-yn-2-yl)benzaniide, 5-fluoro-2-(isdbutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(isopentylamino)-N-(2-methylbut-3-yn-2^ yl)nicqtinamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(2-(trifluoromethoxy)ethylamino)-benzamide, 5-fluoro-N-(2-inethylbut-3-yn-2-yl)-2-(4,4,4-trifluorobutylanTino)benzami

3,5-difluoro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamirio)benza 2-(2,2-difluorpethylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)nicotinainide, 2-(2,2- difluoropropylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)nicotinamide 2-(3,3- '

difluoropropylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)nicOtina

2- (2,2-difluOropropylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-ehloro-2-(3,3-difluoropropylamino)-N-(2-niethylbut-3-yn-2-yl)nicotinamide, 4,5-difluoro-N-(2-methylbut- 3- yn-2-yl)-2-(neopentylamino)benzamide, 4,5-difluoro-2-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, 4,5-difluoro-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzamide, 2-(butylamino)-iV-(2-methylbut-3-yn-2-yl)benzamide, 2-(ethylamino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 4,5-difluoro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 4,5-difluoro-2-(isopropylamino)-N-(2-metliylbut-3-yn-2-yl)benzamide, N-(3,5-dimethylhex-l-yn-3-yl)-4,5-difluoro-2-(isobutylaniino)benzamide, N-(3,4-dimethylpent-l-yn-3-yl)-4,5-difluoro-2-(isobutylamino)benzamide, 4,5-difluoro-2-(isobutylamino)-N-(3-methylhex- 1 -yn-3-yl)benzamide, 4-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, N-(2-methylbut-3-yn-2-yl)-4-(trifluoromethyl)-2-(3,3,3-trifluoropropylamino)benzamide, 4-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 4-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)-benzamide, N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethoxy)-2-(3,3,3-trifluoropropylamino)-benzamide, 5-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)-benzamide, 5-methyl-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropyIamino)benzamide, N-(2-methylbut-3-yn-2-yl)-5-(methylthio)-2-(3,3,3-trifluoropropylamino)benzamid N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 2-(isqbutylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, N-(2-methylbut-3-yn-2-yl)-2-(neopentylamino)benzamide, 2-(te^butylamino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzarmde, 4-fluoro-2-(isopropylamino)-N;-(2-methylbut-3-yn-2-yl)benzamide, 2-(methylamino)-N-(2-methylbut-3-yn-2-yl)-4-(trifluoromethyl)benzamide, 2-(methylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethpxy)benzamide, 2-(cyclopropyIanuno)-4,5-difluoro-N-(2-methy^^

yl)benzamide, N-(3,4-dimethylpent-l-yn-3-yl)-2-(ethylamino)-4,5-difluorobenzamide, 2-(isobutylamino)-4,5-dimethoxy-N-(2-methylbut-3-yn-2-yl)benzamide, 2-(2-hiethoxy-ethylamino)-N-(2-methylbut-3-yn-2-yl)-4-(trifluoromethyl)benzamide, 2-(cyclopropyl-amino)-4-fluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 2-(cyclopropylamino)-5-fluoro-N-(2-methylbut-3-yn-2~yl)benzamide, 5-fluoro-2-(isopropylamino)-iV-(2-methylbut-3-yn-2-yl)benzamide, 2-(isopropylamino)-5-methyl-N-(2-methylbut-3-yn-2-yl)benzamide, 4-methyl-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzainide, 5-cHloro-3- fluoro-2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, 5-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(4,4,4-trifluorobutylamino)benzamide, 2-(3-methoxybenzylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3-fluorobenzylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-(propylamino)-6-(trifluoromethyl)-nicotinamide, 2-(butylan ino)-N-(2-niethylbut-3-yn-2-yl)nicotinaniide, 2-(iert-butylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(butylaimno)-5-fluoro-A -(3-methylpent-l-yn-3-yl)benzamide, 2-(ethylamino)-N-(3-ethylpent- l-yn-3-yl)-5-fluorobenzamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 2-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)nicotinaniide, 2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)nicotinamide, 2-(ethylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)nicotinamide, 4-(½rt-butylamino)-iV-(2-methylbut-3-yn-2-yl)-2-(trifluoro-methyl)pyrimidine-5-carboxamide, N-(2-methylbut-3-yn-2-yl)-4-(tert-pentylamino)-2-(trifluoromethy^pyrimidine-S-carboxamide, 4-(isopropylamino)-N-(2-methylbut^3-yn-2-yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, 2-(tert-butylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)nicotinamide, 6-chloro-2-(isopropylamino)-N:(2-methylbut-3-yn-2-yl)nicotinamide, 6-chloro-2-(ethylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro- 2- (isopropylamino)-N-(2-methylbut-3-yn-2-yl)-6-moφholinonicotinamide, N-(2-methylbut- 3- yn-2-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-6-(trifluoromethyl)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-((tetrahydro-2H-pyran-4-yl)methylamino)-6-(trifluoromethyl)-nicotinamide, 2-(cyclopropylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)-nicotinamide, 2,3-dimethyl-N-(2-methylbut-3-yn-2-yl)- lH-indole-7-earboxamide, 7V-(3-ethylpent-l-yn-3-yl)-lH-indble-7-carboxamide, N-(3-ethylpent-l-yn-3-yl)-l,2,3,4-tetrahydroquinoline-8-carboxamide, 2-(3-fluorophenylamino)-N-(2-methylbat-3-yh-2-yl)nieotinamide, 2-(2-fluorophenylamino)-N-(2-methylbut-3-yn-2-yl)nic0tinamid , 2-(4,4-difluorocyclohexylaminO)-N-(2-methylbut-3-yn-2-yl)nicotinarnide, 5-bromo-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzan ide, N-(2-methylbut-3-yn-2-yl)÷2-( 1 , 1 , 1-trifluoro-2-methylpropan-2-ylamino)nicotinamide, N-(2-methylbut-3-yn-2-yI)-4-(propylaniinb)thiophene-3-carb0xamide, N-(2-methylbut-3-yn-2-yl)-2-(phenyIamino)-nicotinamide, 2-(¾^butylamino)-N-(2-rnethylbut-3-yn-2-yl)-5-(trifluoromethyl)-nicotinamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(phenylairdno)nieotinamide, 2-(butylamino)-N-(2-methylbut-3-yn-2-yl)thiophene-3-carboxamide, 2-(4-fluorophenyI-amino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, N-(2-methylbut-3-yn-2-yl)

pentafIuoropropylamino)pyrimidine-5-carboxan ide, 2-(3,3-difluorocycl0butylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 3-((4-chlorophenyl)amino)-N-(2-methylbut-3-yn-2-yl)isonicotinamide, 2-(3,3-difluoropropylan ino)-3,5-difluoro-N-(2-metHylbut-3-yl)benzamide, 3-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)thiophene-2-carboxamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(3-methylisothiazol-5-ylamino)nicotinamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(pyridin-3-ylamino)nicotinamide, 5-chloro-2-(3,3-difluorocyclobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(6-cyclopentylpyridin-3-ylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,3-difluorocyclo-butylaminp)-N-(2-methylbut-3-yn-2-yl)-5-(triflupro

yn-2-yl)-2-(phenethylamino)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-(3-phenylpropyl-amino)nicotinamide, 5-fluorp-2-(3-(4-fluorophenoxy)propylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(2-(4-fluorophenoxy)ethylamino)-N-(2-methylbut-3:yn-2-yl)nicotinamide, 5-chlorp-2-(3-ethoxypropylamino)-N-(2-methylbut-3-yn-^

2-(2-te^butoxyethylamirio)-5-chloro-N-(2-methylbut-3-yn-2-yl)nicoti 5-chlpro-2-(2-ethoxyethylamino)-N-(2-methylbut-3-yn-2-yl)nicotinaniide, 2-(3-fluoro-4-methyl-phenylaminp)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3-chloro:4-methpxyphenyl-amino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,5-difluorophenylamino)-N-(2-methylbut-3-yn-2-yl)nicPtinamide, 2-(3,3-difluprocyclobutylamino)-5-(difluoromethyl)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-bromo-2-(ethylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-ethoxy-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzamide, 2-(tert-butylaminp)-5-chloro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3 ,3-difluprocyclobutyl-amino)-5-fluPro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(4-fluorpphenylamino)-N-(2-metliylbut-3-yn-2-yl)nicotinaniide, 5-fluoro-N-(2-n ethylbut-3-yn-2-yl)-2-( 1 , 1 , 1 -trifluoropf0pan-2-ylaniino)nieotinamide, 4-(4-chlorophenylamino)-N'(2-methylbut-3-yn-2-yl)nicotiriamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(phenyiamino)nicotinamide, N-(2-methylbut-3-yn-2-yl)-4-(4-(trifluoromethyl)^^

butylaniino)-5-flUoro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,3-difluoroeyclpbutyl-arnino)-N-(3-ethylpent-l-yn-3-yl)-5-fluoronicotinamide, 2-(3,3-difluorocyclobutylamino)-5-fluorp-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2-(3-fluoro-5-methoxypheriylamino)-N-(2-methylbut-3-yn-2-yl)nicptinamide, 2-(3-flupro-5-methpxyphenylamino)-N-(3-niethylpent- 1 -yn-3-yl)nicotinamide, 2-(3-chloro-5-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3-chloro-5-methPxyphenylamino)-N-(3-methylpent-l-yn-3-yl)-

nicotinamide, 2-(2-fluoro-3-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)nicOtihamide, 2-(2-fluoro-3-methoxyphenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 5-fluoro-2-(4-fluorophenylamino)-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, 5-fluoro-N-(3-methylpent- 1- yn-3-yl)-2-(phenylamino)nicotinamide, 2-(2,4-difluorophenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2,4-difluorophenylamino)-N-(3-methylpent-l-yn-3-yl)-nicotinamide, 5-fluoro-2-(3-fluorophenylarmno)-A^-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(3-fluorophenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 5-chloro-2-(3,3-difluorocyclobutylamino)-N-(3-methylpent- l-yn-3-yl)nicotinamide, 2-(3-cyanophenyl-amino)-5-fluoro-iV-(3-methylpent- l-yn-3-yl)nicotinamide, 2-(2-fluoro-5-methoxyphenyl- . amino)-iV-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2-fluoro-5-methoxyphenylamino)-iV-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2-(3-cyano-4-fluorophenylamino)-N-(2-methylbut-3-yn- 2- yl)nicotinamide, 2-(3-cyano-4-fluorophenylamino)-iV-(3-methylpent- l-yn-3-yl)-nicotinamide, 2-(3-cyano-5-fluorophenylaniino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3-fluorophenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinarnide, 2-(2-fluorophenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 2-(3,5-difluorophenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 2-(3-cyano-5-fluorophenylamino)-N-(3-methylpent- 1 -yn-3-yl)-nicotinamide, 2-(2-chlorp-5-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2-chloro-5-methoxyphenylamino)-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, N-(3-methylpent- 1 -yn-3-yl)-2-(phenylamino)nicotinamide, 2-(4,4-difluorocyclohexylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 2-(3-chloro-4-methoxyphenylamino)-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2-(4-fluoro-3-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(4-fluoro-3-methoxyphenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 2-(3,4-difluof ophenylamino)-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2-(4-chloro-3-methoxyphenylaniino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(4-chlOro-3-; methoxyphenylamino)-/V-(3-methylpent- 1 -yn-3-yl)nicotinamide, or 2-(4-nuorophenylamino)-/V-(3-methylpent- l -yn-3-yl)nicotinamide.

The terms employed herein have the meanings indicated below. The term "at least one" ; employed in the meanings below refers to one or several, such as one. For example, the term "at least one fluorine" refers to one or several fluorines, for example three, two, or one fluorines, such as three fluorines.

The term "halo" or "halogen", as employed herein as such or as part of another group, refers to fluorine, chlorine, bromine, or iodine.

The term "(Ci-C2)alkyl", as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 1 or 2 carbon atom(s). Representative examples of (Ci-C2)alkyl include methyl and ethyl.

The term "(CrC3)alkyl", as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 1 , 2, or 3 carbon atom(s). Representative examples of (Ci-C3)alkyl include methyl, ethyl, n-propyl and isopropyl.

The term "(C1-C )alkyl",; as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety* containing 1 , 2, 3 , or 4 carbon atom(s). Representative examples of (Q-G alkyl include methyl, ethyl, n-propyl, isopropyj, n-butyl, isobutyl, .vet-butyl and ½rr-butyl. .

The term "(C1-C5)alkyl", as employed herein as such or as part of another group, refers to a saturated hydrocarbon group haying a straight or branched moiety, containing, 1,, 2, 3, 4, or 5, carbon atom(s). Representative examples of (C1-Cs)alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, and neopentyl.

The term "(Ci-C )alkyl", as employed herein as such or as part of another group, refers to a saturated hydrocarbon group having a straight or branched moiety, containing 1, 2, 3, 4, 5, or 6 carbon atorn(s). Representative examples of (Ci-C6)alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, terr-pentyl, neopentyl and n-hexyl.

The term "cyclo(C3-C6)alkyl", as employed herein as such or as part of another group, refers to a saturated hydrocarbon group haying cyclic moiety, containing 3, 4, 5, or ,6 carbon, atom(s). Representative examples of cyclo(C3-C6)alkyl include, but are not lirnited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term "(Q-Cijalkoxy", as employed herein as such or as part of another group, refers to an (C1-C2)alkyl group, as defined herein, bonded to an oxygen atom. Representative

examples of (C1-C2)alkoxy include methoxy and ethoxy.

The term "(CrC3)alkoxy", as employed herein as such or as part of another group, refers to an (CrC3)alkyl group, as defined herein, bonded to an oxygen atom. Representative examples of (CrC3)alkoxy include, but are not limited to, methoxy, ethoxy, and n-propoxy.

The term "(C1-C )alkoxy", as employed herein as such or as part of another group, refers to an (C]-C4)alkyl group, as defined herein, bonded to an oxygen atom. Representative examples of (C1-C4)alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy.

The term "(C1-C5)alkoxy", as employed herein as such or as part of another group, refers to an (Ci-C5)alkyl group, as defined herein, bonded to an oxygen atom. Representative examples of (Ci-C5)alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 2,2-dimefhylpropoxy, and 3-methylbutoxy.

The term "(Ci-C6)alkoxy", as employed herein as such or as part of another group, refers to an (C1-C6)alkyl group, as defined herein,, bonded to an oxygen atom. Representative examples of (Ci-C6)alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, .vi'obutoxy, teri-butoxy, 2,2-dimethylpropoxy, 3-methylbutoxy, and n-hexoxy. . ,

The terms "(drQ alkyl-S-", (C,-C4)alkyl-S-", "(C C5)alkyl-S-;', or "(C,-C6)alkyl-S-'\ as employed herein as such or as part of another group, refer to an (Ci-C2)alkyl? (Ci-C4)alkyl, (Ci-C5)alkyl, or (Ci-C6)alkyl group, as defined herein, bonded to a sulfur atom.

Representative examples of (C1-C2)alkyl-S-, (C1-C4)alkyl-S-, (C1-C5)alkyl-S-, or

(C1-C6)alkyl-S- include, but are not limited to, thiomethyl, thioethyl, thiopropyl, and thiobutyl.

The term "(C1-C )alkyl(C=0)", as employed herein as such or as part of another group, refers to a (Ci-C6)alkyl group, as defined herein, bonded to a carbonyl group,. Representative examples include, but are not limited to, acetyl, ethylcarbonyl, propylcarbonyl, and isopropylcarbonyl.

The term "(Ci-C6)alkoxy(Ci-C6)alkyl", as employed herein as such or as part of another

group, refers to at least one (C1-C6)alkoxy group, as defined herein, bonded to an

(Ci-C6)alkyl group, as defined herein. When there are several (Q-C6)alkoxy groups, the (CrC^alkoxy groups can be identical or different. Representative examples of

(Ci-C6)alkoxy(CrC6)alkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 1-methyl-2-propoxyethyl, 1-methoxy-l-methylethyl, and 4-methoxybutyl.

The term "(C1-C6)alkyl-S-(C1-C6)alkyl," as employed herein as such or as part of another group, refers to at least one (C1-C6)alkyl-S- group, as defined herein, bonded to a

(Ci-C6)alkyl group, as defined herein. Representative examples of (Q-C^alkyl-S-(CrC6)alkyl include, but are not limited to, methyl thiomethyl, ethylthiomethyl,

propylthiomethyl; 2-m thylthioethyl, 2-ethylthioethyl, S^-dimethylthioethyli' l^methyl-2-propylthioethyl, 1 -methylthio- 1 -methylethyl, and 4-methylthiobutyI. ! ' ' " ; : :

The terms ' C1-C5)alkyl-(S=Q)-'',or ''(C1-C6)alkyl-(S=p)-, as employed herein as such or as part of another; group, refers to, a (Ci-C5)alkyl or (C1-C6)alkyl group, as defined herein, bonded to a sulfoxide group. Representative examples of (C C5)alkyl-(S=0)- or d-C6)alkyl-(S=0)- include, but are not limited to, methylsulfoxide, ethylsulfoxide, prop isulfoxide, arid isopropylsulfoxide. ; i . ■ ;

The terms "(Ci-C5)alkyl-(0=S=0)-" or "(CrC6)alkyl-(0=S=p)-", as employed herein as such or as part of another group, refers to a (C|-C5)alkyl or (Ci-C6)alkyl group, as defined herein, bonded to a sulfone group. Representative or

include, but are not limited to, methylsulfone, ethylsulfone,

propyl. sul one, and isopropylsulfone. , - ,

(Ci-Q)alkyl, or (d-C^alkyl group, as defined herein. When there are several halogens, the halogens can be attached to the same or different carbon atom and the halogens can be identical or different; Representative examples of halo(CrC2)alkyl, halo(Ci-C3)alkyl, halo(C1-C4)alkyi, halo(C1-C5)alkyl, or halo(C1-C6)alkyl include, but are not limited to, fluoromethyl, difluoro methyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 1 ,2,2-trifluoroethyl, 3-fluoropropyl, 1 , 1 -difluoropropyl,, 1 ,3-difluoropropyl, 2,2-difluoropropyl, 3,3-difluoropropyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoroprppyl, 4,4,4-trifluorobutyl, l,l,l-trifluoro-2-methylpropanyl, and l,l,l-trifluoropropan-2-yl.

The term "halo(CrC6)alkyl-S-", as employed herein as such or as part of another group, refers to a halo(CrC6)alkyl group, as defined herein, bonded to a sulfur atom.

Representative .examples of halo(C1-C6)alkyl-S- include, but are not limited to,

fluoromethane thiol, 1-fluoroethanethiol, 2-fluoroefhanethiol, and l-fluoropropane-2-thiol.

The terms "halo(Ci-C2)alkoxy", "haloCd-C^alkoxy", "halo(C C5)alkoxy" or

"halo(C1-C6)alkoxy", as employed herein as such or as part of another group, refer to at least one halogen bonded to a (CrC2)alkoxy, (CrC4)alkoxy, (Q-Q alkoxy, or (Ci-C6)alkoxy group, as defined herein., When there are several halogens, the halogens can be attached to the same or different carbon atom and the halogens can be identical or different. , Representative examples of halo(CrC2)alkoxy, halo(Ci-C4)alkoxy, halo(CrC5)alkoxy, or halo(C|-C6)alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, frifluororriethoxy, 2-fluorbethoxy, 2,2,2-trifIuoroethoxy, 3-fluoropropoxy,

3,3,3-trifluoropropoxy, and 4-fluorobutoxy. '■· '·"■

The term "halo(Ci-C6)alkoxy(C1-C6)alkyl", as employed herein as such or as part of another group, refers to at least one halo(Ci-C6)alkoxy group, as defined herein, bonded to a

(Ci-C6)alkyl group, as defined herein. When there are several halo(C|-C6)alkoxy groups, the halo(Ci-C(,)alkoxy groups can be attached to the same or different carbo atom and the halo(Ci-C6)alkoxy groups can be identical or different. Representative examples vof halo.OOi-C6)alk0xy(C1-C6)alkyl include, but are not limited to, fluoromethoxymethyl, ■

difluoromethoxyfnethyl, trifluoromethoxymethyl, and 2-trifluoromethoxyethyl.

The term "(Ci-C6)alkoxy(CirC6)alkoxy", as employed herein as such or as part of another group, refers to at least one (Ci-C )alkoxy group, as defined herein, bonded to a

(C1-C6)alkoxy group, as defined herein. When there are several (Q-C^alkoxy groups, the (Ci-C(,)alkoxy groups can be attached to the same or different carbo atom and the (Ci-C())alkoxy groups can be identical or different. Representative examples of (C1-C6)alkoxy-(C i-C6)alkoxy include, but are not limited to, methoxymethoxy, propoxymethoxy, ! 1 i 2-methoxyethoxy, 2-ethoxyethoxy, 2-butdxyethoxy, 2,2-dimethoxyeth0xy, 1-methyl-

2-prppoxyethoxy, 2-methqxypropoxy, and 4-methoxybutoxy.

The term "(C1-C6)alkylamifto", as employed herein as such or as part of another group, refers to one or two (CrC6)alkyl group(s), as defined herein, bonded to an amino group. When there are two (Ci-C6)alkyl groups, the (C1-C )alkyl groups can be identical or different. Representative examples of (C1-C6)alkylamino include, but are not limited to, N-methylamino, N-ethylamino, N-butylamino, N,N-dimethylamino, and N,N-diethylamino.

The term "halo(C1-C6)alkylamino", as employed herein as such or as part of another group, refers to one or two halo(Q-C6)alkyl group(s), as defined herein, bonded to an amino group. When there are two halo(Ci-C6)alkyl groups, the halo(C1-C6)alkyl groups can be identical or different. When there is one halo(Ci-C6)alkyl group, the other group bonded to an amino group can be H or (Ci-C6)alkyl. Representative examples of halo(Ci-C6)alkylamiiio include, but are not limited to, ,3,3-trifluoropropylamino and 2,2-difluoroethyl(mBthyl)amino.;

The terms "heterocyclyl" or "heterocyclic ring", as employed herein as such or as part of another group, refer to a 5, 6, or 7 membered saturated or unsaturated monocyclic. group containing 1 or 2 ring heteroatom(s) each independently selected from N, O, and S or to an 8, 9, or 10 membered saturated or unsaturated bicyclic group containing 1 or 2 ring heteroatom(s) each independently selected from N, O, and S. Representative examples of ; heterocyclyl include, but are not limited to, pyrrolidin-l-yl, piperidin- l-yl, 3,6-dihydro-2H-pyran-4-yl, tetrahydro-2H-pyran-4-yl, morpholino, pyridin-3-yl, and

2,3-dihydrobenzofuran-5-yl. ' " '

The term "heterocyclyl(Ci-C3)alkyl", as employed herein as such or as part of another group, refers to a heterocyclyl group, as defined herein, bonded to a (Cj-C3)alkyl group, as defined herein. Representative examples of hcterocyclyl(Ci-C3)alkyl include, but are- not limited to, (tetrahydro-2H-pyran-4-yl)methyl, morpholinomethyl, and

3-(pyrrolidin- 1 -yl)pr pyl. '. . :

The term "phenyl(C|-C3)alkyl", as employed herein as such or as part of another group, refers to a phenyl group, bonded to a (C!-C3)alkyl group, as defined herein. Representative examples of phenyl(C1-C3)alkyl include, but are not limited to, benzyl and phenethyl.

The term "phenyl(Ci-C3)alkoxy", as employed herein as such or as part of another group, refers to a phenyl group, bonded to a (C]-C3)alkoxy group, as defined herein. Representative examples of phenyl(CrC3)alkoxy include, but are not limited to, phenoxy.

The term "phenyl(C1-C6)alkoxy(Ci-C6)alkyl", as employed herein as such or as part of another group, refers to at least one phenyl(CrC6)alkoxy group, as defined herein, bonded to a (C1-C6)alkyl group, as defined herein. Representative examples of phenyl(Ci-C6)alkoxy(Ci-C6)alkyl include, but are not limited to, phenylmethoxymethyl,

phenylmethoxyethyl, phenylethoxyethyl, phenylmethoxypropyl, and phenyletoxyethyl.

The term "phenoxy", as employed herein as such or as part of another group, refer to an phenyl group, as defined, herein, bonded to an oxygen atom.

The term "phenoxy(C1-C3)alkyl", as employed herein as such or as part of another group, refers to a phenoxy group, bonded to a (Q-C^alkyl group, as defined herein. Representative examples of phenoxy(C1-C3)alkyl include, but are not limited to, phenoxymethyl, phenoxyethyl, and phenoxypropyl. .. , .

The expression "compounds of the present disclosure" as employed herein refers to the compounds of formula I.

The "pharmaceutically acceptable salts" according to the present disclosure include therapeutically active, non-toxic, base and and acid salt forms, which the compounds of formula I are able to form with both organic and inorganic bases and acids. Representative examples of pharmaceutically acceptable base addition salt forms, for example, metal or amine salts, include, but are riot limited to, ammonium salts, lithium, sodium, potassium, calcium, magnesium, aluminum and zinc salts, salts with organic bases, such as N-methyl-D-glucamine, hydrabamine salts and salts with amino acids, such as arginine, lysine, and the like. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates and oxalates, fumarates, and succinates.

Pharmaceutically acceptable esters, when applicable, may be prepared by known methods

using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols. Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, w-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and benzyl esters.

The present disclosure includes all the possible geometric isomers, for example Z and E isomers (c s and trans isomers), of the compounds, as well as all the possible optical isomers, such as diastereomers and enantiomers, of the compounds. Furthermore, the present disclosure includes both the individual isomers and any mixtures thereof, such as racemic mixture. The individual isomers may be obtained using the corresponding isomeric forms of the starting: material or they may be separated after the preparation of the end : compound according to: conventional separation methods. For the separation of Optical ' isomers, such as enantiomers, from the mixture thereof, conventional resolution niethods, ffdr:exampTe: fractional^ chromatography, may be used.

The compounds of formula I can be prepared by a variety of synthetic routes analogously to, or according to methods' known iri the literature using suitable starting materials. Referring to Scheme 1, the compounds of formula I can be prepaied from suitably substituted aromatic l-amin -2;-carbOxylic esters ( 1) or aromatic l -halo-2-carbocylic esters (2). Referring to Scheme 2, the same compounds can be prepared from the corresponding carboxylic acids. The substituted of the amine, Ri , can be attached to the aromatic core, for example, using some of the methods A-F. ■ ; , ,..· .· . · . ;

A. Reductive amination, using a suitable aldehyde and a reducing agent, such as sodium tris(acetoxy)borohydride or sodium cyanoborohydridc.

B. Using a two step procedure where the amine is acylated using a suitable acylation method, and subsequently reduced with a suitable reducing agent, such as borane dimethyl sufide complex.

C. When starting material is an ester: alkylation, using a suitable alkylating agent, such as an alkyl halide or alkyl sulfonate ester.

D. The conditions of the Buchwald-Hartwig reaction, using a suitable amine and a suitable Pd-catalyst system.

E. Aromatic substitution, using a suitable amine, especially when Y is N, and W is F or CI.

F. The conditions of the copper mediated Ullman reaction, using a suitable amine and a source of Cu(I), when W is CI, Br, I, or other suitable leaving group.

G. In those cases where an ester is used, the ester is hydrolysed to give the

corresponding acid.

H. The carboxylic acid can be converted to an amide using a suitable amine, and some of the known amide, coupling methods, or by converting the carboxylic acid to the corresponding acyl chloride, to form the amides of formula I.

Scheme 1.

Scheme 2.

Alternatively, the amide coupling reaction can be performed prior to the construction of the aromatic ring substitution pattern and the attachment of the suitable amine substituent.

In similar manner, the aboved mentioned strategies can be applied when the aromatic core is a five membered heterocycle, such as a tiophene, pyrrole, tiazole, oxazole or pyrazole.

The starting materials depicted above, of formulae 1 and 2, are commercially available or can be prepared via synthetic routes known in the literature. The required amines of formula 4, branched at the oc-position, are commercially available or can be prepared using the method illustrated in Scheme 3. (Kopka et al., Journal of Organic Chemistry, 1980, vol. 45, 4616 - 4622).

4.

Scheme 3.

A person skilled in the art realizes that any starting material or intermediate in the reactions described above can be protected, if necessary, in a manner known in the art. Any protected functionality can subsequently be deprotected in a manner known in the art.

The synthetic routes described above are meant to illustrate the preparation of the compounds of formula I and the preparation is by no means limited thereto, that is, there are also other possible synthetic methods which are within the general knowledge of a person skilled in the art.

The compounds of formula I may be converted, if desired, into their pharmaceutically acceptable salt or ester forms using methods known in the art.

The present disclosure will be explained in more detail by the following examples. The examples are meant for illustrating purposes only and do not limit the scope of the invention defined in the claims.

Normal phase and reverse phase flash chromatography was performed using CombiFlash instruments together with disposable Redisep columns (Teledyne ISCO). Preparative HPLC purifications were performed with a Waters preparative HPLC/MS autopurification system equipped with an XBridge Prep C18 (5μπι, 30 x 150 mm) column. Typically, a gradient of water/acetonitrile with 0.1% formic acid was used as eluent. Microwave heating was performed using microwave reactors from Biotage. The structures of the products were confirmed by 1H NMR. The spectra were measured with a Bruker Avance 400 instrument. LC-MS analyses were performed using a Waters Acquity UPLC MS with an SQD or TQ detector, a Waters 2690 Micromass ZQ4000 or an Agilent 1100 Series LC/MS instrument:

The following general abbreviations are used: EDCI=l-(3-dimethylaminopropyl)-3-

ethylcarbodiimide hydrochloride, DIPEA= Ν,Ν-disopropylethylamine, HOBt=l- ' hydroxybenzotriazole, DCM=dichloromethane, EtOAc=ethyl acetate, DMF=N,N-dimethylformamide, DCE=l,2-dichloroethane, NMP=N-methylpyrrolidone, MeOD-J = deuterated methanol, CDC13- = deuterated chloroform, HATU=(l-[Bis(dimethylamino)-methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate),

ACN=acetonitrile, LiHMDS=lithium hexamethyl-disilazide, THF= tetrahydrofuran, BH3-DMS=borane dimethylsulfide.

Preparation of the compounds of the present disclosure

EXAMPLE l: 5-FIuoro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropyIamino)-nicotinamide

Step 1: 5-Fiuorb-2-(3,3,3-trifluoropropylamino)nicotinic acid

2-Chloro15-fluoropyridine-3-carboxylic acid (0.800 g, 4.56 mmolX 3,3,3-trifluoropropylarnine Hydrochloride (1.022 g, 6.84 mmol),' potassium carbonate (L07l g, 7.75 rhm l), 'copper(I) bromide (0.033 g, 0.228 mmol), copper (0.017 g, 0.273 mmol) and N,N-dimethyl formamide (13 ml) were added to a microwave vial. The reaction riiixture was irradiated at 150°C for 60 minutes at high absorbance. DCM and water were added to the reaction mixture and the mixture was acidified with HCl. The layers were separated and the organic phase was washed twice with water. The organic phase was evaporated to dryness to yield 1.054 g of the title compound. : " lH NMR (400 MHz, MeOD-ii) δ ppm 2.36 - 2.61 (m, 2 H) 3.77 (t, 2 H) 7.92 - 8.12 (m, 2 H) 8.17 - 8.30 (m,. l H):

Step 2: 5-Fluoro-N-(2-methyIbut-3-yn-2-yl)-2-(3,353-trifIuoropropylamino)

nicotinamide

5-Fluoro-2-(3,3,3-triflu0r0propylamino)nicotinic acid (1000 riig, 3.97 mmol),

dichloromethane (30 nil), l-(3-dimethylaminopropyl)-3-ethylcarbodiirnide hydrochloride (912 mg, 4.76 mmol), 1 -hydroxybenzotriazole (536 mg, 3.97 mmol), N,N- r

diisop'ropylethylarhine; DIPEA (0.424 ml, 2.432 mmol) and l.l-dimethylpropargyramirie1 (1.381 ml, 7.93 mmol) were stirred at room temperature for 3 hours. The reaction riiixture was washed once with 1M NaOH, 1M HCl and water. The organic phase was dried and evaporated to dryness. The product was purified by flash chromatography to yield 673 mg'of the title compound.

1H NMR (400 MHz, CDC -d) δ ppm 1.67 - 1.80 (s, 6 H) 2.34 - 2.57 (m, 2 H) 2.41 (s, 1H) 3.62 - 3.76 (m, 2 H) 5.97 (br. s., 1 H) 7.32 (dd, 1 H) 8.00 (br. s., 1 H) 8.13 (d, 1 H).

EXAMPLE 2: iV-(2-Methylbut-3-yn-2-yl)-5-(trifluoromethyl)-2-(3,3,3-trifluoropropylamino) nicotinamide

Step 1: 5-(Trifluoromethyl)-2-(3,3,3-trifluoropropylamino)nicotinic acid

A mixture of 2-chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (0.32 g, 1.42 mmol), 3,3,3-trifluoropropylamine hydrochloride (0.36 g, 2.41 mmol), copper (5.4 mg, 0.085 mmol), copper(I)bromide (10.2 mg, 0.071 mmol) and potassium carbonate (0.33 g, 2.41 mmol) in DMF (2 ml) was heated in a microwave reactor at 150°C for 2 h. The mixture was diluted with ethyl acetate and washed with 0.5 M citric acid solution. The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude was purified by reverse phase column chromatography. Yield: 0.102 g.

lH NMR (400 MHz, CD3OD) 5 ppm 2.57 (qt, 2 H), 3.86 (t, 2 H), 8.36 (d, 1 H), 8.53 (d, 1 H).

Step 2: N-(2-Methylbut-3-yn-2-yl)-5-(trifluoroniethyl)-2-(3,3,3-trifluoropropylamino)-nicotinamide

A mixture of 5-(trifluoromethyl)-2-(3,3,3-trifluoropropylarnino)nicotinic acid (102 mg, 0.34 mmol), 1,1-dimethylpropargylamine (0.039 ml, 0.37 mmol), EDCI (78 mg, 0.405), DIPEA (0.12 ml, 0.68 mmol) and HOBt (23 mg, 0.17 mmol) in DMF (2 ml) was stirred overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with 2 M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 61 mg.

Ή NMR (400 MHz, CDC13) δ ppm 1.75 (s, 6 H), 2.40 - 2.54 (m, 2 H), 2.42 (s, 1H), 3.72 -3.81 (m, 2 H), 6.19 (bs, 1 H), 7.68 (d, 1 H), 8.43 (dd, 1 H), 8.62 (t, 1 H).

EXAMPLE 3: 5-Chloro-N-(2-^

Step l: 5-ChIoro-2r(propylaniino)benzoic acid

2-Amino-5-chlorobenzoic acid (1.166 mmol, 0.2 g) was dissolved in dry DCE,

propionaldehyde (1.224 mmol, 0.089 ml) and glacial acetic acid (2.91 mmol, 0.167 ml) were added at 0°C. Sodium triaeetoxy borohydride (2.331 mmol, 0.494 g) was added in one portion and the reaction mixture was stirred over-night. The reaction mixture was extracted with water and the water-phase was washed with EtOAc. The combined organic-phases were extracted with aqueous Na2C03 and NaCl and finally dried over Na2S04, filtered and evaporated. The product was purified by flash chromatography to yield 71 mg of the title compound.

1H NMR (400 MHz, CDC13) 6 ppm 1.03 (t, 3 H) 1.71 (tq, 2 H) 3.17 (t, 2 H) 6.64 (d, 1 H) 7.32 (dd, 1 H) 7.93 (d, 1 H).

Step 2: 5-ChIoro-N-(2-methyIbut-3-yn-2-yI)-2-(propylamino)benzamide

5rChloro-2-(propylamino)benzoic acid (0.332 mmol, 71 mg), DIPEA (0.399 mmol, 0.069 ml), HOBT (0.432 mmol, 58.4 mg), 1,1-dimethylpropargylamine (0.399 mmol, 0.042 ml), and EDCI (0.432 mmol, 83 mg) were dissolved in 5 ml DCM. Reaction was stirred overnight arid extracted three times with 1 M NaOH. The organic-phase was evaporated to dryness arid purified by preparative HPLC to give 35 mg of the title compound. ' lH NMR (400 MHz, CDC13) 6 ppm 0.99 (t, 3 H) 1.66 (tq, 2 H) 1.73 (s, 6 H) 2.39 (s, 1 II) 3 7 (t, 2 H) 6.03 (br. s., 1 H) 6.59 (d, 1 H) 7.20 (dd, 1 H) 7.24 (d, 1 H) 7.45 (d, 1 H).

EXAMPLE 4: 5:Chloro'2-(isopropyIamino)-N-(2-methylbut-3-yn-2-yl)benzamide

Step 1 : 5-Chloro-2-(isopropylamino)benzoic acid

2,5-Dichlorobenzoic acid (1.309 mmol, 250 mg), propan-2-amine (2.62 mmol, 0.223 ml), potassium acetate (2.62 mmol, 257 mg), copper(II) acetate monohydrate (0,131 mmol,.26.1 mg) and triethylamine (1.571 mmol, 0.219 ml) in 3 ml DMF were heated to 180°C for 50 min using a microwave reactor. Water was added to the reaction mixture and the solution was made acidic with HQ and extracted two times with EtOAc. The organic phase was dried over Na2S04, filtered and evaporated and used as such without any further , , purification. . . , <

Ή NMR (400 MHz, CD3OD) δ ppm 1.25 (d, 6 H) 3.73 (spt, 1 H) 6.75 (d, LH) 7.29 (dd, 1 H) 7.81 (d, 1 H) ' ·'■■■'·■ ■■■

Step 2: 5-ChIoro-2-(is0propylamino)-N-(2-methylbut-3-yn-2-yl)benzami

405 mg of the 5-chloro-2-(prop'ylamino)benzoic acid reaction mixture, DIPEA (0.682 mmol, 0.119 ml), HOBT (0.739 mmol, 100 mg), 1,1-dimethylpropargylamine (0.682 mmol, 0.072

ml), and EDCI (0.739 mmol, 142 mg) were dissolved in 5 ml DCM. Reaction was stirred oyer-night, diluted with DCM and extracted three times with 1 M NaOH. The organic-phase was dried over Na2S0 , filtered, evaporated to dryness and purified by preparative HPLC to give 4 mg of the title compound.

1H NMR (400 MHz, CDC13) δ ppm 1.23 (d, 6 H) 1.73 (s, 6 H) 2.39 (s, 1 H) 3.61 (spt, 1 H) 6.00 (br. s., 1 H) 6.62 (d, 1 H) 7.20 (dd, 1 H) 7.24 (d, 1 H).

EXAMPLE 5: 5-Chloro-2-(2,2-difluoroethyIamino)-N-(2-methylbut-3-yn-2-yl)benzamide

Step 1: 5-ChIoro-2-(2,2-difluoroethylamino)benzoic acid

Methyl 2,5-dichlorobenzoate (0.975 mmol, 0.2 g), 2,2-difluoroethylamine ,( 1,951 mmol, 0.138 ml), potassium acetate (1.951 mmol, 191 mg), copper(II) acetate monohydrate (0,098 mmol, 0.019 g) and triethylamine (1.171 mmol, 0.163 ml) in 4 ml DMF were heated to 180°C for 45 min using a microwave reactor. The reaction mixture was purified with preparative HPLC to give 84,1 mg of title compound. , ... .

lH NMR (400 MHz, CD,OD) δ ppm 3.67 (td, 2 H) 6.01 (tt, 1 H) 6.86 (d, 1 H) 7.34 (dd, 1 H) 7.85 (d, 1 H).

Ste 2: 5-ChIoro-2-(2,2-difluoroethylamino)-N-(2-methylbut-3-yn-2-yl)benzamide

5-Chloro-2-(2,2-difluoroethylamino)benzoic acid (0.357 mmol, 84.1 mg), DIPEA (0.428 mmol, 0.075 ml), HOBT (0.464 mmol, 62.7 mg), 1,1-dimethylpropargylamine (0.428 mmol, 0.045 ml), and EDCI (0.464 mmol, 89 mg) were dissolved in 5 ml DCM. The reaction mixture was stirred over-night, diluted with DCM and extracted twice with 1 M NaOH . The organic-phase was dried over Na2S04, filtered, evaporated to dryness and purified by column chromatography to give 95 mg of the title compound.

Ή NMR (400 MHz, CD3OD) δ ppm 1.68 (s, 6 H) 2.67 (s, 1 H) 3.61 (td, 2 H) 6.00 (tt, 1 H) 6.83 (d, 1 H) 7.28 (dd, 1 H) 7.48 (d, 1 H).

EXAMPLE 6: iV-(2-Methylbut-3-yn-2-yl)-7-(3,3,3-trifluoropropylainino)-2,3-dihydrobenzo[b] [ 1 ,4 ldioxine-6-carboxamide

Step 1: 7-(3,33-Trifluoropropytemino)-2,3-dihy^

acid

7-Amino-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid (0.512 mmol, 100 mg) was dissolved in 7 ml dry DCE. 3,3,3-Trifluoropropanal (0.666 mmol, 0:057 ml) and glacial ' : acetic acid (1.281 mmol, 0.073 ml) were added at 0°C. Sodium triacetoxy borohydride (1.025 mmol, 0.217 g) was added in one portion and the reaction mixture was stirred ovef-night. The reaction mixture was extracted with acidic water and brine, dried over Na2S04, filtered and evaporated to dryness. The product was used directly without any further purification. The title compound was obtained in quantitative yield.

Ή NMR (400 MHz, CD3OD) 6 ppm 2.50 (qt, 2 H) 3.44 (t, 2 H) 4. Π 4.20 (m, 2 H) 4.27" 4.31 (m, 2 H) 6.19 (s, 1 H) 7.41 (s, 1 H).

Step 2: N-(2-MethyIbut -yn-2-yl)-7^3,3,3 rifluoropropyIamino)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamide

7-(3,3,3-Trifluoropropylarruno)-2,3-dihydro^ afcid (0.512 mmol, 149 mg);DIPE A (0.6*14 mmol, 0.107'ml), HOBT (0.665 mmol; 90 mg); 1, 1- - dimethylpropargylaiiiine (0.614 mmol, 0.065 ml), and 'EDO (0.665 mmol, 128 mg) were; dissolved -in 5 nil DCM. Reaction was stirred over-night and extracted twice With 1 M ! NaOH. The organic-phase was isolated with a phase-separator, evaporated to dryness and purified by column chromatography to give 126 mg of the title compound.

1H NMR (400 MHz, CD3OD) δ ppm 1.66 (s, 6 H) 2.49 (qt, 2 H) 2.64 (s, 1 Ή) 3.37 (t, 2 H) 4.15" 4.21 (m, 2 H) 4.23" 4.32 (m, 2 H) 6.21 (s, 1 H) 7.07 (s, 1 H).

EXAMPLE 7: 6-(IsobutyIamino)-N-(2-methyIbut-3-yn-2-yl)benzo[d][l,3]dioxoIe-5-carboxamide

Step 1: 6-(Isobutylamino)benzo[d][l,3]dioxole-5-carboxylic acid

6-Anunobenzo[d][l,3]dioxole-5-carboxylic acid (0.828 mmol, 150 mg) was dissolved in 7 ml dry DCE. Isobutyraldehyde. (.0.994 mmol, 0.09 ml) and glacial acetic acid, (2.07 mmol, 0.1.19 ml), were added at 0°C. Sodium triacetoxy borohydride (1.656 mmol, 351 mg) was added in one portion and the reaction mixture was stirred over-night. The reaction mixture was diluted with DCM, extracted with acidic water and brine and finally dried over Na2S04, filtered and evaporated. 143 mg of the title compound was obtained.

1H NMR (400 MHz, CD3OD) δ ppm 1.03 (d, 6 H) 1.93 (spt, 1 H) 2.99 (d, 2 H) 5.89 (s, 2 H) 6.30 (s, 1 H) 7.28 (s, 1 H). * ' ··; , :' , · · ■.

Step 2: 6-(IsobutyIamino)-N-(2-methylbut-3-yn-2-yI)benzo[d][l,3]dioxoIe-5-carboxamide

6-(Isobutylamino)benzo[d][l,3]dioxole-5-carboxylic acid (0.603 mmol, 143 mg), DIPEA (0.723 mmol, 0.126 ml), HOBT (0.784 mmol, 106 mg), 1,1-dimethyl-propargylamine (0.723 mmol, 0.076 ml), and EDCI (0.784 mmol, 150 mg) were dissolved in 5 ml DCM. Reaction was stirred over-night and extracted twice with 1 M NaOH. The organic -phase was isolated with a phase-separator, evaporated to dryness and purified by column chromatography to give 106 mg of the title compound in 58 % yield.

1H NMR (400 MHz, CD3OD) δ ppm 1.02 (d, 6 H) 1.66 (s, 6 H) 1.91 (tspt, 1 H) 2.63 (s, 1 H) 2.93 (d, 2 H) 5.87 (s, 2 H) 6.31 (s, 1 H) 7.02 (s, 1 H).

EXAMPLE 8: 8-(Isobutylamino)^

benzo[b][l,4]dioxepine-7-carboxamide

Step 1: 8-(IsobutyIamino)-3,4-dihydro-^ acid

8-Aminp-3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxylic acid (0.717 mmol, 150 mg) was dissolved in 7 ml dry DCE. Isobutyraldehyde (0.860 mmol, 0.079 ml) and glacial acetic acid (1.793 mmol, 0.103 ml) were added at 0°C. Sodium triacetoxy borohydride (1.434 mmol, 304 mg) was added in one portion and the reaction mixture was stirred over-night.

The reaction mixture was diluted with DCM, extracted with acidic water and brine and . finally dried over Na2S04, filtered and evaporated. The product was used directly without any further purification. The title compound was obtained in quantitative yield.

Ή NMR (400 MHz, CD3OD) 6 ppm 1.02 (d, 6 H) 1.92 (tspt, 1 H) 2.00 (s, 1 H) 2.14 (m, 2

H) 2.95 (d, 2 H) 4.06 (m, 2 H) 4.21 (m, 2 H) 6.26 (s, 1 H) 7.51 (s, 1 H).

Step 2: 8-(Isobutylamino)-N-(2-methylbut-3-yn-2-yI)-3,4-dihydro-2H-benzo[b][l,4]dioxepine-7-carboxamide

8-(Isobutylamino)-3,4-dihydro-2H-benzo[ bj r i ,4Jdioxepine-7-carboxylic acid (0.716 mmol, 190 mg), DIPEA (0.859 mmol, 0.150 ml), HOBT (0.931 mmol, 126 mg), 1 , 1 -dimethylpropargylamine (0.859 mmol, 0.090 ml), and EDCI (0.931 mmol, 178 mg) were dissolved in 5 ml DCM. Reaction was stirred over-night and extracted twice with 1 M NaOH. The organic -phase was isolated with a phase-separator, evaporated to dryness and purified by column chromatography and preparative HPLC to give 129:2 mg of the title compound.

1H NMR (400 MHz, CDC13) δ ppm 0.97 (d, 6 H) 1.71 (s, 6 H) 1.92. (tspt, 1 H) 2.1 ί 2.23 (m, 2 H) 2.36 (s, 1 H) 2.88 (dd, 2 H) 4.04 4.14 (m, 2 H) 4.16 4.25 (m, 2 H) 5.92 (s, 1 H) 6.26 (s, 1 H) 6.99 (s, 1 H) 7.49 (br. t., 1 H).

EXAMPLE 9: 7-(Isobutylamino)-N-(2-methylbut-3-yn-2-yl)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxamide

Step 1: 7-(Isobutylamino)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxyIic acid

7-Amino-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid (0.769 mniol, 150 mg) was dissolved in 7 ml dry DCE. Isobutyraldehyde (0.922 mmol, 0.084 ml) and glacial acetic acid (1.921 mmol, 0.110 ml) were added at 0°C. Sodium triacetoxy borohydride (1.537 mmol, 326 mg) was added in one portion and the reaction mixture was stirred over-night. The . , reaction mixture was diluted with DCM, extracted with acidic water and brine and finally dried over Na2S04, filtered and evaporated. The product was used directly without any further purification. The title compound was obtained in quantitative yield.

'H NMR (400 MHz, CD3OD) δ ppm 1.02 (d, 6 H) 1.92 (tspt, 1 H) 2.93 (d, 2 H) 4.12 4.20 (m, 2 H) 4.23" 4v31 (m, 2 H) 6.15 (s, 1 H) 7.38 (s, 1 H).

Step 2: 7-(Isobutylatoino)-N-(2-methylbut-3-yn-^^

6- carboxamide '

7- (Isobutylamino)-2,3-dihydrobenzo[b][l,4]dioxine-6-carboxylic acid (0.768 mmol, 193 mg), DIPEA (0.922 mmol, 0.161 ml), HOBT (0.998 mmol, 135 mg), 1,1- :

dimethylpropargylarnine (0.922 mmol, 0.097 ml), and EDCI (0.998 mmol, 1 1 mg) were , dissolved in 5 ml DCM. Reaction was stirred over-night and extracted twice with 1 M NaOH. The organic-phase was isolated with a phase-separator, evaporated to dryness and purified by flash chromatography to give 178 mg of the title compound.

Ή NMR (400 MHz, CD3OD) δ ppm 1.01 (d, 6 H) 1.66 (s, 6 H) 1.90 (tspt, 1 H) 2.63 (s, 1 H) 2.87 (d, 2 H) 4.14 4.20 (m, 2 H) 4.22 4.27 (m, 2 H) 6.16 (s, 1 H) 7.03 (s, 1 H).

EXAMPLE 10: 2-(2,2- ifluoroethylamino)-iV-(2-methyIbut-3-yn-2-yl)-5-(trifluoroinethyl)benzamide

Step 1 : 2-(2,2-Difluoroethylamino)-5-(trifluoromethyl)benzoic acid

2-Chloro-5-(trifluoromethyl)benzoic acid (1.781 mmol, 0.40 g), 2,2-difluoro-ethanamine (3.56 mmol, 0.251 ml), potassium acetate (3.56 mmol, 0.350 g), copper(II) acetate monohydrate (0.178 mmol, 36 mg), triethylamine (1.781 mmol, 0.248 ml) in 6 ml DMF were heated to 180°C for 25 min using a microwave reactor. Water was added to the reaction mixture and the solution was extracted twice with EtOAc. The organic-phase was dried over Na2S04, filtered, evaporated and purified by flash chromatography to give 238 mg of the title compound in 50 % yield.

lH NMR (400 MHz, CDC13 and CD3OD) δ ppm 3.68 (td, 2 H) 5.94 (tt, 1 H) 6.81 (d, 1 H) 7.58 (dd, 1 H) 8.25 (d, 1 H).

Step 2: 2-(2,2-Difluoroethylamino)-N-(2-methylbut-3-yn-2-yl)-5-(triflu0romethyl)-benzamide

2-(2,2-Difluoroethylamirio)-5 tnfluoromethyl)benzoic acid (0.884 mmol, 238 mg), DIPEA (1.061 mmol, 0/185 ml), HOBt (1.149 mmol, 155 mg), 1 , l-dimethyl-propargylamine ( 1.061 mmol, 0.1 12 ml), and EDCI ( 1.149 mmol, 220 mg) were dissolved in 5 ml DCM. Reaction was stirred over-night and diluted with DCM, extracted three times 1 M NaOH. The organic-phase was dried over Na2S04, filtered, evaporated to dryness' and purified by preparative HPLC to give 104.5 mg of the title compound in 35 % yield.

Ή NMR (400 MHz, CDC13) δ ppm 1.75 (s, 6 H) 2.41 (s, 1 H) 3.62 (tdd, 2 H) 5.89 (tt, 1 H) 6.16 (br. s., 1 H) 6.79 (d, 1 H) 7.47" 7.57 (m, 2 H) 8.32 (br. t., 1 H).

EXAMPLE 11: N-(2-MethyIbut-3-yn-2-yI)-2-(trifluoromethyl)-4-(3,3,3-trifluoropropyIamino)pyrimidine-5-carboxamide

Step 1: Ethyl 2-(trifluoromethyI)-4-(3 53-trifluoropropyIamino)pyrimidine-5-carboxylate

Ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (1.178 mmol, 0.3 g), 3,3,3-trifluoropropylamine hydrochloride (2.357 mmol, 0.352 g) and triethylamine (2.357 mmol,

0.328 ml) in 2 ml EtOH were heated to 160°C for 30 minutes using a microwave reactor.

Solvents were removed under reduced pressure and the water-phase was extracted with

EtOAc four times. The combined: organic phases were dried over Na2S04, filtered and evaporated to dryness to give 349 mg of the title compound.

Ή NMR (400 MHz, DMSO-d6) δ ppm 1.34 (t, 3 H) 2.55 2.74 (m, 2 H) 3.80 (td, 2 H) 4.36 (q, 2 H) 8.77 (t, 1 H) 8.89 (d, 1 H).

Step 2: 2-(Trifluoromethyl)-4-(3,3,3-trifluoropropylamino)pyrimidiiie-5-carboxylic acid

Ethyl 2-(trifluoromethyl)-4-(3,3,3-trifluoropropylarnino)pyrimidine-5-carboxylate (1.054 mmol, 349 mg), was dissolved in 10 ml THF and 1 ml of a 5M aqueous NaOH solution. The reaction mixture was refluxed for 2 h. THF was removed under reduced pressure and the solution was made acidic and extracted with DCM three times. The organic-phase was dried over Na2S0 , filtered and evaporated to dryness to give 287 mg of the title compound.

1H NMR (400 MHz, DMSO- "■ ■ " '

Step 2: N-(2-Methylbut-3-yn-2-yl)-2-(2,2,3,3?3-pentafluoropropylamino)benzamide

A mixture of 2-(2,2,3,3,3-peritafluoropropylamino)benzoic acid (70 mg, 1 eq), 1,1-d i methy lpropargy l amine (0 03 ml, 1.1 eq), EDCI (60 mg, 1.2 eq), D1PEA (0.09 mi; 2 eq) and HOBt (18 mg, 0.5 eq) in lO ml DCM was stirred overnight. The mixture was washed with 2 M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 33 mg. Ή NMR (400 MHz, CDCI3) δ ppm 1.74 (s, 6 H), 2.39 (s, 1 H), 3.86 (td, 2 H), 6.12 (bs, 1 H), 6.70 (ddd, 1 H), 6.78 (d, 1 H), 7.29 - 7.37 (m, 2 H), 8.06 (t, 1 H).

EXAMPLE 20: 2-(2,2-DifluoroethyIamino)-5-fluoro-iV-(3-methyIpent-l-yn-3-yl)nicotinamide

Step 1 : 2-(2,2-DifluoroethyIamino)-5-nuoronicotinic acid

2-Chlorp-5-fluoropyridine-3-carboxylic acid (0.199 ml, 1.709 mmol), 2,2^

difluorpethylamine (0.205 ml, 2.91 mmol), copper powder (6.5 mg, 0.103 mmol), copper(l) bromide ( 12.0 mg, 0.085 mmol), potassium carbonate (0.283 g, 2,051 mmol) and dry DMF (2 ml) were heated by microwave irradiation at 150 °C for 1 h. Some EtOAc was addqd and organic phase was washed 2 times with 0.5 M citric acid, dried over N;a2S04, filtered arid evaporated. 0,335 g of the title compound was obtained.

1H NMR (400 MHz, CDC13) δ ppm 3.88 (td, 2 H) 5.81 - 6.13 (m, 1 H) 7.95 (dd, 1 H) 7.99 (br. s, 1 H) 8.16 (d, 1 H)

Step 2: 2-(2,2-Difluoroethylamino)-5-fluoro-N-(3-methylpent-l-yn-3-yl)nicotin¾m

2-(2,2-Difluoroethylamino)-5-fluoronicotinic acid (0.100 g, 0.454 mmol), 3-amino-3-methyl-l-pentyne hydrochloride (0.061 g, 0.454 mmol), 1-hydroxybenzotriazole (0.068 g, 0.500 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.096 g, 0.500 mmol) and N,N-diisopropylethylamine (0.166 ml, 0.954 mmol) in DCM (5 ml) were stirred at room temperature overnight. Some DCM was added and organic phase was washed with 1 M HC1 and 1 M Na2C03, dried over Na2S04, filtered and evaporated. The crude product was purified by preparative HPLC. 0.024 g of the title compound was obtained.

1H NMR (400 MFlz, CDC1.V) 6 ppm 1.06 (t, 3 H) 1.72 (s, 3 H) 1.90 (dq, 1 H) 2.16 (dq, 1 H) 2.44 (s, 1 H) 3.82 (tdd, 2 H) 5.79 - 6.13 (m, 2 H) 7.32 - 7.39 (m, 1 H) 8.04 (t, 1 H) 8.10 (d, 1

H) : . . . . . ; . ; , .. , . ;

EXAMPLE 21: 2-(CyclobutyIamino)-3-nuoro-N-(2-methylbut-3-yn-2-yl)benzamide

A mixture of 2-amino-3-nuoro-iV-(2-methylbut-3-yn-2- l)benzamide (75 mg, 034 mmol), cyclobutanone (0.05 ml, 0.7 mmol), glacial acetic acid (0.1 17 ml, 2.0 mmol) in 1 ,2-dichloroethane (4 ml) was stirred. Sodium triacetoxy borohydride (0.20 g, 0.95 mmol) was added and the mixture was stirred for two days. The reaction was quenched with saturated NaHC03 (aq) and extracted with EtOAc. The combined organic layers were dried and evaporated to dryness. Preparative HPLC gave 1.5 mg of the title compound. . Ή NMR (400 MHz, CDCI3) δ ppm 1.55 - 1.71 (m, 2 H), 1.73 (s, 6 H), 1.84 - 1.97 (m, 2 H), 2.25 - 2.35 (m, 2 H), 2.38 (s, 1 H), 3.87 - 3.97 (m, 1 H), 5.46 (d, 1 H), 6.80 (td, 1 H), 7.07 (ddd, 1 H), 7.42 - 7.45 (m, 1 H), 7.55 (bs, 1 H).

EXAMPLE 22: 5-Fluoro-iV-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)-benzamide

Step 1: Methyl 5-fluoro-2-(2,2,2-trifluoroethyIamino)benzoate

A mixture of methyl 2-amino-5-fluorobenzoate (0.5 g, 2.96 mmol), sodium

cyanoborohydride (0.39 g, 6.2 mmol) and DCM (8 ml) was stirred at 0°C. Trifluoroacetic acid (2.85 ml, 38,4 mmol) was added. Trifluoroacetaldehyde hydrate (0.59 ml, 2.5 equiv)

was added dropwise. The mixture was stirred for 7 days. The mixture was filtrated and the filtrate was purified by flash chromatography. Yield: 18 mg.

1H NMR (400 MHz, CDC13) 6 ppm 3.82 - 3.87 (m, 2 H), 3.89 (s, 3 H), 6.74 (dd, 1 H), 7.16 (dddd, 1 H), 7.61 - 7.66 (m, 1 H), 7.99 (t, 1 H).

Step 2: 5-Fluoro-2-(2,2,2-trifluoroethylamino)benzoic acid

A solution of methyl 5-fluoro-2-(2,2,2-trifluoroethylamino)benzoate (18 mg, 0.07 mmol) in THF (3 ml) with 1M NaOH (2 ml) was stirred for 3 h at room temperature. The solvent was evaporated. The crude was treated with diluted HCl and the solid separated was dried under vacuum. The crude product, containing salts, was used as such in the next step.

Ή NMR (400 MHz, D20) δ ppm 3.86 (q, 2 H), 6.87 (dd, 1 H), 7.09 (td, 1 H), 7.43 (dd, 1

- ! ^ L w^. .-. ,, , - ■ , ,· , : - > >■; , - ,„ U : r , ;v! , -, Ι ί Μ.

Step 3: 5-Fluoro-N-(2-raethylbut-3-yn-2-yI)-2-(2,2,2 rifluoroethylamino)benzamide

A mixture of 5-fluorQT2-(2,2,2-trifluoroethylamino)benzoic acid (30 mg, 1 eq), 1,1-dimethylpropargylamine (0.015 ml, 1.1 eq), EDCI (29 mg, 1.2 eq), DIPEA (0.066 ml, 3 eq) and HOBt (8.55 mg, 0.5 eq) in 5 ml DCM was stirred overnight. The mixture was washed with 2 M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 2.3 mg; Ή NMR (400 MHz, CDC13) 5 ppm 1.74 (s, 6 H), 2.41 (s, 1 H), 3.78 (qd, 2 H), 6.04 (bs, 1 H), 6.75 (dd, 1 H), 7.04 - 7.08 (m, 2 H), 7.80 (t, 1 H).

EXAMPLE 23: 2-(Cyclobutylamino)-iV-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyI)-benzamide · "

2-ArninorN-(2-methylbutr3-yn-2-yl)

cyclobutanone (0.079 ml, 1.055 mmol)), glacial acetic acid (0.191 ml, 3.33 mmol) and 1,2-dichloroethane (4 ml) .were charged in a flask. Sodium triacetoxy borohydride (0.33 g, 2.8 1.6 mmol) was added and the mixture stirred overnight. The reaction was quenched with , saturated NaHC03 (aq) and extracted with EtOAc. The combined Organic layers were dried and evaporated to dryness. Purification by preparative HPLC gave 66 mg of the title compound.

lH NMR (400 MHz, CDC13) δ ppm 1.75 (s, 6 H), 1.78 - 2.03 (m, 4 H), 2.37 - 2.49 (m, 2 H), 2.41 (s, 1H), 3.86 - 3.99 (m, 1 H), 6.09 (bs, 1 H), 6.55 (d, 1 H), 7.40 - 7.46 (m, 1 H), 7.47 - 7.50 (m, 1 H), 8.08 (d, 1 H).

EXAMPLE 24: 2-(Cyclobutylamino)-5-fluoro-iV-(2-methylbut-3-yn-2-yl)benzamide

Step 1: Methyl 2-(cyclobutyIamino)-5-fluorobenzoate

Methyl 2-amino-5-fluorobenzoate (0.5 g, 3.0 mmol), cyclobutanone (0.42 ml, 5.6 mmol), glacial acetic acid (1.0 ml, 17.7 mmol) and 1 ,2-dichloroethane (10 ml) were charged in a flask. Sodium triacetoxy borohydride (1.75 g, 8.3 mmol) was added and the mixture stirred overnight. The reaction was quenched with saturated NaHC03 (aq) and extracted with EtOAc. The combined organic layers were dried and evaporated to dryness. The crude product was used in the next step.

1H NMR (400 MHz, CDC13) δ ppm 1.75 - 1.99 (m, 4 H), 2.40 - 2.48 (m, 2 H), 3.85 (s, 3 H), 3.88 - 3.97 (m, 1 H), 6.49 (dd, 1 H), 7.08 (ddd, 1 H), 7.54 - 7.64 (m, 2 H).

Step 2: 2-(Cyclobutylamino)-5-fluorobenzoic acid

A solution of methyl 2-(cyclobutyiamino)-5-fluorobenzoate (0.7 g, 3.13 mmol) in THF (3 ml) with lM NaOH (l4 ml) was stirred at 60°C for 4 h. The solvents were evaporated and the residue was diluted with teri-butyl methyl ether. The mixture was acidified by adding 2M HCl. The solvent was evaporated, and the residue washed with heptanc-DCM to give 1.33 g of a crude product. . i

1H NMR (400 MHz, CDC13) δ ppm 1.78 - 2.12 (m, 2 H), 2.27 - 2.41 (m, 2 H), 2.56 - 2.71 (m, 2 H), 4.04 (quin, 1 H), 7.44 (ddd, 1 H), 7.67 (dd, 1 H), 7.90 (dd, 1 H), 11.24 (bs, 2 H).

Step 3: 2-(Cyclobutylamino)-5-fluoro-iV-(2-methylbut-3-yn-2-yl)benzamide

A mixture of 2-(cyclobutylamino)-5-fluorobenzoic acid (100 mg, 0.48 mmol), 1,1-dimethylpropargylamine (0.055 ml, 0.53 mmol), EDCI (110 mg, 0.57 mmol), DIPEA (0.17 ml, 0.96 mmol) and HOBt (32 mg, 0.24 mmol) in DMF (3 ml) was shaken overnight. Water (3 ml) was added. The aqueous mixture was extracted with EtOAc (3 ml). The organic layer was washed with 2M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 40 mg. : : ' ' : '

1H NMR (400 MHz, CDC13) δ ppm 1.73 (s, 6 H), 1.75 - 1.98 (m, 4 H), 2.35 - 2.44 (m, 2 H), 2.40 (s, 111), 3.79 - 3.90 (m, 1 H), 6.09 (bs, 1 II), 6.48 (dd, 1 H), 6.95 - 7.06 (m, 2 H), 729

(bS, 1 H). . ■■ : ! , . : ■. . - . ■,. ; .. .· .-

EXAMPLE 25: 2-(CycIobutylamino)-5-fluoro-N-(2-methyIbut-3-yn-2-yl)nicotinamide

Step 1: 2-(Cyclobutylamino)-5-fluoronicotinic acid

A mixture of 2-chloro-5-fluoropyridine-3-carboxylic acid (0.13 ml, 1.14 mmol),

cyclobutylamine (0.14 g, 1.94 mmol), copper powder (4.34 mg, 0.068 mmol),

copper(I)bromide (8.17 mg, 0.057 mmol), potassium carbonate (0.19 g, 1.37 mmol) in DMF (1 ml) was heated at 150°C for 4 h using a microwave reactor. The mixture was diluted with ethyl acetate and washed with 0.5M citric acid solution. The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude product was purified by reverse phase column chromatography. Yield: 0.171 g.

1H NMR (400 MHz, CDC13) 6 ppm 1.73 - 1.83 (m, 2 H), 1.88 - 2.00 (m, 2 H), 2.39 - 2.50 (m, 2 H), 4.54 - 4.59 (m, 1 H), 7.89 (dd, 1 H), 8.23 (d, 1 H). . - u , ; ;

Step i: 2-(Cycidbutylai irt6)-5-flu6ro-N-(2-methylbut-3-yn-2-yl)nico^

A mixture of 2-(cyclobutylamino)-5-fluoronicotinic acid (170 mg, 0.81 mmol), 1 , 1-dimethylpropargylamine (0.094 ml, 0.90 mmol), EDCI (187 mg, 0.98 mmol), DIPEA (0.28 ml, 1.6 mmol) and HOBt (0.41 mmol) in 3 ml DMF was shaken overnight. Water (3 n l) was added. The aqueous mixture was extracted with EtOAc (3 ml). The' organic layer was washed with 2M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 139 mg.

1H NMR (400 MHz, CDC13) 6 ppm 1.66 - 1.79 (m, 2 H), 1.73 (s, 6H), 1.83 - 1.96 (m, 2 H), 2.33 - 2.42 (rri, 2 H), 2.42 (s, 1H), 4.39 - 4.50 (m, 1 H), 6.26 (s, 1 H), 7.34 (dd, 1 II), 7.90 (d, 1 H), 8.06 (d, 1 H).

EXAMPLE 26: 5-Chloro-2-(isopropylarnino)-iV-(2-methy!but-3-yn-2-yI)nicotinamide

Step 1: 5-Chloro-2-(isoprppylamino)nicotinic acid

2,5-Dichloronicotinic acid (0.2 g, 1,04 mmol), isopropylamine (0.1 g, 1.77 mmol), copper powder (3.97 mg, 0.063 mmol), copper(I)bromide (7.47 mg, 0.052 mmol), potassium carbonate (0.17 g, 1.25 mmol) in DMF (1 ml) were irradiated at 150°C for 4 h using , ; microwaves. The mixture was diluted with ethyl acetate and washed with 0.5M citric acid solution. The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude was purified by reverse phase column chromatography. Yield: 133 mg. ,

1H NMR (400 MHz, CDC13) δ ppm 1.27 (d, 6 H), 4.28 - 4.37 (m, 1 H), 7.68 (bs, 1 H), 8.12 (d, 1 H), 8.26 (d, 1 H).

Step 2: 5-Chloro-2-(isopropylamino)-N-(2-methyIbut-3-yn-2-yl)nicotinamide

5-Chloro-2-(isopropylamino)nicotinic acid (133 mg, 0.62 mmol), 1,1-dimethylpropargylamine (0.072 ml, 0.68 mmol), EDCI (143 mg, 0.74 mmol), DIPEA (0.22 ml, 1.24 mmol) and HOBt (42 mg, 0.31 mmol) in 3 ml DMF was shaken overnight. Water (10 ml) was added. The aqueous mixture was extracted with EtOAc (15 ml). The organic layer was washed with 2 M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 98 mg.

1H NMR (400 MHz, CDC13) δ ppm 2.02 (d, 6 H), 2.81 (s, 1 H), 4.42 - 4.54 (m, 1 H), 8, 11 (d, 1 H), 8.38 (d, 1 H). ' 1

EXAMPLE 27: 5-ChIoro-2-(cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide

Step 1: 5-Chloro-2^(cyclobutylamino)nieotinic acid

2,5-diphlpronicotinic acid (0.2 g, 1.04 mmol), cyclobutylamine (Q.13;g, 1.77 mmol), copper powder (3.97 mg, 0.063 mmol), cppper(I)bromide (7.47 mg, 0.052 mmol),. potassium . , , carbonate (0.17 g, 1.25 mmol) and DMF (1 ml) were placed in microwave reaction vial and irradiated at 150°C for 4 h. The mixture was diluted with ethyl acetate and washed with 0:5M citric acid solution. The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude was purified by reverse phase flash chromatography. Yield: 0.1.1 g. Ή NMR (400 MHz, CDCI3) δ ppm 1.73 - 1.82 (m, 2 H), 1.87 - 1.99 (m, 2 H), 2.39 - 2.48 (m, 2 H), 4.51 - 4.62 (m, 1 H), 8.09 (d, 1 H), 8.24 (d, 1 H).

Step 2: 5-Chroro-2-(cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide

A mixture of 5-ehlord-2-(cyclobutylamino)nicotinic acid (110 mg, 0.48 mmol), 1,1-dimethylpropargylamine (0 56 ml, 0.53 mmol), EDCI ( 112 mg, 0.58 mmol), DIPEA (0.17 ml, 0.97 mmol) and HOBt (33 mg, 0.24 mmol) in DMF (3 ml) was shaken overnight. Water (3 ml) was added. The aqueous mixture was extracted with EtOAc (3 ml). The organic layer was washed with 2M Na2C03; evaporated to dryness and purified by preparative HPLC. Yield: 79 mg. ; ; : - Ή NMR (400 MHz, CDC13) δ ppm 1.69 - 1.78 (m, 2 H), 1.74 (s, 6H), 1.86 - 1.99 (m, 2 H), 2,34 - 2.41 (m, 2 H),.2.42 (s, 1 H), 4.40 - 4.55 (m, 1 H), 6.16 (bs, 1 H), 7.48 (d, 1 H), 8.09 (d, I H), 8. 12 (d, 1 I I).

EXAMPLE 28: 2-(Isopropylamino)-N-(2-methylbut-3-yn-2-yI)-5-(trifluoromethyl)-nicotinamide

Step 1: 2-(IsopropyIamino)-5-(trifluoromethyl)nicotinic acid

2-Chloro-5-(trifluoromethyl)pyridine-3-carboxylic acid (0.2 g, 0.89 mmol), isopropylamine (89 mg, 1.5 mmol), copper powder (3.38 mg, 0.053 mmol), copper(I)bromide (6.36 mg, 0.044 mmol), potassium carbonate (0.15 g, 1.06 mmol) and DMF (1 ml) were placed in microwave reaction vial and irradiated at 150°C for 4 h. The mixture was diluted with ethyl acetate and washed with 0.5M citric acid solution. The organic layer was dried over . anhydrous sodium sulphate and evaporated. The crude was purified by reverse phase flash chromatography. Yield: 98 mg.

1H NMR (400 MHz, CD3OD) δ ppm 1.29 (d, 6 H), 4.39 (spt, 1 H), 8.33 (dd, 1 H), 8.45 -8.49 (m, l H).

Step 2: 2-(isopr0pyiamiri0)^

A mixture of 2-(isopropylamino)-5-(trifluoromethyl)nicotinic acid (98 mg, 0.40 mmol), 1 , 1 -dimethylpropargylamine (0.046 ml, 0.43 mmol), EDCI (91 mg, 0.47 mmol), DIPEA (0.14 ml, 0.79 mmol) and HOBt (27 mg, 0.20 mmol) in 3 ml DMF was stirred overnight. Water (3 ml) was added. The aqueous mixture was extracted with EtOAc (3 ml). The organic layer was washed with 2 Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 61 mg. :V r ' " " ' '' ' ί ι ''' '' ι

1H NMR (400 MHz, CDC13) S ppm 1.25 (d, 6 H), 1.75 (s, 6 H), 2.42 (s, 1 H), 4.27 - 4.41 (m, 1 H), 6.15 (bs, I H), 7.65 (d, 1 H), 8.32 (d, 1 H), 8.41 (dd, 1 H). ' ' ' : ' '

EXAMPLE 29: 5-Fluoro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropyl-amino)nicotinamide

Step 1 : 5-FIuoro-2-(2,2,3,3,3-pentafluoropropylamino)nicotinic acid

2-Chloro-5-fluoropyridine-3-carboxylic acid (0.2 ml, 1.7 1 mmol), 2,2,3,3,3- < , pentafluoropropylamine (0,43 g, 2,91 mmol), copper powder (6.52 rng, 0. 1 mmol), : ; ' ; copper(I)bromide (12 mg, 0.085 mmol), potassium carbonate (0.28 g, 2.05 mmol) and DMF

(2 ml) were placed in microwave reaction vial and irradiated at 150°C for 4 h. The mixture Was diluted with ethyl acetate and washed with 0.5M citric acid solution. The organic layer was dried over anhydrous sodium sulphate and evaporated. The crude was purified by reverse phase flash chromatography. Yield: 80 mg.

1H NMR (400 MHz, CD3OD) 5 ppm 4.38 - 4.47 (td, 2 H), 8.01 (dd, 1 H), 8.23 (d, 1 H).

Step 2: 5-Fluoro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropylamino) nicotinamide

A mixture of 5-fluoro-2-(2,2,3,3,3-pentafluoropropylamino)nicotinic acid (80 mg, 0.28 mmol), 1, 1-dimethylpropargylamine (0.032 ml,0.30 mmol), EDCI (64 mg, 0.33 mmol), DIPEA (0.097 ml,0.56 mmol) and HOBt (19 mg, 0.14 mmol) in 3 ml DMF was shaken overnight. Water (5 ml) was added. The aqueous mixture was extracted with EtOAc ( 10 ml). The rganic layer Was washed with 2M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 33 mg. ; '

lH NMR (400 MHz, CDC13) 6 ppm 1.74 (s, 6 H), 2.42 (s, 1 H), 4.28 (tdd, 2 H), 6.07 (bs, 1 H), 7.3 (dd, 1 H), 8. 12 (d, I H), 8. 17 (t, 1 H). ' ? - ; '

EXAMPLE 30: 5- ethyl-1V-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropyl-amino)benzamide

Step 1: 5-MethyI-2-(2,2,3,3j3-pentafluoropropylamino)benzoic acid

2-Bromo-5-methylbenzoic acid (0.5 g), 2,2,3, 3,3-pentafluoropropylamine (0,49 ml), potassium acetate (0.46 g), copper(Ii)acetate monohydrate (46 mg) and triethylamine (0.39 ml) in DMF (2 ml) were placed in a microwave reaction vial and irradiated at 180°C for 2 h.

The mixture, was cooled, diluted with ethyl acetate and neutralized with dilute HCl solution.

The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and evaporated. The material was purified by flash chromatography. Yield: 46 mg.

Ή NMR (400 MHz, CDC13) δ ppm 2.26 (s, 3 H), 3.91 (t, 2 H), 6.70 (d, 1 H), 7.26 - 7.29 (m,

1' H), 7.83 (m, 2 H).

Step 2: 5-MethyI-N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropyl-amino)benzamide

A mixture of 5-methyl-2-(2,2,3,3,3-pentafluoropropylamino)benzoic acid (42 mg, 0.15 mmol), 1 , 1 -dimethylpropargylamine (0.02 ml, 0.16 mmol), EDO (34 mg, 0.18 mmol), DIPEA (0.05 ml, 0.30 mmol) and HOBt (10 mg, 0.07 mmol) in 2 ml DMF was shaken overnight. Water (3 ml) was added. The aqueous mixture was extracted with EtOAc (3 ml). The organic layer was washed with 2M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 16 mg.

Ή NMR (400 MHz, CDC13) δ ppm 1.74 (s, 6 H), 2.26 (s, 3 H), 2.39 (s, 1 H), 3.77 - 3.90 (m, 2 H), 6.11 (bs, 1 H), 6.69 (d, 1 H), 7.10 - 7.18 (m, 2 H), 7.81 (t, 1 H).

EXAMPLE 31: 5-FIuoro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3-pentafluoropropylamino) benzamide

Step 1: 5-Fluoro-2-(2,2,3,3,3-pentafluoropropylamino)benzoic acid

Methyl 2-bromo-5-fluorobenzoate (0.32 ml), 2,2,3,3,3-pentafluoropropylamine (0.46 ml), potassium acetate (0.42 g), copper(TI)acetate monohydrate (43 mg) and triethylamine (0.36 ml) and DMF (2 ml) were placed in a microwave reaction vial and irradiated at 180°C for 2 h. The mixtur was cooled, diluted with ethyl acetate and neutralized with dilute HC1 solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic. layer was dried oyer anhydrous sodium sulphate and evaporated. The product was purified by reverse phase flash column chromatography. Yield: 69 mg.

Ή NMR (400 MHz, CD3OD) δ ppm 4.06 (t, 2 H), 6.89 (dd, 1 H), 7.19 (ddd, 1 H), 7.61 (dd, 1 H).

Step 2: 5-Fluoro-N-(2'methylbut-3-yn-2-yl)-2-(2,2,3^^-pentafluoropropylamino)-benzamide

A mixture ol' 5-fluoro-2-(2,2,3,3,3-pentafluoropropylamino)benzoic acid (69 mg, 0.24 V mmol), 1 , 1 -dimethylpropargylamine (0.028 ml, 0.26 mmol), EDCI (55 mg, 0.29 mmol), DIPEA (0.084 ml, 0.48 mmol) and HOBt ( 16 mg, 0.12 mmol) in DMF (2 ml) was shaken overnight. Water (5 ml) was added. The aqueous mixture was extracted with EtOAc (5 ml). The organic layer was washed with 2M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 27 mg.

Ή NMR (400 MHz, CDC13) δ ppm 1.74 (s, 6 H), 2.40 (s, 1 H), 3.83 (td, 2 H), 6.08 (bs, 1 ' H), 6.72 (dd, 1 H), 7.03 - 7.11 (m, 2 H), 7.72 (t, 1 H).

EXAMPLE 32: 5-ChIoro-2-(2,2-difluoroethylamino)-N-(2-methylbut-3-yn-2-yI)nicotinamide

Step 1: 5-Chloro-2-(2,2-difluoroethylamino)nicotinic acid

2,5-Dichloronicotinic acid (0.3 g, 1 eq), 2,2-difluoroethylamine (0.19 ml, 1.7 eq), copper powder (5.96 mg, 0.06 eq), copper(I)bromide (11 mg, 0.05 eq), potassium carbonate (0.26 g, 1.2 eq) and DMF (1 ml) were placed in microwave reaction vial and irradiated at 150°C for 4 h. The mixture was diluted with ethyl acetate and washed with 0.5M citric acid solution. The organic layer was dried over anhydrous sodium sulphate and evaporated- The crude product was purified by reverse phase column chromatography. Yield: 0.176 g.

1H NMR (400 MHz, CD3OD) δ ppm 3.91 (td, 2 H), 6.03 (tt, 1 H), 8.15 (d, 1 H), 8.24 (d, 1

H). - ■

Step 2: 5-ChIoro-2-(2,2-difluoroethylamino)-N-(2-methyIbut-3-yn-2-yl)nicotinamide

A mixture of 5-chl0ro-2-(2,2-diiluoroethyiam acid (176 mg, 0.74 mmol), 1,1-dimethylpropargylamine (0.086 ml, 0.82 mmol), EDCI (171 mg, 0.89 mmol), D1PEA (0.26 ml, 1.49 mmol) and HOBt (50 mg, 0.37 mmol) in 2 ml DMF was shaken overnight. Water (3 ml) was added. The aqueous mixture was extracted with EtOAc (3 ml). The organic layer was washed with 2M Na2C03, evaporated to dryness and purified by preparative HPLC. Yield: 33 mg.

1H NMR (400 MHz, CDC13) δ ppm 1.74 (s, 6 H), 2.42 (s, 1 H), 3.83 (tdd, 2 H), 5.96 (tt, 1 H), 6.06 (bs, lH), 7.52 (dd, 1 H), 8.14 (d, 1 H), 8.28 (t, 1 H).

EXAMPLE 33: 5-FIuoro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)-nicotinamide

Step 1 : 5 Fluoro-2-(2,2,2-trifluoroethylamino)nicotinic acid

2-Chloro-5-fluoropyridine-3-carboxylic acid (0.2 ml, 1 eq), 2,2,2-trifluoroethylamine (0.23 ml, 1.7 eq), copper (6.52 mg, 0.06 eq), copper(I)bromide (12 mg, 0.05 eq), potassium . ; carbonate (0.28 g, 1.2 eq) and DMF (1 ml) were placed in microwave reaction vial and irradiated at 150°C for 4 h. The mixture was diluted with ethyl acetate and washed with 0.5M citric, acid solution. The, organic layer was dried over anhydrous sodium sulphate and evaporated. The crude was purified by reverse phase column chromatography. Yield: 0.41 g. 1H NMR (400 MHz, CD3OD) δ ppm 4.32 (q, 2 H), 7.99 (dd, 1 H), 8.22 (d, 1 H).

Step 2: 5-FIuor0 -(2-methyIbut-3-yn-2-yI)-2-(2,2,2-trifluoroethyIamihb)nicot

A mixture of 5-fluoro-2-(2,2,2-trifluoroethylamino)nicotinic acid (100 mg, 0.42 mmol), 1,1-dimethylpropargylamine (0.05 ml, 0.46 mmol), EDCI (97 mg, 0.50 mmol), DIPEA (0.15 ml, 0.84 mmol) and HOBt (28 mg, 0.21 mmol) in 2 ml DMF was shaken overnight. Water (5 ml) was added. The aqueous mixture was extracted with EtOAc (5 ml). The organic layer was washed with 2M Na2C03, evaporated to dryness and purified by flash chromatography. Yield: 60 mg.

1H NMR (400 MHz, CDCI3) δ ppm 1.75 (s, 6 H), 2.42 (s, 1 H), 4.21 (qd, 2 H), 6.05 (bs, 1 H), 7.36 (dd, 1 H), 8.13 (d, 1 H), 8.22 (t, 1 H).

EXAMPLE 34: 5-Chloro-N-(2-methylbut-3-yn-2-yl)-2 2,2,2-trifluoroethylamino)-nicotinamide

Step 1: Ethyl-2-(2,2,2-trifluoroethylamino)nicotinate

Ethyl-2-chloronicotinate (0.803 ml, 5.39 mmol) and 2,2,2-trifIuoroethylamine ( 1 .291 ml, 16.16 mmol) were added to a rnicrowave vial. The reaction mixture was irradiated at 150°C for 3 hours at high absorbance. The reaction mixture was diluted ith DCM and washed once with water. The organic phase was dried and evaporated to dryness to yield 1.275 g of the title compound. . .

1H NMR (400 MHz, CDC13) δ ppm 1.39 (t, 3 H) 4.23 - 4.43 (m, 4 H) 6.66 (dd, 1 H) 8.17 (dd, 1 H) 8.29 (m, 2 H) ■ ■ "

Step 2: Ethyl-5-chloro-2-(2,2,2-trifluoroethylamino)nicotinate

Ethyl-2-(2,2,2-trifluoroethylamino)nicotinate (3.45 g, 13.90 mmol), iV-chlorosuccinimide (2.227 g, 16.68 nimol) and N,N-dimethylformarnide (15 ml) were stirred at room

temperature overnight. Water was added to the reaction mixture and the mixture was acidified with 1M HC1 solution. The acidic water phase was extracted thiee times with ethyl acetate and once with DCM. The organic phase was evaporated to dryness arid DCM was added. The organic phase was washed three times with water, dried and evaporated to dryness to yield 4.0 g of the title compound.

Ή NMR (400 MHz, CCDI3-J) δ ppm 1.34 - 1.47 (t, 3 H) 4.19 - 4.45 (m, 4 H) 8.08 - 8.18 (m, 1 H) 8.20 - 8.35 (m, 2 H).

Step3: 5-Chloro-2-(2,2,2-trifluoroethylamino)nicotinic acid

The mixture of ethyl-5-chloro-2-(2,2,2-trifluoroethylamino)nicotinate (5.25 g, 18.68 mmol), potassium hydroxide (3.14 g, 56.0 mmol), methanol (25 ml) and water (5 ml) was stirred at room temperature overnight. The solvent was evaporated, water was added to the

evaporation residue and the mixture was acidified with 5M HC1 solution. The formed precipitation was filtered and washed once with water. The precipitation was dried in a vacuum oven at 40°C overnight to yield 4.4 g of the title compound.

1H NMR (400 MHz, MeOD- ) δ ppm 4.34 (q, 2 H) 8.18 (d, 1 H) 8.26 (d, 1 H)

Step 4: 5-Chlorp-Nn(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethyIamifto)nicotin

5-Chloro-2-(2,2,2-trifluoroethylamino)nicotinic acid (2.2 g, 8.66 mmol), DCM (15 ml), EDCI ( 1.992 g, 10.39 mmol), HOBt (1.17 g, 8.66 mmol), DIPEA (3.02 ml, 17.32 mmol) and 1 , 1 -dimethylpropargylamine (1.185 ml, 11.26 mmol) were stirred at room temperature 1 ! overnight. The reaction mixture was washed once with 1M aOH solution, once with 1 M HC1 solution arid once with water. The organic phase was dried and evaporated to dryness. The product was purified by flash chromatography to yield 1.6 g of the title compound. Ή NMR (400 MHz, CDCl3-¾ δ ρριη 1.75 (s, 6 H) 2.42 (s, 1 H) 4.22 (m, 2 H) 6.04 (br. s., 1 H) 7.54 (d, 1 H) 8.18 (d, 1 H) 8.42 (br. s., 1 H)

EXAMPLE 35: N-(2-Methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethyIamino)-5-(trifluoromethyl)nicotinamide

Step 1 : 2-(2,2,2-Trifluoroethylamino)-5-(trifluoromethyl)nicotinic acid

2-Chloro-5-(tri fluoromethyl )pyridi ne-3-carboxyl ic acid (0.3 g, 1 eq), 2,2,2-trifluoroethyt-amine (0.18 ml, 1.7 eq), copper (5.07 mg, 0.06 eq), copper(I)bromide (9.5 mg, 0.05 eq), s potassium carbonate (0.22 g, 1.2 eq) in DMF (1 ml) were placed in a microwave reaction vial and irradiated at 150°C for 4 h. The mixture was diluted with ethyl acetate and washed with 0.5M citric acid solution. The organic layer was dried over anhydrous sodium sulphate and evaporated;. The crude product was purified by reverse phase column chromatography. Yield: 42 mg.

Ή NMR (400 MHz, DMSO- ) δ ppm 4.47 (q, 2 H), 8.31 (d, 1 H), 8.67 (d, 1 H), 8.90 (bs, 1

H).

Step 2: N 2-Methylbut-3-yn-2-yl)-2 2,2,2 rifluoroethylamino)-5-(trifluoromethyl) nicotinamide

A mixture of 2-(2,2,2-trifluoroethylamino)-5-(trifluoromethyl)nicotinic acid (42 mg, 0.146 mmol), 1,1-dimethylpropargylamine (0.017 ml, 0.16 mmol), EDCI (33 mg, 0.18 mmol), DIPEA (0.05 ml, 0.29 mmol) and HOBt (9.85 mg, 0.07 mmol) in 1 ml DMF was shaken overnight. Water (5 ml) was added. The aqueous mixture was extracted with EtOAc (5 ml). The organic layer was washed with 2M Na2CQ3, evaporated to dryness and purified by preparative HPLC. Yield: 21 mg.

Ή NMR (400 MHz, CDC13) 6 ppm 1.77 (s, 6 H), 2.44 (s, 1 H), 4.29 (qd, 2 H), 6.14 (bs, 1 H), 7.73 (d, 1 H), 8.47 (dd, 1 H), 8.87 (t, 1 H).

CLAIMS

1. A compound of Formula I,

(I)

A and B form together with the atoms to which they are attached,

wherein the atoms marked with * and *' are bonded to the parent molecular moiety; X is CR5 or N;

Y is CR6 or N;

Z is CR4 or N, provided that when Y or X is N, then Z is not N;

Ri is (C C6)alkyl, cyclo(C3-C6)alkyl, halo(CrC6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkpxy(,C1-C6)alkyl, (CrC6)alkyl-S-(C C6)alkyl, heterocyclyl,

heterocyclyl(C1-C3)alkyl, phenyl, phenyl(C1-C3)alkyl, or phenoxy(d-C6)alkyl, wherein said cyclo(C3-C6)alkyl, heterocyclyl, or phenyl is unsubstituted or substituted with 1 or 2 substituerit(s) each independently being halogen, (Ci-C5)alkyl, halo(C1-C5)alkyl, (Ci- C5)alkoxy, cyclo(C3-C6)alkyl, CN, halo(C1-C5)alkoxy, (C1-C5)alkyl-S-, (CrC5)alkyl- (S=0)-, (CrC5)alkyl-(0=S=0)-, (C1-C3)alkylamino or di(C C3)alkylamino;

R2 is (Ci C6)alkyl;

R3 is (Ci-C6)alkyl;

R4 is H, halogen, (C1-C6)alkyl, (d-Ceialkoxy, halo(C1-C6)alkyl, haloid -C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, (CrC6)alkyl-S-, (C C6)alkylamino, halo(C

C6)alkylamino, (CrC6)alkyl(C=0), CN, or heterocyclyl;

R5 is H, halogen, (C1-C6)alkyl, cyclb(C3-C6)alkyl, (d-C6)alkoxy, halo(C1-C6)alkyl, (Cr C^alkoxy CrC^alkyl, haloCd-Ceialkoxy, (CrC6)alkoxy(d-C6)alkoxy, (C C6)alkyl-

S-, (CrC6)alkyl-(S=0)-, (C C6)alkyl-(0=S=0)-, haloCd-Q alkyl-S-, haloCd- C6)alkylamino, (C C^alk l^O), or CN; and

R6 is H, halogen, (Q-C^alkyl, or halo(C!-C6)alkyl;

or Ri and ^ form, together with the atoms to which they are attached, a condensed 5 or 6 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom to which R\ is attached, 0 or 1 further heteroatom selected from N, O, and S, wherein said heterocyclic ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being (Q-C^alkyl or halogen;

or R4 and R5 form, together with the carbon ring atoms to which they are attached, a condensed 5, 6 or 7 membered saturated or unsaturated carbocyclic ring or a condensed

5, 6, or 7 membered saturated or unsaturated heterocyclic ring containing 1 or 2 heteroatom(s) selected from N, O, and S, wherein said carbocyclic or heterocyclic ring is unsubstituted or substituted with 1 or 2 substituent(s) each independently being (Q- C2)alkyl or halogen;

or a pharmaceutically acceptable salt or ester thereof;

with the proviso that the compound is not 2-(methylamino)-N-(2-methylbut-3-yn-2- yl)benzamide or N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzarnide.

2. The compound according to claim I, wherein

Ά and B form, together with the atoms to which they are attached,

Z is CR4 or N;

Ri is (C1-C6)alkyl, cyclo(C3-C6)alkyl, halo(CrC6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, heterocyclyl, heterocyclyl(C1-C3)alkyl, phenyl, phenyl(C1-C3)alkyli or phenoxy(C1-C )aJkyl, wherein said cyclo(C3-C )alkyl, heterocyclyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (Cj -C3)alkyl, halo(Ci-C3)alkyl, (C1-C3)alkoxy, cyclo(C3- C6)alkyl, or CN;

R2 is (CrC6)alkyl;

R3 is (C C6)alkyl;

R4 is H, halogen, (CrC6)alkyl, CN or heterocyclyl;

R5 is H, halogen, (Q-Q alkyl, (CrC6)alkoxy, halo(C C6)alkyl, halo(C1-C6)alkoxy, (C1-C6)alkyl-S-, or CN; and

R6 is H or halogen;

or Ri and R6 form, together with the atoms to which they are attached, a condensed 5 or 6 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom to which R\ is attached, 0 further heteroatoms, wherein said heterocyclic ring is unsubstituted or substituted with 2 substituent(s) each independently being (Q-C2)alkyl;

or R4 and R5 form, together with the carbon ring atoms to which they are attached, a condensed 5, 6 or 7 membered saturated heterocyclic ring containing 1 or 2

heteroatom(s) which are O, wherein said heterocyclic ring is unsubstituted.

The compound according to any one of claims 1 or 2, wherein

A and B form, together with the atoms to which they are attached,

Z is CR4 or N; ' .·

Ri is (C,-C6)alkyl, cyclo(CVC6)alkyl, halo(C1-C6)alkyl, (CrC6)alkoxy(C C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, heterocyclyl, heterocyclyl(C1-C3)alkyl, phenyl, phenyl(CrC3)alkyl, or phenoxy(Ci-C6)alkyl, wherein said cyclo(C3-C6)alkyl, heterocyclyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (Ci-C3)alkyl, halo(C1-C3)alkyl, (C1-C3)alkoxy, or cyclo(C3-C6)alkyl;

R2 is (CrC6)alkyl;

R3 is (Ci-C6)alkyl;

R^t is H, halogen, (C1-C6)alkyl, (C C6)alk0xy, haloCQ-Ceialkyl, CN or heterocyclyl; R5 is H, halogen, (d-C6)alkyl, (C C6)alkoxy, halo(C1-C6)alkyl, halo(C C6)alkoxy, (C1-C6)alkyl-S-,.or CN; and

R6 is H or halogen;

or Rt and R6 form, together with the atoms to which they are attached, a condensed 5 or 6 membered saturated or unsaturated heterocyclic ring containing, in addition to the nitrogen atom to which R] is attached, 0 further heteroatoms, wherein said heterocyclic ring is unsubstituted or substituted with 2 substituent(s) each independently being (Q- C2)alkyl;

or R4 and R5 form, together with the carbon ring atoms to which they are attached, a condensed 5, 6 or 7 membered saturated heterocyclic ring containing 1 or 2

heteroatom(s) which are O, wherein said heterocyclic ring is unsubstituted.

4. The compound according to any one of claims 1 to 3, wherein

X is CR5 or ;

Y is CR6 or N; ' ■■■' '■. ■ .■ <. · ■ · . ■ ■■ ■ ■ ■■■ . ■ ■ .

Z is CR4; ■ · ■ ■ '

Ri is (C C6)alkyl, cyclo(C3-C6)alky , halo(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(Ci-C6)alkyl, or phenyl, wherein said cyclo(C3-C6)alkyl, or phenyl is Unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (C C3)alkyl or (Ci-C3)alkoxy;

R2 is (Ci-C3)alkyl;

R3 is (C,-C3)alkyl; . ■ . i

R4 is H, halogen, (CrC^alkoxy, or halo(Ci-C4)alkyl;

R5 is H, halogen, (Q-G alkyl, (Ci-C^alkoxy, haloCQ-G alkyl, halo(C1-C )alkoxy, or

(Ci-C alkyl-S-; and

R6 is H or halogen.

5. The compound according to any one of claims 1 to 4, wherein

X is CRs or N;

Y is CR6 or N;

Z is CR4;

Ri is, (C1-C6)alkyl, cyclo(C3-C6)alkyl, halo(C1-C6)alkyl, or phenyl, wherein said cyclo(C3-C6)alkyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (C1-C3)alkyl or (C!-C3)alkoxy;

R2 is (Ci-C3)alkyl;

R3 is (Ci-C3)alkyl;

R4 is H, halogen, (C1-C4)alkoxy or halo(Ci-C4)alkyl;

R is H, halogen, (C1-C4)alkyl, (CrC^alkoxy, halo(C1-C4)alkyl, halo(CrC4)alkoxy or (C C4)alkyl-S-; and

R6 is H or halogen.

The compound according to any one of claims 1 to 5, wherein

X is CR5;■ . ■ - : - ; - ' ' :

Y is CR6; '

Z is CR4; · '

Ri is, (Ci-C(l)alkyl, cyclo(C3-C6)alkyl, halo(Ci-C6)alkyl or phenyl, wherein said cyclo(C3-C6)alkyl, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (Q-C^alkyl or. (C1-C2)alkoxy;

R2 is (Ci-C2)alkyl;

R3 is (C,-C2)alkyl;

R4 is tt, halogen, (C1-C2)alkoxy or halo(CrC2)alkyl;

R5 is H, halogen, (Ci-C2)alkyl, (Q-C^alkoxy, halo(C1-C2)alkyl, halo(C1-C2)alkoxy or (Q-C2)alkyl-S-; and

R is H or halogen.

The compound according to any one of claims 1 to 5, wherein

X is CR5;

Y is N;

Z is CR4:

Ri is, (C C6)alkyl, cyclo(C -C6)alkyl, halo(C C6)alkyl or phenyl, wherein said cyclo(C3-C6)alkyi, or phenyl is unsubstituted or substituted with 1 or 2 substituent(s) each independently being halogen, (CrC2)alkyl or (Q-C2)alkoxy;

R2 is (d-C^alkyl; ' . ,

R3 is (C,-C2)alkyl;

R4 is H, halogen, (C1-C2)alkoxy or halo(CrC2)alkyl; and

R5 is H, halogen, (CrC2)alkyl, (Ci-C2)alkoxy, halo(Cj-C2)alkyl, halo(CrC2)alkoxy or (CrC2)alkyl-S-.

8. The compound according to any one of claims 1 to 4, wherein

X is CR5 or N;

Y is CR6 or N;

ZisCR4;

R] is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2

substituent(s) each independently being halogen, (CrC3)alkyl or (Q-C^alkoxy;

R2is (C1-C3)alkyl;

R3 is (C,-C3)alkyl; !'

R4 is H, halogen, (Ci-C)alkoxy, or halo(Ci-C4)alkyl;

R5 is H, halogen, (CrC4)alkyl, (C C)alkoxy, halo(CrC)alkyl, halo(Ci-C)alkoxy, or (CrC^alkyl-S-; and

R6 is H or halogen.

9. The compound according to any one of claims 1 to 5 or 7 to 8, wherein

XisCR5;

Y is N; ■ . = , ,. .. . ·...: .. .

ZisCR4; ■ ' ■· ': ■· '

Ri is phenyl, wherein said phenyl is unsubstituted or substituted with 1 or 2

substituent(s) each independently being halogen, (Ci-C2)alkyl or (C1-C2)alkoxy;

R2 is (C,-C2)alkyl; ' - '

R3 is (Ci-C2)alkyl;

R4 is II, halogen, (C C2)alkoxy or halo(Ci-C2)alkyl; and

R5 is H, halogen, (C C2)alkyl, (C1-C2)alkoxy, halo(C C2)alkyl, halo(C1-C2)alkoxy or

(C,-C2)alkyl-S-.

10. The compound according to any one of claims 1 to 4, wherein X is CR5, Y is N, and Z is

11. The compound according to any one of claim 1 to 4, wherein X is CR5, Y is CR6, and Z is CRj.

12. The compound according to claim 1, wherein the compound is 5-fluoro-N-(2- methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)nicotinamide, N-(2-methylbut-3- yn-2-yl)-5-(trifluoromethyl)-2-(3,3,3-trifluoropropylamino)nicotinamide, 5-chloro-N-(2 methylbut-3-yn-2-yl)-2-(propylamino)benzamide, 5-chloro-2-(isopropylamino)-N-(2- methylbut-3-yn-2-yl)benzamide, 5-chloro-2-(2,2-difluoroethylamino)-N-(2-methylbut- 3-yn-2-yl)benzamide, N-(2-methylbut-3-yn-2-yl)-7-(3,3,3-trifluoropropylamino)-2,3- dihydrobenzo[b] [ 1 ,4]dioxine-6-carboxamide, 6-(isobutylamino)- V-(2-methylbut-3-yn- 2-yl)benzo[d][ 1 ,3]dioxole-5-carboxamide, 8-(isobutylamino)-N-(2-methylbut-3-yn-2- yl)-3,4-dihydro-2H-benzo[b] [ 1 ,4]dioxepine-7-carboxamide, 7-(isobutylamino)-N-(2- methylbut-3-yn-2-yl)-2,3-dihydrobenzo[b] [ 1 ,4]dioxine-6-carboxamide, 2-(2,2- difluoroethylamino)-N-(2-methylbut-3-yn-2-yl)-5-(triiluoromethyl)benzamide, N-(2- methylbut-3-yn'2-yl)-2-(trifluoromethyl)-4-(3,3,3-triiluoropropylamino)pyrirnidine-5- carboxamide, N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)-2-(3,3,3-trifluoropropyl- amin0)benzamide, 4-chlorO-N-(2-methylbut-3-yn-2-yl)-2-(propylamiiio)benzamide, 5- chlorq-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylarfnno)benzamide, 3-fluoro-N- (2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 3-fluoro-N-(2- methylbut-3-yn-2-yl)-2-(propylamino)benzamide, 2-(cyclobutylamino)-4,5-difluoro-N- (2-methylbut-3-yn-2-yl)benzamide, N-(2-methylbut-3-yn-2-yl)-2-(2,2,3,3,3- pentaflUoropropylamino)-5-(triflUoro methyl)benzamide, N-(2-rnethylbut-3-yn-2-yl)-2- (2,2,3, 3,3-pentafluoropropylamino)benzamide, 2-(2,2-difluoroethylamino)-5-fluoro-N- (3-methylpent-l-yn-3-yl)nicotinamide, 2-(cyclobutylamino)-3-fluoro-N-(2-methylbut-3 yn-2-yl)benzamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-triiluor0ethylamino)- benzamide, 2-(cyciobutyIamino)-N-(2-methylbut-3-yn-2-yl)-5- (trifluoromethyl)benzarriide, 2-(cyclobutylamino)-5-fluoro-N-(2-methylbut-3-yn-2- yl)berizamide, 2-(cyclobutylamino)-5-fluoro-iV-(2-methylbut-3-yn-2-yl)nicotinamide, 5 chl0ro-2-(isopropylarnino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-chloro-2- (cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(isopropylamino)-N-(2- methylbut-3-yn-2-yl)-5-(trifluoromethyl)nicotinamide, 5-fluoro-N-(2-methylbut-3-yh-2 yl)-2-(2,2,3,3,3-pentafluoropropylamino)nicotinamide, 5-methyl-N-(2-methylbut-3-yn- 2-yl)-2-(2,2,3,3,3-pentafluoropropylamino)benzamide, 5-fluoro-N-(2-methylbut-3-yn-2 yl)-2'(2,2,3,3,3-pentafluOropropylamin0)benzamide, 5-chloro-2-(2,2-difluoroethyl- amino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2- (2,2,2-trifluofoethylamino)nicotinamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethyl-amino)-5-(trifluoromethyl)nicotinamide, 5-cyano-2-(cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)benzariiide, 4-cyano-2-(cyclobutylamino)-iV-(2-methylbut-3-yn-2-yl)benzamide, 4,5-difluoro-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)-benzamide, N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)-5-(trifluoromethyl)benzamide, 5-methyl-N-(2-methylbut-3-yn-2-yl)-2-(2,2,2-trifluoroethylamino)benzamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)nicotinamide, 2-(butylamino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 5-bromo-N-(3-ethylpent- 1 -yn-3-yl)-2-(2-methoxyethylamino)-benzamide, 5-chloro-N-(3-ethylpent- 1 -yn-3-yl)-2-(2-methoxyethylamino)benzamide, N-(3-ethylpent-l-yn-3-yl)-4,5-difluoro-2-(2-methoxyethylamino)benzamide, N-(3-ethylpent- 1 -yn-3-yl)-2-(2-methoxyethylamino)-5-(trifluoromethyl)benzamide, N-(3-ethylpent-l-yn-3-yl)-5-iodo-2-(2-methoxyethylamino)benzamide, 2-(2-methoxyethyl-aniino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)benzamide, 2-(butylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 5-iodo-2-(2-methoxyethylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, 5-fluoro-2-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(isopentylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(2-(trifluoromethoxy)ethylamino)benzamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(4,4,4-trifluorobutylamino)benzamide, 3,5-difluoro N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 2-(2,2-difluoroethylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)nicotinam

difluofopropylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,3-difluoropropylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)nicotinaniide, 5-ehloro-2-(2,2-difluoroprop.ylaminO)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-chloro-2-(3,3-difl oropropylaniino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 4,5-difluoro-N-(2 methylbut-3-yn-2-yl)-2-(neopentylamino)benzamide, 4,5-difluoro-2-(isobutylamino)-iV-(2-methylbut-3-yn-2-yl)benzamide, 4,5-difluorO-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzamides, 2-(butylamino)-N-(2-methylbut-3-yn-2-yl)benzan ide, 2-(ethylamino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 4,5-difluoro-N-(2-methylbut-3-yn-2-yl)-2-(3 -trifluoropropylamino)benzamide, 4,5-difluoro-2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)benzamide, N-(3,5-dimethylhex- 1 -yn-3-yl) 4i5-difluoro-2-(isobutylaraino)benzamide , N-(3,4-dimethylpent- l-yn-3-yl)-4,5-difIuoro-2-(isobutylamino)benzamide, 4,5-difluoro-2-(isobutylamino)-N-(3-methylhex- 1- yri-3-yl)benzamide, 4-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropyl-amino)benzamide, N-(2-methylbut-3-yn-2-yl)-4-(trifluoromethyl)-2-(3,3,3-trifluoropropylamino)benzamide, 4-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 4-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzamide, N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethoxy)-2-(3,3,3-trifluoropropylamino)benzamide, 5-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)benzamide, 5-methyl-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylaminp)benzamide, N-(2-methylbut-3-yn-2-yl)-5-(methylthio)-2-(3,3,3-trifluoropropylamino)benzamide, N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropyl-an ino)benzamide( 2-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)benzaniide, N-(2-methylbut-3-yn-2-yl)-2-(neopentylamino)benzan ide, 2-(tert-butylamino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 4-fluoro-2-(isopropylamino)-N-(2-meth.ylbut-3-yn-2-yl)benzamide, 2-(methylamino)-iV-(2-niethylbut-3-yn-2-yl)-4-(trifluoromethyl)-benzamide, 2-(methylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethoxy)-benzamide, 2-(cyclopropylamino)-4,5-difluoro-N-(2-methylbut-3-yn-2-yl)benzamide, N-(3,4-dimethylpent-l-yn-3-yl)-2-(ethylamino)-4,5-difluorobenzamide, 2-(isobutyiamino)-4,5-dimethoxy-N-(2-methylbut-3-yn-2-yl)benzamide, 2-(2-methoxy-ethylamino)-iV-(2-methylbut-3-yn-2-yl)-4-(trifluoromethyl)benzarnide, 2-(cyclopropyl-amino)-4-fluoro-N-(2-methylbut-3-yn-2-yl)benzan ide, 2-(cyclopropylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)benzamide, 5-fluoro-2-(isopropylamino)-iV-(2-methylbut-3-yn-2-yl)benzamide, 2-(isopropylamino)-5-methyl-N-(2-methylbut-3-yn-2-yl)benzaniide, 4-methyl-N-(2-methylbut-3-yn-2-yl)-2-(3 ,3-trifluoropropylan ino)benzaTnide, 5-Ghloro-3-fluoro-2-(isopropylanTdno) -(2-methylbut-3-yn-2-yl)benzamide, 5-methoxy-N-(2-methylbut-3-yn-2-yl)-2-(4,4,4-trifluorobutylamino)benzarnidei 2-(3-methoxy-benzylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3-fluorobenzylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-(propylarnino)-6-(trifluoromethyl)nicotinamide, 2-(butylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide,

2- (tert-butylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(butylamino)-5-fluoro-N-(3-methylpent-l-yn-3-yl)benzamide, 2-(ethylamino)-N-(3-ethylpent-l-yn-3-yl)-5-fluorobenzamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(3,3,3-trifluoropropylamino)- berizamide, 2-(isobutylamino)-N-(2-methylbut 3-yn-2-yl)-6-(trifluoromethyl)-nicotinamide, 2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)-nicotinamide, 2-(ethylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoroniethyl)-nicotinamide, 4-(iert-butylamino)-N-(2-methylbut-3-yn-2-yl)-2-(trifluoroniethyl)-pyrimidine-5-carboxamide, N-(2-methylbut-3-yn-2-yl)-4-(tert-pentylamino)-2-(trifluoromethyl)pyrimidine-5-carboxarnide, 4-(isopropylamino)-N-(2-methylbut-3-yn- 2- yl)-2-(trifluoromethyl)pyrimidine-5-carboxamide, 2-(tert-butylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)nicotinamide, 6-chloro-2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 6-chloro-2-(ethylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(isopropylamino)-N-(2-methylbut-3-yn-2-yl)-6-morpholinonicotinamide, V-(2-methylbut-3-yn-2-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-6-(trifluoromethyl)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-((tetrahydro-2H-pyran-4-yl)methylamino)-6-(trifluoromethyl)nicotinamide, 2-(cyclopropylamino)-N-(2-methylbut-3-yn-2-yl)-6-(trifluoromethyl)nicotinamide, 2,3-dimethyl-N-(2-methylbut- 3- yn-2-yl)-lH-indole-7-carbqxamide, N-(3-ethylpent-l-yn-3-yl)-lH-indole-7-carboxamide, N-(3-ethylpent- 1 -yn-3-yl)- 1 ,2,3,4-tetrahydroquinoline-8-carboxamide, 2-(3-fluorophenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2-fluorophenyl-amino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(4,4-difluorocyclohexylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-bromo-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)-benzamide, N-(2-methylbut-3-yn-2-yl)-2-( 1, 1, 1 -trifluoro-2-methyl-propan-2-ylamino)nicotinamide, N-(2-methylbut-3-yn-2-yl)-4-(propylamino)thiophene-3-carboxamide, N-(2-methylbut-3-yn-2-yl)-2-(phenylamino)nicotinamide, 2-(iert-butylamino)-N-(2-methylbut-3-yn-2-yl)-5-(trifluoromethyl)-nicotinaniide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(phenylamino)nicotinamide, 2-(butylamino)-N-(2-methylbut-3-yn-2-yl)thiophene-3-carboxamidc, 2-(4-fluorophenylamino)-N-(2-methylbut-3-yn-2-;yl)nicotinaniide, N-(2-methylbut-3-yn-2-yl)-4-(2,2,3,3,3-pentafluoropropylamino)-pyrimidine-5-carboxamide, 2-(3,3-difluorocyclobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 3-((4-chlorophenyl)amino)-N-(2-metb.ylbut-3-yn-2-yl)isonicotinamide., 2-(3,3-difluoropropylamino)-3,5-difluoro-N-(2-metliylbut-3-yn-2-yl)benzamide, 3-(isobutylamino)-N-(2-methylbut-3-yn-2-yl)thiophene-2-carboxamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(3-methylisothiazol-5-ylamino)nicotinamide, 5-chloro-N-(2-methylbut-3-yn-2-yl)-2-(pyridin-3-ylamino)nicotinamide, 5-chloro-2-(3,3-difluoro-

cyclobutylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(6-cyclopentylpyridin-3-ylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,3-difluorocyclobutyl-amino)-N-(2-rnethylbut-3-yn-2-yl)-5-(trifluoromethyl)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-(phenethylamino)nicotinamide, N-(2-methylbut-3-yn-2-yl)-2-(3-phenylpropylarnino)nicotinamide, 5-fluoro-2-(3-(4-fluoiophenoxy)propylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(2-(4-fluorophenoxy)ethylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-chloro-2-(3-ethoxypropylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2-teri-butoxyethylamino)-5-chloro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-chloro-2-(2-ethoxyethylamino)-N-(2-methylbut-3-yn-2-yl)-nicotinamide, 2-(3-fluOro-4-methylphenylamino)-jV-(2-methylbut-3-yn-2-yl)-nicotinamide, 2-(3-chloro-4-methoxyphenylamino)-iV-(2-methylbut-3-yn-2-yl)-nicotinamide, 2-(3,5-difluorophenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,3-difluOrocyclobutylamino)-5-(difluoromethyl)-N-(2-methylbut-3-yn-2-yl)-nicotinaniide, 5-bromo-2-(ethyiamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-ethoxy-N-(2-methylbut-3-yn-2-yl)-2-(propylamino)benzamide, 2-(iert-butylamino)-5-chloro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,3-difluorocyclobutylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(4-fluorophenylamino)-N-(2-methylbut-3 -yn-2-yl)nicotinamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-( 1, 1, 1-trifluoropropan-2-ylamino)nicotinamide, 4-(4-chlorophenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-N-(2-methylbut-3-yn-2-yl)-2-(phenylamino)-nicotinamide, N-(2-methylbut-3-yn-2-yl)-4-(4-(trifluoromethyl)phenylamino)-pyrimidine-5-carboxamide, 2-(tert-butylamino)-5-fluoro-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(3,3-difluorocyclobutylamino)-N-(3-ethylpent-l-yn-3-yl)-5-fluoronieotinamide, 2-(3,3-difluorocyclobutylamino)-5-fluoro-N-(3-methylpent-l-yn-3-yl)nicotinamide, 2-(3-fluoro-5-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)-nicotinamide, 2-(3-fluoro-5-methoxyphenylamino)-N-(3-methylpent- l-yn-3-yl)-nicotinamide, 2-(3-chloro-5-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)-nicotinamide, 2-(3-chloro-5-methoxyphenylamino)-N-(3-methylpent-l-yn-3-yl)-nicotinamide, 2-(2-fluoro-3-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)-nicotinamide, 2-(2-fluoro-3-methoxyphenylamino)-N-(3-methylpent- 1 -yn-3-yl)-nicotinamide, 5-fluoro-2-(4-fluorophenylamino)-N-(3-methylpent- 1 -yn-3-yl)-nicotinamide, 5-fluoro-N-(3-methylpent- 1 -yn-3-yl)-2-(phenylaminb)nicotinamide, 2- (2,4-difluorophenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2,4- difluorophenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 5-fluoro-2-(3- fluorophenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 5-fluoro-2-(3- fiuorophenylamino)-N-(3-n ethylpent-l-yn-3-yl)nicotinaniide, 5-chloro-2-(3,3- difluorocyclobutylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 2-(3-cyanophenyl- amino)-5-fluoro-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2-(2-fluoro-5-methoxy- phenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2-fluoro-5-methoxyphenyl- amino)- V-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2-(3-cyano-4-fluorophenylamino)-N- (2-methylbut-3-yn-2-yl)nicotinamide, 2-(3-cyano-4-fluorophenylan ino)-iV-(3- methylpent-l-yn-3-yl)nicotinamide, 2-(3-cyano-5-fluorophenylamino)-N-(2-methylbut- 3-yn-2-yl)nicotinamide, 2-(3-fluorophenylamino)-iV-(3-methylpent-l-yn-3-yl)- nicQtinamide, 2-(2-fluorophenylamino)-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, 2- (3,5-difluorophenylamino)-N-(3-niethylpent-l-yn-3-yl)nicotinamide, 2-(3-cyano-5- fluorophenylamino)-N-(3-methylpent- l-yn-3-yl)nicotinamide, 2-(2-chloro-5- methoxyphenylaminq)-N-(2-methylbut-3-yn-2-yl)nicotinamide, 2-(2-chloro-5- methoxyphenylamino)-N-(3-methylpent- 1 -yn-3-yl)nicotinamide, N-(3-methylpent- 1 -yn- 3-yl)-2-(phenylamino)nicotinamide, 2-(4,4-difluorocyclohexylamino)-N-(3-methylpent- l-yn-3-yl)nicotinamide, 2-(3-chloro-4-methoxyphenylamino)-iV-(3-methylpent- l-yn-3- yl)nicotinamide, 2-(4-fluoro-3-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)- nicotinamide, 2-(4-fluoro-3-methoxyphenylamino)-N-(3-methylpent-l-yn-3-yl)- nicotinamide, 2-(3,4-difluorophenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, 2- (4-chloro-3-methoxyphenylamino)-N-(2-methylbut-3-yn-2-yl)nicotinan ide, 2-(4- chl0ro-3-methoxyphenylamino)-N-(3-methylpent-l-yn-3-yl)nicotinamide, or 2-(4- fluorophenylamino)-N-(3-methylpent- 1 -yn-3-yl)nicotinamide

13. The compound according to any one of claims 1 to 10 for use as a medicament.

14. The compound according to any one of claims 1 to 1 1 for use in the treatment of a

disorder, condition or disease mediated by TRPAl receptor activity.

15. The compound according to claim 12, wherein the disorder, condition or disease is neuropathic pain, pain in diabetic polyneuropathy, postoperative pain, cancer pain, migraine, asthma, COPD, cough, pain in osteoarthritis, pain in rheumatoid arthritis, inflammatory bowel disease, or diabetes.

16. A method for the treatment of a disorder, condition, or disease mediated by TRPAl receptor activity, which method comprises administering to a mammal in need of such treatment an effective amount of at least one compound according to claim 1.

17. The method according to claim 14, wherein the disorder, condition or disease is

neuropathic pain, pain in diabetic polyneuropathy, postoperative pain, cancer pain, migraine, asthma, COPD, cough, pain in osteoarthritis, pain in rheumatoid arthritis, inflammatory bowel disease, or diabetes.

18. A pharmaceutical composition comprising at least one compound according to any one of claims Ϊ to 10 and a pharmaceutically acceptable carrier, diluents, and/or excipient.

19. The pharmaceutical composition according to claim 16, wherein the composition further comprises at least one other active ingredient.