Sulfoximides as NaV1.8 inhibitors

Abstract

The present invention relates to a compound # imgabs0 # according to general formula (I) which is useful as an inhibitor of NaV1.8 and is useful in the treatment of pain.

Description

[0001] The present invention relates to compounds of general formula (I)

[0002]

[0003] which are used as inhibitors of Na V 1.8 and can be used for the treatment of pain.

[0004] Normal pain sensation (nociception) mainly serves as a survival mechanism, which is a way for the body to protect itself by alerting (further) tissue damage and disease caused by harmful stimuli. For example, acute pain occurs when the external environment (temperature, pressure, chemicals) activates modality-specific receptors (nociceptors) and ion channels in the skin. The peripheral terminals of pain-signaling neurons (whose cell bodies are found in the dorsal root ganglion [DRG] and trigeminal ganglion [TG]) convert external stimuli into electro-chemical generator potentials. Specific voltage-gated sodium channels (Na V s) integrate and amplify these generator signals until the threshold of the action potential [AP] is reached. Thus, a harmful stimulus starting in the periphery ultimately leads to the discharge of action potentials, which travel towards the central nervous system, first forming synapses with neurons in the spinal cord and then traveling towards the brain. Na V also plays a role in supporting the propagation of action potentials to the central terminals within the spinal cord. At the end of its journey along the somatosensory pathway, the action potential signal is interpreted by the brain as pain (Lumpkin and Caterina, Nature (2007), Vol. 445, pp. 858 - 865; and Crawford and Caterina Toxicologic Pathology (2020) 48(1)-174; Goodwin G and McMahon S.B. Nature Reviews Neuroscience (2021) Vol. 22, pp. 263 - 274; Bennett D.L. et al. Physiol Rev 99(2019) Vol. 99, pp. 1079 - 1151).

[0005] Abnormal persistent neuropathic pain is the result of a lesion or disease in this somatosensory pathway. In response to nerve injury or inflammation, abnormal changes in ion channel expression lead to hyperexcitability of pain-signaling neurons and their nerves / axons, resulting in pathological pain.

[0006] Voltage-gated Na V1.8 sodium channels are therapeutic targets for analgesia because of their restricted expression profile (almost exclusively in peripheral sensory tissues), their location along the pain pathway (free nerve endings, sciatic nerve, and DRG), their prominent physiological role in pain signaling (supporting AP propagation and facilitating repetitive AP firing), and the supporting genetic / pharmacological phenotype evidence (human / animal studies indicating that changes in Na V 1.8 function result in parallel changes in pain sensitivity).

[0007] Regarding the expression profile of Na V 1.8 along the pain pathway, it was initially named SNS (sensory neuron specific) (Akopian A.N. et al. Nature (1996) Vol. 379, pp. 257 - 261) or PN3 (peripheral nerve 3) (Sangameswaran L. et al. J. Biol. Chem. (1996) Vol. 271, pp. 5953 - 5956) as it was first mainly found in peripheral sensory neurons of the dorsal root ganglion (DRG) and trigeminal ganglion (TG). Similarly, Na V 1.8 is localized to free nerve endings where pain signaling is initiated in the skin (Persson A.K. et al., Mol. Pain. (2010) 6:84), and is diffusely localized along the entire length of the unmyelinated axons of the sciatic nerve (Rush A.M. et al., Eur. J. Neurosci (2005) Vol. 22, pp. 39 - 49).

[0008] In contrast, Na V 1.8 is expressed at very low levels in non - neuronal tissues such as the heart and skeletal muscle, as well as in the CNS (including the brain and spinal cord) (9, 10, 338, 406) (Akopian A.N. op. cit.; Akopian A.N. et al. Nat. Neurosci (1999) Vol. 2, pp. 541 - 548; Novakovic S.D. et al. J. Neurosci. (1998) Vol. 18, pp. 2184 - 2187; and Sagameswaran L. op. cit.).

[0009] Regarding Na VAs for the physiological effects of 1.8, it contributes most of the inward current during the rising phase of the all-or-none action potential of nociceptive sensory neurons (Blair NT et al. J. Neuro sci. (2003) Vol. 23, pp. 10338-10350 and Renganathan M et al. J. Neurophysiol (2001) Vol. 86, pp. 629-640), and also contributes most of the current in subsequent spikes during the repetitive discharge of DRG neurons (Choi JS J Neurophysiol (2011) Vol. 106, pp. 3173-3184; and Tan ZY et al. J. Neurosci. (2014) Vol. 34, pp. 7190-7197).

[0010] Genetic and pharmacological studies have found that Na V 1.8 gain-of-function mutations (Faber CG et al. (2012) Ann. Neurol Vol 71 pp 26-39; Han C et al. J. Neurol Neuros urg Psychiatry (2014) Vol. 85 pp 499-505; and Kist AM et al. PLoS One (2016) Vol. 11 e0161789; Eijkenboom I. et al. J. Neurol Neurosurg Psychiatry (2019) 90(3) pp 342-352); loss-of-function (knockout) studies in mice reduced pain sensitivity, especially in nociception (Laird JM et al. J. Neurosci (2002) J. Neurosci Vol. 22 pp 8352-8356; Jarvis MF et al. Proc Natl Acad Sci USA (2007) Vol. 104, pp. 8520-8525; Joshi S.K. et al. Pain (2006) Vol. 123, pp. 75-82) and in a neuropathic model (Roza C. et al. J Physiol (2003) Vol. 550, pp. 921-926); Na V1.8 Selective small molecule inhibitors alleviate pain in rodents, particularly in inflammatory and neuropathic models (Jarvis et al., op. cit.; Kort M. E. et al., Bioorg Med Chem Lett (2010) Vol. 20, pp. 6812 - 6815; Scanio M. J. et al., Bioorg Med Chem (2010) Vol. 18, pp. 7816 - 7825; Payne C. E. et al., Br J Pharmacol (2015) Vol. 172, pp. 2654 - 2670).

[0011] Currently, non - selective Na V channel inhibitors are used to treat epilepsy, arrhythmias, and chronic pain (Hille, B. J. Gen. Physiol. (1977) Vol. 69, pp. 497 - 515; Hille. B, Ion Channels of Excitable Membranes (1992), pp. 391 - 421; Sunderland, Mass., Sinauer Associates, Inc., 3rd ed.; Hondeghem L. M. and Katzung B. G., Annu. Rev. Pharmacol. Toxicol. (1984) Vol. 24, pp. 387 - 423; Catterall W. A., Trends Pharmacol. Sci. (1987) Vol. 8, pp. 57 - 65) – however, due to dose - limiting adverse side effects associated with inhibition of Na V 1.1 / Na V 1.2 / 1.6 (seizure propensity), inhibition of Na V 1.4 (muscle weakness / paralysis), inhibition of Na V 1.5 (risk of arrhythmias), the efficacy of all these analgesics is limited.

[0012] There is a need to develop a Na V 1.8 selective small molecule inhibitor as an effective and safe analgesic.

[0013] Na V 1.8 inhibitors are also known from WO2020 / 092187, WO2020 / 092667, WO2009 / 049180, WO2009 / 049183, WO2009 / 049181, and WO2021 / 113627.

[0014] The object of the present invention is to provide novel compounds which are Na VAn inhibitor of 1.8, preferably a selective inhibitor, and preferably having advantages over the compounds of the prior art. The novel compound should be particularly suitable for the treatment of pain.

[0015] The subject matter of the claims of this patent has achieved this purpose.

[0016] Surprisingly, it has been found that the compounds according to the invention are highly selective inhibitors of the Na V 1.8 channel.

[0017] The present invention relates to compounds according to general formula (I)

[0018]

[0019] wherein

[0020] One of A1, A2 and A3 represents C-R3, and the other two of A1, A2 and A3 independently of one another represent CR' or N;

[0021] R' independently represents H, F, CH3, CH2F, CHF2, CF3 or OCH3;

[0022] L represents CH2, CH(CH3) or CH(CH2CH3);

[0023] R1 represents C 3-10 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or dispiroalkyl, 4- to 10-membered heterocycloalkyl or 5- to 11-membered heterobicycloalkyl;

[0024] R2 represents H or C 1-6 -alkyl;

[0025] R3 represents S(O)(NR3a)R3b or S(NR3a)2R3b;

[0026] R3a represents H, C 1-6 -alkyl, C(O)C 1-5 -alkyl, C(O)C 1-5 -alkyl-NH2, C(O)C 1-5 -alkyl-NH-CH3, C(O)C 1-5 -alkyl-N(CH3)2, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heterocycloalkyl or C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl);

[0027] R3b represents NH2, C 1-6 -alkyl, C 3-10 -cycloalkyl, C1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heteroalkyl, or C 1-6 -alkylene-(4- to 10-membered heteroalkyl);

[0028] Alternatively, R3a and R3b each represent (CH2) 3-5 and together with the atom to which they are attached form a ring;

[0029] R4 represents H, F, Cl, Br, CN, CHF2, CH2F, CF3, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or bisspiroalkyl, 4- to 10-membered heteroalkyl, C 1-6 -alkylene-(4- to 10-membered heteroalkyl), NH2, N(H)(C 1-6 -alkyl), N(C 1-6 -alkyl)2, O-C 1-6 -alkyl, O-C 3-10 -cycloalkyl, O-C 1-6 -alkylene-C 3-10 -cycloalkyl, O-(4- to 6-membered heteroalkyl), or O-C 1-6 -alkylene-(4- to 6-membered heteroalkyl);

[0030] R5 represents H, F, Cl, Br, CN, CHF2, CH2F, CF3, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heteroalkyl, C 1-6 -alkylene-(4- to 10-membered heteroalkyl), NH2, N(H)(C 1-6 -alkyl), N(C 1-6 -alkyl)2, O-C 1-6 -alkyl, O-C 3-10 -cycloalkyl, O-C 1-6 -alkylene-C 3-10 -cycloalkyl, O-(4- to 6-membered heteroalkyl), or O-C 1-6 -alkylene-(4- to 6-membered heteroalkyl);

[0031] wherein C 1-6 -alkyl and C 1-6 -alkylene are each independently straight-chain or branched in each case;

[0032] wherein C 1-6 -alkyl, C1-6 -alkylene, C 3-10 -cycloalkyl, C 3-6 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or dispiroalkyl, 4- to 10-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 11-membered heterobicycloalkyl are each independently unsubstituted or substituted by one, two, three, four or more substituents independently selected from the group consisting of: F, Cl, CN, C 1-6 -alkyl, C 1-6 -alkylene-OH, C 1-6 -alkylene-OCH3, CF3, CF2H, CFH2, C(O)-C 1-6 -alkyl, OH, ═O, OCF3, OCF2H, OCFH2, O-C 1-6 -alkyl, C 1-4 -alkylene-O-C 1-4 -alkylene-O-CH3, C 0-4 -alkylene-O-(C 1-4 -alkylene-O) 1-4 -CH3, NH2, NH-C 1-6 -alkyl, N(C 1-6 -alkyl)2 or 4- to 6-membered heterocycloalkyl;

[0033] The compound is in the form of a free compound or a physiologically acceptable salt thereof.

[0034] In a preferred embodiment, the compound according to the invention is present in the form of a free compound. For the purposes of the specification, "free compound" preferably means that the compound according to the invention is not present in the form of a salt. Methods for determining whether a chemical substance is present as a free compound or as a salt are known to those skilled in the art, such as 14 N or 15 N solid state NMR, X-ray diffraction, X-ray powder diffraction, IR, Raman, XPS. 1 1H-NMR recorded in solution can also be used to consider the presence of protonation.

[0035] In another preferred embodiment, the compound according to the invention is present in the form of a physiologically acceptable salt. For the purposes of this specification, the term "physiologically acceptable salt" preferably refers to a salt obtained from a compound according to the invention and a physiologically acceptable acid or base.

[0036] According to the present invention, the compounds according to the present invention can exist in any possible form including solvates, co-crystals, and polymorphs. For the purposes of this specification, the term "solvate" preferably refers to an adduct of (i) a compound according to the present invention and / or its physiologically acceptable salt and (ii) one or more solvents in different molecular equivalents.

[0037] Further, the compounds according to the present invention can exist in the form of racemates, enantiomers, diastereomers, tautomers, or any mixture thereof.

[0038] The compounds according to the present invention can have one or more stereocenters. A person skilled in the art can tell whether the depicted compound has one or more stereocenters by observing the chemical structure.

[0039] For some compounds according to the present invention that have one or more stereocenters and whose chemical structures have been disclosed in the examples of the present application, the chemical structure includes bold bonds and / or dashed bonds to indicate the relative structural orientation of the substituents that are connected to the superior structure by the bold bonds and / or dashed bonds. If the bold bonds and / or dashed bonds are depicted in the form of wedges, the absolute stereochemical configuration of the compound is known and thus indicated. If the bold bonds and / or dashed bonds are depicted as straight bonds (i.e., without wedges), the absolute stereochemical configuration of the compound has not been determined. In this case, the bold bonds and / or dashed bonds are only used to indicate that the particular compound exists in the form of one enantiomer or one diastereomer (e.g., a cis-diastereomer (i.e., a mixture of two cis-enantiomers) or a trans-diastereomer (i.e., a mixture of two trans-enantiomers)). All compounds according to the present invention that have one or more stereocenters but whose chemical structures disclosed in the examples of the present application do not contain bold bonds and / or dashed bonds exist in the form of a mixture of stereoisomers.

[0040] The present invention also includes isotopologues of the compounds of the present invention, wherein at least one atom of the compound is replaced by an isotope different from the major isotope occurring in nature of the corresponding atom, and any mixture of such isotopologues of the compound. Preferred isotopes are 2 H (deuterium), 3 H (tritium), 13 C, and 14 C. Isotopologues of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art.

[0041] According to the present invention, the terms "C 1-6 -alkyl" and "C 1-4"-Alkyl" preferably means an acyclic and preferably saturated hydrocarbon residue which may be straight-chain (i.e. unbranched) or branched and which may be unsubstituted or mono- or polysubstituted (e.g. disubstituted or trisubstituted) and which contains 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) and 1 to 4 (i.e. 1, 2, 3 or 4) carbon atoms respectively. Preferably, C 1-6 -alkyl and C 1-4 -alkyl are saturated. Preferred C 1-6 -alkyl is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl. Particularly preferred C 1-6 -alkyl is selected from C 1-4 -alkyl. Preferred -C 1-4 -alkyl is selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0042] According to the present invention, the terms "C 1-6 -alkylene" and "C 1-4"-alkylene" refers to a straight-chain or branched, and preferably saturated, aliphatic residue which may be unsubstituted or mono- or poly-substituted (e.g., di- or tri-substituted), and is preferably selected from the group consisting of: CH2, CH(CH3), CH2CH2, CH2CH(CH3), CH(CH3)CH2, CH2CH2CH2, CH(CH3)CH2CH2, CH2CH(CH3)CH2, CH2CH2CH(CH3), CH2CH2CH2CH2, CH(CH3)CH2CH2CH2, CH2CH(CH3)CH2CH2, CH2CH2CH(CH3)CH2, CH2CH2CH2CH(CH3), CH2CH2CH2CH2CH2, CH(CH3)CH2CH2CH2CH2, CH2CH(CH3)CH2CH2CH2, CH2CH2CH(CH3)CH2CH2, CH2CH2CH2CH(CH3)CH2, CH2CH2CH2CH2CH(CH3) and CH2CH2CH2CH2CH2CH2; more preferably CH2, CH(CH3), CH2CH2, CH2CH(CH3) and CH(CH3)CH2, most preferably CH2 and CH(CH3), and especially CH2. Preferably, C 1-6 -alkylene is selected from C 1-4 -alkylene-.

[0043] According to the present invention, the terms "C 3-10 -cycloalkyl" and "C 3-6 -cycloalkyl" preferably mean monocyclic aliphatic hydrocarbons containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms as ring members and 3, 4, 5 or 6 carbon atoms as ring members, respectively, where the hydrocarbon can in each case be saturated or unsaturated (but not aromatic), unsubstituted or mono- or poly-substituted.

[0044] Preferably, C 3-10 -cycloalkyl and C 3-6 -cycloalkyl are saturated. C 3-10 -cycloalkyl and C 3-6 -cycloalkyl can be combined with the respective upper general structure via any desired and possible ring member of the cycloalkyl. 3-10 -cycloalkyl and C 3-6 -cycloalkyl are not condensed with another ring system and are not bridged.

[0045] Preferred C 3-10 -cycloalkyl are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. Preferred C 3-10 -cycloalkyl is selected from C 3-6 -cycloalkyl.

[0046] According to the present invention, the term "4- to 11-membered bicycloalkyl" preferably means a bicyclic aliphatic hydrocarbon containing 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms as ring members, wherein the hydrocarbon can in each case be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted. The bicyclic system can share a common bond (fused ring) or can be bridged.

[0047] Preferably, the 4- to 11-membered bicycloalkyl is saturated. The 4- to 11-membered bicycloalkyl can be attached to the respective general structure above via any desired and possible ring member of the 4- to 11-membered bicycloalkyl.

[0048] Preferred 4- to 11-membered bicycloalkyls are selected from the group consisting of bicyclo[1.1.0]butyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl and bicyclo[3.3.0]octyl.

[0049] According to the present invention, the term "5- to 11-membered spiroalkyl or dispiroalkyl" means a spiro or dispirocyclic aliphatic hydrocarbon containing 5, 6, 7, 8, 9, 10 or 11 carbon atoms as ring members, wherein the hydrocarbon can in each case be saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted. The spirocyclic system shares a common carbon atom connecting the respective rings. In the case of a dispirocyclic system, there are three rings, and two of these three rings share a common carbon atom connecting these rings.

[0050] Preferably, the 5- to 11-membered spiroalkyl or dispiroalkyl is saturated. The 5- to 11-membered spiroalkyl or dispiroalkyl can be attached to the respective general structure above via any desired and possible ring member of the 5- to 11-membered spiroalkyl or dispiroalkyl.

[0051] Preferred 5- to 11-membered spiroalkyls or dispiroalkyls are selected from the group consisting of spiro[2.2]pentyl, spiro[2.3]hexyl, spiro[3.3]heptyl and dispiro[2.0.2.1]heptyl.

[0052] According to the present invention, the terms "4- to 10-membered heterocycloalkyl" and "4- to 6-membered heterocycloalkyl" preferably mean monocyclic heterocyclic aliphatic saturated or unsaturated (but not aromatic) residues having 4 to 10, i.e., 4, 5, 6, 7, 8, 9 or 10 ring members and 4 to 6, i.e., 4, 5 or 6 ring members, respectively, where in each case at least one (and if appropriate also two or three carbon atoms) is replaced by a heteroatom or heteroatom group, the heteroatom or heteroatom group each independently of one another being selected from the group consisting of O, S, S(=O), S(=O)2, N, NH and N(C 1-4 -alkyl) such as N(CH3), where the carbon atoms of the ring may be unsubstituted or mono- or polysubstituted. Preferably, the 4- to 10-membered heterocycloalkyl and the 4- to 6-membered heterocycloalkyl contain only one heteroatom or heteroatom group within the ring.

[0053] Preferably, the 4- to 10-membered heterocycloalkyl and the 4- to 6-membered heterocycloalkyl are saturated. The 4- to 10-membered heterocycloalkyl and the 4- to 6-membered heterocycloalkyl are not condensed with a further ring system and are not bridged.

[0054] If not otherwise indicated, the 4- to 10-membered heterocycloalkyl and the 4- to 6-membered heterocycloalkyl can be attached to the general structure above via any desired and possible ring member of the heterocyclic aliphatic residue. In a preferred embodiment, the 4- to 10-membered heterocycloalkyl and the 4- to 6-membered heterocycloalkyl are attached to the general structure above via a carbon atom.

[0055] Preferred 4- to 10-membered heterocycloalkyls are selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl 1,1-dioxide, oxepanyl, piperidinyl, piperidinone, azetidinyl, pyrrolidinyl, pyrrolidone, 4-methylpiperazinyl, morpholinone, dioxanyl, piperazinyl, tetrahydropyrrolyl, azepanyl, dioxepanyl, oxazepanyl, diazepanyl, thiazolidinyl, tetrahydrothienyl, tetrahydropyridyl, dithiolanyl, dihydropyrrolyl, dioxolanyl, dihydropyridyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, N-methylpyridinone, pyrazolidinyl, pyranyl; dihydroquinolinyl, dihydroisoquinolinyl, dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroindolyl; more preferably oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl 1,1-dioxide, oxepanyl, piperidinyl, piperidinone, azetidinyl, pyrrolidinyl, pyrrolidone, 4-methylpiperazinyl, morpholinone, dioxanyl, piperazinyl and tetrahydropyrrolyl.

[0056] Preferred 4- to 6-membered heterocycloalkyl groups are selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thianyl, thianyl 1,1-dioxide, piperidinyl, piperidinonyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, 4-methylpiperazinyl, morpholinonyl, dioxanyl, piperazinyl, pyrrolinyl, thiazolidinyl, tetrahydrothienyl, tetrahydropyridyl, dithiolanyl, dihydropyrrolyl, dioxolanyl, dihydropyridyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, N-methylpyridinonyl, pyrazolidinyl and pyranyl; more preferably oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thianyl, thianyl 1,1-dioxide, piperidinyl, piperidinonyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, 4-methylpiperazinyl, morpholinonyl, dioxanyl, piperazinyl and pyrrolinyl.

[0057] According to the present invention, the term "5- to 11-membered heterobicycloalkyl" preferably means a bicyclic heteroaliphatic saturated or unsaturated (but not aromatic) hydrocarbon containing 5, 6, 7, 8, 9, 10 or 11 ring members, where in each case at least one (and if appropriate also two or three carbon atoms) is replaced by a heteroatom or heteroatom group, which heteroatom or heteroatom group is independently selected from the group consisting of O, S, S(=O), S(=O)2, N, NH and N(C 1-4 -alkyl) such as N(CH3), where the carbon atoms of the ring can be unsubstituted or mono- or polysubstituted. The bicyclic system can share a common bond (fused ring) or can be bridged.

[0058] Preferably, the 5- to 11-membered heterobicycloalkyl is saturated. The 5- to 11-membered heterobicycloalkyl can be attached to the respective general structure above via any desired and possible ring member of the 5- to 11-membered heterobicycloalkyl.

[0059] A preferred 5- to 11-membered heterobicycloalkyl is 2-oxabicyclo[2.1.1]hexyl.

[0060] Regarding the terms "C 1-6 -alkyl", "C 1-4 -alkyl", "C 1-6 -alkylene", "C 1-4 -alkylene", "C 3-10 -cycloalkyl", "C 3-6For “C₃ - C₇ - cycloalkyl”, “4 - to 11 - membered bicycloalkyl”, “5 - to 11 - membered spiroalkyl or dispiroalkyl”, “4 - to 10 - membered heterocycloalkyl”, “4 - to 6 - membered heterocycloalkyl” and “5 - to 11 - membered heterobicycloalkyl”, the term “substituted” in the sense of the present invention means that one or more hydrogen atoms are each independently of one another singly substituted (monosubstituted) or multiply substituted (polysubstituted) by at least one substituent, for example disubstituted, trisubstituted or tetrasubstituted; more preferably monosubstituted, disubstituted or trisubstituted. In the case of multiple substitution, i.e. in the case of polysubstituted residues such as disubstituted or trisubstituted residues, these residues can be polysubstituted on different atoms or on the same atom, for example trisubstituted on the same carbon atom, as in the case of -CF₃, -CH₂CF₃, or disubstituted, as in the case of 1,1 - difluorocyclohexyl, or disubstituted at different points, as in the case of 1 - chloro - 3 - fluorocyclohexyl. Multiple substitution can be carried out using the same substituents or using different substituents.

[0061] If a residue occurs several times within a molecule, this residue can have different meanings for different substituents: If for example both R₄ and R₅ represent C 1-6 -alkyl, then C 1-6 -alkyl can represent for example methyl for R₄ and 2 - propyl for R₅.

[0062] According to the present invention, C 1-6 -alkyl, C 1-4 -alkyl, C 1-6 -alkylene, C 1-4 -alkylene, C 3-10 -cycloalkyl, C 3-6 -cycloalkyl, 4 - to 11 - membered bicycloalkyl, 5 - to 11 - membered spiroalkyl or dispiroalkyl, 4 - to 10 - membered heterocycloalkyl, 4 - to 6 - membered heterocycloalkyl and 5 - to 11 - membered heterobicycloalkyl are each independently of one another unsubstituted or monosubstituted or polysubstituted, more preferably unsubstituted or substituted by one, two, three, four or more substituents independently of one another selected from the group consisting of: F, Cl, CN, C 1-6 -alkyl, C 1-6 -alkylene - OH, C 1-6 -alkylene - OCH₃, CF₃, CF₂H, CFH₂, C(O)-C 1-6 -alkyl, OH, ═O, OCF₃, OCF₂H, OCFH₂, O - C 1-6 -alkyl, C 1-4 -alkylene - O - C 1-4 -alkylene - O - CH₃, C 0-4 -alkylene - O-(C 1-4 -alkylene - O)1-4 -CH3, NH2, NH-C 1-6 -alkyl, N(C 1-6 -alkyl)2 or 4- to 6-membered heteroalkyl; preferably F, CH3, CF3, CF2H, CFH2, OCH3, CN, =O, OH, NH2, N(CH3)2, and oxetanyl; more preferably F, CH3, CF3, CF2H, and CFH2; and most preferably CF3.

[0063] Preferably, C 1-6 -alkylene is unsubstituted.

[0064] According to the present invention, one of A1, A2, and A3 represents C-R3, and the other two of A1, A2, and A3 each independently represents CH or N.

[0065] In a preferred embodiment,

[0066] (i) A1 represents C-R3; A2 represents N; and A3 represents CR', preferably CH;

[0067] (ii) A1 represents C-R3; A2 represents CR', preferably CH; and A3 represents CR', preferably CH; or

[0068] (iii) A1 represents C-R3; A2 represents N; and A3 represents N; or

[0069] (iv) A1 represents C-R3; A2 represents CR', preferably CH; and A3 represents N; or

[0070] (v) A1 represents CR', preferably CH; A2 represents C-R3; and A3 represents CR', preferably CH; or

[0071] (vi) A1 represents N, A2 represents C-R3, and A3 represents CR', preferably CH; or

[0072] (vii) A1 represents N, A2 represents C-R3, and A3 represents N.

[0073] According to the present invention, R' independently represents H, F, CH3, CH2F, CHF2, CF3, or OCH3.

[0074] In a preferred embodiment, R' represents H.

[0075] According to the present invention, L represents CH2, CH(CH3), or CH(CH2CH3).

[0076] In a preferred embodiment, L represents CH2.

[0077] According to the present invention, R1 represents C3-10 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or dispiroalkyl, 4- to 10-membered heterocycloalkyl or 5- to 11-membered heterobicycloalkyl.

[0078] In a preferred embodiment, R1 represents C 3-10 -cycloalkyl, which is unsubstituted or substituted with one, two, three, four or more substituents independently selected from each other from F, CH3, OCH3, CN, CHF2 and CF3.

[0079] Preferably, R1 is selected from cyclopropyl, methylcyclopropyl, dimethylcyclopropyl, fluorocyclopropyl, difluorocyclopropyl, trifluoromethylcyclopropyl, trifluoromethylmethylcyclopropyl, methyldifluorocyclopropyl, trifluoromethyldifluorocyclopropyl, dimethyldifluorocyclopropyl, cyclobutyl, methylcyclobutyl, dimethylcyclobutyl, fluorocyclobutyl, difluorocyclobutyl, trifluoromethylcyclobutyl, trifluoromethylmethylcyclobutyl, methyldifluorocyclobutyl, trifluoromethyldifluorocyclobutyl, dimethyldifluorocyclobutyl, cyclopentyl, methylcyclopentyl, dimethylcyclopentyl, fluorocyclopentyl, difluorocyclopentyl, trifluoromethylcyclopentyl, trifluoromethylmethylcyclopentyl, methyldifluorocyclopentyl, trifluoromethyldifluorocyclopentyl, dimethyldifluorocyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, fluorocyclohexyl, difluorocyclohexyl, trifluoromethylcyclohexyl, trifluoromethylmethylcyclohexyl, methyldifluorocyclohexyl, trifluoromethyldifluorocyclohexyl, dimethyldifluorocyclohexyl, cycloheptyl, methylcycloheptyl, dimethylcycloheptyl, fluorocycloheptyl, difluorocycloheptyl, trifluoromethylcycloheptyl, trifluoromethylmethylcycloheptyl, methyldifluorocycloheptyl, trifluoromethyldifluorocycloheptyl, dimethyldifluorocycloheptyl, cyclooctyl, methylcyclooctyl, dimethylcyclooctyl, fluorocyclooctyl, difluorocyclooctyl, trifluoromethylcyclooctyl, trifluoromethylmethylcyclooctyl, methyldifluorocyclooctyl, trifluoromethyldifluorocyclooctyl, dimethyldifluorocyclooctyl, cyclononyl, methylcyclononyl, dimethylcyclononyl, fluorocyclononyl, difluorocyclononyl, trifluoromethylcyclononyl, trifluoromethylmethylcyclononyl, methyldifluorocyclononyl, trifluoromethyldifluorocyclononyl, dimethyldifluorocyclononyl, cyclodecyl, methylcyclodecyl, dimethylcyclodecyl, fluorocyclodecyl, difluorocyclodecyl, trifluoromethylcyclodecyl, trifluoromethylmethylcyclodecyl, methyldifluorocyclodecyl, trifluoromethyldifluorocyclodecyl and dimethyldifluorocyclodecyl.

[0080] More preferably, R1 is selected from cyclopropyl, dimethylcyclopropyl, trifluoromethylmethylcyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, methyltrifluoromethylcyclobutyl, difluorocyclobutyl, methyldifluorocyclobutyl, cyclopentyl, difluorocyclopentyl, methyldifluorocyclopentyl, trifluoromethylcyclopentyl, trifluoromethyldifluorocyclopentyl, cyclohexyl, difluorocyclohexyl and methyldifluorocyclohexyl.

[0081] In a preferred embodiment, R1 represents C 3-10-cycloalkyl, which is substituted by CH3 and optionally substituted by one, two, three, four or more substituents independently selected from each other from F, OCH3, CN, CHF2 and CF3, wherein the C substituted by CH3 3-10 -the carbon atom of the cycloalkyl is connected to L. Preferred representatives include, but are not limited to, methyl difluorocyclobutyl and methyl difluorocyclopentyl.

[0082] In a further preferred embodiment, R1 represents a 4- to 11-membered bicycloalkyl which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from each other from F, CH3, OCH3, CN, CHF2 and CF3.

[0083] Preferably, R1 is selected from bicyclo[1.1.1]pentyl, methylbicyclo[1.1.1]pentyl, methoxybicyclo[1.1.1]pentyl, difluoromethylbicyclo[1.1.1]pentyl, trifluoromethylbicyclo[1.1.1]pentyl, fluorobicyclo[1.1.1]pentyl, difluorobicyclo[1.1.1]pentyl, methyldifluorobicyclo[1.1.1]pentyl, trifluoromethyldifluorobicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, methylbicyclo[2.1.0]pentyl, trifluoromethylbicyclo[2.1.0]pentyl, fluorobicyclo[2.1.0]pentyl, difluorobicyclo[2.1.0]pentyl, methyldifluorobicyclo[2.1.0]pentyl, trifluoromethyldifluorobicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, methylbicyclo[3.1.0]hexyl, trifluoromethylbicyclo[3.1.0]hexyl, fluorobicyclo[3.1.0]hexyl, difluorobicyclo[3.1.0]hexyl, methyldifluorobicyclo[3.1.0]hexyl, trifluoromethyldifluorobicyclo[3.1.0]hexyl, bicyclo[2.2.0]hexyl, methylbicyclo[2.2.0]hexyl, trifluoromethylbicyclo[2.2.0]hexyl, fluorobicyclo[2.2.0]hexyl, difluorobicyclo[2.2.0]hexyl, methyldifluorobicyclo[2.2.0]hexyl, trifluoromethyldifluorobicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, methylbicyclo[2.1.1]hexyl, trifluoromethylbicyclo[2.1.1]hexyl, fluorobicyclo[2.1.1]hexyl, difluorobicyclo[2.1.1]hexyl, fluorobicyclo[2.1.1]hexyl, difluorobicyclo[2.1.1]hexyl, methyldifluorobicyclo[2.1.1]hexyl, trifluoromethyldifluorobicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, methylbicyclo[4.1.0]heptyl, trifluoromethylbicyclo[4.1.0]heptyl, fluorobicyclo[4.1.0]heptyl, difluorobicyclo[4.1.0]heptyl, methyldifluorobicyclo[4.1.0]heptyl, trifluoromethyldifluorobicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, methylbicyclo[2.2.1]heptyl, trifluoromethylbicyclo[2.2.1]heptyl, fluorobicyclo[2.2.1]heptyl, difluorobicyclo[2.2.1]heptyl, methyldifluorobicyclo[2.2.1]heptyl, trifluoromethyldifluorobicyclo[2.2.1]heptyl, bicyclo[3.3.0]octyl, methylbicyclo[3.3.0]octyl, trifluoromethylbicyclo[3.3.0]octyl, fluorobicyclo[3.3.0]octyl, difluorobicyclo[3.3.0]octyl, methyldifluorobicyclo[3.3.0]octyl and trifluoromethyldifluorobicyclo[3.3.0]octyl.

[0084] More preferably, R1 is selected from bicyclo[1.1.1]pentyl, trifluoromethyl-bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, difluorobicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, difluorobicyclo[3.1.0]hexyl, methyldifluorobicyclo[3.1.0]hexyl, trifluoromethyldifluorobicyclo[3.1.0]hexyl, bicyclo[2.2.0]hexyl, methylbicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, fluorobicyclo[2.1.1]hexyl, difluorobicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, difluorobicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, fluorobicyclo[2.2.1]heptyl, bicyclo[3.3.0]octyl, and fluorobicyclo[3.3.0]octyl.

[0085] In other preferred embodiments, R1 represents a 5- to 11-membered spiroalkyl or dispiroalkyl group, which is unsubstituted or substituted with one, two, three, four, or more substituents independently selected from F, CH3, OCH3, CN, CHF2, and CF3.

[0086] Preferably, R1 is selected from spiro[2.2]pentyl, methylspiro[2.2]pentyl, fluorospiro[2.2]pentyl, difluorospiro[2.2]pentyl, methyldifluorospiro[2.2]pentyl, spiro[2.3]hexyl, methylspiro[2.3]hexyl, fluorospiro[2.3]hexyl, difluorospiro[2.3]hexyl, methyldifluorospiro[2.3]hexyl, spiro[3.3]heptyl, methylspiro[3.3]heptyl, fluorospiro[3.3]heptyl, difluorospiro[3.3]heptyl, methyldifluorospiro[3.3]heptyl, and dispiro[2.0.2.1]heptyl.

[0087] More preferably, R1 is selected from spiro[2.2]pentyl, difluorospiro[2.2]pentyl, spiro[2.3]hexyl, methylspiro[2.3]hexyl, fluorospiro[2.3]hexyl, methyldifluorospiro[2.3]hexyl, spiro[3.3]heptyl, and dispiro[2.0.2.1]heptyl.

[0088] In a further preferred embodiment, R1 represents a 4- to 10-membered heterocycloalkyl group, which is unsubstituted or substituted with one, two, three, four, or more substituents independently selected from F, CH3, OCH3, CN, CHF2, and CF3.

[0089] Preferably, R1 is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl 1,1-dioxide, oxepanyl, piperidinyl, piperidone, azetidinyl, pyrrolidinyl, pyrrolidone, 4-methylpiperazinyl, morpholinone, dioxanyl, piperazinyl, pyrrolidinyl, azepanyl, dioxepanyl, oxazepanyl, diazepanyl, thiazolidinyl, tetrahydrothienyl, tetrahydropyridyl, dithiolanyl, dihydropyrrolyl, dioxolanyl, dihydropyridyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, N-methylpyridone, pyrazolidinyl, pyranyl; dihydroquinolinyl, dihydroisoquinolinyl, dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroindolyl.

[0090] In a further preferred embodiment, R1 represents a 5- to 11-membered heterobicycloalkyl group which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from each other from F, CH3, OCH3, CN, CHF2 and CF3.

[0091] Preferably, R1 represents 2-oxabicyclo[2.1.1]hexyl or methyl 2-oxabicyclo[2.1.1]hexyl.

[0092] According to the present invention, R2 represents H or C 1-6 -alkyl.

[0093] Preferably, R2 represents H.

[0094] According to the present invention, R3 represents S(O)(NR3a)R3b or S(NR3a)2R3b, preferably S(O)(NR3a)R3b.

[0095] S(O)(NR3a)R3b defines sulfoximine or sulfonimidamide, while S(NR3a)2R3b defines thiodiimide.

[0096] According to the present invention, R3a represents H, C 1-6 -alkyl, C(O)C 1-5 -alkyl, C(O)C 1-5 -alkyl-NH2, C(O)C 1-5 -alkyl-NH-CH3, C(O)C 1-5 -alkyl-N(CH3)2, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heterocycloalkyl or C 1-6-alkylene-(4- to 10-membered heterocycloalkyl).

[0097] In a preferred embodiment, R3a represents H, C 1-6 -alkyl, C(O)C 1-5 -alkyl, C(O)C 1-5 -alkyl-NH2, C(O)C 1-5 -alkyl-NH-CH3, C(O)C 1-5 -alkyl-N(CH3)2. Preferably, R3a represents H, CH3, C(O)CH3 or C(O)CH2NHCH3.

[0098] According to the present invention, R3b represents NH2, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heterocycloalkyl or C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl);

[0099] In a preferred embodiment, R3b represents NH2, C 1-6 -alkyl or C 3-10 -cycloalkyl. Preferably, R3b represents NH2, CH3, CH2CH3 or cyclopropyl.

[0100] According to the present invention, R3a and R3b can alternatively mean (CH2) 3-5 and together with the atom to which they are attached form a ring.

[0101] Preferably, R3a and R3b mean (CH2)3 and together with the atom to which they are attached form a ring.

[0102] When R3 represents S(NR3a)2R3b, R3a preferably represents H (i.e., S(NH)2R3b), and R3b preferably represents C 1-6 -alkyl (i.e., S(NH)2C 1-6 -alkyl).

[0103] According to the present invention, R4 represents H, F, Cl, Br, CN, CHF2, CH2F, CF3, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or bisspiroalkyl, 4- to 10-membered heterocycloalkyl, C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl), NH2, N(H)(C 1-6 -alkyl), N(C 1-6-alkyl)2, O-C 1-6 -alkyl, O-C 3-10 -cycloalkyl, O-C 1-6 -alkylene-C 3-10 -cycloalkyl, O-(4- to 6-membered heterocycloalkyl) or O-C 1-6 -alkylene-(4- to 6-membered heterocycloalkyl).

[0104] In a preferred embodiment, R4 represents C 1-6 -alkyl.

[0105] Preferably, R4 is selected from CHF2, CH2F, CF3, CH2CHF2, CH2CH2F, CH2CF3, CF2CH3, CHFCH3, CF2CF3, CHFCF3, CH(CHF2)(CH3), CH(CH2F)(CH3), CH(CF3)(CH3), CH3, CH2CH3, CH(CH3)2.

[0106] More preferably, R4 represents CF2CH3.

[0107] In other preferred embodiments, R4 represents C 3-10 -cycloalkyl, which is unsubstituted or substituted with one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3.

[0108] Preferably, R4 is selected from cyclopropyl, methylcyclopropyl, difluoromethylcyclopropyl, trifluoromethylcyclopropyl, cyanocyclopropyl, methoxycyclopropyl, fluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, cyclobutyl, methylcyclobutyl, difluoromethylcyclobutyl, trifluoromethylcyclobutyl, cyanocyclobutyl, methoxycyclobutyl, fluorocyclobutyl, difluorocyclobutyl, trifluorocyclobutyl, cyclopentyl, methylcyclopentyl, difluoromethylcyclopentyl, trifluoromethylcyclopentyl, cyanocyclopentyl, methoxycyclopentyl, fluorocyclopentyl, difluorocyclopentyl, trifluorocyclopentyl, cyclohexyl, methylcyclohexyl, difluoromethylcyclohexyl, trifluoromethylcyclohexyl, cyanocyclohexyl, methoxycyclohexyl, fluorocyclohexyl, difluorocyclohexyl and trifluorocyclohexyl.

[0109] More preferably, R4 is selected from cyclopropyl, methylcyclopropyl, difluoromethylcyclopropyl, trifluoromethylcyclopropyl, cyanocyclopropyl, methoxycyclopropyl, fluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl and difluorocyclopentyl.

[0110] In a further preferred embodiment, R4 represents a 4- to 11-membered bicycloalkyl, which is unsubstituted or substituted with one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3.

[0111] Preferably, R4 represents bicyclo[1.1.1]pentyl.

[0112] In a further preferred embodiment, R4 represents a 5- to 11-membered spiroalkyl group, which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from each other from F, CH3, OCH3, CN, CHF2 and CF3.

[0113] Preferably, R4 represents spiro[2.2]pentyl or spiro[2.3]hexyl.

[0114] In other preferred embodiments, R4 represents O-C 1-6 -alkyl, which is unsubstituted or substituted by one, two, three, four or more F. Preferably, R4 is selected from O-CHF2, O-CH2F, O-CF3, O-CH2CHF2, O-CH2CH2F, O-CH2CF3, O-CF2CH3, O-CHFCH3, O-CF2CF3, O-CHFCF3, O-CH3, O-CH2CH3 or O-CH(CH3)2.

[0115] More preferably, R4 represents O-CHF2.

[0116] According to the present invention, R5 represents H, F, Cl, Br, CN, CHF2, CH2F, CF3, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heterocycloalkyl, C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl), NH2, N(H)(C 1-6 -alkyl), N(C 1-6 -alkyl)2, O-C 1-6 -alkyl, O-C 3-10 -cycloalkyl, O-C 1-6 -alkylene-C 3-10 -cycloalkyl, O-(4- to 6-membered heterocycloalkyl) or O-C 1-6 -alkylene-(4- to 6-membered heterocycloalkyl).

[0117] In a preferred embodiment, R5 represents C 1-6 -alkyl or Cl.

[0118] Preferably, R5 represents CHF2, CH2F, CF3, CH2CHF2, CH2CH2F, CH2CF3, CF2CH3, CHFCH3, CF2CF3, CHFCF3, CH(CHF2)(CH3), CH(CH2F)(CH3), CH(CF3)(CH3), CH3, CH2CH3, CH(CH3)2 or Cl.

[0119] More preferably, R5 represents CF3, CHF2, CH3 or Cl.

[0120] In a particularly preferred embodiment, the compounds according to the invention are selected from the group consisting of

[0121] 1 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0122] 3 1-((3,3-difluorocyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0123] 4 1-((3,3-difluorocyclopentyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0124] 5 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0125] 7 3-cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0126] 9 1-((4,4-difluorocyclohexyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0127] 11 1-((4,4-difluoro-1-methylcyclohexyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfonimidoyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0128] 13 3-(1,1-Difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-((2-(trifluoromethyl)cyclobutyl)methyl)-1H-pyrazole-5-carboxamide

[0129] 15 3-(1,1-Difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1H-pyrazole-5-carboxamide

[0130] 17 3-Cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0131] 21 3-Cyclopropyl-1-((2-fluorospiro[3.3]hept-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0132] 23 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1H-pyrazole-5-carboxamide

[0133] 25 3-Cyclopropyl-1-((3-fluorobicyclo[1.1.1]pent-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0134] 27 3-Cyclopropyl-1-((6,6-difluorospiro[3.3]hept-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0135] 29 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0136] 31 3-(1,1-Difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-pyrazole-5-carboxamide

[0137] 33 1-((3,3-Difluorocyclopentyl)methyl)-3-(difluoromethoxy)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0138] 34 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(N,S-dimethylsulfinimidoyl)pyridin-4-yl)-4-methyl-1H-pyrazole-5-carboxamide

[0139] 36 3-Cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-N-(2-(N,S-dimethylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0140] 44 1-((4,4-Difluoro-1,2-dimethylcyclopentyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0141] 45 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0142] 46 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(5-(S-methylsulfinimidoyl)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0143] 47 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(6-(S-methylsulfinimidoyl)pyridazin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0144] 48 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(ethylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0145] 49 N-(2-(Cyclopropanesulfinimidoyl)pyridin-4-yl)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0146] 50 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-methyl-6-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0147] 51 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(1-oxo-4,5-dihydro-3H-1lλ 6- isothiazol-1-yl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0148] 52 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-aminosulfamidimidoyl phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0149] 53 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(methyl(phenyl)-λ6-thiurane diimide))-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0150] 54 N-(3-(N-acetyl-S-methylsulfamidimidoyl)phenyl)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0151] 55 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methyl-N-(methylglycyl)sulfamidimidoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0152] 56 3-Cyclobutyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfamidimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0153] 57 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(3,3-difluorocyclobutyl)-N-(2-(S-methylsulfamidimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0154] 58 3-(Bicyclo[1.1.1]pent-1-yl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfamidimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0155] 59 3-Cyclopentyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfamidimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0156] 60 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(3,3-difluorocyclopentyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0157] 61 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(spiro[2.3]hexan-5-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0158] 62 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(2-fluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0159] 63 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0160] 64 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(spiro[2.2]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0161] 65 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(2-methylcyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0162] 66 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(2-(difluoromethyl)cyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0163] 67 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-pyrazole-5-carboxamide

[0164] 68 3-(1-cyanocyclopropyl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0165] 69 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-methylcyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0166] 70 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0167] 71 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-methoxycyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0168] 72 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,3-difluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0169] 73 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(1,2,2-trifluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0170] 74 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,2-difluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0171] 75 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0172] 76 4-Chloro-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0173] 77 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0174] 78 3-Cyclopropyl-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-1-(spiro[2.2]pentan-1-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0175] 79 3-Cyclopropyl-1-((2,2-difluorospiro[2.2]pentan-1-yl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0176] 80 3-Cyclopropyl-1-(dispiro[2.0.2 4 .1 3 heptan-7-ylmethyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0177] 81 3-Cyclopropyl-1-((1,2-dimethylcyclopropyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0178] 82 3-Cyclopropyl-1-((1-methyl-2-(trifluoromethyl)cyclopropyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0179] 83 1-(Bicyclo[2.1.0]pentan-1-ylmethyl)-3-cyclopropyl-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0180] 84 3-Cyclopropyl-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-1-(spiro[2.3]hexan-5-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0181] 85 3-Cyclopropyl-1-((5-methylspiro[2.3]hexan-5-yl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0182] 86 3-Cyclopropyl-1-((1-methyl-3-(trifluoromethyl)cyclobutyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0183] 87 3-Cyclopropyl-1-((1-fluorospiro[2.3]hexan-5-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0184] 88 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-pyrazole-5-carboxamide

[0185] 89 3-Cyclopropyl-1-((3,3-difluorocyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0186] 90 3-Cyclopropyl-1-((5,5-difluorobicyclo[2.1.0]pentan-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0187] 91 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-(spiro[2.3]hexan-4-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0188] 92 3-Cyclopropyl-1-((6,6-difluoro-4-methylspiro[2.3]hexan-4-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0189] 93 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-(spiro[3.3]heptan-1-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0190] 94 3-Cyclopropyl-1-((2-methylbicyclo[2.2.0]hexan-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0191] 95 3-Cyclopropyl-1-((3,3-difluorobicyclo[3.1.0]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0192] 96 3-Cyclopropyl-1-((4,4-difluorobicyclo[3.1.0]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0193] 97 3-Cyclopropyl-1-((5-fluorooctahydropentalen-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0194] 98 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1-((1-(trifluoromethyl)cyclopentyl)methyl)-1H-pyrazole-5-carboxamide

[0195] 99 3-Cyclopropyl-1-((4,4-difluoro-2-methylcyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0196] 100 3-Cyclopropyl-1-((4,4-difluoro-2-(trifluoromethyl)cyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0197] 101 3-Cyclopropyl-1-((3,3-difluoro-5-methylbicyclo[3.1.0]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0198] 102 3-Cyclopropyl-1-((3,3-difluoro-5-(trifluoromethyl)bicyclo[3.1.0]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0199] 103 3-Cyclopropyl-1-((2,2-difluorobicyclo[2.1.1]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0200] 104 3-Cyclopropyl-1-((3,3-difluorobicyclo[2.1.1]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0201] 105 3-Cyclopropyl-1-((4-fluorobicyclo[2.1.1]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0202] 106 3-Cyclopropyl-1-((4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0203] 107 3-Cyclopropyl-1-((4,4-difluorobicyclo[4.1.0]heptan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0204] 108 3-(Bicyclo[1.1.1]pentan-1-yl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0205] 109 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0206] 110 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0207] 111 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0208] 112 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0209] 113 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide

[0210] 114 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0211] 115 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0212] 116 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0213] 117 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-4-(difluoromethyl)-N-(3-(S-methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide

[0214] 118 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0215] 119 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methylsulfinyl)phenyl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0216] 120 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-1H-pyrazole-5-carboxamide

[0217] 121 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(3-(S-methylsulfinyl)phenyl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-1H-pyrazole-5-carboxamide

[0218] 122 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-methoxybicyclo[1.1.1]pent-1-yl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0219] 123 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-methoxybicyclo[1.1.1]pent-1-yl)-N-(3-(S-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0220] 124 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-methoxybicyclo[1.1.1]pent-1-yl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0221] 125 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-methoxybicyclo[1.1.1]pent-1-yl)-N-(3-(S-methylsulfinimidoyl)phenyl)-1H-pyrazole-5-carboxamide

[0222] 126 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(4-fluoro-3-(S-methylsulfinimidoyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0223] 127 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(3-fluoro-5-(S-methylsulfinimidoyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0224] 128 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-fluoro-5-(S-methylsulfinimidoyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0225] 129 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-fluoro-3-(S-methylsulfinimidoyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0226] 130 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-(difluoromethyl)sulfinimidoyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0227] 131 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-N-(3-(S-(trifluoromethyl)sulfinyl)phenyl)-1H-pyrazole-5-carboxamide

[0228] 132 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0229] 133 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-3-(1-fluorocyclopropyl)-1H-pyrazole-5-carboxamide

[0230] 134 3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1-((2-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazole-5-carboxamide

[0231] 135 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide

[0232] 136 3-cyclopropyl-1-((2,2-difluorospiro[2.3]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0233] 137 3-(bicyclo[1.1.1]pentan-1-yl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide

[0234] 138 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-1H-pyrazole-5-carboxamide

[0235] 139 3-(bicyclo[1.1.1]pentan-1-yl)-1-((2-(difluoromethyl)cyclopropyl)methyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0236] 140 1-((2-Acetyl-2-azaspiro[3.3]heptan-5-yl)methyl)-3-cyclopropyl-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0237] 141 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(4-fluoro-3-(S-methylsulfinimidoyl)phenyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0238] 142 N-(2-(N-Cyano-S-methylsulfinimidoyl)pyridin-4-yl)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0239] 143 3-(tert-Butyl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0240] 144 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazole-5-carboxamide

[0241] 145 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-(difluoromethyl)cyclopropyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0242] 146 3-(Bicyclo[1.1.1]pentan-1-yl)-1-((2-(difluoromethyl)cyclopropyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0243] 147 3-(Bicyclo[1.1.1]pentan-1-yl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1-(((trans)-2-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazole-5-carboxamide

[0244] 148 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2-fluoropropan-2-yl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0245] 150 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methyl-N-(oxetan-3-carbonyl)sulfamoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0246] 151 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfamoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0247] 152 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(N-(2,3-dihydroxypropyl)-S-methylsulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0248] 153 1-((2-Azaspiro[3.3]hept-5-yl)methyl)-3-cyclopropyl-N-(2-(S-methylsulfamoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0249] The compounds are in the form of the free compounds or their physiologically acceptable salts.

[0250] In a preferred embodiment, the compounds according to the invention are inhibitors of Na V 1.8. In the context of the present invention, the term "inhibitor of Na V 1.8" preferably means that the corresponding compound exhibits an IC50 value of at most 10 μM (10·10 -6 mol / L), more preferably at most 1 μM, still more preferably at most 500 nM (10 -9 mol / L), even more preferably at most 100 nM and most preferably at most 10 nM against Na V 1.8 in a patch clamp assay.

[0251] The following experimental section describes the preferred assays for testing the potency of the compounds and the method for determining the IC50 against Na V 1.8.

[0252] In a preferred embodiment, the compounds according to the invention are selective inhibitors of Na V 1.8. In the context of the present invention, the term "selective inhibitor of Na V 1.8" preferably means that the corresponding compound preferably does not exhibit an inhibitory effect on Na V 1.1, Na V 1.2, NaV 1.4, Na V 1.5 and Na V Any inhibitory activity of 1.6. Those skilled in the art know the suitable ways for determining whether a compound has inhibitory effects on any of Na V 1.1, Na V 1.2, Na V 1.4, Na V 1.5 and Na V 1.6.

[0253] Therefore, the present invention relates to the compounds according to the present invention for inhibiting Na V 1.8.

[0254] Therefore, another aspect of the present invention relates to the compounds according to the present invention for treating pain. Still another aspect of the present invention relates to a method for treating pain, which comprises administering an effective amount of the compounds according to the present invention to a subject in need (preferably a human).

[0255] A further aspect of the present invention relates to the compounds according to the present invention as a medicament.

[0256] Another aspect of the present invention relates to a pharmaceutical dosage form comprising the compounds according to the present invention. Preferably, the pharmaceutical dosage form comprises the compounds according to the present invention and one or more pharmaceutical excipients, such as physiologically acceptable carriers, additives and / or auxiliary substances; and optionally one or more further pharmacologically active ingredients. Examples of suitable physiologically acceptable carriers, additives and / or auxiliary substances are fillers, solvents, diluents, colorants and / or binders. These substances are known to those skilled in the art (see H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendorf).

[0257] The pharmaceutical dosage form according to the present invention is preferably for systemic, topical or local administration, preferably for oral administration. Therefore, the pharmaceutical dosage form can be in liquid, semi-solid or solid form, such as in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, films, capsules, plasters, suppositories, ointments, creams, lotions, gels, emulsions, aerosols, or in the form of multi-particles, such as in the form of pellets or granules, which are pressed into tablets, poured into capsules or suspended in liquids as appropriate, and can also be administered as such.

[0258] The pharmaceutical dosage forms according to the invention are preferably prepared by means of conventional means, devices, methods and processes known in the art. The amount of the compound according to the invention to be administered to a patient can vary and depends, for example, on the patient's weight or age and also on the type of administration, the indication and the severity of the condition. Preferably, 0.001 to 100 mg / kg, more preferably 0.05 to 75 mg / kg and most preferably 0.05 to 50 mg of the compound according to the invention are administered per kg of patient body weight.

[0259] Accordingly, another aspect of the invention relates to a pharmaceutical dosage form according to the invention for the treatment of pain. A further aspect of the invention relates to a method for treating pain, which comprises administering to a subject in need thereof (preferably a human) a pharmaceutical dosage form according to the invention. Examples

[0260] Experimental protocol

[0261] The following abbreviations are used in the description of the experimental protocol: ABPR = automatic backpressure regulator; ADDP = 1'-(azodicarbonyl)dipiperidine, aq. = aqueous solution; Boc = tert-butoxycarbonyl; Brettphos-Pd-G3 = [(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)-methanesulfonate-methanesulfonate; DAST = diethylaminosulfur trifluoride, DCE = dichloroethane, DCM = dichloromethane; DIAD = diisopropyl azodicarboxylate; DIPEA = N,N-diisopropylethylamine; DMF = N,N-dimethylformamide; DMP = Dess–Martin periodinane, DMSO = dimethyl sulfoxide; dppf = 1,1′-bis(diphenylphosphino)ferrocene, EDC or EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EtOAc = ethyl acetate; Et2O = diethyl ether; EtOH = ethanol; h = hour; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; Hex = hexane; HMPA = hexamethylphosphoramide, HPLC = high performance liquid chromatography; HOBt = hydroxybenzotriazole; ITX = isopropylthioxanthone; KHMDS = potassium bis(trimethylsilyl)amide; LAH = lithium aluminum hydride, LCMS = liquid chromatography-mass spectrometry; LiHMDS = lithium bis(trimethylsilyl)amide; MeCN = acetonitrile; MeI = methyl iodide; MeOH = methanol; MeSO2Cl = methanesulfonyl chloride; min = minute; Ms = methanesulfonyl; MTBE = methyl tert-butyl ether; NIS = N-iodosuccinimide; NMO = N-methylmorpholine N-oxide, NMR = nuclear magnetic resonance; NP = normal phase; PE = petroleum ether; PG = protecting group; PIDA = (diacetoxyiodo)benzene; prep. = preparation; rt = room temperature; R t = retention time; sat. = saturated; SEM = 2-(trimethylsilyl)ethoxymethyl; SFC = supercritical fluid chromatography; SM = starting material; TBAF = tetra-n-butylammonium fluoride; TBDMS = tert-butyldimethylsilyl; TCFH = chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, TEA = triethylamine; Tf = trifluoromethanesulfonyl; TFA = trifluoroacetic acid, THF = tetrahydrofuran; TMSCF3 = trifluoromethyltrimethylsilane; Ts = p-toluenesulfonyl.

[0262] General synthetic scheme

[0263] As illustrated in Scheme 1, the compounds of the present invention can be prepared by N-alkylating an alkyl 1H-pyrazole-5-carboxylate of general formula (A) with an appropriately functionalized alkylating agent of general formula (B) (wherein Y is a leaving group such as Br, Cl, OTs, OMs, OTf) under basic conditions to obtain a compound of general formula (C). Alternatively, an intermediate of general formula (C) can be prepared by a Mitsunobu reaction between an alkyl 1H-pyrazole-5-carboxylate of type (A) and an alcohol of general formula (B) (wherein Y is OH) (Chem. Rev. 2009, 109, 6, 2551–2651). The alcohol of general formula (B) (wherein Y = OH) is commercially available, or can be prepared as described in the present invention, or synthesized according to standard procedures known to those skilled in the art. The intermediate of general formula (C) can be hydrolyzed to a carboxylic acid of general formula (D).

[0264] Scheme 1: L, R1, R4, R5 are as defined in claim 1.

[0265]

[0266] In some embodiments, the intermediate needs to bear one or more protecting groups such as SEM (trimethylsilylethoxymethyl) or Bn (benzyl), and the protecting group is deprotected using standard deprotection protocols known in the art after N-alkylation (T.W. Green, P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999). In some embodiments, functional group interconversions are used, such as fluorination using, for example, DAST (Synthesis, 2002, 2561-2578) or difluoromethylation using sodium 2-chloro-2,2-difluoroacetate (Chem. Soc. Rev, 2021, 50, 8214-8247).

[0267] Scheme 2: L, R1, R4, R5 are as defined in claim 1.

[0268]

[0269] As illustrated in Scheme 2, the intermediate of general formula (F) can also be obtained by N-alkylating an alkyl 4-iodo-1H-pyrazole-5-carboxylate of general formula (E) with a suitably functionalized alkylating agent of general formula (B) (where Y is a leaving group such as Br, Cl, OTs, OMs, OTf) under basic conditions to give the intermediate of general formula (F). The introduction of substituent R5 (e.g., via trifluoromethylation with TMSCF3 in the presence of CuI or Suzuki coupling followed by ester hydrolysis) gives the intermediate of general formula (D). In addition, a reaction sequence of palladium-catalyzed vinylation, osmium-catalyzed dihydroxylation and diol cleavage (using NaIO4) and subsequent fluorination with, for example, DAST can be used to install the CHF2 moiety, which gives the intermediate of general formula (D) after ester hydrolysis, where R5 = CHF2. Alternatively, a Mitsunobu reaction between an alkyl 4-iodo-1H-pyrazole-5-carboxylate of general formula (E) and an alcohol of general formula (B) (where Y is OH) can be used to obtain the intermediate of general formula (F).

[0270] Scheme 3: R4, R5 are as defined in claim 1.

[0271]

[0272] As illustrated in Scheme 3, an alkyl 1H-pyrazole-5-carboxylate of general formula (A) can also be obtained using an alkyl 4-iodo-1H-pyrazole-5-carboxylate of general formula (E) with a sequence consisting of: introduction of a protecting group, subsequent introduction of substituent R5 (e.g., via trifluoromethylation with TMSCF3 in the presence of CuI or Suzuki coupling), and subsequent deprotection. Suitable protecting groups are, for example, SEM (trimethylsilylethoxymethyl). Standard protection / deprotection protocols are known in the art (T.W.Green, P.G.M.Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, New York, 1999).

[0273] As illustrated in Scheme 4, amide coupling of an intermediate of general formula (D) with a (hetero)arylamine of general formula (H) can be used in the presence of a carboxylic acid activating reagent (preferably HATU or POCl3) and a base (preferably pyridine or DIPEA). )The intermediate is converted into a compound of general formula (I) (March's Advanced Organic Chemistry, 2007, 6th Edition, pp. 1427 - 1474). Alternatively, an intermediate of general formula (I) can be synthesized from an intermediate of general formula (C) using a (hetero)arylamine of general formula (H) under basic conditions. Preferred bases include KHMDS. Additional protocols known to those skilled in the art can be used, such as the conversion of a compound of general formula (I) to a compound of general formula (J) by preparing an alkylsulfinylimine from a thioalkane (Chem. Eur. J, 2021, 27, 17293–17321).

[0274] Scheme 4: L, R1, R2, R4, R5, R', A1, A2, A3 are as defined in claim 1. B1, B2, B3 can each independently be CR' or N or C-S-alkyl, where at least one of B1 / B2 / B3 is C-S-alkyl.

[0275]

[0276] As illustrated in Scheme 5, an acid of general formula (K) can be converted into a ketone of general formula (M) via a standard sequence of functional group interconversions. Preferred methods for effecting this conversion include, for example, first performing an activation step of the acid (e.g., formation of a Weinreb amide), and subsequently treating it with a carbon nucleophile (e.g., an organomagnesium compound or organolithium compound of general formula (L)) (Synthesis, 2019, 51, 2792 - 2808). A ketone of general formula (M) can be converted into a compound of general formula (O) by deprotonating (M) using a base (e.g., LiHMDS or KOtBu) and adding the resulting enolate to a compound of general formula (N). A compound of general formula (O) can be treated with hydrazine or hydrazine hydrate to obtain a compound of general formula (A). Similar reaction sequences have been described in detail in the literature (e.g., Bioorg. & Medchem Lett. 2007, 17, 5620 - 5623, European Journal of Medicinal Chemistry, 2016, 109, 350 - 359).

[0277] Scheme 5: R4, R5 are as defined in claim 1.

[0278]

[0279] The alkyl 1H-pyrazole-5-carboxylates of general formula (A), the organomagnesium or organolithium compounds of general formula (L), and the alkyl oxalates of general formula (N) are commercially available or can be prepared as described in the present invention or synthesized according to standard procedures known to those skilled in the art.

[0280] As illustrated in Scheme 6, the acid of general formula (K) can be converted to the ketone of general formula (Q) via a standard sequence of functional group interconversions. Preferred methods for effecting this conversion include, for example, first performing an activation step of the acid (e.g., formation of a Weinreb amide) and subsequently treating it with a carbon nucleophile (e.g., an organomagnesium or organolithium compound of general formula (L)) (Synthesis, 2019, 51, 2792 - 2808). The ketone of general formula (Q) can be converted to the compound of general formula (R) by deprotonating (Q) using a base (e.g., LiHMDS) and adding the resulting enolate to a compound of general formula (R). The compound of general formula (R) can be treated with hydrazine or hydrazine hydrate to obtain the compound of general formula (S). The compound of general formula (E) can be obtained by iodinating (e.g., with NIS) the compound of general formula (S).

[0281] Similar reaction sequences have been described in detail in the literature (e.g., Bioorg. & Medchem Lett. 2007, 17, 5620 - 5623, European Journal of Medicinal Chemistry, 2016, 109, 350 - 359).

[0282] Scheme 6: R4 is as defined in claim 1.

[0283]

[0284] The alkyl 1H-pyrazole-5-carboxylates of general formula (A), the organomagnesium or organolithium compounds of general formula (P), the ketones of general formula (Q), and the alkyl oxalates of general formula (N) are commercially available or can be prepared as described in the present invention or synthesized according to standard procedures known to those skilled in the art.

[0285] As illustrated in Scheme 7, an amide having the general formula (T) can be converted to a compound having the general formula (I) together with a (hetero)aryl halide having the general formula (U) via transition metal-catalyzed coupling using, for example, a copper or palladium-based catalyst having a suitable ligand. Alternatively, an amide having the general formula (T) can be converted to a compound having the general formula (J) together with an aryl halide having the general formula (V) via transition metal-catalyzed coupling using, for example, a copper or palladium-based catalyst having a suitable ligand. Suitable catalysts and ligands include, for example, Brettphos-Pd-G3 or a combination of CuI / Cu(I) trifluoromethanesulfonate benzene complex with DMEDA, trans-1,2-diaminocyclohexane, or trans-N,N'-dimethylcyclohexane-1,2-diamine. If an aryl halide having the general formula (V) (wherein R3 = S(O)(NPG)alkyl) is used in Step 1, deprotection needs to be carried out using methods known to those skilled in the art to obtain the compound having the general formula (J). Suitable protecting groups include Boc, and deprotection can be achieved using, for example, TFA under acidic conditions. The amide having the general formula (T) can be prepared using standard methods used in the art, such as amide coupling of an acid having the general formula (D) or treatment of an ester having the general formula (C) with the corresponding amine.

[0286] Scheme 7: L, R1, R2, R4, R5, R', A1, A2, A3 are as defined in claim 1. B1, B2, B3 can each independently be CR' or N or C-S-alkyl, wherein at least one of B1 / B2 / B3 is C-S-alkyl. X = halogen.

[0287]

[0288] As illustrated in Scheme 8, a compound having the general formula (J) wherein R3 = S(O)(NH)alkyl can be converted to a compound having the general formula (J) wherein R3 = S(O)(NRX)alkyl (RX = alkyl, acyl) via a reaction known to those skilled in the art. Alkylation can be achieved by treating with an alkylating agent such as an epoxide under Lewis acid catalysis or Chan-Lam type coupling (Chem. Eur. J, 2021, 27, 17293–17321). Acylation can be achieved using standard amide coupling conditions known to those skilled in the art. Protection / deprotection may be necessary and is known to those skilled in the art.

[0289] Scheme 8: L, R1, R2, R4, R5, R', A1, A2, A3 are as defined in claim 1. RX = alkyl, acyl.

[0290]

[0291] Intermediate 1

[0292] (3,3-Difluorocyclopentyl)methyl methanesulfonate

[0293]

[0294] To a stirred solution of (3,3-difluorocyclopentyl)methanol (1.20 g) in DCM (20 mL) at 0 °C was added TEA (2.90 mL) and MsCl (0.82 mL), and the resulting mixture was stirred at rt for 2 h. The reaction mixture was washed with ice-cold NH4Cl solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound (1.5 g), which was used without further purification.

[0295] Intermediate 2

[0296] (3,3-Difluorocyclobutyl)methyl methanesulfonate

[0297]

[0298] To a stirred solution of (3,3-difluorocyclobutyl)methanol (5.0 g) in DCM (100 mL) at 0 °C was added Et3N (12 g) and MsCl (12 g), and the mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (80 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (7.3 g, crude), which was used without further purification.

[0299] Intermediate 3

[0300] (3,3-Difluorocyclobutyl)methyl benzoate

[0301]

[0302] Under rt conditions, NaOH (2 M, 35 mL) was added to a stirred solution of methyl 3,3-difluorocyclobutane-1-carboxylate (5.0 g) in MeOH (50 mL), and the mixture was heated at 60 °C for 4 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was acidified with saturated KHSO4 solution to maintain a pH of approximately 2. The precipitate was collected by filtration and co-evaporated with toluene under reduced pressure. The residue was dissolved in DMF (50 mL), and K2CO3 (20.3 g) and BnBr (8.4 mL) were added sequentially at rt, and the mixture was stirred for 16 h. The reaction mixture was quenched by adding crushed ice and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with cold brine, dried (Na2SO4) and evaporated to dryness under reduced pressure, and the residue was purified by CombiFlash chromatography (SiO2, 0 - 10% EtOAc / Hex) to give the title compound (6.5 g, 86%). 1 1H-NMR (400 MHz, CDCl3): 7.39 - 7.30 (m, 5H), 5.15 (s, 2H), 3.00 - 2.80 (m, 5H).

[0303] Intermediate 4

[0304] (3,3-Difluoro-1-methylcyclobutyl)methyl benzoate

[0305]

[0306] At -78 °C, 1 M KHMDS (17.7 mL) and MeI (2.2 mL) were added to a stirred solution of benzyl 3,3-difluorocyclobutane-1-carboxylate (Intermediate 3, 2.0 g) in THF (60 mL) under Ar(g), and the mixture was stirred at -78 °C for 8 h, then at rt for 16 h. The reaction mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with Na2S2O3 solution and cold brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 15% EtOAc / Hex) to give the title compound (1.2 g, 57%). 1 1H-NMR (400 MHz, CDCl3): 7.40 - 7.34 (m, 5H), 5.16 (s, 2H), 3.11 - 3.00 (q, 2H), 2.48 - 2.37 (m, 2H), 1.50 (t, 3H).

[0307] Intermediate 5

[0308] (3,3-Difluoro-1-methylcyclobutyl)methanol

[0309]

[0310] Part 1: To a stirred solution of benzyl 3,3-difluoro-1-methylcyclobutane-1-carboxylate (Intermediate 4, 0.40 g) in EtOH (2 mL) was added portionwise 5 M NaOH (1.66 mL) at rt, and the mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was diluted with water and washed with EtOAc (20 mL). The aqueous phase was acidified with KHSO4 solution and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give 3,3-difluoro-1-methylcyclobutane-1-carboxylic acid (0.25 g, crude).

[0311] Part 2: LAH (1 M in THF, 3.65 mL) was added dropwise to a stirred solution of 3,3-difluoro-1-methylcyclobutane-1-carboxylic acid (Part 1, 0.25 g) in Et2O (10 mL) at 0 °C, and the resulting mixture was stirred for 2 h. The reaction mixture was cooled to 0 °C, and ice-cold Na2SO4 was added dropwise. The aqueous phase was extracted with EtOAc (4 x 100 mL), and the combined organic layers were dried (Na2SO4) and concentrated to give the title compound (0.16 g, crude).

[0312] Intermediate 100

[0313] Spiro[2.0.2 4 .1 3 hept-7-ylmethanol

[0314]

[0315] To a solution of dispiro[2.0.2 4 .1 3 heptane-7-carboxylic acid (0.2 g) in Et2O (10.0 mL) at 0 °C was added LAH (2.4 M in THF, 1.2 mL). The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled to 0 °C again and quenched with saturated Na2SO4 solution. The aqueous portion was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried (Na2SO4), and the organic layer was evaporated under reduced pressure to give the title compound, which was used in the next step without further purification (0.18 g, crude).

[0316] Intermediate 101

[0317] 1-(Hydroxymethyl)bicyclo[2.1.1]hexan-2-one

[0318]

[0319] Part 1: To a solution of methyl 2-(hydroxymethyl)acrylate (10.0 g) in DCM (150 mL) at rt was added benzyl trichloroacetimidate (32.2 mL) and trifluoromethanesulfonic acid (catalytic). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give methyl 2-((benzyloxy)methyl)acrylate (12.0 g, 68%).

[0320] Part 2: To a solution of methyl 2-((benzyloxy)methyl)acrylate (12.0 g) in a mixture of THF-H2O (8:1) (5 mL) at rt was added LiOH·H2O (7.3 g). The reaction was stirred at rt for 4 h. The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous portion was acidified to pH ~2 with saturated KHSO4 solution at 0 °C and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure to give 2-((benzyloxy)methyl)acrylic acid, which was used in the next step without further purification. Yield: (10.0 g, 89%).

[0321] Part 3: To a solution of 2-((benzyloxy)methyl)acrylic acid (10.0 g) in DCM (70 mL) at rt was added EDC·HCl (15.0 g), DIPEA (27.3 mL) and N,O-dimethylhydroxylamine hydrochloride (9.42 g). The reaction was stirred at rt for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give 2-((benzyloxy)methyl)-N-methoxy-N-methylacrylamide (8.0 g, 65%). LCMS m / z = 236 [M+H] + 。

[0322] Part 4: To a solution of 2-((benzyloxy)methyl)-N-methoxy-N-methylacrylamide (8.0 g) in THF (100.0 mL) at 0 °C was added allylmagnesium chloride (2 M in THF, 34.0 mL). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give 2-((benzyloxy)methyl)hex-1,5-dien-3-one (5.0 g, 68%). LCMS m / z = 217 [M+H] + .

[0323] Part 5: A solution of 2-((benzyloxy)methyl)hex-1,5-dien-3-one (2.5 g) in acetonitrile (100 mL) was degassed for 15 min, followed by the addition of ITX (0.29 g) at rt. The reaction mixture was then placed under irradiation at 365 nm (UV lamp) for 16 h. The reaction mixture was evaporated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give 1-((benzyloxy)methyl)bicyclo[2.1.1]hexan-2-one (1.5 g, 60%).

[0324] Part 6: To a solution of 1-((benzyloxy)methyl)bicyclo[2.1.1]hexan-2-one (1.0 g) in MeOH (30.0 mL) at rt was added 10% Pd / C (50% wet, 0.1 g). The reaction mixture was then stirred under H2-balloon pressure for 16 h. The reaction mixture was filtered through a sintered funnel, and the filtrate was evaporated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give the title compound (0.38 g, 65%).

[0325] Intermediate 102

[0326] Spiro[2.2]pentan-1-ylmethanol

[0327]

[0328] To a solution of spiro[2.2]pentane-1-carboxylic acid (0.9 g) in Et2O (30 mL) at 0 °C was added LAH (2.4 M in THF, 5.0 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled to 0 °C and quenched with saturated Na2SO4 solution. The mixture was then filtered through a sintered funnel with a bed of diatomaceous earth, and the filtrate was evaporated under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give the title compound (0.4 g, 51%). LCMS m / z = 97 [M-H] - .

[0329] Intermediate 103

[0330] (6,6-Difluoro-4-methylspiro[2.3]hexan-4-yl)methanol

[0331]

[0332] Part 1: To a stirred solution of 6-oxaspiro[2.3]hexane-4-carboxylic acid (1.0 g) in DMF (15 mL) at rt was added K2CO3 (1.5 g) and BnBr (0.9 mL). The reaction mixture was stirred for 16 h. The reaction mixture was diluted with ice water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with cold brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to give the crude compound, which was purified by CombiFlash chromatography (SiO2, 0 - 50% EtOAc / Hex) to give benzyl 6-oxaspiro[2.3]hexane-4-carboxylate (1.5 g, 91%).

[0333] Part 2: To 6-oxaspiro[2.3]hexane-4-carboxylic acid benzyl ester (1.7 g) at 0 °C was added DAST (4.4 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with EtOAc and quenched by the addition of cold saturated NaHCO3 solution and stirred for 30 min. The mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 10% EtOAc / Hex) to give benzyl 6,6-difluorospiro[2.3]hexane-4-carboxylate (1.4 g, 75%).

[0334] Part 3: To a stirred solution of benzyl 6,6-difluorospiro[2.3]hexane-4-carboxylate (2.5 g) in THF (50 mL) at -78 °C was added KHMDS (1 M, 30.0 mL) and MeI (2.5 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched by addition of aqueous NH4Cl and extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with cold brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to give the crude compound, which was purified by CombiFlash chromatography (SiO2, 0-10% EtOAc / Hex) to give benzyl 6,6-difluoro-4-methylspiro[2.3]hexane-4-carboxylate (1.6 g, 60%).

[0335] Part 4: To a solution of benzyl 6,6-difluoro-4-methylspiro[2.3]hexane-4-carboxylate (2.0 g) in EtOH (15 mL) at rt was added 5N NaOH (8 mL). The reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous portion was acidified to pH ~2 with 2N HCl. The aqueous portion was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with cold brine, dried over Na2SO4 and concentrated under reduced pressure to give 6,6-difluoro-4-methylspiro[2.3]hexane-4-carboxylic acid (1.0 g, 75%).

[0336] Part 5: To a stirred solution of 6,6-difluoro-4-methylspiro[2.3]hexane-4-carboxylic acid (1.5 g) in Et2O (75 mL) at 0 °C was added dropwise LAH (2 M in THF, 9.0 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled again to 0 °C and ice-cold saturated Na2SO4 solution was added dropwise. The aqueous portion was extracted with Et2O (4 × 500 mL). The combined organic portions were dried over Na2SO4 and concentrated. The residue was purified by CombiFlash column chromatography (SiO2, 0-100% EtOAc / Hex) to give the title compound (1.1 g, 79%).

[0337] Intermediate 104

[0338] (2,2-Difluorospiro[2.2]pentan-1-yl)methanol

[0339]

[0340] To a solution of 2,2-difluorospiro[2.2]pentane-1-carboxylic acid (0.2 g) in Et2O (15 mL) at 0 °C was added LAH (2.4 M in THF, 1.12 mL). The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was cooled again to 0 °C and quenched with saturated Na2SO4 solution. The reaction mixture was filtered and the filtrate was diluted with EtOAc. The organic portion was washed with water and brine, dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 50% EtOAc / Hex) to give the title compound (0.12 g, 66%).

[0341] Intermediate 6

[0342] (3,3-Difluoro-1-methylcyclobutyl)methyl methanesulfonate

[0343]

[0344] To a stirred solution of (3,3-difluoro-1-methylcyclobutyl)methanol (0.40 g) in DCM (15 mL) at 0 °C was added Et3N (0.88 mL) and MsCl (0.23 mL). The resulting mixture was stirred at rt for 2 h. The reaction mixture was then washed with ice-cold NH4Cl solution (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the title compound (0.16 g, crude).

[0345] Intermediate 7

[0346] (4-Fluorobicyclo[2.2.1]heptan-1-yl)methanol

[0347]

[0348] To a stirred solution of 4-fluorobicyclo[2.2.1]heptane-1-carboxylic acid (0.25 g) in THF (15 mL) at rt was added dropwise borane dimethyl sulfide complex (0.3 mL). The reaction mixture was stirred for 16 h. The reaction mixture was quenched with methanol and concentrated under reduced pressure to give the crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give the title compound (0.20 g, 88%).

[0349] Intermediate 105

[0350] Dispiro[2.0.2 4 .1 3 hept-7-ylmethyl ester

[0351]

[0352] At 0 °C, MsCl (0.4 mL) and Et3N (1.4 mL) were added to a solution of bis-spiro[2.0.2 4 .1 3 hept-7-ylmethanol (Intermediate 100, 0.4 g) in DCM (15.0 mL). The resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with cold water and extracted with DCM (2 x 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound, which was used in the next step without further purification (0.65 g, crude).

[0353] Intermediate 106

[0354] (3-Oxobicyclo[3.1.0]hexan-1-yl)methyl methanesulfonate

[0355]

[0356] Part 1: To a stirred solution of but-2-yne-1,4-diol (5.0 g) in DCM (100 mL) at 0 °C was added imidazole (7.9 g) and TBDMS chloride (10.53 g) portionwise. The resulting reaction mixture was stirred at 0 °C for 2 h under an argon atmosphere. The reaction mixture was quenched with cold water (250 mL) and extracted with DCM (2 × 250 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-ol (10.4 g, crude), which was used directly in the next step without further purification.

[0357] Part 2: To a stirred solution of 4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-ol (10 g) in DCM (200 mL) at 0 °C was added DMP (42.4 g) portionwise. The resulting reaction mixture was stirred at 0 °C - rt for 6 h under an argon atmosphere. The reaction mixture was filtered through a bed of Celite, and the Celite bed was washed with excess DCM (300 mL). The filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 3% EtOAc / PE) to give 4-((tert-butyldimethylsilyl)oxy)but-2-ynal (7.1 g, 61% over 2 steps).

[0358] Part 3: At 0 °C, allylmagnesium chloride (1 M in THF, 105.9 mL) was added dropwise to a stirred solution of 4-((tert-butyldimethylsilyl)oxy)but-2-ynal (7.0 g) in THF (105 mL). The resulting reaction mixture was stirred at 0 °C - rt for 3 h under an argon atmosphere. The reaction mixture was quenched with saturated NH4Cl solution (250 mL) at 0 °C and extracted with ethyl acetate (2 × 200 mL). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO 2，7 % EtOAc / PE) to give 7-((tert-butyldimethylsilyl)oxy)hept-1-en-5-yn-4-ol (5.6 g, 66%).

[0359] Part 4: At rt, PtCl2 (194 mg) was added to a stirred solution of 7-((tert-butyldimethylsilyl)oxy)hept-1-en-5-yn-4-ol (3.5 g) in toluene (70 mL). The resulting reaction mixture was stirred at 85 °C for 8 h under an argon atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 2% EtOAc / PE) to give 1-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[3.1.0]hexan-3-one (1.62 g, 46%).

[0360] Part 5: At 0 °C, TBAF (1 M in THF, 8.0 mL) was added to a stirred solution of 1-(((tert-butyldimethylsilyl)oxy)methyl)bicyclo[3.1.0]hexan-3-one (1.6 g) in THF (32 mL). The resulting reaction mixture was stirred at 0 °C - rt for 2 h under an argon atmosphere. The reaction mixture was quenched with saturated NaHCO3 solution (50 mL) at 0 °C and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 1-(hydroxymethyl)bicyclo[3.1.0]hexan-3-one (890 mg, crude), which was used directly in the next step without further purification.

[0361] Part 6: Under an argon atmosphere at 0 °C, TEA (0.961 g) was added to a stirred solution of 1-(hydroxymethyl)bicyclo[3.1.0]hexan-3-one (0.8 g) in DCM (15 mL), and then MsCl (1.08 g) was added dropwise. The reaction mixture was stirred at 0 °C - rt for 4 h. The reaction mixture was quenched with cold water (20 mL) and extracted with DCM (2 × 25 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (1.0 g, crude), which was used in the next step without further purification.

[0362] Intermediate 107

[0363] (3,3-Difluoro-1-methylcyclopentyl)methyl trifluoromethanesulfonate

[0364]

[0365] Part 1: Under an argon atmosphere at 0 °C, DAST (169 mL) was added to a stirred solution of ethyl 3-oxocyclopentane-1-carboxylate (50 g) in DCM (750 mL). The resulting reaction mixture was stirred at rt for 24 h. The reaction mixture was quenched with cold saturated NaHCO3 solution (1.5 L) and extracted with DCM (2 × 1.0 L). The combined organic layers were washed with water (800 mL) and brine (800 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give ethyl 3,3-difluorocyclopentane-1-carboxylate (52 g, crude), which was used directly in the next step without further purification.

[0366] Part 2: At -5 °C, LiHMDS (1 M, 365 mL) in THF was added to a stirred solution of ethyl 3,3-difluorocyclopentane-1-carboxylate (50.0 g) in THF (70 mL), and the mixture was stirred at 0 °C for 30 minutes under an argon atmosphere. A solution of methyl iodide (59.83 g) in THF (1.0 L) was added to the reaction mixture and the mixture was stirred at 0 °C - rt for 12 h. The reaction mixture was slowly quenched with saturated aqueous NH4Cl solution (1.0 L) and extracted with EtOAc (2 × 1.0 L). The combined organic layers were washed with water (700 mL) and brine (700 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give ethyl 3,3-difluoro-1-methylcyclopentane-1-carboxylate (51 g, crude), which was used directly in the next step without further purification.

[0367] Part 3: Under an argon atmosphere at 0 °C, LAH (1 M, 398.5 mL) in THF was added to a stirred solution of ethyl 3,3-difluoro-1-methylcyclopentane-1-carboxylate (51.0 g) in THF (1.02 L). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was slowly poured into crushed ice (1 kg), and the pH was adjusted to approximately 6 with 1 N aqueous HCl. The mixture was stirred well and then extracted with EtOAc (2 × 1.0 L). The combined organic layers were washed with water (700 mL) and brine (700 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 15% EtOAc / PE) to give (3,3-difluoro-1-methylcyclopentyl)methanol (20.2 g, 42% over 3 steps).

[0368] Part 4: Under an argon atmosphere at 0 °C, pyridine (21.06 g) was added to a stirred solution of (3,3-difluoro-1-methylcyclopentyl)methanol (20 g) in DCM (400 mL), followed by the dropwise addition of trifluoromethanesulfonic anhydride (48.88 g). The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with water (500 mL) and extracted with DCM (2 × 500 mL). The combined organic layers were washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (37.8 g, crude), which was used directly in the next step without further purification.

[0369] Intermediate 108

[0370] 1-(Spiro[2.3]hexan-5-yl)ethan-1-one

[0371]

[0372] Part 1: At 0 °C, Cs2CO3 (16.1 g) and iodomethane (3.0 mL) were added to a stirred solution of 3-methylenecyclobutane-1-carboxylic acid (3.7 g) in MeCN (50 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was poured into ice water (100 mL) and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give methyl 3-methylenecyclobutane-1-carboxylate (2.0 g, 48%).

[0373] Part 2: To a stirred solution of diethylzinc (43.6 mL) in DCM (40 mL) was added TFA (4.8 mL) in DCM (2 mL). Then, methylene iodide (5.2 mL) in DCM (2 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. Then, methyl 3-methylenecyclobutane-1-carboxylate (3.5 g) in DCM (5 mL) was added dropwise at 0 °C and the mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude material which was purified by column chromatography (SiO2, 4 - 5% EtOAc / PE) to give methyl spiro[2.3]hexane-5-carboxylate (3.5 g, 90%).

[0374] Part 3: To a stirred solution of methyl spiro[2.3]hexane-5-carboxylate (4.0 g) in MeOH:H2O (1:1, 40 mL) at 0 °C was added LiOH·H2O (3.6 g). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with cold water (50 mL), the aqueous layer was acidified to pH ~ 2 with 1N HCl aqueous solution and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give spiro[2.3]hexane-5-carboxylic acid (2.2 g, 61%).

[0375] Part 4: To a stirred solution of spiro[2.3]hexane-5-carboxylic acid (2.2 g) in Et2O (20 mL) at -78 °C was added MeLi (1.6 M in Et2O, 3.6 mL) and the mixture was allowed to warm to rt over 2 h. The reaction mixture was poured into ice water (50 mL) and extracted with Et2O (3 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure (bath temperature below 30 °C) to give the title compound (1.0 g, 47%).

[0376] Intermediate 109

[0377] 1-(1-Methoxycyclopropyl)ethan-1-one

[0378]

[0379] Part 1: To a stirred solution of 1-hydroxycyclopropanecarboxylic acid (5.0 g) in DMF (60 mL) at 0 °C was added NaH (60% in mineral oil, 5.9 g). The reaction mixture was stirred at 0 °C for 30 minutes, then MeI (10.0 mL) was added at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was poured into saturated NH4Cl (50 mL) solution. The aqueous phase was extracted with MTBE (100 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure at low temperature to give methyl 1-methoxycyclopropanecarboxylate (6.1 g, 95%).

[0380] Part 2: A solution of methyl 1-methoxycyclopropanecarboxylate (6.4 g) in 50% aqueous NaOH (64 mL) and methanol (64 mL) was heated to 80 °C in a sealed tube and maintained for 16 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The resulting crude product was diluted with ice water (100 mL) and washed with MTBE (50 mL). The aqueous layer was acidified to pH ~ 4 with NaHSO4 solution and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and concentrated at low temperature to give 1-methylcyclopropane-1-carboxylic acid (5.2 g, 91%). LCMS m / z = 115 [M-H] - 。

[0381] Part 3: To a stirred solution of 1-methoxycyclopropane-1-carboxylic acid (10.2 g) in DCM (500 mL) at 0 °C were added methoxy(methyl)amine hydrochloride (11.0 g), EDCI·HCl (24.0 g), HOBt (17.0 g) and Et3N (44 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with ice-cold 1 M HCl (100 mL) aqueous solution. The aqueous layer was extracted with DCM (3 × 500 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give a crude product, which was purified by CombiFlash chromatography (SiO2, 0-30% EtOAc / Hex) to give N,1-dimethoxy-N-methylcyclopropane-1-carboxamide (9.0 g, 64%).

[0382] Part 4: To a stirred solution of N,1 - dimethoxy - N - methylcyclopropane - 1 - carboxamide (2.2 g) in Et2O (30 mL) at 0 °C was added MeMgBr (3 M in Et2O, 14 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution (80 mL) and extracted with Et2O (2 × 80 mL). The combined organic layers were dried over Na2SO4, filtered through a silica gel bed and concentrated under reduced pressure at 20 °C to give the title compound (1.5 g, 95%).

[0383] Intermediate 110

[0384] 1-(3-Fluorobicyclo[1.1.1]pentan-1-yl)ethan-1-one

[0385]

[0386] Part 1: To a stirred solution of 3 - fluorobicyclo[1.1.1]pentane - 1 - carboxylic acid (50.0 g) in DMF (500 mL) at rt was added HATU (219.17 g), DIPEA (148.71 g) and N,O - dimethylhydroxylamine hydrochloride (112.40 g), and the resulting reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2 × 250 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 10 - 15% EtOAc / PE) to give 3 - fluoro - N - methoxy - N - methylbicyclo[1.1.1]pentane - 1 - carboxamide (50 g, 75%). LCMS m / z = 174 [M + H] + 。

[0387] Part 2: To a stirred solution of 3 - fluoro - N - methoxy - N - methylbicyclo[1.1.1]pentane - 1 - carboxamide (50 g) in THF (250 mL) at 0 °C was added MeMgBr (3 M in Et2O, 144.3 mL), and the mixture was stirred from 0 °C to rt for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution (500 mL) and extracted with Et2O (2 × 250 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (50.0 g, crude), which was used directly in the next step without further purification.

[0388] Intermediate 111 - 112

[0389] The title compound was prepared from the appropriate acid using a method similar to that described for Intermediate 110.

[0390]

[0391] Intermediate 113

[0392] 1-((trans)-2-Methylcyclopropyl)ethan-1-one

[0393]

[0394] Part 1: To a solution of (trans)-2-methylcyclopropane-1-carboxylic acid (9.0 g) in DCM (250 mL) at rt was added methoxy(methyl)amine hydrochloride (11.5 g), EDCI·HCl (24.2 g), HOBt (17.1 g) and Et3N (5.0 mL). The reaction mixture was stirred at rt for 16 h. The reaction was quenched with ice-cold aqueous HCl (1 M) and the layers were separated. The aqueous layer was extracted with DCM (3 × 500 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, 0 - 35% EtOAc / Hex) to give (trans)-N-methoxy-N,2-dimethylcyclopropane-1-carboxamide (4.5 g, 35%).

[0395] Part 2: To a solution of (trans)-N-methoxy-N,2-dimethylcyclopropane-1-carboxamide (4.5 g) in Et2O (100 mL) at 0 °C was added MeMgBr (3 M in Et2O, 28.3 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with Et2O (2 × 300 mL). The organic layer was dried over Na2SO4, filtered through a silica gel bed and concentrated at 20 °C to give the title compound (1.2 g, 43%), which was used in the next step without any purification.

[0396] Intermediate 114

[0397] 1-(Bicyclo[1.1.1]pentan-1-yl)ethan-1-one

[0398]

[0399] Part 1: Oxalyl chloride (4.62 mL) and DMF (0.3 mL) were added to a stirred solution of bicyclo[1.1.1]pentane-1-carboxylic acid (4.0 g) in DCM (100 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h. Then a mixture of methoxy(methyl)amine hydrochloride (5.2 g) and DIPEA (17.7 mL) in DCM (20 mL) was added dropwise to the reaction mixture at 0 °C. The reaction mixture was stirred at rt for another 2 h. The reaction mixture was diluted with ice water and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 0 - 30% EtOAc / Hex) to give N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide (3.0 g, 54%).

[0400] Part 2: MeMgBr (3 M in Et2O, 12.5 mL) was added to a stirred solution of N-methoxy-N-methylbicyclo[1.1.1]pentane-1-carboxamide (2.3 g) in Et2O (50 mL) at 0 °C, and the mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with Et2O (3 x 70 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure (low temperature: about 20 °C) to give the title compound (1.3 g, 80%), which was used directly in the next step without further purification.

[0401] Intermediate 115

[0402] 1-(2,2-Difluorocyclopropyl)ethan-1-one

[0403]

[0404] MeLi (1.6 M in Et2O, 38.4 mL) was added to a stirred solution of 2,2-difluorocyclopropane-1-carboxylic acid (5.0 g) in Et2O (50 mL) at -78 °C, and the mixture was allowed to warm slowly to rt over 2 h. The reaction mixture was poured into ice water (100 mL) and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with water (150 mL) and brine (150 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure (bath temperature below 30 °C) to give the title compound (2.0 g, crude), which was used directly in the next step without further purification.

[0405] Intermediate 116

[0406] 1-(2-Fluorocyclopropyl)ethan-1-one

[0407]

[0408] At -78 °C, MeLi (1.6 M in Et2O, 48 mL) was added to a stirred solution of 2-fluorocyclopropane-1-carboxylic acid (4.0 g) in Et2O (40 mL), and the mixture was allowed to warm slowly to rt over 2 h. The reaction mixture was poured into ice water (50 mL) and extracted with MTBE (3 × 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure (bath temperature below 30 °C) to give the title compound (4.0 g, crude), which was used directly in the next step without further purification.

[0409] Intermediate 18

[0410] Ethyl 3-acetyl-1H-pyrazole-5-carboxylate

[0411]

[0412] To a solution of InCl3 (3.25 g) in water (200 mL) at rt was added but-3-yn-2-one (5.0 g) and ethyl diazoacetate (9.31 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with ice water and extracted with EtOAc (3 x 300 mL). The combined organic matter was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (7.5 g, 56%). LCMS m / z = 183 [M+H] + 。

[0413] Intermediate 19

[0414] Ethyl 3-(1,1-difluoroethyl)-1H-pyrazole-5-carboxylate

[0415]

[0416] DAST (17.4 mL) was added dropwise to a solution of ethyl 3-acetyl-1H-pyrazole-5-carboxylate (Intermediate 18, 6.0 g) in DCM (150 mL) at 0 °C, and the resulting mixture was stirred at rt for 16 h. The reaction was quenched with cold saturated NaHCO3 solution and extracted with DCM (3 x 100 mL). The combined organic matter was dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 40% EtOAc / Hex) to give the title compound (6 g, 89%). LCMS m / z = 205 [M+H] + 。

[0417] Intermediate 20

[0418] Methyl 3-(benzyloxy)-1H-pyrazole-5-carboxylate

[0419]

[0420] To a stirred solution of methyl 3-hydroxy-1H-pyrazole-5-carboxylate (10 g) in DMF (180 mL) at rt was added Cs2CO3 (25.24 g) and benzyl bromide (8.36 mL), and the mixture was stirred at rt for 1 h. The reaction was quenched with crushed ice and extracted with EtOAc (3 x 300 mL). The combined organics were washed with cold brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 20% EtOAc / Hex) to afford the title compound (12 g, 73%). LCMS m / z = 233 [M+H] + 。

[0421] Intermediate 117

[0422] Methyl 3-(1-fluorocyclopropyl)-1H-pyrazole-5-carboxylate

[0423]

[0424] Part 1: To a stirred solution of 1-(1-fluorocyclopropyl)ethan-1-one (4.0 g) in THF (40 mL) at -78 °C under a nitrogen atmosphere was added LiHMDS (1 M in THF, 58.7 mL), and the mixture was stirred for 1 h. Then dimethyl oxalate (6.93 g) was added to the reaction mixture at -78 °C and the resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give methyl 4-(1-fluorocyclopropyl)-2,4-dioxobutanoate (6.0 g, crude), which was used directly in the next step without further purification.

[0425] Part 2: To a stirred solution of methyl 4-(1-fluorocyclopropyl)-2,4-dioxobutanoate (6.0 g) in acetic acid (40 mL) at rt was added N2H4·H2O (3.1 mL). The resulting reaction mixture was then heated to 80 °C and maintained for 16 h. The reaction mixture was cooled to rt, diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated NaHCO3 solution (50 mL), water (15 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude material which was purified by column chromatography (SiO2, 25% EtOAc / PE) to give the title compound (2.9 g, 40% over two steps). LCMS m / z = 185 [M+H] + 。

[0426] Intermediate 118 - 127

[0427] The title compound was prepared from the appropriate ketone using a method similar to that described for Intermediate 117 (Part 1 was at a suitable reaction time between 1 - 16 h and Part 2 was at a suitable reaction time between 4 - 16 h and a suitable reaction temperature between 80 - 100 °C).

[0428]

[0429]

[0430] Intermediate 128

[0431] Methyl 3-cyclobutyl-1H-pyrazole-5-carboxylate

[0432]

[0433] Part 1: To a stirred solution of 1-cyclobutylethan-1-one (4.0 g) and dimethyl oxalate (4.2 g) in toluene (30 mL) at 0 °C was added potassium tert-butoxide (5.4 g) in THF portionwise. The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated 1N HCl solution (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give methyl 4-cyclobutyl-2,4-dioxobutanoate (4.2 g, 83%) which was used directly in the next step without further purification. LCMS m / z = 185 [M+H] + 。

[0434] Part 2: To a stirred solution of methyl 4-cyclobutyl-2,4-dioxobutanoate (4.0 g) in acetic acid (6.0 mL) at 0 °C was added N2H4·H2O (2.1 g). The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution (50 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 25% EtOAc / PE) to give the title compound (2.0 g, 81%). LCMS m / z = 181 [M+H] + 。

[0435] Intermediate 129

[0436] Ethyl 3-(1-cyanocyclopropyl)-1H-pyrazole-5-carboxylate

[0437]

[0438] To a solution of 1-acetylcyclopropane-1-carbonitrile (4.2 g) in dry THF (80 mL) at rt was added tBuOK (1 M in THF, 46.2 mL) and the mixture was stirred for 15 min, followed by addition of diethyl oxalate (5.6 mL). The reaction mixture was stirred at rt for 16 h. Then, N2H4·H2O (2.7 mL) and acetic acid (5.7 mL) were added to the reaction mixture. The mixture was heated to reflux and maintained for 4 h. The reaction mixture was concentrated and diluted with EtOAc (200 mL). The organic layer was basified with saturated NaHCO3 solution (pH ca. 8) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4 and concentrated to give a crude product, which was purified by column chromatography (SiO2, 0 - 50% EtOAc / Hex) to give the title compound (2.2 g, 28%). LCMS m / z = 206 [M+H] + 。

[0439] Intermediates 130 - 134

[0440] The title compound was prepared from the appropriate ketone using a method similar to that described for Intermediate 129 (at a suitable reaction time between 2 - 4 h under reflux conditions).

[0441]

[0442]

[0443] Intermediate 135

[0444] Ethyl 3-(2-hydroxypropan-2-yl)-1H-pyrazole-5-carboxylate

[0445]

[0446] Under rt, 2-diazoacetate (9.758 g) was slowly added to a stirred solution of zinc trifluoromethanesulfonate (5.186 g), 2-methylbut-3-yn-2-ol (6.0 g) and Et3N (14.91 mL). The resulting reaction mixture was heated to 100 °C and maintained for 8 h. The reaction mixture was slowly quenched with ice water (120 mL) and extracted with EtOAc (2 × 75 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, 10-15% EtOAc / PE) to give the title compound (2.0 g, 14%). LCMS m / z = 199 [M+H] + 。

[0447] Intermediate 136

[0448] Ethyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-1H-py razole-5-carboxylate

[0449]

[0450] Part 1: To a solution of ethyl 5-acetyl-2H-pyrazole-3-carboxylate (Intermediate 18, 1.50 g), (3,3-difluoro-1-methyl-cyclobutyl)methanol (1.35 g) and ADDP (2.49 g) in THF (80 mL) was added dropwise tributylphosphine (2.5 g). The mixture was stirred at rt for 16 h. Then, EtOAc (100 mL) and saturated NaHCO3 solution (30 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, 5% EtOAc / Hex) to give ethyl 5-acetyl-2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]pyrazole-3-carboxylate (2.03 g, 82%). LCMS m / z = 301 [M+H] + 。

[0451] Part 2: Ethyl 5-acetyl-2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]pyrazole-3-carboxylate (750 mg) and scandium(III) trifluoromethanesulfonate (61 mg) were dissolved in 15 mL of DCM. Then, 3,3-difluoroprop-2-en-1-amine hydrochloride (650 mg) and DIPEA (1.7 mL) in 10 mL of DCE were added, and the reaction mixture was heated to 60 °C and maintained for 16 h. The mixture was then cooled to 0 °C, and then DIPEA (1.7 mL) and (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (1.6 g) were added. The reaction mixture was then stirred at rt for 1 h. The mixture was filtered through a sintered funnel, and the funnel was washed with 100 mL of DCM. The organic layer was washed with saturated NH4Cl solution (30 mL). The layers were separated and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography to give ethyl 5-[1-[3,3-difluoroallyl-(2,2,2-trifluoroacetyl)amino]vinyl]-2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]pyrazole-3-carboxylate (510 mg, 43%).

[0452] Part 3: Ethyl 5-[1-[3,3-difluoroallyl-(2,2,2-trifluoroacetyl)amino]vinyl]-2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]pyrazole-3-carboxylate (720 mg) was dissolved in MeCN (15 mL) under a nitrogen atmosphere. Then, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (17 mg) dissolved in MeCN (1 mL) was added, and the resulting mixture was irradiated at 450 nm (95% intensity, using Lucent instrument) at rt for 16 h. An aliquot of (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (17 mg) dissolved in MeCN (1 mL) was added, and the reaction was irradiated under the same conditions for 24 h. The reaction mixture was then diluted with EtOAc and washed with saturated NaHCO3 solution. The layers were separated, dried over MgSO4, and the solvent was removed under reduced pressure. The residue was purified via column chromatography (SiO2, 10% EtOAc / Hex) to give ethyl 2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]-5-[5,5-difluoro-3-(2,2,2-trifluoroacetyl)-3-azabicyclo[2.1.1]hexan-4-yl]pyrazole-3-carboxylate (580 mg, 80%).

[0453] Part 4: To a solution of ethyl 2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]-5-[5,5-difluoro-3-(2,2,2-trifluoroacetyl)-3-azabicyclo[2.1.1]hexan-4-yl]pyrazole-3-carboxylate (580 mg) in EtOH (4 mL) was added NaOH (74 mg), and the mixture was stirred for 15 minutes. The mixture was diluted with EtOAc (30 mL) and washed with water (5 mL). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, 50% EtOAc / Hex) to give ethyl 5-(5,5-difluoro-3-azabicyclo[2.1.1]hexan-4-yl)-2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]pyrazole-3-carboxylate (370 mg, 80%). LCMS m / z = 376 [M+H] + 。

[0454] Part 5: Ethyl 5-(5,5-difluoro-3-azabicyclo[2.1.1]hexan-4-yl)-2-[(3,3-difluoro-1-methyl-cyclobutyl)methyl]pyrazole-3-carboxylate (270 mg) was dissolved in degassed THF (2 mL), and then N-(benzyloxy)-1-[4-(trifluoromethyl)phenyl]isobutyramide (528 mg) in 2 mL of degassed THF was added. The mixture was heated to 60 °C and maintained for 16 h. The mixture was diluted with EtOAc (50 mL) and washed with saturated NH4Cl solution (10 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, 5% EtOAc / Hex) to give the title compound (80 mg, 31%). LCMS m / z = 361 [M+H] + 。

[0455] Intermediate 21

[0456] Ethyl 3-cyclopropyl-4-iodo-1H-pyrazole-5-carboxylate

[0457]

[0458] NIS (26.27 g) was added portionwise to a solution of ethyl 3-cyclopropyl-1H-pyrazole-5-carboxylate (15 g) in DCM (150 mL) at 0 °C, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with saturated sodium thiosulfate (200 mL) at 0 °C and extracted with DCM (2 x 250 mL). The combined organic layers were washed with saturated NaHCO3 (250 mL), brine (200 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 2-5% EtOAc / Hex) to give the title compound (25 g, 90%). LCMS m / z = 307 [M+H] + 。

[0459] Intermediate

[0460] The title compound was prepared from the appropriate pyrazole using a method similar to that described for Intermediate 21 (at a suitable reaction time between 2-16 h and a suitable reaction temperature between 0 °C - rt).

[0461]

[0462]

[0463] Intermediate 142

[0464] Methyl 3-(1-fluorocyclopropyl)-4-iodo-1H-pyrazole-5-carboxylate

[0465]

[0466] To a stirred solution of methyl 3-(1-fluorocyclopropyl)-1H-pyrazole-5-carboxylate (Intermediate 117, 2.9 g) in MeCN (30 mL) at rt was added NIS (5.314 g) and trifluoroacetic acid (1 mL). The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with hypo solution (saturated aqueous Na2S2O3, 50 mL), water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (SiO2, 4% EtOAc / PE) to give the title compound (4.0 g, 82%). LCMS m / z = 311 [M+H] + 。

[0467] Intermediates 143 - 156

[0468] The title compound was prepared from the appropriate pyrazole using a method similar to that described for Intermediate 142 (at a suitable reaction time between 2 - 16 h and a suitable reaction temperature between 0 - 80 °C).

[0469]

[0470]

[0471]

[0472] Intermediate 157

[0473] Ethyl 3-(1-cyanocyclopropyl)-4-iodo-1H-pyrazole-5-carboxylate

[0474]

[0475] To a solution of ethyl 3-(1 - cyanocyclopropyl)-1H - pyrazole - 5 - carboxylate (Intermediate 129, 2.8 g) in DMF (30 mL) at 0 °C was added NIS (9.22 g), and the mixture was heated to 90 °C and maintained for 16 h. The reaction mixture was diluted with EtOAc (300 mL), washed with a Na2S2O3 solution (100 mL), water (100 mL) and brine (100 mL), and dried over Na2SO4. The organic layer was evaporated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 30% EtOAc / Hex) to give the title compound (2.6 g, 57%).

[0476] Intermediate 22

[0477] Ethyl 3-cyclopropyl-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate

[0478]

[0479] To a solution of ethyl 3 - cyclopropyl - 4 - iodo - 1H - pyrazole - 5 - carboxylate (Intermediate 21, 20 g) in DCM (200 mL) at 0 °C was added DIPEA (34.4 mL), and the solution was stirred for 30 min, after which a solution of SEM - Cl (15.6 mL) in DCM (100 mL) was added dropwise at 0 °C. The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with ice - water and extracted with DCM (2 x 250 mL). The combined organic layers were washed with brine (250 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 5% EtOAc / Hex) to give the title compound (22 g, 90%). 1H-NMR (400 MHz, DMSO-d6): δ 5.61 (s, 2H), 4.33 (q, 2H), 3.45 (t, 2H), 1.89 - 1.85 (m, 1H), 1.34 (t, 3H), 0.96 - 0.90 (m, 2H), 0.78 - 0.73 (m, 4H), -0.09 (s, 9H).

[0480] Intermediate 158

[0481] The title compound was prepared from the appropriate pyrazole using a method similar to that described for Intermediate 22.

[0482]

[0483] Intermediate 23

[0484] Ethyl 3-cyclopropyl-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-py razole-5-carboxylate

[0485]

[0486] To a solution of ethyl 3-cyclopropyl-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (Intermediate 22, 10 g) in DMF (60 mL) at rt was added KF (4.0 g), TMSCF3 (23.8 mL) and CuI (8.72 g), and the reaction mixture was heated in a sealed tube at 90 °C for 10 h. The reaction mixture was cooled to rt, diluted with cold water (300 mL), filtered through diatomaceous earth and washed with EtOAc (800 mL). The filtrate was washed with water (3 x 100 mL), brine (200 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 2 - 5% EtOAc / Hex) to give the title compound (7.8 g, 78%). 1 H-NMR (400 MHz, DMSO-d6): δ 5.57 (s, 2H), 4.35 (quin, 1H), 3.52 - 3.45 (m, 2H), 1.29 (q, 3H), 0.96 - 0.74 (m, 6H), -0.08 (s, 9H).

[0487] Intermediate 159

[0488] The title compound was prepared from the appropriate pyrazole using a method similar to that described for Intermediate 23.

[0489]

[0490] Intermediate 24

[0491] Ethyl 3-cyclopropyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0492]

[0493] To a solution of ethyl 3-cyclopropyl-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (Intermediate 23, 4.7 g) in EtOH (35 mL) was added 4 M HCl in dioxane (25 mL), and the mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (800 mL), washed with saturated NaHCO3 (200 mL), water (2 x 100 mL), brine (250 mL), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 60% EtOAc / Hex) to afford the title compound (1.8 g, 58%). LCMS m / z = 249 [M+H] + 。

[0494] Intermediate 160

[0495] The title compound was prepared from the appropriate pyrazole using a method similar to that described for Intermediate 24.

[0496]

[0497] Intermediate 25

[0498] Ethyl 3-(1,1-difluoroethyl)-4-iodo-1H-pyrazole-5-carboxylate

[0499]

[0500] The title compound (9 g, 92%) was prepared from ethyl 3-(1,1-difluoroethyl)-1H-pyrazole-5-carboxylate (Intermediate 19) using a method similar to that described for Intermediate 21. LCMS m / z = 331 [M+H] + 。

[0501] Intermediate 26

[0502] Ethyl 3-cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-4-iodo-1H-pyrazole-5-carboxylate

[0503]

[0504] At rt, to a solution of ethyl 3-cyclopropyl-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 21, 1.8 g) in DMF (12 mL) was added (3,3-difluorocyclopentyl)methyl methanesulfonate (1.5 g) and K2CO3 (1.22 g), and the resulting mixture was heated to 90 °C and maintained for 16 h. The reaction mixture was diluted with ice water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by Combiflash chromatography (SiO2, 0 - 30% EtOAc / Hex) to give the title compound (1.5 g, 60%). LCMS m / z = 425 [M+H] + 。

[0505] Intermediate 161

[0506] Ethyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-methylcyclopropyl)-4-(trifluoromethyl)-1H-py razole-5-carboxylate

[0507]

[0508] At rt, to a solution of ethyl 3-(1-methylcyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 160, 0.43 g) in DMF (10 mL) was added (3,3-difluoro-1-methylcyclobutyl)methyl methanesulfonate (0.42 g) and Cs2CO3 (1.34 g). The reaction mixture was heated to 90 °C and maintained for 1 h. The mixture was diluted with ice water and extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 15% EtOAc / Hex) to give the title compound (0.35 g, 56%). LCMS m / z = 381 [M+H] + 。

[0509] Intermediate 162

[0510] The title compound was prepared from the appropriate pyrazole and alkylating agent using a method similar to that described for Intermediate 161.

[0511]

[0512]

[0513] Intermediate 163

[0514] Methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-iodo-1H-pyrazole-5-car boxylate

[0515]

[0516] Under RT, to a stirred solution of methyl 3-(1-fluorocyclopropyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 142, 4.0 g) in MeCN (40 mL) was added K2CO3 (5.341 g) and (3,3-difluoro-1-methylcyclobutyl)methyl methanesulfonate (Intermediate 6, 5.527 g). The reaction mixture was heated to 80 °C and maintained for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 5% EtOAc / PE) to give the title compound (3.0 g, 54%). LCMS m / z = 429 [M+H] + 。

[0517] Intermediates 164 - 171

[0518] The title compound was prepared from the appropriate pyrazole and the appropriate mesylate (ROM) using a method similar to that described for Intermediate 163.

[0519]

[0520]

[0521]

[0522] Intermediate 172

[0523] Ethyl 3-cyclopropyl-1-((3,3-difluorobicyclo[3.1.0]hexan-1-yl)methyl)-4-iodo-1H-pyrazole-5-carboxylate

[0524]

[0525] Under an argon atmosphere at 0 °C, to a stirred solution of ethyl 3-cyclopropyl-4-iodo-1-((3-oxabicyclo[3.1.0]hexan-1-yl)methyl)-1H-pyrazole-5-carboxylate (Intermediate 171, 400 mg) in DCM (5 mL) was added DAST (1.56 g). The resulting reaction mixture was stirred at 0 °C - RT for 48 h. The reaction mixture was quenched with saturated NaHCO3 solution (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 5% EtOAc / PE) to give the title compound (300 mg, 71%).

[0526] Intermediate 27

[0527] Ethyl 1-((3,3-difluorocyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-iodo-1H-pyrazole-5-carboxylate

[0528]

[0529] The title compound (0.8 g, 60%) was prepared from ethyl 3-(1,1-difluoroethyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 25) and (3,3-difluorocyclobutyl)methyl methanesulfonate (Intermediate 2) using a method similar to that described for Intermediate 26. LCMS m / z = 435 [M+H] + 。

[0530] Intermediate 173

[0531] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-iodo-1H-pyrazole-5-carboxylic acid Ethyl ester

[0532]

[0533] To a solution of ethyl 3-(1,1-difluoroethyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 25, 3.0 g) and (3,3-difluoro-1-methylcyclobutyl)methyl methanesulfonate (Intermediate 6, 2.5 g) in DMF (20 mL) at rt was added Cs2CO3 (5.9 g), and the reaction mixture was heated to 90 °C and maintained for 5 h. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with cold brine (100 mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the crude material, which was purified by CombiFlash column chromatography (SiO2, 0 - 5% EtOAc / Hex) to give the title compound (1.4 g, 34%). LCMS m / z = 449 [M+H] + 。

[0534] Intermediate 28

[0535] Ethyl 3-cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0536]

[0537] Under rt conditions, KF (0.5 g), CuI (1.12 g), and TMSCF3 (3.05 mL) were added to a solution of ethyl 3-cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 26, 1.25 g) in DMF (20 mL), and the reaction mixture was heated in a sealed tube at 90 °C for 16 h. The mixture was cooled to rt, diluted with cold water (300 mL), and filtered through Celite. The filtrate was extracted with EtOAc (3 x 100 mL), washed with brine (200 mL), dried (Na2SO4), and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 5% EtOAc / Hex) to afford the title compound (0.9 g, 83%). LCMS m / z = 367 [M+H] + 。

[0538] Intermediate 29

[0539] 1-((3,3-Difluorocyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid Ethyl ester

[0540]

[0541] The title compound (0.2 g, 46%) was prepared from ethyl 1-((3,3-difluorocyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 27) using a method similar to that described for Intermediate 28. LCMS m / z = 377 [M+H] + 。

[0542] Intermediate 174

[0543] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole- Methyl 5-carboxylate

[0544]

[0545] Under rt, to a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 163, 3.0 g) in DMF (30 mL) was added KF (0.614 g) and CuI (2.060 g). The mixture was degassed with argon for 15 minutes. Then, CF3Si(CH3)3 (5.2 mL) was added to the reaction mixture under rt and the resulting reaction mixture was heated to 100 °C and maintained for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 5% EtOAc / PE) to give the title compound (1.5 g, 58%). LCMS m / z = 371 [M+H] + 。

[0546] Intermediates 175 - 194

[0547] The title compound was prepared from the appropriate pyrazole using a method similar to that described for Intermediate 174 (at a suitable reaction time between 16 - 20 h and a suitable reaction temperature between 90 - 100 °C).

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554] Intermediate 195

[0555] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-3-(1-(trifluoromethyl)cyclopropyl)- Methyl 1H-pyrazole-5-carboxylate

[0556]

[0557] Under rt conditions, HMPA (2.25 g) and CuI (1.23 g) were added to a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-iodo-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazole-5-carboxylate (Intermediate 168, 1.2 g) in DMF (10 mL), and the mixture was degassed with argon for 5 minutes. Then, methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.41 g) was added to the reaction mixture under rt conditions. The resulting reaction mixture was heated to 100 °C and maintained for 16 h. The reaction mixture was cooled to rt, diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, 5-6% EtOAc / PE) to give the title compound (830 mg, 78%). LCMS m / z = 421 [M+H] + 。

[0558] Intermediates 196 - 198

[0559] The title compound was prepared from the appropriate pyrazole using a method similar to that described for Intermediate 195.

[0560]

[0561]

[0562] Intermediate 199

[0563] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole- 5-carboxylic acid

[0564]

[0565] Under 0 °C conditions, LiOH·H2O (0.850 g) was added to a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 174, 1.5 g) in THF (6 mL), MeOH (6 mL) and water (6 mL). Then the resulting reaction mixture was stirred at rt for 2 h. The mixture was concentrated under reduced pressure and diluted with water (30 mL). The pH was adjusted to approximately 4 - 5 with 1N aqueous HCl solution (10 mL), and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (1.4 g, 97%). LCMS m / z = 355 [M-H] - 。

[0566] Intermediates 200 - 202, 204 - 218

[0567] The title compound is prepared from the appropriate ester using a method similar to that described for Intermediate 199 (at a suitable reaction time between 2 - 16 h and under a suitable THF:MeOH:water mixture between 1:1:1 to 4:1:1 or 2.5:2.5:1).

[0568]

[0569]

[0570]

[0571]

[0572]

[0573] Intermediate 219

[0574] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoro methyl)-1H-pyrazole-5-carboxylic acid

[0575]

[0576] Ethyl 5-(2,2 - difluoro - 1 - bicyclo[1.1.1]pentyl)-2-[(3,3 - difluoro - 1 - methylcyclobutyl)methyl]-4-(trifluoromethyl)pyrazole - 3 - carboxylate (Intermediate 194, 40 mg) was dissolved in EtOH (1 mL), and then an aqueous solution of NaOH (2 mol / L) (0.056 mL) was added. The mixture was heated to 50 °C and maintained for 30 minutes. The solvent was evaporated, and the residue was dissolved in DCM (10 mL) and washed with 1 M HCl (5 mL). The layers were separated and the organic phase was evaporated to dryness to give the title compound (35 mg, 95%). LCMS m / z = 402 [M + H] + .

[0577] Intermediate 30

[0578] 3-Cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0579]

[0580] LiOH·H2O (0.12 g) was added to a solution of ethyl 3-cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 28, 0.7 g) in a mixture of THF / MeOH / H2O (2 / 2 / 1; 25 mL) at rt, and the mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous phase was acidified to pH 2 with saturated KHSO4 solution at 0 °C and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure to give the title compound (0.6 g, 90%). LCMS m / z = 339 [M+H] + 。

[0581] Intermediate 220

[0582] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-methylcyclopropyl)-4-(trifluoromethyl)-1H-pyra zole-5-carboxylic acid

[0583]

[0584] LiOH·H2O (0.27 g) was added to a solution of ethyl 1-[(3,3-difluoro-1-methylcyclobutyl)methyl]-3-(1-methylcyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 161, 0.62 g) in a mixture of EtOH-THF-H2O (2:2:1) (25 mL) at rt, and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and acidified to pH ca. 2 with saturated NaHSO4 solution. The resulting mixture was extracted with EtOAc (3 × 80 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.60 g, crude), which was used in the next step without further purification. Yield: quantitative (0.60 g, crude).

[0585] Intermediate 221

[0586] The title compound was prepared from the appropriate ester using a method similar to that described for Intermediate 220.

[0587]

[0588] Intermediate 222

[0589] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-(trifluoromethyl)-1H-pyra zole-5-carboxylic acid

[0590]

[0591] To a solution of ethyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 182, 500 mg) in THF (8 mL) was added LiOH·H2O (97 mg), and the mixture was stirred for 16 h. The reaction mixture was concentrated, diluted with water (50 mL) and washed with Et2O (2 × 50 mL). The aqueous layer was acidified to pH about 5 - 6 with saturated NaHSO4 solution and extracted with DCM (2 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (385 mg, 83%).

[0592] Intermediate 31

[0593] Methyl 3-(benzyloxy)-4-iodo-1H-pyrazole-5-carboxylate

[0594]

[0595] The title compound (2.8 g, 73%) was prepared from methyl 3-(benzyloxy)-1H-pyrazole-5-carboxylate (Intermediate 20) using a method similar to that described for Intermediate 21. LCMS m / z = 359 [M + H] + 。

[0596] Intermediate 32

[0597] Methyl 3-(benzyloxy)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate

[0598]

[0599] To a stirred solution of methyl 3-(benzyloxy)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 31, 2.7 g) in DCM (35 mL) at 0 °C was added DIPEA (3.75 mL), and the mixture was stirred at 0 °C for 0.5 h. At 0 °C, SEM-Cl (1.6 mL) was added to the reaction mixture, and the mixture was stirred at rt for 1 h. The reaction was quenched with crushed ice and extracted with DCM (3 x 100 mL). The combined organic matter was washed with cold brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 15% EtOAc / Hex) to give the title compound (3 g, 81%). LCMS m / z = 489 [M + H] + 。

[0600] Intermediate 33

[0601] 3-(Benzyloxy)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1 H- Pyrazole-5- Methyl carboxylate

[0602]

[0603] To a stirred solution of methyl 3-(benzyloxy)-4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (Intermediate 32, 5 g) in DMF (70 mL) at rt was added CuI (3.9 g), anhydrous KF (1.78 g) and TMSCF3 (10.6 mL). The reaction mixture was heated at 90 °C for 16 h in a sealed tube, diluted with ice water and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with cold brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by CombiFlash chromatography (SiO2, 0 - 15% EtOAc / Hex) to give the title compound (3.5 g, 79%).

[0604] Intermediate 34

[0605] Methyl 3-(benzyloxy)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0606]

[0607] To a stirred solution of methyl 3-(benzyloxy)-4-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxylate (Intermediate 33, 6.7 g) in MeOH (30 mL) at 0 °C was added 4M dioxane / HCl (48 mL), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was quenched with saturated NaHCO3 solution at 0 °C to maintain the pH at about 8. The aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to dryness in vacuo. The residue was purified by CombiFlash chromatography (SiO2, 0 - 50% EtOAc / Hex) to give the title compound (3.2 g, 68%). LCMS m / z = 301 [M+H] + 。

[0608] Intermediate 35

[0609] 3-Acetyl-4-methyl-1 H- Ethyl pyrazole-5-carboxylate

[0610]

[0611] At reflux temperature, pentane-2,4-dione (200 g) was added to a stirred solution of KOH (112 g) in ethanol (15 vol), followed by ethyl diazoacetate (258 g), and the resulting reaction mixture was stirred at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure, diluted with water (50 volumes), and the pH was adjusted to about 2 with 3 N aqueous HCl at 15 - 20 °C. The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (150 g, 38%), which was used without further purification. LCMS m / z = 197 [M+H] + 。

[0612] Intermediate 36

[0613] Ethyl 3-(1,1-difluoroethyl)-4-methyl-1H-pyrazole-5-carboxylate

[0614]

[0615] To a stirred solution of ethyl 3-acetyl-4-methyl-1H-pyrazole-5-carboxylate (Intermediate 35, 100 g, 510 mmol) in DCM (1 L) at 0 °C was added DAST (164 g), and the reaction mixture was stirred at rt for 12 h. The reaction mixture was quenched with 50% aqueous NaHCO3 (500 mL) and extracted with DCM (2 × 200 mL). The combined organic layers were washed with water (150 mL), brine (150 mL), dried (Na2SO4), and evaporated to dryness in vacuo. The residue was purified by column chromatography (SiO2, 10% EtOAc / PE) to give the title compound (40 g, 35%). LCMS m / z = 219 [M+H] + 。

[0616] Intermediate 37

[0617] Methyl 3-(benzyloxy)-1-((3,3-difluorocyclopentyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0618]

[0619] To a solution of methyl 3-(benzyloxy)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 34, 1.0 g) and (3,3-difluorocyclopentyl)methanol (0.68 g) in THF (30 mL) at 0 °C was added PPh3 (1.3 g), and after 5 min, DIAD (1.0 mL) was added at 0 °C, and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by CombiFlash chromatography (SiO2; 0 - 20% EtOAc / Hex) to give the title compound (1 g, 72%). LCMS m / z = 419 [M+H] + 。

[0620] Intermediates 38 - 52, 223 - 239

[0621] The title compound was prepared from the appropriate pyrazole and alcohol (at a suitable temperature between 0 - 90 °C) using a method similar to that described for Intermediate 37.

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629] Intermediate 240

[0630] Ethyl 3-cyclopropyl-4-(trifluoromethyl)-1-((1-(trifluoromethyl)cyclopentyl)methyl)-1H-pyrazole-5-carboxylate

[0631]

[0632] To a stirred solution of ethyl 3 - cyclopropyl - 4 - (trifluoromethyl)-1H - pyrazole - 5 - carboxylate (Intermediate 24, 0.2 g) in toluene (4 mL) in a microwave vial at rt was added [1 - (trifluoromethyl)cyclopentyl]methanol (0.16 g), PPh3 (0.25 g) and DIAD (0.2 mL). The mixture was heated to 100 °C under microwave irradiation and maintained for 1.5 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2; 0 - 10% EtOAc / Hex) to give the title compound (0.3 g, 93%). LCMS m / z = 399 [M + H] + 。

[0633] Intermediates 241 - 244

[0634] The title compound was prepared from the appropriate pyrazole and alcohol using a method similar to that described for Intermediate 240.

[0635]

[0636]

[0637] Intermediate 245

[0638] Ethyl 5-carboxylate

[0640]

[0641] At -20 °C, DAST (1.79 mL) was added to a stirred solution of ethyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(2-hydroxypropan-2-yl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 229, 1.5 g) in DCM (15 mL), and the mixture was allowed to warm to rt over 2 h. The reaction mixture was quenched slowly with ice water (100 mL) and extracted with DCM (2 × 65 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 8-10% EtOAc / PE) to give the title compound (1.0 g, 66%). LCMS m / z = 445 [M+H] + 。

[0642] Intermediate 246

[0643] Ethyl pyrazole-5-carboxylate

[0645]

[0646] At 0 °C, DAST (2.9 mL) and EtOH (0.1 mL) were added to a solution of ethyl 3-cyclopropyl-1-((2-oxobicyclo[2.1.1]hexan-1-yl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 227, 1.0 g) in DCM (15.0 mL). The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0-40% EtOAc / Hex) to give the title compound. LCMS m / z = 379 [M+H] + 。

[0647] Intermediate 53

[0648] Methyl 1-((3,3-difluorocyclopentyl)methyl)-3-hydroxy-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate

[0649]

[0650] A solution of methyl 3-(benzyloxy)-1-((3,3-difluorocyclopentyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 37, 1.0 g) in MeOH (30 mL) was degassed with N2 for 15 min and then 10% Pd-C (50% wet weight, 0.5 g) was added at rt. The reaction mixture was stirred at rt for 16 h under a pressure of 1.4 bar (using a H2 balloon). The reaction mixture was filtered through a pad of diatomaceous earth, the filtrate was concentrated under reduced pressure and the residue was purified by Combiflash chromatography (SiO2, 0 - 50% EtOAc / Hex) to give the title compound (0.72 g, 92%). LCMS m / z = 329 [M+H] + 。

[0651] Intermediate 54

[0652] Methyl 1-((3,3-difluorocyclopentyl)methyl)-3-(difluoromethoxy)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate ester

[0653]

[0654] To a stirred solution of methyl 1-((3,3-difluorocyclopentyl)methyl)-3-hydroxy-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 53, 0.3 g) in MeCN (16 mL) was added sodium 2-chloro-2,2-difluoroacetate (0.18 g) and K2CO3 (0.314 g), and the resulting mixture was heated to 80 °C and maintained for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by CombiFlash chromatography (SiO2, 0 - 20% EtOAc / Hex) to give the title compound (0.24 g, 69%). LCMS m / z = 379 [M+H] + 。

[0655] Intermediate 55

[0656] Ethyl 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate ethyl ester

[0657]

[0658] To a stirred solution of ethyl 3-cyclopropyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 24, 1.1 g) in DMF (20 mL) was added (3,3-difluoro-1-methylcyclobutyl)methyl methanesulfonate (Intermediate 6, 1.14 g) and Cs2CO3 (3.61 g), and the reaction mixture was stirred at 90 °C for 1 h. The reaction mixture was diluted with ice water and extracted with EtOAc (3 x 200 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by CombiFlash chromatography (0 - 15% EtOAc / hex) to give the title compound (0.84 g, 56%). LCMS m / z = 367 [M+H] + 。

[0659] Intermediates 56 - 57, 247 - 248

[0660] The title compound was prepared from the appropriate pyrazole and mesylate (ROM) using a method similar to that described for Intermediate 55 (at a suitable reaction time between 1 - 16 h).

[0661]

[0662] Intermediate 58

[0663] Ethyl 1-((3,3-difluorocyclopentyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-1H-pyrazole-5-carboxylate

[0664]

[0665] A mixture of ethyl 1-((3,3-difluorocyclopentyl)methyl)-3-(1,1-difluoroethyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 56, 0.57 g) and Cs2CO3 (0.82 g) in dioxane (13 mL) was degassed with Ar(g) for 15 min, then trimethylcyclotriboroxane (0.35 mL) and PdCl2(dppf)·DCM (52 mg) were added at rt, and the resulting mixture was heated in a sealed tube at 110 °C for 16 h. The reaction mixture was cooled to rt, filtered through a pad of Celite and washed with EtOAc. The filtrate was evaporated under reduced pressure, and the residue was purified by CombiFlash chromatography (SiO2, 0 - 20% EtOAc / Hex) to give the title compound (0.4 g, 93%). LCMS m / z [M+H] + = 337。

[0666] Intermediate 60

[0667] 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid

[0668]

[0669] At rt, LiOH·H2O (0.144 g) was added to a solution of ethyl 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 55, 0.84 g) in a mixture of EtOH / THF / H2O (2:2:1, 25 mL), and the reaction mixture was stirred at rt for 16 h. The reaction mixture was concentrated under reduced pressure, acidified to about pH 2 with saturated NaHSO4 solution, and the aqueous phase was extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with cold brine, dried (Na2SO4) and evaporated to dryness under reduced pressure to give the title compound (0.75 g, 96%). LCMS m / z = 339 [M+H] + 。

[0670] Intermediate 62-77

[0671] The title compound was prepared from the appropriate ester using a method similar to that described for Intermediate 60.

[0672]

[0673]

[0674]

[0675] Intermediate 250

[0676] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-methoxycyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid acid

[0677]

[0678] At rt, LiOH·H2O (0.05 g) was added to a solution of ethyl 1-[(3,3-difluoro-1-methylcyclobutyl)methyl]-3-(1-methoxycyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 180, 0.15 g) in a mixture of THF-H2O (2:1) (9 mL), and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and acidified to pH about 2 with saturated NaHSO4 solution. The aqueous portion was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with cold brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound (0.13 g, 93%). LCMS m / z = 369 [M+H] + 。

[0679] Intermediate 203, 251-261, 299

[0680] The title compound was prepared from the appropriate ester using a method similar to that described for Intermediate 250 (at a suitable reaction temperature between 0 °C and rt, a suitable reaction time between 4 - 16 h, and a suitable THF:water mixture between 5:1 and 4:10).

[0681]

[0682]

[0683]

[0684]

[0685] Intermediate 262

[0686] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole- 5-carboxamide

[0687]

[0688] To a stirred solution of 1 - ((3,3 - difluoro - 1 - methylcyclobutyl)methyl) - 3 - (1 - fluorocyclopropyl) - 4 - (trifluoromethyl) - 1H - pyrazole - 5 - carboxylic acid (Intermediate 199, 1.4 g) in DMF (20 mL) at 0 °C was added DIPEA (2.06 mL), followed by HATU (2.988 g). After 30 min, ammonium chloride (1.041 g) was added at 0 °C. The resulting reaction mixture was stirred at rt under an argon atmosphere for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 30% EtOAc / PE) to give the title compound (300 mg, 21%). LCMS m / z = 356 [M + H] + 。

[0689] Intermediates 263 - 281

[0690] The title compound was prepared from the appropriate acid using a method similar to that described for Intermediate 262 (at a suitable reaction temperature between 0 °C and rt and a suitable reaction time between 1 - 16 h).

[0691]

[0692]

[0693]

[0694]

[0695]

[0696] Intermediate 282

[0697] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(1-fluorocyclopropyl)-1H-pyrazole- 5-carboxamide

[0698]

[0699] Part 1: To a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-iodo-1H-pyrazole-5-carboxylate (Intermediate 163, 5.0 g) in 1,4-dioxane (50 mL) / H2O (10 mL) was added potassium vinyltrifluoroborate (3.128 g) and anhydrous sodium carbonate (3.713 g). The resulting reaction mixture was purged with argon for 5 minutes and then Pd(dppf)Cl2·DCM (0.953 g) was added. The resulting mixture was heated to 80 °C and maintained for 16 h. The reaction mixture was cooled to rt, quenched with cold water (100 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 10 - 20% EtOAc / Hex) to give methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-vinyl-1H-pyrazole-5-carboxylate (1.5 g, 48%). LCMS m / z = 329 [M+H] + 。

[0700] Part 2: To a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-vinyl-1H-pyrazole-5-carboxylate (1.5 g) in THF (15.0 mL) and H2O (3.0 mL) at 0 °C was added osmium tetroxide (4 wt.% aqueous solution, 0.058 g) and sodium periodate (2.931 g). The resulting reaction mixture was stirred at rt for 4 h. The reaction mixture was quenched with a Na2SO3 solution (50 mL) and extracted with EtOAc (2 × 40 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-formyl-1H-pyrazole-5-carboxylate (1.7 g, crude), which was used in the next step without purification. LCMS m / z = 331 [M+H] + .

[0701] Part 3: To a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-formyl-1H-pyrazole-5-carboxylate (1.2 g) in DCM (10 mL) at 0 °C was added DAST (1.44 mL), and the mixture was stirred at rt for 16 h. The reaction mixture was slowly quenched with saturated NaHCO3 solution (30 mL) and extracted with DCM (2 × 30 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 10-20% EtOAc / Hex) to give methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(1-fluorocyclopropyl)-1H-pyrazole-5-carboxylate (700 mg, 62% over two steps). LCMS m / z = 353 [M+H] + .

[0702] Part 4: To a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(1-fluorocyclopropyl)-1H-pyrazole-5-carboxylate (500 mg) in methanol (5 mL) was added 7M NH3 in methanol (10 mL). The resulting reaction mixture was heated to 100 °C in a sealed tube and maintained for 16 h. The excess volatiles were removed under reduced pressure, and the resulting residue was washed with pentane (2 × 20 mL) and dried in vacuo to give the title compound (480 mg, crude), which was used in the next step without further purification. LCMS m / z = 338 [M+H] + .

[0703] Intermediate 283-284

[0704] The title compound was prepared from the appropriate pyrazole using a method similar to that described in Parts 1-3 for Intermediate 282. Suitable bases for Part 1 are K2CO3 or K3PO4, and the reaction temperature is 80-100 °C. With or without the addition of NMO, the suitable reaction time for Part 2 is 1-4 h.

[0705]

[0706] Intermediate 285

[0707] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-fluorobicyclo[1.1.1]pentan-1- yl)-1H-pyrazole-5-carboxamide

[0708]

[0709] A solution of stirred methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-1H-pyrazole-5-carboxylate (Intermediate 283, 800 mg) in ammonia-methanol solution (7 M, 5 mL) was heated to 80 °C and maintained for 16 h. Excess volatiles were removed under reduced pressure to give the crude product, which was purified by column chromatography (SiO2, 15% EtOAc / PE) to give the title compound (550 mg, 72%).

[0710] Intermediate 286

[0711] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-fluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole- 5-carboxamide

[0712]

[0713] To a stirred solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(3-fluorobicyclo[1.1.1]pent-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Intermediate 210, 1.8 g) in toluene (7.5 mL) at rt was added thionyl chloride (3.42 mL), and the mixture was heated to 80 °C and maintained for 3 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with DCM and added to a solution of ammonium chloride (2514.22 mg) and DIPEA (3036.83 mg) in DCM (10 mL) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 × 75 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the title compound (1.3 g, 72%). LCMS m / z = 382 [M+H] + .

[0714] Intermediate 287 / 287a / 287b

[0715]

[0716] To a stirred solution of 4-bromo-2-(methylthio)pyridine (6.0 g) in MeOH (60 mL) at rt was added (diacetoxyiodo)benzene (95.2 g) and (NH4)2CO3 (28.4 g). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 50% EtOAc / PE) to give the racemic title compound (Intermediate 287, 4.0 g, 57%). LCMS m / z = 235 [M+H] + .

[0717] The 4.0 g of the above racemic compound was separated by SFC (ChiralART Cellulose-SC, 250x30 mm, 5 μm; 10% MeOH in CO2) to obtain 1.8 g of the first eluted enantiomer of the title compound (Intermediate 287a) and 1.7 g of the second eluted enantiomer of the title compound (Intermediate 287b).

[0718] Peak 1, Intermediate 287a chiral SFC: Column: Chiralpak IC (4.6x250mm) 5μm, cosolvent: MeOH, flow rate: 3 mL / min; percentage of cosolvent: 10%; ABPR: 98 bar; T: 30 °C; R t = 13.25 min (first elution).

[0719] Peak 2, Intermediate 287b chiral SFC: Column: Chiralpak IC (4.6x250mm) 5μm, cosolvent: MeOH, flow rate: 3 mL / min; percentage of cosolvent: 10%; ABPR: 98 bar; T: 30 °C; R t = 15.35 min (second elution).

[0720] Intermediate 288

[0721] N-((4-Bromopyridin-2-yl)(methyl)(oxo)-l6-thianylidene)cyanamide

[0722]

[0723] To a stirred solution of racemic (4-bromopyridin-2-yl)(imino)(methyl)-l6-thioxanone (Intermediate 287, 500 mg) in DCM (20 mL) at 0 °C was added Et3N (430.5 mg) and cyanogen bromide (270.4 mg, 2.55 mmol). The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with Et2O (2 × 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 10 - 15% EtOAc / PE) to give the title compound (300 mg, 54%).

[0724] Intermediate 289

[0725] 2-(Ethylthio)pyridin-4-amine

[0726]

[0727] To a solution of 2-bromopyridin-4-amine (2.0 g) in DMSO (15 mL) at rt was added Cs2CO3 (9.45 g) and sodium ethanethiolate (1.2 g), and then the mixture was heated to 110 °C and maintained for 16 h. The reaction mixture was diluted with cold water (25 mL) and extracted with EtOAc (3 × 80 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and evaporated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 70% EtOAc / Hex) to give the title compound (1.4 g, 79%). LCMS m / z = 155 [M+H] + 。

[0728] Intermediate 331

[0729] The title compound was prepared from the appropriate aryl bromide and the appropriate thiolate using a method similar to that described for Intermediate 289.

[0730]

[0731] Intermediate 290a / 290b

[0732] tert-Butyl ((4-bromopyridin-2-yl)(methyl)(oxo)-l6-thianylidene)carbamate

[0733]

[0734] Part 1: 4-Bromo-2-methylthio-pyridine (100 g) was dissolved in EtOH (1.00 L) at 20 °C, and then PIDA (316 g) was added. Then, NH4OAc (151 g) was added and the mixture was stirred at 30 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was poured into 6.0 L of an aqueous sodium carbonate solution saturated with sodium chloride. Then the pH was adjusted to 7 - 8 by adding an aqueous sodium carbonate solution saturated with sodium chloride. The mixture was extracted with EtOAc (1.0 L x5). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, EtOAc / PE 1 / 50 - 100%). After concentration under reduced pressure, the residue was triturated with MTBE at 20 °C for 1 h to give 29 g of 4-bromo-2-(methylthio)pyridine (Intermediate 287).

[0735] 17.0 g of the above racemic compound was separated by SFC (Chiralpak AS, 250x50 mm, 10 μm; 20% MeOH in CO2 containing 0.1% NH3) to give 5.85 g of the first eluted enantiomer and 7.54 g of the second eluted enantiomer.

[0736] Peak 1: LCMS m / z = 235 [M+H] + ; Chiral SFC: Column: Chiralpak IG-3 (4.6x50mm) 3μm, co-solvent: MeOH containing 0.05% diethylamine, flow rate: 3 mL / min; percentage of co-solvent: 5 - 40%%; ABPR: 100 bar; T: 35 °C; R t = 1.88 min (first eluting enantiomer).

[0737] Peak 2: LCMS m / z = 235 [M+H] + ; Chiral SFC: Column: Chiralpak IG-3 (4.6x50mm) 3μm, co-solvent: MeOH containing 0.05% diethylamine, flow rate: 3 mL / min; percentage of co-solvent: 5 - 40%%; ABPR: 100 bar; T: 35 °C; R t = 2.02 min (second eluting enantiomer)

[0738] Part 2: To a stirred solution of (4-bromopyridin-2-yl)(imino)(methyl)-l6-thioxanone (first eluting enantiomer, peak 1, 10 g) in THF (150 mL) at 0 °C was added potassium tert-butoxide (1 M in THF, 51.06 mL) and Boc anhydride (19.55 mL). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with ice water and the resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 50% EtOAc / Hex) to give the title compound (intermediate 290a, 12 g, 84%). LCMS m / z = 335 [M+H] + .

[0739] Intermediate 290b was prepared using a method similar to that described for intermediate 290a using the second eluting enantiomer (i.e., peak 2 from Part 1). Yield: 1.8 g, 84%. LCMS m / z = 335 [M+H] + .

[0740] Intermediate 332

[0741] 4-Fluoro-3-(methylthio)aniline

[0742]

[0743] Part 1: A solution of 2-fluoro-5-nitroaniline (2.5 g) in dimethyldisulfide (75 mL) was heated to 100 °C, and then tert-butyl nitrite (technical grade, 90%, 2.64 mL) was added. The mixture was stirred at 100 °C for 1 h. The reaction mixture was concentrated to give a crude material, which was purified by CombiFlash column chromatography (SiO2, 2-4% EtOAc / Hex) to give 1-fluoro-2-(methylthio)-4-nitrobenzene (1.50 g, 50%).

[0744] Part 2: A solution of 1-fluoro-2-(methylthio)-4-nitrobenzene (550 mg) in ethanol (30 mL) was degassed with argon for 15 minutes, and then Pd / C (200 mg) was added at rt. The reaction mixture was stirred under H2-balloon pressure for 16 h. The reaction mixture was filtered and washed with ethanol (50 mL). The crude product was purified by CombiFlash column chromatography (SiO2, 35-45% EtOAc / Hex) to give the title compound (200 mg, 43%). LCMS m / z = 158 [M+H] + 。

[0745] Intermediate 79

[0746] 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(methylthio)pyridin-4-yl)-4- (trifluoromethyl)-1H-pyrazole-5-carboxamide

[0747]

[0748] To a solution of 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Intermediate 60, 0.64 g) in pyridine (10 mL) at 0 °C was added POCl3 (0.4 mL) and 2-(methylthio)pyridin-4-amine (0.53 g), and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with cold water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was dissolved in THF (10 mL) and 1N NaOH (4 mL), and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was diluted with cold water and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0-50% EtOAc / Hex) to give the title compound (0.8 g, 96%). LCMS m / z = 461 [M+H] + 。

[0749] Intermediates 80 - 96, 291, 293 - 295, 296 - 297, 299, 306

[0750] The title compound is prepared from the appropriate carboxylic acid and amine using a method similar to that described for Intermediate 79. Suitable conditions for hydrolysis include a NaOH concentration between 1N - 4M and a temperature of rt or 80 °C.

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759] Intermediate 298

[0760] 3-Cyclopropyl-1-(dispiro[2.0.2 4 .1 3 hept-7-ylmethyl)-N-(2-(methylthio)pyridin-4-yl)-4-(tri fluoromethyl)-1H-pyrazole-5-carboxamide

[0761]

[0762] To a solution of 3 - cyclopropyl - 1 - ({dispiro[2.0.2 4 .13]hept - 7 - yl}methyl)-4-(trifluoromethyl)-1H - pyrazole - 5 - carboxylic acid (Intermediate 249, 0.4 g) in pyridine (10 mL) was added POCl3 (0.3 mL) and 2-(methylthio)pyridin - 4 - amine (0.344 g) at 0 °C. The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure and diluted with cold water. The aqueous portion was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to give a crude product which was purified by CombiFlash column chromatography (SiO2, 0 - 40% EtOAc / Hex) to give the title compound (0.18 g, 33%). LCMS m / z = 449 [M + H] + .

[0763] Intermediates 292, 305, 307 - 309

[0764] The title compound was prepared from the appropriate carboxylic acid and amine (within an appropriate reaction time between 2 - 3 h) using a method similar to that described for Intermediate 298.

[0765]

[0766]

[0767]

[0768]

[0769]

[0770] Intermediate 310

[0771] 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(6-(methylthio)pyridazin-4-yl)-4- (trifluoromethyl)-1H-pyrazole-5-carboxamide

[0772]

[0773] To a solution of 3 - cyclopropyl - 1 - ((3,3 - difluoro - 1 - methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H - pyrazole - 5 - carboxylic acid (Intermediate 65, 200 mg) in DCM (5.0 mL) at rt was added DIPEA (0.26 mL) and HATU (340 mg), followed by 6-(methylthio)pyridazin - 4 - amine (100.0 mg). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 100% EtOAc / Hex) to give the title compound (120 mg, 44%). LCMS m / z = 462 [M + H] + .

[0774] Intermediate 311

[0775] The title compound was prepared from the appropriate carboxylic acid and the appropriate amine using a method similar to that described for Intermediate 310.

[0776]

[0777] Intermediate 312

[0778] 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-methyl-6-(methylthio)pyridin-4- yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0779]

[0780] At rt, to a solution of 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (Intermediate 65, 0.44 g) in MeCN (5 mL) was added 2-methyl-6-(methylthio)pyridin-4-amine (Intermediate 331, 0.2 g), TCFH (581 mg) and DIPEA (1.35 mL). The resulting reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with cold water (20 mL) and extracted with EtOAc (2 × 70 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 10% EtOAc / Hex) to give the title compound (0.16 g, 26%). LCMS m / z = 475 [M+H] + 。

[0781] Intermediate 313

[0782] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(4-fluoro-3-(methylthio)phenyl)-3-(1-fluorocyclopropyl yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0783]

[0784] To a stirred solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 262, 240 mg) in 1,4-dioxane (10 mL) in a sealed tube was added (5-bromo-2-fluorophenyl)(methyl)sulfane (164.22 mg), K2CO3 (111.87 mg) and CuI (12.8 mg). The mixture was degassed with argon for 10 min. Then DMEDA (11.9 mg) was added to the reaction mixture at rt and the mixture was degassed again for 5 min. The resulting reaction mixture was heated to 100 °C and maintained for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL) and filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give a crude product, which was dissolved in EtOAc (30 mL). The organic portion was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, 20-25% EtOAc / PE) to give the title compound (220 mg, 66%). LCMS m / z = 496 [M+H] + 。

[0785] Intermediates 314 - 317

[0786] The title compound was prepared from the appropriate amide and aryl bromide (at an appropriate reaction temperature between 90 - 100 °C) using a method similar to that described for Intermediate 313.

[0787]

[0788]

[0789] Intermediate 318

[0790] 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(5-(methylthio)pyridin-3-yl)-4- (trifluoromethyl)-1H-pyrazole-5-carboxamide

[0791]

[0792] A solution of 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (350 mg, 1.04 mmol), 3-bromo-5-(methylthio)pyridine (252 mg), and Cs2CO3 (1.1 g) in 1,4-dioxane (25 mL) was degassed with argon for 15 min, then CuI (99 mg) and trans-1,2-diaminocyclohexane (60 mg) were added at rt. The reaction mixture was heated to 90 °C and maintained for 16 h. The reaction mixture was cooled to rt, filtered through Celite, and the Celite bed was washed with EtOAc (50 mL). The filtrate was diluted with water (75 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and the solvent was evaporated under reduced pressure to give a crude product, which was purified by reverse-phase preparative HPLC to give the title compound (320 mg, 66%). LCMS m / z = 461 [M+H] + 。

[0793] Intermediate 319

[0794] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(methylthio)phenyl)-4- (Trifluoromethyl)-1H-pyrazole-5-carboxamide

[0795]

[0796] To a stirred solution of methyl 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxylate (Intermediate 174, 300 mg) and 3-(methylthio)aniline (112.79 mg) in THF (10 mL) at -78 °C was added KHMDS (1.2 mL) in 1 M in THF. The reaction mixture was stirred at 78 °C for 0.5 h. The reaction mixture was quenched with saturated NH4Cl solution (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was triturated with pentane, filtered off and dried under reduced pressure to give the title compound (280 mg, 72%). LCMS m / z = 478 [M+H] + 。

[0797] Intermediates 320 - 326

[0798] The title compound was prepared from the appropriate ester and amine using a method similar to that described for Intermediate 319 (at a suitable reaction time of 0.5 - 1 h).

[0799]

[0800]

[0801]

[0802] Intermediates 327a / 327b

[0803] 3-Cyclopropyl-1-((6,6-difluoro-4-methylspiro[2.3]hexan-4-yl)methyl)-N-(2-(methylthio)pyridin-4- yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0804]

[0805] To a stirred solution of 3-cyclopropyl-1-({6,6-difluoro-4-methylspiro[2.3]hexan-4-yl}methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 272, 1.0 g) in 1,4-dioxane (30 mL) was added 4-iodo-2-(methylthio)pyridine (1.0 g) and Cs2CO3 (1.8 g). The reaction mixture was degassed with argon for 10 min. Then, Brettphos-Pd-G3 (0.3 g) was added and the mixture was heated to 110 °C in a sealed tube and maintained for 16 h. The reaction mixture was cooled to rt, filtered through a bed of diatomaceous earth, and the diatomaceous earth bed was washed with 10% MeOH in DCM. The filtrate was concentrated to give the crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 50% EtOAc / Hex), followed by purification by chiral SFC to give the title compound.

[0806] Chiral-SFC (C-amylose-A, 250x30 mm, 5 μm; 20% hexane / iPrOH 60 / 40 in CO2 containing 0.1% iPrNH2)

[0807] Peak 1, Intermediate 327a (0.285 g, 21%). LCMS m / z = 487 [M+H] + ; Chiral SFC: Column: C-Amylose-A (4.6x250 mm) 5 μm, Mobile phase: (hexane / iPrOH 60 / 40 containing 0.1% iPrNH2), Flow rate: 3 mL / min; Percentage of cosolvent: 20%; ABPR: 1500 psi; T: 35 °C; R t = 3.14 min (first elution).

[0808] Peak 2, Intermediate 327b (0.19 g, 19%). LCMS m / z = 473 [M+H] + ; Chiral SFC: Column: C-Amylose-A (4.6x250 mm) 5 μm, Mobile phase: (hexane / iPrOH 60 / 40 containing 0.1% iPrNH2), Flow rate: 3 mL / min; Percentage of cosolvent: 20%; ABPR: 1500 psi; T: 35 °C; R t = 3.71 min (second elution)

[0809] Intermediate 328

[0810] The title compound was prepared from the appropriate amide and aryl iodide using a method similar to that described for Intermediate 327.

[0811]

[0812] Intermediate 329a / 329b

[0813] 1-((2-Acetyl-2-azaspiro[3.3]heptan-5-yl)methyl)-3-cyclopropyl-N-(2-(methylthio)pyridin-4- yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0814]

[0815] Part 1: To a stirred solution of tert-butyl 5-[(3-cyclopropyl-5-{[2-(methylthio)pyridin-4-yl]carbamoyl}-4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl]-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 328, 0.8 g) in DCM (20 mL) at 0 °C was added TFA in DCM (20 mL, 4 M). The reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to give a crude mixture, which was basified with saturated K2CO3 solution and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with cold brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to give 1-({2-azaspiro[3.3]hept-5-yl}methyl)-3-cyclopropyl-N-[2-(methylthio)pyridin-4-yl]-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (0.55 g, 84%). LCMS m / z = 452 [M+H] + 。

[0816] Part 2: To a stirred solution of 1-({2-azaspiro[3.3]hept-5-yl}methyl)-3-cyclopropyl-N-[2-(methylthio)pyridin-4-yl]-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (0.6 g) in DCM (25 mL) at 0 °C was added TEA (0.4 mL) and acetyl chloride (0.2 mL). The resulting mixture was stirred at rt for 16 h. The reaction mixture was diluted with ice water and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0 - 100% EtOAc / Hex), followed by purification by chiral SFC to give the title compound.

[0817] Chiral-SFC (Chiralpak IG, 250x30 mm, 5 μm; 30% iPrOH in CO2)

[0818] Peak 1, Intermediate 329a (0.12 g, 18%). LCMS m / z = 494 [M+H] +; Chiral SFC: Column: Chiralpak IG (4.6 x 250 mm) 5 μm, mobile phase: iPrOH containing 0.5% iPrNH2, flow rate: 3 mL / min; percentage of cosolvent: 40%; ABPR: 1500 psi; T: 35 °C; R t = 1.81 min (first elution).

[0819] Peak 2, Intermediate 329b (0.17 g, 25%). LCMS m / z = 494 [M+H] + ; Chiral SFC: Column: Chiralpak IG (4.6 x 250 mm) 5 μm, mobile phase: iPrOH containing 0.5% iPrNH2, flow rate: 3 mL / min; percentage of cosolvent: 40%; ABPR: 1500 psi; T: 35 °C; R t = 2.04 min (second elution)

[0820] Example 1a / 1b

[0821] 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide synthesized in the following form: Enantiomer 1 (1a) of 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide and Enantiomer 2 (1b) of 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0822]

[0823] Part 1. To a stirred solution of 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 79, 0.8 g) in MeOH (25 mL) was added diacetoxyiodobenzene (5.59 g) and ammonium carbonate (1.66 g), and the mixture was stirred for 2 h. The reaction mixture was washed with water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with cold brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 100% EtOAc / Hex) to give (rac)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide.

[0824] Part 2. (rac)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Part 1) was separated by chiral HPLC (Chiralpak IC, 250 x 21 mm, 5 μm; 80 / 10 / 10 hexane / DCM / EtOH) to give:

[0825] Peak 1, Example 1a (0.16 g, 19%). LCMS m / z = 492 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.73 (s, 1H), 8.66 (d, 1H), 8.36 (s, 1H), 7.79 - 7.77 (m, 1H), 4.42 (s, 1H), 4.17 (s, 2H), 3.15 (s, 3H), 2.78 - 2.67 (m, 2H), 2.33 - 2.24 (m, 2H), 1.96 - 1.93 (m, 1H), 1.05 (s, 3H), 1.00 - 0.96 (m, 2H), 0.86 - 0.82 (m, 2H). Chiral HPLC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm, Mobile phase: hexane / DCM / EtOH / iPrNH2 60 / 20 / 20 / 0.1, Flow rate: 1.0 mL / min, R t = 4.74 min (first elution).

[0826] Peak 2, Example 1b (0.15 g, 17%). LCMS m / z = 492 [M+H] + ; 11H-NMR (400 MHz, DMSO-d6): 11.73 (s, 1H), 8.66 (d, 1H), 8.36 (s, 1H), 7.79 - 7.77 (m, 1H), 4.42 (s, 1H), 4.17 (s, 2H), 3.15 (s, 3H), 2.78 - 2.66 (m, 2H), 2.33 - 2.24 (m, 2H), 1.96 - 1.93 (m, 1H), 1.05 (s, 3H), 1.00 - 0.96 (m, 2H), 0.86 - 0.84 (m, 2H). Chiral HPLC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm, Mobile phase: hexane / DCM / EtOH / iPrNH2 60 / 20 / 20 / 0.1, Flow rate: 1.0 mL / min, R t = 5.47 min (second elution).

[0827] Examples 3 - 31, 46 - 48, 50, 64 - 65, 68 - 69, 71, 75, 78 - 80, 96, 92, 98, 103, 111, 113, 126 - 127, 130 - 141.

[0828] Using a method similar to that described for Example 1 (at a suitable reaction time between 0.5 - 16 hours and a suitable reaction temperature between 0 °C and rt), with or without chiral separation as part 2, prepare the title compound from the appropriate arylthioalkyl (ArSMe) or alkylthioaryl (ArS-alkyl).

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881] Example 33

[0882] 1-((3,3-Difluorocyclopentyl)methyl)-3-(difluoromethoxy)-N-(2-(S-methylsulfinimidoyl)pyridin- 4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0883]

[0884] The title compound (25 mg, 31%) was prepared from 1-((3,3-difluorocyclopentyl)methyl)-3-(difluoromethoxy)-N-(2-(methylthio)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 83) using a method similar to that described for Example 1. LCMS m / z = 418 [M+H] + ; 11H-NMR (400 MHz, DMSO-d6): 11.87 (s, 1H), 8.68 (d, 1H), 8.36 (s, 1H), 7.78 (d, 1H), 7.50 (t, 1H), 4.44 (s, 1H), 4.17 (d, 2H), 3.16 (s, 3H), 2.67 - 2.50 (m, 1H), 2.18 - 1.96 (m, 6H), 1.56 - 1.51 (m, 1H).

[0885] Example 34a / 34b

[0886] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N- (2-(N,S-dimethylsulfinimidoyl)pyridin-4-yl)-4-methyl-1H-pyrazole-5-carboxamide synthesized in the following form: Enantiomer 1 (34a) of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(N,S-dimethylsulfinimidoyl)pyridin-4-yl)-4-methyl- 1H-pyrazole-5-carboxamide and enantiomer 2 (34b) of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(N,S-dimethylsulfinimidoyl)pyridin-4-yl)-4-methyl- 1H-pyrazole-5-carboxamide 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(2- (S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide synthesized in the following form: Enantiomer 2 (70b) of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-

[0887]

[0888] Part 1. To a stirred solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(methylthio)pyridin-4-yl)-1H-pyrazole-5-carboxamide (Intermediate 84, 0.30 g) in MeOH (10 mL) at rt was added diacetoxyiodobenzene (2.25 g) and ammonium carbonate (0.672 g), and the mixture was stirred for 2 h. The reaction mixture was washed with water and extracted with EtOAc (3 x 100 mL). The combined organics were washed with cold brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 50% EtOAc / Hex) to give 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide (105 mg, 32%). LCMS m / z = 462 [M+H] + 。

[0889] Part 2. To a stirred solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide (0.17 g) in dioxane (10 mL) was added pyridine (0.07 mL) and methylboronic acid (0.04 g), and the mixture was degassed with O2 for 15 min, then Cu(OAc)2 (0.1 g) was added and then heated at 100 °C in a sealed tube for 4 h. The reaction mixture was cooled and filtered through celite, and the filtrate was diluted with ice water and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by CombiFlash chromatography (SiO2, 0 - 5% MeOH / DCM), followed by purification by chiral HPLC (Chiralpak IC, 250 x 20 mm, 5 μm; 70 / 15 / 15 / 0.1 Hex / EtOAc / EtOH / iPrNH2) to give:

[0890] Peak 1, Example 34a (20 mg, 11%). LCMS m / z = 476 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.28 (s, 1H), 8.69 (d, 1H), 8.39 (s, 1H), 7.85 - 7.84 (m, 1H), 4.36 (s, 2H), 3.18 (s, 3H), 2.73 - 2.66 (m, 2H), 2.32 - 2.28 (m, 2H), 2.23 (s, 3H), 2.08 - 1.98 (m, 3H), 1.07 (s, 3H). Chiral HPLC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm, Mobile phase: hexane / DCM / EtOH / iPrNH2 60 / 20 / 20 / 0.1, Flow rate: 1.0 mL / min, R t = 4.28 min (first elution).

[0891] Peak 2, Example 34b (12 mg, 7%). LCMS m / z = 476 [M+H] + ; 11H-NMR (400 MHz, DMSO-d6): 11.28 (s, 1H), 8.69 (d, 1H), 8.39 (s, 1H), 7.85 - 7.84 (m, 1H), 4.36 (s, 2H), 3.18 (s, 3H), 2.73 - 2.66 (m, 2H), 2.32 - 2.28 (m, 2H), 2.23 (s, 3H), 2.08 - 1.98 (m, 3H), 1.07 (s, 3H). Chiral HPLC: Column: Chiralpak IC (4.6 x 250 mm) 5 μm, Mobile phase: hexane / DCM / EtOH / iPrNH2 60 / 20 / 20 / 0.1, Flow rate: 1.0 mL / min, R t = 5.64 min (second elution).

[0892] Examples 36 - 39.

[0893] The title compounds were prepared from the appropriate methylthio pyridines (ArSMe) using a method similar to that described for Example 34.

[0894]

[0895]

[0896] Example 70b

[0897] 1H-pyrazole-5-carboxamide 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3- (S-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide synthesized in the following form: Enantiomer 1 (109a) of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5- carboxamide and enantiomer 2 (109b) of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-

[0898]

[0899] To a stirred solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 262, 250 mg) in 1,4-dioxane (10 mL) was added (4-bromopyridin-2-yl)(imino)(methyl)-l6-thiirane (Intermediate 287b) (199 mg) and cesium carbonate (573 mg). The mixture was degassed with argon for 10 minutes. Then trans-N,N'-dimethylcyclohexane-1,2-diamine (30 mg) and Cu(I) trifluoromethanesulfonate benzene complex (44 mg) were added to the reaction mixture at rt, and the mixture was degassed again for 5 minutes. The resulting reaction mixture was heated to 100 °C and maintained for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (15 mL) and filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give a crude product, which was dissolved in EtOAc (50 mL). The organic layer was washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound.

[0900] Peak 2, Example 70b (75 mg, 21%). LCMS m / z = 510 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.85 (s, 1H), 8.67 (d, 1H), 8.37 (s, 1H), 7.79 (d, 1H), 4.43 (s, 1H), 4.29 (s, 2H), 3.16 (s, 3H), 2.81–2.67 (m, 2H), 2.38–2.29 (m, 2H), 1.53–1.44 (m, 2H), 1.21–1.15 (m, 2H), 1.09 (s, 3H); Chiral SFC: Column: (R,R)Whelk-01 (150 x 4.6 mm, 3.5 μm); Cosolvent: MeOH, Flow rate: 3 mL / min; Percentage of cosolvent: 20%; ABPR: 1500 psi; T: 30 °C; R t = 2.24 min (second elution).

[0901] Examples 29, 56 - 59, 61 - 63, 70a, 95, 142 - 145.

[0902] The title compound was prepared using a method similar to that described for Example 70b, with or without chiral separation, from the appropriate amide and aryl bromide (at a suitable reaction time between 12 - 16 hours and a suitable reaction temperature between 80 - 100 °C).

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915] Example 109a / 109b

[0916] (3-(S-methylsulfinimidoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-methoxybicyclo[1.1.1]pent-1-yl)-N-(2- ​ ​ ​

[0917]

[0918] To a stirred solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(methylthio)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 319, 260 mg) in MeOH (10 mL) at rt was added diacetoxyiodobenzene (0.877 g) and ammonium carbonate (0.478 g). The resulting reaction mixture was stirred at rt under an argon atmosphere for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was triturated with pentane, filtered and dried under reduced pressure to give the racemic title compound (240 mg, 87%).

[0919] By chiral-SFC: Chiral ART Cellulose-SC (250×30 mm, 5 μm), 10% iPrOH in CO2 purified residue, obtained:

[0920] Peak 1, Example 109a (100 mg, 36%). LCMS m / z = 509 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.43 (s, 1H), 8.29 (t, 1H), 7.89 - 7.86 (m, 1H), 7.74 (d, 1H), 7.63 (t, 1H), 4.27 (s, 3H), 3.07 (s, 3H), 2.82–2.65 (m, 2H), 2.40–2.28 (m, 2H), 1.52–1.44 (m, 2H), 1.21–1.15 (m, 2H), 1.10 (s, 3H), chiral SFC: column: Chiralpak IC 250x4.6 mm, 5 μm; co-solvent: iPrOH, flow rate: 3 mL / min; percentage of co-solvent: 10%; ABPR: 1500 psi; T: 30 °C; R t = 4.57 min (first elution).

[0921] Peak 2, Example 109b (75 mg, 27%). LCMS m / z = 509 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.43 (s, 1H), 8.29 (t, 1H), 7.89–7.86 (m, 1H), 7.76–7.73 (m, 1H), 7.63 (t, 1H), 4.27 (s, 3H), 3.07 (s, 3H), 2.82–2.66 (m, 2H), 2.38–2.28 (m, 2H), 1.52–1.40 (m, 2H), 1.20–1.16 (m, 2H), 1.10 (s, 3H), chiral SFC: column: Chiralpak IC 250x4.6 mm, 5 μm; co-solvent: iPrOH, flow rate: 3 mL / min; percentage of co-solvent: 10%; ABPR: 1500 psi; T: 30 °C; R t = 6.78 min (second elution).

[0922] Example 122

[0923] ​ (S-Methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0924]

[0925] To a solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(3-methoxybicyclo[1.1.1]pent-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 267, 60 mg) and racemic (4-bromopyridin-2-yl)(imino)(methyl)-l6-thiiranone (Intermediate 287, 43.03 mg) in 1,4-dioxane (5 mL) was added CuI (2.89 mg) and potassium carbonate (31.57 mg), and the mixture was degassed with argon for 10 min. Then DMEDA (2.68 mg) was added to the reaction mixture, and the mixture was degassed again for 5 min. The resulting reaction mixture was heated to 90 °C and maintained for 16 h. The reaction mixture was cooled to rt, diluted with EtOAc (10 mL) and filtered through a pad of diatomaceous earth. The filtrate was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (4 mg, 3% over 3 steps).

[0926] Example 122 (4 mg, 3% over three steps). LCMS m / z = 548 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.77 (s, 1H), 8.65 (d, 1H), 8.35 (s, 1H), 7.77 (d, 1H), 4.42 (s, 1H), 4.22 (s, 2H), 3.25 (s, 3H), 3.15 (s, 3H), 2.85–2.65 (m, 2H), 2.40–2.25 (m, 2H), 2.20 (s, 6H), 1.10 (s, 3H).

[0927] Examples 144, 146 - 147.

[0928] The title compounds were prepared from the appropriate amides and aryl bromides using a method similar to that described for Example 122.

[0929]

[0930]

[0931] Example 148a

[0932] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2-fluoropropan-2-yl)-N-(2- (S-Methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide: 1-((3,3-Difluoro-1-methyl cyclobutyl)methyl)-3-(2-fluoropropan-2-yl)-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl )-1H-pyrazole-5-carboxamide enantiomer 1 (148a)

[0933]

[0934] To a stirred solution of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(2-fluoropropan-2-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Intermediate 271, 200 mg) in 1,4-dioxane (20 mL) was added (4-bromopyridin-2-yl)(imino)(methyl)-l6-thianone (Intermediate 287a, 157.92 mg), CuI (10.64 mg and K2CO3 (84.97 mg), and the mixture was degassed with argon for 10 minutes. Then DMEDA (9.852 mg) was added to the reaction mixture at rt. The resulting reaction mixture was then heated to 100 °C and maintained for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (100 mg, 35%).

[0935] Peak 1, Example 148a LCMS m / z = 512 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.81 (bs, 1H), 8.67 (d, 1H), 8.36 (d, 1H), 7.79 (dd, 1H), 4.42 (s, 1H), 4.24 (s, 2H), 3.15 (s, 3H), 2.84–2.67 (m, 2H), 2.39–2.27 (m, 2H), 1.75 (s, 3H), 1.69 (s, 3H), 1.09 (s, 3H), chiral SFC: column: Chiralpak IC (250x4.6 mm, 5 μm); co-solvent: MeOH; flow rate: 3 mL / min; percentage of co-solvent: 10%; ABPR: 1500 psi; T: 30 °C; R t = 3.38 min (first elution).

[0936] Example 110, 148b.

[0937] The title compound was prepared from the appropriate amide and aryl bromide (under a heating time of 3 - 16 h) using a method similar to that described for Example 148a.

[0938]

[0939]

[0940]

[0941] Example 150a

[0942] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3- (S-Methyl-N-(oxetan-3-carbonyl)iminosulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methyl-N-(oxetan-3- carbonyl)iminosulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide enantiomer 1 (150a)

[0943]

[0944] To a stirred solution of oxetan-3-carboxylic acid (20.078 mg) in DMF (10 mL) at rt was added HATU (112.17 mg) and DIPEA (0.103 mL), followed by the addition of 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Example 109b, 100 mg), and the mixture was stirred for 2 h. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (25 mL) and brine (25 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by preparative HPLC to give the title compound (19 mg, 16%).

[0945] Peak 1, Example 150a (19 mg, 16%). LCMS m / z = 593 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.54 (s, 1H), 8.33 (s, 1H), 7.92 (d, 1H), 7.80–7.69 (m, 2H), 4.75–4.55 (m, 4H), 4.27 (s, 2H), 3.90–3.75 (m, 1H), 3.49 (s, 3H), 2.85–2.70 (m, 2H), 2.40–2.25 (m, 2H), 1.55–1.40 (m, 2H), 1.20–1.13 (m, 2H), 1.10 (s, 3H); Chiral SFC: column: Chiralpak OX-H (250x4.6 mm, 5 μm); co-solvent: MeOH containing 0.5% iPrNH2; flow rate: 3 mL / min; percentage of co-solvent: 20%; ABPR: 1500 psi; T: 30 °C; R t = 2.19 min (first elution).

[0946] Example 150b.

[0947] The title compound was prepared from the appropriate sulfoximine using a method similar to that described for Example 150a.

[0948]

[0949] Example 151a / 151b

[0950] 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3- (N-(2-Hydroxyacetyl)-S-methyliminosulfonyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide: 1-((3, 3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(N-(2-hydroxyacetyl)-S-methyliminosulf onyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide enantiomer 1 (151a) and 1-((3,3-Difluoro-1- methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(N-(2-hydroxyacetyl)-S-methyliminosulfonyl)benz yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide enantiomer 2 (151b)

[0951]

[0952] Part 1: To a stirred solution of 2-((tert-butyldiphenylsilyl)oxy)acetic acid (500 mg) in DMF (5 mL) at 0 °C was added DIPEA (0.83 mL) and HATU (900 mg). The resulting reaction mixture was stirred at 0 °C for 10 min. Then 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Example 109, 800 mg) was added at 0 °C. The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give N-(3-(N-(2-((tert-butyldiphenylsilyl)oxy)acetyl)-S-methylsulfinyl)phenyl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (550 mg, 43%).

[0953] Part 2: To a stirred solution of N-(3-(N-(2-((tert-butyldiphenylsilyl)oxy)acetyl)-S-methylsulfinyl)phenyl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (500 mg) in THF (5 mL) at 0 °C was added TBAF in THF (1 M, 2 mL). Then the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was separated and purified by preparative HPLC to give the racemic title compound (130 mg, 36%).

[0954] Purify the residue by chiral-SFC: Cellulose-4 (250×30 mm, 5 μm), 10% MeOH in CO2 to obtain:

[0955] Peak 1, Example 151a (35 mg, 9%). LCMS m / z = 567 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.53 (s, 1H), 8.28 (s, 1H), 7.96 (d, 1H), 7.77–7.68 (m, 2H), 4.78 (t, 1H), 4.28 (s, 2H), 3.94 (d, 2H), 3.47 (s, 3H), 2.83–2.73 (m, 2H), 2.39–2.27 (m, 2H), 1.53–1.43 (m, 2H), 1.24–1.14 (m, 2H), 1.10 (s, 3H); Chiral SFC: Column: Chiracel OX-H 150x4.6 mm, 5 μm; Cosolvent: MeOH, Flow rate: 3 mL / min; Percentage of cosolvent: 15%; ABPR: 1500 psi; T: 30 °C; R t = 2.30 min (first elution).

[0956] Peak 2, Example 151b (45 mg, 12%). LCMS m / z = 567 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.53 (s, 1H), 8.27 (s, 1H), 7.98–7.91 (m, 1H), 7.78–7.64 (m, 2H), 4.78 (t, 1H), 4.28 (s, 2H), 3.95 (d, 2H), 3.47 (s, 3H), 2.83–2.73 (m, 2H), 2.38–2.27 (m, 2H), 1.51–1.42 (m, 2H), 1.24 - 1.14 (m, 2H), 1.05 (s, 3H); Chiral SFC: Column: Chiracel OX-H 150x4.6 mm, 5 μm; Cosolvent: MeOH, Flow rate: 3 mL / min; Percentage of cosolvent: 15%; ABPR: 1500 psi; T: 30 °C; R t = 2.94 min (second elution).

[0957] Example 152

[0958] 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(N-((R)-2,3-dihydroxyprop yl)-S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide

[0959]

[0960] Part 1: To a solution of racemic 3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (Example 1, 80 mg) in 2-MeTHF (7.0 mL) was added (R)-trimethyl(oxiran-2-ylmethoxy)silane (119 mg) and Ca(NTf2)2 (49 mg). The reaction mixture was heated to 70 °C and maintained for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by reverse-phase preparative HPLC to give the title compound (17 mg, 18%).

[0961] Example 152 LCMS m / z = 566 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 11.75 (s, 1H), 8.69 (d, 1H), 8.31 (s, 1H), 7.80 (d, 1H), 4.14 (s, 2H), 3.69 (s, 1H), 3.19 - 3.17 (m, 2H), 2.70 - 2.50 (m, 2H), 2.33 - 2.26 (m, 3H), 1.93 (s, 1H), 1.26 - 1.14 (m, 6H), 1.04 - 0.96 (m, 2H), 0.83 - 0.73 (m, 4H).

[0962] Example 153a / 153b / 153c / 153d

[0963] 1-((2-Azaspiro[3.3]hept-5-yl)methyl)-3-cyclopropyl-N-(2-(S-methyl iminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide: 1-((2-azaspiro[3.3]hept-5-yl) methyl)-3-cyclopropyl-N-(2-(S-methyliminosulfonyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carbox Diastereomer 1 of the amine (153a), 1-((2-azaspiro[3.3]heptan-5-yl)methyl)-3-cyclopropyl-N-(2-(S-methyl sulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide, Diastereomer 2 (153b), 1- ((2-azaspiro[3.3]heptan-5-yl)methyl)-3-cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(tri fluoromethyl)-1H-pyrazole-5-carboxamide, Diastereomer 3 (153c), and Diastereomer 4 (153d) of 1-((2-azaspiro[3.3]heptan-5-yl)meth yl)-3-cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide Electrophysiology: Voltage-clamp recordings

[0964]

[0965] Part 1: To a stirred solution of tert-butyl 5-{[5-carbamoyl-3-cyclopropyl-4-(trifluoromethyl)-1H-pyrazol-1-yl]methyl}-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 275, 0.5 g) in 1,4-dioxane (15 mL) was added tert-butyl ((4-bromopyridin-2-yl)(methyl)(oxo)-l6-thioxo)carbamate (Intermediate 290b, 0.5 g) and Cs2CO3 (0.42 g). The reaction mixture was purged with argon for 10 min, followed by the addition of CuI (0.022 g) and DMEDA (0.033 g) at rt. The reaction mixture was heated to 110 °C in a sealed tube and maintained for 8 h. The reaction mixture was cooled to rt and filtered through a bed of diatomaceous earth. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by CombiFlash column chromatography (SiO2, 0-80% EtOAc / Hex) and chiral NP purification to give tert-butyl 5-((5-((2-(N-(tert-butoxycarbonyl)-S-methylsulfinyl)pyridin-4-yl)carbamoyl)-3-cyclopropyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate, which was separated into individual diastereoisomers by chiral HPLC.

[0966] Chiral HPLC (Chiralpak IG 250x30 mm, 5 μm; Hex / EtOH 80 / 20)

[0967] Peak 1, Intermediate 330a (0.34 g, 42%). LCMS m / z = 683 [M+H] + ; Chiral HPLC: Column: Chiralpak IG (250x4.6 mm, 5 μm); Mobile phase: Hexane / EtOH / iPrNH2 70 / 30 / 0.1, Flow rate: 1.0 mL / min; R t = 6.24 min (first elution).

[0968] Peak 2, Intermediate 330b (0.27 mg, 33%). LCMS m / z = 683 [M+H] + ; Chiral HPLC: Column: Chiralpak IG (250x4.6 mm, 5 μm); Mobile phase: Hexane / EtOH / iPrNH2 70 / 30 / 0.1, Flow rate: 1.0 mL / min; R t = 7.91 min (second elution).

[0969] Intermediates 330c / 330d were prepared using a method similar to that described for Intermediate 330a / 330b using Intermediate 290a from Part 1.

[0970] Chiral HPLC (Chiralpak IG 250x30mm, 5μm; Hex / EtOH 90 / 10)

[0971] Peak 1, Intermediate 330c (0.256 g, 33%). LCMS m / z = 683 [M+H] + ; Chiral HPLC: Column: Chiralpak IG (250x4.6mm, 5μm); Mobile phase: Hexane / EtOH / iPrNH2 70 / 30 / 0.1, Flow rate: 1.0 mL / min; R t = 5.70 min (first elution).

[0972] Peak 2, Intermediate 330d (0.245 mg, 30%). LCMS m / z = 683 [M+H] + ; Chiral HPLC: Column: Chiralpak IG (250x4.6mm, 5μm); Mobile phase: Hexane / EtOH / iPrNH2 70 / 30 / 0.1, Flow rate: 1.0 mL / min; R t = 6.43 min (second elution).

[0973] Part 2: To a stirred solution of tert-butyl 5-((5-((2-(N-(tert-butoxycarbonyl)-S-methylsulfinimidoyl)pyridin-4-yl)carbamoyl)-3-cyclopropyl-4-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 330a, 0.15 g) in DCM (10 mL) at 0 °C was added TFA (4 M in DCM; 5 mL). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was basified with saturated NaHCO3 solution and extracted with EtOAc (3 x 80 mL). The combined organic portions were washed with cold brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to give a crude product, which was purified by RP preparative HPLC to give the title compound (153a).

[0974] Example 153a (17 mg, 16%). LCMS m / z = 483 [M+H] + ; 1H-NMR (400 MHz, DMSO-d6): δ 8.64 - 8.63 (m, 1H), 8.43 (s, 1H), 7.83 - 7.82 (m, 1H), 4.40 - 4.35 (m, 1H), 4.18 - 4.13 (m, 1H), 4.09 - 4.07 (m, 1H), 3.68 - 3.66 (m, 1H), 3.60 - 3.55 (m, 2H), 3.27 (s, 3H), 2.84 - 2.80 (m, 1H), 2.18 - 2.12 (m, 2H), 2.02 - 1.99 (m, 1H), 1.91 - 1.90 (m, 1H), 1.66 - 1.64 (m, 1H), 1.00 - 0.91 (m, 4H).

[0975] Example 153b was prepared using Intermediate 330b by a method similar to the method described for Part 2 of Example 153a.

[0976] Example 153b (16 mg, 15%). LCMS m / z = 483 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6): δ 8.58 - 8.57 (m, 1H), 8.33 (s, 1H), 7.69 - 7.68 (m, 1H), 4.31 - 4.30 (m, 1H), 4.13 - 4.08 (m, 1H), 3.81 - 3.74 (m, 4H), 3.14 (s, 3H), 2.66 - 2.65 (m, 1H), 1.98 - 1.92 (m, 3H), 1.77 - 1.76 (m, 1H), 1.57 - 1.52 (m, 1H), 0.95 - 0.84 (m, 4H).

[0977] Example 153c was prepared using Intermediate 330c by a method similar to the method described for Part 2 of Example 153a.

[0978] Example 153c (24 mg, 22%). LCMS m / z = 483 [M+H] + ; 1 H-NMR (400 MHz, DMSO-d6): δ 8.58 - 8.57 (m, 1H), 8.33 (s, 1H), 7.71 - 7.70 (m, 1H), 4.31 - 4.24 (m, 1H), 4.13 - 4.08 (m, 2H), 3.74 - 3.73 (m, 1H), 3.41 - 3.40 (m, 2H), 3.14 (s, 3H), 2.66 - 2.65 (m, 1H), 1.98 - 1.92 (m, 3H), 1.76 - 1.74 (m, 1H), 1.56 - 1.52 (m, 1H), 0.95 - 0.84 (m, 4H).

[0979] Example 153d was prepared using Intermediate 330d by a method similar to the method described for Part 2 of Example 153a.

[0980] Example 153d (18 mg, 17%). LCMS m / z = 483 [M+H] + ; 1 1H-NMR (400 MHz, DMSO-d6): 8.58 - 8.57 (m, 1H), 8.33 (s, 1H), 7.71 - 7.70 (m, 1H), 4.31 - 4.24 (m, 1H), 4.13 - 4.08 (m, 2H), 3.74 - 3.73 (m, 2H), 3.41 - 3.34 (m, 2H), 3.14 (s, 3H), 2.66 - 2.65 (m, 1H), 1.98 - 1.92 (m, 3H), 1.76 - 1.74 (m, 1H), 1.56 - 1.52 (m, 1H), 0.95 - 0.84 (m, 4H).

[0981] Example 114

[0982] The title compound was prepared from the appropriate amide and aryl bromide by a method similar to the method described for Example 153.

[0983]

[0984] The following exemplary embodiments can be synthesized according to a general protocol and similarly to the above synthetic procedures:

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994] ​

[0995] Using the following NaV 1.8 Recombinant cell lines were recorded: HEK-Na V 1.8 (NM_006514.1) and b3 (NM_018400.3).

[0996] The sodium current was measured in whole-cell configuration using the patch-clamp technique with the Qube384 (Sophion A / S, Copenhagen, Denmark) automated voltage-clamp platform. For cell lines expressing Na V 1.8, a "multi-well" plate was used, while for recombinant cell lines expressing other subtypes, a "single-well" plate was used. Appropriate filters (for minimum seal resistance and minimum current magnitude) and series resistance compensation (for high-quality sodium channel recordings) were applied. Data were collected at ambient room temperature or 19 °C.

[0997] The extracellular recording solution contained (in mM): NaCl 145 mM, KCl 4 mM, CaCl2 2 mM, MgCl2 1 mM, HEPES 10 mM, glucose 10 mM, pH 7.4 (NaOH). The intracellular recording solution contained (in mM): CsF 120 mM, CsCl 20 mM, NaCl 10 mM, EGTA 10 mM, HEPES 10 mM, pH 7.2 (CsOH). Currents were recorded at a sampling frequency of 25 kHz and filtered at 5 kHz. Series resistance compensation was applied at 65%.

[0998] Vehicle (VEH) was the control condition where cells were exposed to 0.3% DMSO without compound. All runs included a VEH control that was exposed to the same voltage protocol to assess non-compound-related phenomena (such as run-down) and then used to isolate the compound-dependent effects on current.

[0999] To examine state-dependent inhibition, the following voltage sequence was applied every 20 seconds:

[1000] Starting from a resting membrane potential of -120 mV, a first test pulse (P1; 20 ms to -10 mV) was applied to examine channels in the resting state, followed by a brief recovery (100 ms to -120 mV), and then the membrane voltage was held at V 1 / 2 (Voltage held for 4 seconds to obtain half resting channels and half inactivated channels), followed by a second test pulse (P2; 20 ms to -10 mV) to examine channels in the inactivated state, followed by another brief recovery (20 ms to -120 mV) and a final third test pulse (P3; 20 ms to -10 mV) to examine recovered channels.

[1001] To examine frequency-dependent inhibition, a 10 Hz protocol and a 20 Hz protocol were applied; i.e.,

[1002] Starting from a resting membrane potential of -120 mV, 40 pulses (10 ms to -10 mV) were applied at 10 Hz (pulse interval 100 ms) and then at 20 Hz (pulse interval 50 ms).

[1003] During a control period (lasting approximately 5 minutes) to establish a baseline and during a compound period (lasting approximately 12 minutes) when the test compound (or vehicle) was applied, each parameter (P1, P2, P3, P40 from 10 Hz, and P40 from 20 Hz) was recorded. For each parameter, the value at the end of the compound period was normalized against the vehicle baseline; as follows

[1004]

[1005] To account for any changes in the Na + current signal during the compound period (due to compound-independent cumulative inactivation or biophysical changes over time), a dedicated section of the recording wells in each 384-well plate was used for vehicle-only exposure. These vehicle-only recordings were used to correct for any apparent "run-up" or "run-down" in the experiment.

[1006]

[1007] The adjusted inhibition was calculated as follows:

[1008]

[1009] The percent inhibition was determined and the IC 50 value was calculated using a 4-parameter logistic model within XLFit software (IDBS, Boston MA):

[1010]

[1011] where A and B are the maximum and minimum inhibitions, C is the IC 50 concentration and D is the (Hill) slope.

[1012] The potency data for example compounds are summarized in the table below (Category A: human NaV1.8 IC 50 ≤ 0.1 μM; Category B: 0.1 μM < human NaV1.8 IC 50 ≤ 1 μM; Category C: 1 μM < human NaV1.8 IC 50 ≤ 10 μM; "n.d.": not determined):

[1013]

[1014]

Claims

1. A compound according to general formula (I): wherein one of A1, A2 and A3 represents C-R3, and the other two of A1, A2 and A3 independently represent CR' or N; R' independently represents H, F, CH3, CH2F, CHF2, CF3 or OCH3; L represents CH2, CH(CH3) or CH(CH2CH3); R1 represents C 3-10 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or dispiroalkyl, 4- to 10-membered heterocycloalkyl or 5- to 11-membered heterobicycloalkyl; R2 represents H or C 1-6 -alkyl; R3 represents S(O)(NR3a)R3b or S(NR3a)2R3b; R3a represents H, C 1-6 -alkyl, C(O)C 1-5 -alkyl, C(O)C 1-5 -alkyl-NH2, C(O)C 1-5 -alkyl-NH-CH3, C(O)C 1-5 -alkyl-N(CH3)2, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heterocycloalkyl or C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl); R3b represents NH2, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heterocycloalkyl or C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl); or R3a and R3b denote (CH2) 3-5 and together with the atom to which they are attached form a ring; R4 represents H, F, Cl, Br, CN, CHF2, CH2F, CF3, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or bisspiroalkyl, 4- to 10-membered heterocycloalkyl, C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl), NH2, N(H)(C 1-6 -alkyl), N(C 1-6 -alkyl)2, O-C 1-6 -alkyl, O-C 3-10 -cycloalkyl, O-C 1-6 -alkylene-C 3-10 -cycloalkyl, O-(4- to 6-membered heterocycloalkyl) or O-C 1-6 -alkylene-(4- to 6-membered heterocycloalkyl); R5 represents H, F, Cl, Br, CN, CHF2, CH2F, CF3, C 1-6 -alkyl, C 3-10 -cycloalkyl, C 1-6 -alkylene-C 3-10 -cycloalkyl, 4- to 10-membered heterocycloalkyl, C 1-6 -alkylene-(4- to 10-membered heterocycloalkyl), NH2, N(H)(C 1-6 -alkyl), N(C 1-6 -alkyl)2, O-C 1-6 -alkyl, O-C 3-10 -cycloalkyl, O-C 1-6 -alkylene-C 3-10 -cycloalkyl, O-(4- to 6-membered heterocycloalkyl) or O-C 1-6 -alkylene-(4- to 6-membered heterocycloalkyl); wherein C 1-6 -alkyl and C 1-6 -alkylene are each independently of the other straight-chain or branched in each case; Wherein C 1-6 -alkyl, C 1-6 -alkylene, C 3-10 -cycloalkyl, C 3-6 -cycloalkyl, 4- to 11-membered bicycloalkyl, 5- to 11-membered spiroalkyl or dispiroalkyl, 4- to 10-membered heterocycloalkyl, 4- to 6-membered heterocycloalkyl and 5- to 11-membered heterobicycloalkyl are each independently unsubstituted or substituted by one, two, three, four or more substituents independently selected from the group consisting of: F, Cl, CN, C 1-6 -alkyl, C 1-6 -alkylene-OH, C 1-6 -alkylene-OCH3, CF3, CF2H, CFH2, C(O)-C 1-6 -alkyl, OH, =O, OCF3, OCF2H, OCFH2, O-C 1-6 -alkyl, C 1-4 -alkylene-O-C 1-4 -alkylene-O-CH3, C 0-4 -alkylene-O-(C 1-4 -alkylene-O) 1-4 -CH3, NH2, NH-C 1- 6-alkyl, N(C 1-6 -alkyl)2 or 4- to 6-membered heterocycloalkyl; the compound is in the form of a free compound or a physiologically acceptable salt thereof.

2. The compound according to any one of the preceding claims, wherein (i) A1 represents C-R3, A2 represents N, and A3 represents CH; (ii) A1 represents C-R3, A2 represents CH, and A3 represents CH; or (iii) A1 represents C-R3, A2 represents N, and A3 represents N; or (iv) A1 represents C-R3, A2 represents CH, and A3 represents N; or (v) A1 represents CH, A2 represents C-R3, and A3 represents CH; or (vi) A1 represents N, A2 represents C-R3, and A3 represents CH; or (vii) A1 represents N, A2 represents C-R3, and A3 represents N.

3. The compound according to claim 1, wherein L represents CH2.

4. The compound according to any one of the preceding claims, wherein R1 represents -C 3-10 -cycloalkyl, which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3; Preferably selected from cyclopropyl, methylcyclopropyl, dimethylcyclopropyl, fluorocyclopropyl, difluorocyclopropyl, trifluoromethylcyclopropyl, trifluoromethylmethylcyclopropyl, methyldifluorocyclopropyl, trifluoromethyldifluorocyclopropyl, dimethyldifluorocyclopropyl, cyclobutyl, methylcyclobutyl, dimethylcyclobutyl, fluorocyclobutyl, difluorocyclobutyl, trifluoromethylcyclobutyl, trifluoromethylmethylcyclobutyl, methyldifluorocyclobutyl, trifluoromethyldifluorocyclobutyl, dimethyldifluorocyclobutyl, cyclopentyl, methylcyclopentyl, dimethylcyclopentyl, fluorocyclopentyl, difluorocyclopentyl, trifluoromethylcyclopentyl, trifluoromethylmethylcyclopentyl, methyldifluorocyclopentyl, trifluoromethyldifluorocyclopentyl, dimethyldifluorocyclopentyl, cyclohexyl, methylcyclohexyl, dimethylcyclohexyl, fluorocyclohexyl, difluorocyclohexyl, trifluoromethylcyclohexyl, trifluoromethylmethylcyclohexyl, methyldifluorocyclohexyl, trifluoromethyldifluorocyclohexyl, dimethyldifluorocyclohexyl, cycloheptyl, methylcycloheptyl, dimethylcycloheptyl, fluorocycloheptyl, difluorocycloheptyl, trifluoromethylcycloheptyl, trifluoromethylmethylcycloheptyl, methyldifluorocycloheptyl, trifluoromethyldifluorocycloheptyl, dimethyldifluorocycloheptyl, cyclooctyl, methylcyclooctyl, dimethylcyclooctyl, fluorocyclooctyl, difluorocyclooctyl, trifluoromethylcyclooctyl, trifluoromethylmethylcyclooctyl, methyldifluorocyclooctyl, trifluoromethyldifluorocyclooctyl, dimethyldifluorocyclooctyl, cyclononyl, methylcyclononyl, dimethylcyclononyl, fluorocyclononyl, difluorocyclononyl, trifluoromethylcyclononyl, trifluoromethylmethylcyclononyl, methyldifluorocyclononyl, trifluoromethyldifluorocyclononyl, dimethyldifluorocyclononyl, cyclodecyl, methylcyclodecyl, dimethylcyclodecyl, fluorocyclodecyl, difluorocyclodecyl, trifluoromethylcyclodecyl, trifluoromethylmethylcyclodecyl, methyldifluorocyclodecyl, trifluoromethyldifluorocyclodecyl and dimethyldifluorocyclodecyl; More preferably selected from cyclopropyl, dimethylcyclopropyl, trifluoromethylmethylcyclopropyl, cyclobutyl, trifluoromethylcyclobutyl, methyltrifluoromethylcyclobutyl, difluorocyclobutyl, methyldifluorocyclobutyl, cyclopentyl, difluorocyclopentyl, methyldifluorocyclopentyl, trifluoromethylcyclopentyl, trifluoromethyldifluorocyclopentyl, cyclohexyl, difluorocyclohexyl and methyldifluorocyclohexyl; A bicycloalkyl group having 4 to 11 carbon atoms, which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3; Preferably selected from bicyclo[1.1.1]pentyl, methylbicyclo[1.1.1]pentyl, methoxybicyclo[1.1.1]pentyl, difluoromethylbicyclo[1.1.1]pentyl, trifluoromethylbicyclo[1.1.1]pentyl, fluorobicyclo[1.1.1]pentyl, difluorobicyclo[1.1.1]pentyl, methyldifluorobicyclo[1.1.1]pentyl, trifluoromethyldifluorobicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, methylbicyclo[2.1.0]pentyl, trifluoromethylbicyclo[2.1.0]pentyl, fluorobicyclo[2.1.0]pentyl, difluorobicyclo[2.1.0]pentyl, methyldifluorobicyclo[2.1.0]pentyl, trifluoromethyldifluorobicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, methylbicyclo[3.1.0]hexyl, trifluoromethylbicyclo[3.1.0]hexyl, fluorobicyclo[3.1.0]hexyl, difluorobicyclo[3.1.0]hexyl, methyldifluorobicyclo[3.1.0]hexyl, trifluoromethyldifluorobicyclo[3.1.0]hexyl, bicyclo[2.2.0]hexyl, methylbicyclo[2.2.0]hexyl, trifluoromethylbicyclo[2.2.0]hexyl, fluorobicyclo[2.2.0]hexyl, difluorobicyclo[2.2.0]hexyl, methyldifluorobicyclo[2.2.0]hexyl, trifluoromethyldifluorobicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, methylbicyclo[2.1.1]hexyl, trifluoromethylbicyclo[2.1.1]hexyl, fluorobicyclo[2.1.1]hexyl, difluorobicyclo[2.1.1]hexyl, fluorobicyclo[2.1.1]hexyl, difluorobicyclo[2.1.1]hexyl, methyldifluorobicyclo[2.1.1]hexyl, trifluoromethyldifluorobicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, methylbicyclo[4.1.0]heptyl, trifluoromethylbicyclo[4.1.0]heptyl, fluorobicyclo[4.1.0]heptyl, difluorobicyclo[4.1.0]heptyl, methyldifluorobicyclo[4.1.0]heptyl, trifluoromethyldifluorobicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, methylbicyclo[2.2.1]heptyl, trifluoromethylbicyclo[2.2.1]heptyl, fluorobicyclo[2.2.1]heptyl, difluorobicyclo[2.2.1]heptyl, methyldifluorobicyclo[2.2.1]heptyl, trifluoromethyldifluorobicyclo[2.2.1]heptyl, bicyclo[3.3.0]octyl, methylbicyclo[3.3.0]octyl, trifluoromethylbicyclo[3.3.0]octyl, fluorobicyclo[3.3.0]octyl, difluorobicyclo[3.3.0]octyl, methyldifluorobicyclo[3.3.0]octyl and trifluoromethyldifluorobicyclo[3.3.0]octyl; more preferably selected from bicyclo[1.1.1]pentyl, trifluoromethyl-bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, difluorobicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, difluorobicyclo[3.1.0]hexyl, methyldifluorobicyclo[3.1.0]hexyl, trifluoromethyldifluorobicyclo[3.1.0]hexyl, bicyclo[2.2.0]hexyl, methylbicyclo[2.2.0]hexyl, bicyclo[2.1.1]hexyl, fluorobicyclo[2.1.1]hexyl, difluorobicyclo[2.1.1]hexyl, bicyclo[4.1.0]heptyl, difluorobicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl, fluorobicyclo[2.2.1]heptyl, bicyclo[3.3.0]octyl and fluorobicyclo[3.3.0]octyl; a 5- to 11-membered spiroalkyl or dispiroalkyl group, which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from each other from F, CH3, OCH3, CN, CHF2 and CF3; preferably selected from spiro[2.2]pentyl, methylspiro[2.2]pentyl, fluorospiro[2.2]pentyl, difluorospiro[2.2]pentyl, methyldifluorospiro[2.2]pentyl, spiro[2.3]hexyl, methylspiro[2.3]hexyl, fluorospiro[2.3]hexyl, difluorospiro[2.3]hexyl, methyldifluorospiro[2.3]hexyl, spiro[3.3]heptyl, methylspiro[3.3]heptyl, fluorospiro[3.3]heptyl, difluorospiro[3.3]heptyl, methyldifluorospiro[3.3]heptyl and dispiro[2.0.2.1]heptyl; more preferably selected from spiro[2.2]pentyl, difluorospiro[2.2]pentyl, spiro[2.3]hexyl, methylspiro[2.3]hexyl, fluorospiro[2.3]hexyl, methyldifluorospiro[2.3]hexyl, spiro[3.3]heptyl and dispiro[2.0.2.1]heptyl; a 4- to 10-membered heteroalkyl group, which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from each other from F, CH3, OCH3, CN, CHF2 and CF3; preferably selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl 1,1-dioxide, oxepanyl, piperidinyl, piperidinone, azetidinyl, pyrrolidinyl, pyrrolidone, 4-methylpiperazinyl, morpholinone, dioxanyl, piperazinyl, tetrahydropyrrolyl, azepanyl, dioxepanyl, oxazepanyl, diazepanyl, thiazolidinyl, tetrahydrothienyl, tetrahydropyridyl, dithiolanyl, dihydropyrrolyl, dioxolanyl, dihydropyridyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, N-methylpyridinone, pyrazolidinyl, pyranyl; dihydroquinolinyl, dihydroisoquinolinyl, dihydroindolyl, dihydroisoindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroindolyl; or -5 to 11-membered bicycloalkyl which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3; preferably 2-oxa-bicyclo[2.1.1]hexyl or methyl 2-oxa-bicyclo[2.1.1]hexyl.

5. The compound according to any one of the preceding claims, wherein R2 represents H.

6. A compound according to any one of the preceding claims, wherein R3a represents H, C 1-6 -alkyl C(O) C 1-5 -alkyl, C(O) C 1-5 -alkyl -NH2, C(O) C 1-5 -alkyl -NH-CH3, C(O) C 1-5 -alkyl -N(CH3)2; preferably H, CH3, C(O)CH3 or C(O)CH2NHCH3.

7. A compound according to any one of the preceding claims, wherein R3b represents NH2, C 1-6 -alkyl or C 3-10 -cycloalkyl; preferably NH2, CH3, CH2CH3 or cyclopropyl.

8. The compound according to any one of claims 1 to 6, wherein R3a and R3b mean (CH2)3 and together with the atoms to which they are attached form a ring.

9. The compound according to any one of the preceding claims, wherein R4 represents -C 1-6 -alkyl; preferably selected from CHF2, CH2F, CF3, CH2CHF2, CH2CH2F, CH2CF3, CF2CH3, CHFCH3, CF2CF3, CHFCF3, CH(CHF2)(CH3), CH(CH2F)(CH3), CH(CF3)(CH3), CH3, CH2CH3, CH(CH3)2; more preferably CF2CH3; -C 3-10 -cycloalkyl, which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3; preferably selected from cyclopropyl, methylcyclopropyl, difluoromethylcyclopropyl, trifluoromethylcyclopropyl, cyanocyclopropyl, methoxycyclopropyl, fluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, cyclobutyl, methylcyclobutyl, difluoromethylcyclobutyl, trifluoromethylcyclobutyl, cyanocyclobutyl, methoxycyclobutyl, fluorocyclobutyl, difluorocyclobutyl, trifluorocyclobutyl, cyclopentyl, methylcyclopentyl, difluoromethylcyclopentyl, trifluoromethylcyclopentyl, cyanocyclopentyl, methoxycyclopentyl, fluorocyclopentyl, difluorocyclopentyl, trifluorocyclopentyl, cyclohexyl, methylcyclohexyl, difluoromethylcyclohexyl, trifluoromethylcyclohexyl, cyanocyclohexyl, methoxycyclohexyl, fluorocyclohexyl, difluorocyclohexyl and trifluorocyclohexyl; more preferably selected from cyclopropyl, methylcyclopropyl, difluoromethylcyclopropyl, trifluoromethylcyclopropyl, cyanocyclopropyl, methoxycyclopropyl, fluorocyclopropyl, difluorocyclopropyl, trifluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl and difluorocyclopentyl; -4 to 11-membered bicycloalkyl which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3; preferably bicyclo[1.1.1]pentyl; -5 to 11-membered spiroalkyl which is unsubstituted or substituted by one, two, three, four or more substituents independently selected from F, CH3, OCH3, CN, CHF2 and CF3; preferably spiro[2.2]pentyl or spiro[2.3]hexyl; or -O-C 1-6 -alkyl, which is unsubstituted or substituted with one, two, three, four or more F; preferably selected from O-CHF2, O-CH2F, O-CF3, O-CH2CHF2, O-CH2CH2F, O-CH2CF3, O-CF2CH3, O-CHFCH3, O-CF2CF3, O-CHFCF3, O-CH3, O-CH2CH3 or O-CH(CH3)2; more preferably O-CHF2.

10. A compound according to any one of the preceding claims, wherein R5 represents C 1-6 -alkyl or Cl; preferably CHF2, CH2F, CF3, CH2CHF2, CH2CH2F, CH2CF3, CF2CH3, CHFCH3, CF2CF3, CHFCF3, CH(CHF2)(CH3), CH(CH2F)(CH3), CH(CF3)(CH3), CH3, CH2CH3, CH(CH3)2 or Cl; more preferably CF3, CHF2, CH3 or Cl.

11. The compound according to any one of the preceding claims, selected from the group consisting of 1 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 3 1-((3,3-Difluorocyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 4 1-((3,3-Difluorocyclopentyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 5 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 7 3-Cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 9 1-((4,4-Difluorocyclohexyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 11 1-((4,4-Difluoro-1-methylcyclohexyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 13 3-(1,1-Difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-((2-(trifluoromethyl)cyclobutyl)methyl)-1H-pyrazole-5-carboxamide 15 3-(1,1-Difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1H-pyrazole-5-carboxamide 17 3-Cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 21 3-Cyclopropyl-1-((2-fluorospiro[3.3]hept-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 23 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1-((3-(trifluoromethyl)bicyclo[1.1.1]pent-1-yl)methyl)-1H-pyrazole-5-carboxamide 25 3-Cyclopropyl-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 27 3-Cyclopropyl-1-((6,6-difluorospiro[3.3]heptan-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 29 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 31 3-(1,1-Difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-pyrazole-5-carboxamide 33 1-((3,3-Difluorocyclopentyl)methyl)-3-(difluoromethoxy)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 34 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(N,S-dimethylsulfinyl)pyridin-4-yl)-4-methyl-1H-pyrazole-5-carboxamide 36 3-Cyclopropyl-1-((3,3-difluorocyclopentyl)methyl)-N-(2-(N,S-dimethylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 44 1-((4,4-Difluoro-1,2-dimethylcyclopentyl)methyl)-3-(1,1-difluoroethyl)-4-methyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 45 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 46 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(5-(S-methylsulfinyl)pyridin-3-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 47 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(6-(S-methylsulfinyl)pyridazin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 48 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(ethylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 49 N-(2-(Cyclopropanesulfinyl)pyridin-4-yl)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 50 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-methyl-6-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 51 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(1-oxo-4,5-dihydro-3H-1lλ 6- isothiazol-1-yl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 52 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-aminosulfinylphenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 53 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(methyl(phenyl)-λ6-sulfanediamide))-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 54 N-(3-(N-Acetyl-S-methylsulfinimidoyl)phenyl)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 55 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methyl-N-(methylglycyl)sulfinimidoyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 56 3-Cyclobutyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 57 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3,3-difluorocyclobutyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 58 3-(Bicyclo[1.1.1]pent-1-yl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 59 3-Cyclopentyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 60 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3,3-difluorocyclopentyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 61 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-3-(spiro[2.3]hex-5-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 62 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2-fluorocyclopropyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 63 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 64 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(spiro[2.2]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 65 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2-methylcyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 66 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2-(difluoromethyl)cyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 67 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-3-(2-(trifluoromethyl)cyclopropyl)-1H-pyrazole-5-carboxamide 68 3-(1-Cyanocyclopropyl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 69 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-methylcyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 70 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 71 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-methoxycyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 72 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,3-difluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 73 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(1,2,2-trifluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 74 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,2-difluorocyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 75 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 76 4-Chloro-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1,1-difluoroethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 77 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 78 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-(spiro[2.2]pentan-1-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 79 3-Cyclopropyl-1-((2,2-difluorospiro[2.2]pentan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 80 3-Cyclopropyl-1-(dispiro[2.0.2 4 .1 3 hept-7-ylmethyl)-N-(2-(S-methylsulfinimidoyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 81 3-Cyclopropyl-1-((1,2-dimethylcyclopropyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 82 3-Cyclopropyl-1-((1-methyl-2-(trifluoromethyl)cyclopropyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 83 1-(Bicyclo[2.1.0]pentan-1-ylmethyl)-3-cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 84 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-(spiro[2.3]hexan-5-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 85 3-Cyclopropyl-1-((5-methylspiro[2.3]hexan-5-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 86 3-Cyclopropyl-1-((1-methyl-3-(trifluoromethyl)cyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 87 3-Cyclopropyl-1-((1-fluorospiro[2.3]hexan-5-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 88 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1-((3-(trifluoromethyl)cyclobutyl)methyl)-1H-pyrazole-5-carboxamide 89 3-Cyclopropyl-1-((3,3-difluorocyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 90 3-Cyclopropyl-1-((5,5-difluorobicyclo[2.1.0]pent-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 91 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-(spiro[2.3]hexan-4-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 92 3-Cyclopropyl-1-((6,6-difluoro-4-methylspiro[2.3]hexan-4-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 93 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1-(spiro[3.3]heptan-1-ylmethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 94 3-Cyclopropyl-1-((2-methylbicyclo[2.2.0]hex-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 95 3-Cyclopropyl-1-((3,3-difluorobicyclo[3.1.0]hex-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 96 3-Cyclopropyl-1-((4,4-difluorobicyclo[3.1.0]hex-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 97 3-Cyclopropyl-1-((5-fluorooctahydropentalen-2-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 98 3-Cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1-((1-(trifluoromethyl)cyclopentyl)methyl)-1H-pyrazole-5-carboxamide 99 3-Cyclopropyl-1-((4,4-difluoro-2-methylcyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 100 3-Cyclopropyl-1-((4,4-difluoro-2-(trifluoromethyl)cyclopentyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 101 3-Cyclopropyl-1-((3,3-difluoro-5-methylbicyclo[3.1.0]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 102 3-Cyclopropyl-1-((3,3-difluoro-5-(trifluoromethyl)bicyclo[3.1.0]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 103 3-Cyclopropyl-1-((2,2-difluorobicyclo[2.1.1]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 104 3-Cyclopropyl-1-((3,3-difluorobicyclo[2.1.1]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 105 3-Cyclopropyl-1-((4-fluorobicyclo[2.1.1]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 106 3-Cyclopropyl-1-((4-fluorobicyclo[2.2.1]heptan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 107 3-Cyclopropyl-1-((4,4-difluorobicyclo[4.1.0]heptan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 108 3-(Bicyclo[1.1.1]pentan-1-yl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 109 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 110 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(3-fluorobicyclo 1.1.1]Pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 111 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-fluorobicyclo 1.1.1]Pentan-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 112 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-fluorobicyclo 1.1.1]Pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 113 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-fluorobicyclo 1.1.1]pentan-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide 114 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 115 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 116 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 117 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2,2-difluorobicyclo[1.1.1]pentan-1-yl)-4-(difluoromethyl)-N-(3-(S-methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide 118 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 119 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-methylsulfinyl)phenyl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 120 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-1H-pyrazole-5-carboxamide 121 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(3-(S-methylsulfinyl)phenyl)-3-(2,2,3-trifluorobicyclo[1.1.1]pentan-1-yl)-1H-pyrazole-5-carboxamide 122 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-methoxybicyclo 1.1.1]pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 123 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(3-methoxybicyclo 1.1.1]Pent-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 124 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-methoxybicyclo 1.1.1]Pent-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 125 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(3-methoxybicyclo 1.1.1]Pent-1-yl)-N-(3-(S-methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide 126 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 127 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-fluoro-5-(S-methylsulfinyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 128 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-fluoro-5-(S-methylsulfinyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 129 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-fluoro-3-(S-methylsulfinyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 130 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(3-(S-(difluoromethyl)sulfinyl)phenyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 131 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-4-(trifluoromethyl)-N-(3-(S-(trifluoromethyl)sulfinyl)phenyl)-1H-pyrazole-5-carboxamide 132 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 133 1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-3-(1-fluorocyclopropyl)-1H-pyrazole-5-carboxamide 134 3-(1-Fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1-((2-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazole-5-carboxamide 135 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methylsulfinyl)phenyl)-1H-pyrazole-5-carboxamide 136 3-Cyclopropyl-1-((2,2-difluorospiro[2.3]hexan-1-yl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 137 3-(Bicyclo[1.1.1]pentan-1-yl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-1H-pyrazole-5-carboxamide 138 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-4-(difluoromethyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-3-(3-fluorobicyclo 1.1.1]pentan-1-yl)-1H-pyrazole-5-carboxamide 139 3-(Bicyclo[1.1.1]pentan-1-yl)-1-((2-(difluoromethyl)cyclopropyl)methyl)-N-(3-(S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 140 1-((2-Acetyl-2-azaspiro[3.3]heptan-5-yl)methyl)-3-cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 141 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(4-fluoro-3-(S-methylsulfinyl)phenyl)-3-(3-fluorobicyclo 1.1.1]pentan-1-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 142 N-(2-(N-Cyano-S-methylsulfinyl)pyridin-4-yl)-3-cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 143 3-(tert-Butyl)-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 144 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-3-(1-(trifluoromethyl)cyclopropyl)-1H-pyrazole-5-carboxamide 145 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-(difluoromethyl)cyclopropyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 146 3-(Bicyclo[1.1.1]pentan-1-yl)-1-((2-(difluoromethyl)cyclopropyl)methyl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 147 3-(Bicyclo[1.1.1]pentan-1-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1-(((trans)-2-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazole-5-carboxamide 148 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(2-fluoropropan-2-yl)-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 150 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(S-methyl-N-(oxetan-3-carbonyl)sulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 151 1-((3,3-Difluoro-1-methylcyclobutyl)methyl)-3-(1-fluorocyclopropyl)-N-(3-(N-(2-hydroxyacetyl)-S-methylsulfinyl)phenyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 152 3-Cyclopropyl-1-((3,3-difluoro-1-methylcyclobutyl)methyl)-N-(2-(N-(2,3-dihydroxypropyl)-S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide 153 1-((2-Azaspiro[3.3]heptan-5-yl)methyl)-3-cyclopropyl-N-(2-(S-methylsulfinyl)pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide The compound is in the form of a free compound or a physiologically acceptable salt thereof.

12. A pharmaceutical dosage form comprising the compound according to any one of claims 1 to 11.

13. The pharmaceutical dosage form according to claim 12, which is used for treating pain.

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