USOO8907101B2

(12) United States Patent (10) Patent No.: US 8,907,101 B2 Beaudoin et al. (45) Date of Patent: *Dec. 9, 2014

(54) SULFONAMIDE DERIVATIVES C07D 40/12 (2006.01) (71) Applicants: Pfizer Limited, Sandwich (GB); Icagen, C07D 417/12 (2006.01) Inc., Durham, NC (US) A613 L/496 (2006.01) (72) Inventors: Serge Beaudoin, Cary, NC (US); (52) U.S. Cl. Michael Christopher Laufersweiler, CPC ...... C07D 417/12 (2013.01); C07F 9/6539 Maineville, OH (US); Christopher John (2013.01); A61 K3I/675 (2013.01); A61 K Markworth, Bellingham, WA (US); 31/454 (2013.01); C07D 285/08 (2013.01); Brian Edward Marron, Durham, NC A6IK3I/433 (2013.01); C07D 263/50 (US); David Simon Millan, Sandwich (2013.01); A61K 45/06 (2013.01); A61 K (GB); David James Rawson, Sandwich 31/4439 (2013.01); COID 277/18 (2013.01); (GB); Steven Michael Reister, Cary, NC C07D 413/12 (2013.01); C07D 417/14 (US); Kosuke Sasaki, Osaka (JP); (2013.01); A61 K3I/501 (2013.01); A61 K Robert Ian Storer, Sandwich (GB); 31/427 (2013.01); C07D 275/03 (2013.01); Paul Anthony Stupple, Sandwich (GB); A6 IK3I/506 (2013.01); A61 K3I/4545 Nigel Alan Swain, Sandwich (GB); (2013.01); C07D 401/12 (2013.01); A61 K Christopher William West, Cary, NC 3 1/496 (2013.01) (US); Shulan Zhou, Chapel Hill, NC USPC ...... 546/290; 544/333; 514/345; 514/256 (US) (58) Field of Classification Search None (73) Assignees: Pfizer Limited, Sandwich (GB); Icagen, See application file for complete search history. Inc., Durham, NC (US) (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. U.S. PATENT DOCUMENTS This patent is Subject to a terminal dis 3,905,971 A 9, 1975 Miller claimer. 4,782,056 A 11/1988 Rosner et al. (21) Appl. No.: 13/968,561 (Continued) (22) Filed: Aug. 16, 2013 FOREIGN PATENT DOCUMENTS (65) Prior Publication Data EP O532239 3, 1993 US 2013/0338111A1 Dec. 19, 2013 EP O569 193 11, 1993 (Continued) Related U.S. Application Data OTHER PUBLICATIONS (63) Continuation of application No. 13/400,356, filed on Feb. 20, 2012, now Pat. No. 8,541,588, which is a Hong, Guizhu, et al., PPARy activation enhances cell surface ENaCa continuation of application No. 12/685,913, filed on via up-regulation of SGK1 in human collecting duct cells, The Jan. 12, 2010, now Pat. No. 8,153,814. FASEB Journal, Oct. 2003, pp. 1966-1968, vol. 17. (60) Provisional application No. 61/258,760, filed on Nov. (Continued) 6, 2009, provisional application No. 61/245,726, filed on Sep. 25, 2009, provisional application No. Primary Examiner — Heidi Reese 61/143,920, filed on Jan. 12, 2009. (74) Attorney, Agent, or Firm — J. Michael Dixon (51) Int. Cl. (57) ABSTRACT A6 IK3I/44 (2006.01) C07D 21 1/72 (2006.01) The present invention relates to compounds of the formula CO7D 40/00 (2006.01) C07F 9/6539 (2006.01) A6 IK3I/675 (2006.01) (I) A6 IK3 L/454 (2006.01) CO7D 285/08 (2006.01) A6 IK3I/433 (2006.01) CO7D 263/50 (2006.01) A6 IK 45/06 (2006.01) A6 IK3I/4439 (2006.01) CO7D 413/2 (2006.01) and pharmaceutically acceptable salts, Solvates or tautomers CO7D 417/4 (2006.01) thereof, to processes for the preparation of intermediates A6 IK3I/50 (2006.01) used in the preparation of, and compositions containing Such A6 IK3I/427 (2006.01) compounds, and the uses of such compounds, in particular for C07D 275/03 (2006.01) the treatment of pain. A6 IK3I/506 (2006.01) A6 IK3 L/4545 (2006.01) 8 Claims, No Drawings US 8,907.101 B2 Page 2

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US 8,907,101 B2 1. 2 SULFONAMIDE DERVATIVES by tetrodotoxin (TTX-sensitive or TTX-s) and those which are resistant to blocking by tetrodotoxin (TTX-resistant or CROSS REFERENCE TTX-r). There are three members of the subgroup of TTX-resistant This application is a continuation of U.S. patent applica sodium channels. The SCN5A gene product (Na, 1.5, H1) is tion Ser. No. 13/400,356 filed Feb. 20, 2012, which is a almost exclusively expressed in cardiac tissue, is thought to continuation of U.S. patent application Ser. No. 12/685.913 play a central role in the generation of the cardia action filed Jan. 12, 2010 now U.S. Pat. No. 8,153,814 issued Apr. 4, potential and propagation of electrical impulses in the heart, 2012, which claims benefit under 35 USC 119(e) of U.S. and has also been shown to underlie a variety of cardiac 10 arrhythmias and conduction disorders (Liu H. et al., Am. J. Provisional Application 61/143,920, filed Jan. 12, 2009; U.S. Pharmacogenomics, 3(3): 173-9 (2003)). Consequently, Provisional Application 61/245,726, filed Sep. 25, 2009; and blockers of Nav1.5 have found clinical utility in treatment of U.S. Provisional Application 61/258,760, filed Nov. 6, 2009. such disorders (Srivatsa U, et al., Curr: Cardiol. Rep., 4(5): This invention relates to sulfonamide derivatives. More 401-10 (2002)), but binding of drugs to Nav1.5 may also particularly, this invention relates to heteroaryl substituted 15 result in abnormal cardiac rhythms. The remaining TTX Sulphonamide derivatives and to processes for the preparation resistant sodium channels, Nav1.8 (SCN10A, PN3, SNS) and of intermediates used in the preparation of compositions Nav1.9 (SCN11A, NaN, SNS2) are expressed in the periph containing, and the uses of Such derivatives. eral nervous system and show preferential expression in pri The sulfonamide derivatives of the present invention are mary nociceptive neurons. Human genetic variants of these Sodium channel modulators and have a number of therapeutic channels have not been associated with any inherited clinical applications, particularly in the treatment of pain. disorder. However, aberrant expression of Nav1.8 has been Voltage-gated Sodium channels are found in all excitable found in the CNS of human multiple sclerosis (MS) patients cells including myocytes of muscle and neurons of the central and also in a rodent model of MS (Black, JA, et al., Proc. Natl. and peripheral nervous system. In neuronal cells, sodium Acad. Sci. USA, 97(21): 11598-602 (2000)). Evidence for channels are primarily responsible for generating the rapid 25 involvement in nociception is both associative (preferential upstroke of the action potential. In this manner Sodium chan expression innociceptive neurons) and direct (genetic knock nels are essential to the initiation and propagation of electrical out). Nav1.8-null mice exhibited typical nociceptive behavior signals in the nervous system. Proper and appropriate func in response to acute noxious stimulation but had significant tion of Sodium channels is therefore necessary for normal deficits in referred pain and hyperalgesia (Laird J. M. et al., J. 30 Neurosci., 22(19):8352-6 (2002)). function of the neuron. Consequently, aberrant sodium chan The TTX-sensitive subset of Voltage-gated sodium chan nel function is thought to underlie a variety of medical disor nels is expressed in a broader range of tissues than the TTX ders (see Hubner CA, Jentsch TJ, Hum. Mol. Genet., 11 (20): resistant channels and has been associated with a variety of 2435-45 (2002) for a general review of inherited ion channel human disorders. The Na1.1 channel well exemplifies this disorders) including epilepsy (Yogeeswari et al., Curr. Drug 35 general pattern, as it is expressed in both the central and Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D., Proc. peripheral nervous system and has been associated with sev Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)) myotonia (Can eral seizure disorders including Generalized Epilepsy with non, SC, Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, Febrile Seizures Plus, types 1 and 2 (GEFS+1, GEFS+2), J N et al., J. Neurobiol., 61(1): 55-71 (2004)). See Table A, Severe Myoclonic Epilepsy of Infancy (SMEI), and others below. 40 (Claes, L, et al., Am. J. Hum. Genet., 68: 1327-1332 (2001): Escayg, A., Am. J. Hum. Genet., 68: 866-873 (2001); Lossin, TABLE A C, Neuron, 34: 877-884 (2002)). The Nav1.2 channel is TTX largely, if not exclusively, expressed in the central nervous Gene Primary IC-50 Disease system and quantitative studies indicate it is the most abun Type Symbol tissue nM association indications 45 dant VGSC of the CNS. Mutations of Nav1.2 are also asso Na1.1 SCN1A CNS, 10 Epilepsy Pain, seizures, ciated with seizure disorders (Berkovic, S. F., et al., Ann. PNS leO Neurol., 55: 550-557 (2004)) and Nav1.2-null “knockout” degeneration mice exhibit perinatal lethality (Planells-Cases Ret al., Bio Na1.2 SCN2A CNS 10 Epilepsy Epilepsy, phys.J., 78(6):2878-91 (2000)). Expression of the Nav1.4 leO 50 degeneration gene is largely restricted to skeletal muscle and, accordingly, Na1.3 SCN3A CNS 15 — Pain mutations of this gene are associated with a variety of move Na1.4 SCN4A Sk. 25 Myotonia Myotonia ment disorders (Ptacek, L. J., Am. J. Hum. Genet., 49: 851 muscle 854 (1991); Hudson AJ, Brain, 118(2): 547-63 (1995)). The Na1.5 SCN5A Heart 2000 Arrhythmia Arrhythmia majority of these disorders are related to hyperactivity or Na1.6 SCN8A CNS/ 6 — Pain, 55 PNS movement “gain-of-function' and have been found to respond to treat disorders ment with sodium channel blockers (Desaphy J. F. et al., J. Na1.7 SCN9A PNS 25 Erythermalgia Pain Physiol., 554(2): 321-34 (2004)). Na1.8 SCN10A PNS SOOOO Pain Neither the SCN3A nor the SCN8A VGSC genes have Na1.9 SCN11A PNS 1OOO - Pain been conclusively linked to heritable disorders in humans. 60 Loss-of-function mutations of the SCN8A gene are known in There are currently at least nine known members of the mice and yield increasingly debilitating phenotypes, depen family of voltage-gated sodium channel (VGSC) alpha sub dent upon the remaining functionality of the gene products units. Names for this family include SCNX, SCNAX, and (Meisler M H, Genetica, 122(1): 37-45 (2004)). Homozy Nax.x. The VGSC family has been phylogenetically divided gous null mutations cause progressive motor neuron failure into two subfamilies Nalx (all but SCN6A) and Na2.x 65 leading to paralysis and death, while heterozygous null ani (SCN6A). The Nav1.x subfamily can be functionally subdi mals are asymptomatic. Homozygous med' mice have nearly vided into two groups, those which are sensitive to blocking 90% reduction in functional Nav1.6 current and exhibit dys US 8,907,101 B2 3 4 tonia and muscle weakness but are still viable. Evidence for of the SCN9A gene and the CIP phenotype (Goldberg et al. Nav1.6 being important for nociception is largely associative Clin Genet. 71 (4): 311-9 (2007), Ahmad et al, Hum Mol. as Nav1.6 is expressed at high levels indorsal root ganglia and Genet. 1; 16(17): 2114-21 (2007)). can be found in spinal sensory tracts (TZoumaka E. J. Neu Sodium channel-blocking agents have been reported to be rosci. Res., 60(1): 37-44 (2000)). It should be noted however effective in the treatment of various disease states, and have that expression of Nav1.6 is not restricted to sensory neurons found particular use as local anesthetics and in the treatment of the periphery. Like the Nav1.6 channel, expression of the of cardiac arrhythmias. It has also been reported that sodium Nav1.3 VGSC can also be detected in both the central and channel-blocking agents may be useful in the treatment of peripheral nervous system, though levels in the adult CNS are pain, including acute, chronic, inflammatory and/or neuro generally much higher than PNS. During development and 10 pathic pain; see, for example, Wood, J N et al., J. Neurobiol., the early postnatal period, Nav1.3 is expressed in peripheral 61(1): 55-71 (2004). Preclinical evidence demonstrates that neurons but this expression wanes as the animal matures Sodium channel-blocking agents can Suppress neuronal firing (Shah BS, J. Physiol., 534(3): 763-76 (2001); Schaller K L, in peripheral and central sensory neurons, and, it is via this Cerebellum, 201): 2-9 (2003)). Following neuronal insult, mechanism, that they may be useful for relieving pain. In Nav1.3 expression is upregulated, more closely mimicking 15 Some instances, abnormal or ectopic firing can originate from the developmental expression patterns (Hains BC, J. Neuro injured or otherwise sensitized neurons. For example, it has sci., 23(26): 8881-92 (2003)). Coincident with the recurrence been shown that sodium channels can accumulate in periph of Nav1.3 expression is the emergence of a rapidly re-priming eral nerves at sites of axonal injury and may function as Sodium current in the injured axons with a biophysical profile generators of ectopic firing (Devor et al. J. Neurosci., 132: similar to Nav1.3 (Leffler A, et al., J. Neurophysiol., 88(2): 1976 (1993)). Changes in sodium channel expression and 650-8 (2002)). Treatment of injured axons with high levels of excitability have also been shown in animal models of inflam GDNF has been shown to diminish the rapidly repriming matory pain where treatment with proinflammatory materials Sodium current and reverse thermal and mechanical pain (CFA, Carrageenan) promoted pain-related behaviors and related behaviors in a rat model of nerve injury, presumably correlated with increased expression of sodium channel Sub by down-regulating the expression of Nav1.3 (Boucher T. J. 25 units (Gouldet al., Brain Res., 824(2): 296-9 (1999); Blacket Curr. Opin. Pharmacol., 1(1): 66-72 (2001)). Specific down al., Pain, 108(3): 237-47 (2004)). Alterations in either the regulation of Nav1.3 via treatment with antisense oligonucle level of expression of, or distribution of sodium channels, otides has also been shown to reverse pain-related behaviors therefore, may have a major influence on neuronal excitabil following spinal cord injury (Hains BC.J. Neurosci., 23 (26): ity and pain-related behaviors. As such there is a desire to seek 8881-92 (2003)). 30 new Sodium channel modulators. The Na1.7 (PN1, SCN9A)VGSC is sensitive to blocking WO-A-2005/054176 discusses peroxisome proliferator by tetrodotoxin and is preferentially expressed in peripheral activated receptor modulators. sympathetic and sensory neurons. The SCN9A gene has been EP-A-1088.819 discusses 6-azauracil derivatives, which cloned from a number of species, including human, rat, and are stated to be thyroid receptor ligands. rabbit and shows ~90% amino acid identity between the 35 International patent application WO-A-2005/013914 human and rat genes (Toledo-Aral et al., Proc. Natl. Acad. (publication date 17 Feb. 2005) discloses compounds, in par Sci. USA, 94(4): 1527-1532 (1997)). ticular heteroarylamino sulfonylphenyl derivatives, which An increasing body of evidence suggests that Na1.7 may are useful as inhibitors of voltage gated Sodium channels with play a key role in various pain states, including acute, inflam a number of therapeutic uses, including the treatment of pain. matory and/or neuropathic pain. Deletion of the SCN9A gene 40 International patent application WO-A-2008/118758 in nociceptive neurons of mice led to a reduction in mechani (publication date 2 Oct. 2008) discloses compounds, in par cal and thermal pain thresholds and reduction or abolition of ticular aryl Sulphonamides, which are sodium channel modu inflammatory pain responses (Nassar et al., Proc Natl Acad lators with a number of therapeutic uses, particularly for the Sci USA, 101(34): 12706-11 (2004)). In humans, Na1.7 pro treatment of pain. tein has been shown to accumulate in neuromas, particularly 45 International patent application WO-A-2009/012242 painful neuromas (Kretschmer et al., Acta. Neurochir. (publication date 22 Jan. 2009) discloses compounds, in par (Wien), 144(8): 803-10 (2002)). Gain of function mutations ticular N-thiazolylbenzenesulfonamides, which are sodium of Na, 1.7, both familial and sporadic, have been linked to channel modulators with a number of therapeutic uses, par primary erythermalgia, a disease characterized by burning ticularly for the treatment of pain. pain and inflammation of the extremities (Yang et al., J. Med. 50 However, there remains a need for still further new sodium Genet., 41(3): 171-4 (2004), and paroxysmal extreme pain channel modulators, including modulators which are poten disorder (Waxman, SG Neurology. 7: 69(6): 505-7 (2007)). tially able to block activity at a given sodium channel. The Congruent with this observation is the report that the non compounds of the present invention described herein are selective Sodium channel blockers lidocaine and mexiletine selective Nav1.7 channel modulators. In particular, they show can provide symptomatic relief in cases of familial eryther 55 an affinity for the Nav1.7 channel which is greater than their malgia (Legroux-Crepel et al., Ann. Dermatol Venereol., 130: affinity for Nav1.5 channels. Preferred compounds of the 429-433) and carbamazepine is effective in reducing the invention show selectivity for the Nav1.7 channel as com number and severity of attacks in PEPD (Fertleman et al. pared with the Nav1.5. Advantageously, the compounds of Neuron. 52(5):767-74 (2006). Further evidence of the role of the invention show little or no affinity for the Nav1.5 channel. Nav1.7 in pain is found in the phenotype of loss of function 60 The compounds of the present invention, being Nav 1.7 mutations of the SCN9A gene. Cox and colleagues (Nature, modulators, are therefore potentially useful in the treatment 444(7121):894-8 (2006)) were the first to report an associa of a wide range of disorders, particularly pain. The treatment tion between loss-of-function mutations of SNC9A and con of pain is a preferred use. All forms of pain are potentially genital indifference to pain (CIP), a rare autosomal recessive treatable with the compounds of the present invention includ disorder characterized by a complete indifference or insensi 65 ing acute pain; chronic pain; neuropathic pain; inflammatory tivity to painful stimuli. Subsequent studies have revealed a pain; visceral pain; nociceptive pain including post-Surgical number of different mutations that result in a loss of function pain; and mixed pain types involving the viscera, gastrointes US 8,907,101 B2 5 6 tinal tract, cranial structures, musculoskeletal system, spine, each R' is independently selected from the group consist urogenital system, cardiovascular system and CNS, including ing of halo, cyano, amino, hydroxy, (C-C)alkyl, halo(C- cancer pain, back and orofacial pain. C.)alkyl, hydroxy(C-C)alkyl, (C-C)alkoxy, halo(C-C) Other conditions that may be treated with the compounds alkoxy, (C-C)alkoxy(C-C)alkyl, —C(O)H, —C(O)(C- of the present invention include anal fissure, neuronal injury, C.)alkyl, and —C(O)N(R): spinal injury and epilepsy. each R is independently hydrogen, (C-C)alkyl, halo(C- It is an objective of the invention to provide new Nav1.7 C.)alkyl, hydroxy(C-C)alkyl, or (C-C)cycloalkyl; or, channel modulators and that, preferably, such new modula where a nitrogen is substituted with two R groups, each tors are Suitable for further development as drug candidates. independently selected from (C-C)alkyl, halo(C-C)alkyl, 10 or hydroxy(C-C)alkyl, they may be taken together with the Preferred compounds should bind potently to the Nav1.7 Natom to which they are attached to form a 4- to 6-membered channel, show functional activity as Nav1.7 channel modu ring which, when so formed, may therefore optionally be lators, and preferably show little affinity for other sodium Substituted with hydrogen, alkyl, halo, hydroxy, hydroxy channels, particularly Nav1.5. Furthermore, the preferred alkyl or haloalkyl: compounds should have one or more of the following 15 B is phenyl or Het, wherein, when B is Het it is attached improved properties: be well absorbed from the gastrointes to the oxy linker at a ring carbon atom, and wherein B is tinal tract; be metabolically stable; have an improved meta optionally further substituted on a ring carbon atom with one bolic profile, in particular with respect to the toxicity or or more substituents selected from the group consisting of allergenicity of any metabolites formed; or possess favour halo, cyano, hydroxy, (C-C)alkyl, halo(C-C)alkyl, (C- able pharmacokinetic properties whilst still retaining their C.)alkoxy, halo(C-C)alkoxy, cyano(C-C)alkyl, amino, activity profile as Nav1.7 channel modulators. It is further (C-C)alkylamino, di(C-C)alkylamino, amino(C-C) preferred that they should also be non-toxic and demonstrate alkyl, (C-C)alkylamino(C-C)alkyl, di(C-C)alkyl few side-effects. Furthermore, such preferred drug candi amino(C-C)alkyl, trifluoromethylthio. hydroxy(C-C) dates should preferably exist in a physical form that is stable, alkyl, (C-C)alkoxy(C-C)alkyl, -C(O)R’, —C(O)OR, non-hygroscopic and easily formulated. Preferred com 25 –OC(O)R’, C(O) N(R), —CH C(O)R’, —CH2— pounds of the present invention are selective for the Nav1.7 C(O)OR, CH, OC(O)R, CH, C(O) N(R), channel over Nav1.5, which may potentially lead to one or S(O).R. S(O)N(R), (C-Cs)cycloalkyl, and (C-Cs)cy more improvements in the side-effect profile. Without wish cloalkyl (C-C)alkyl, and/or ing to be bound by theory, such selectivity, is thought to Het is optionally substituted on a ring nitrogen atom with advantageously reduce any cardiovascular side effects which 30 a substituent selected from the group consisting of (C-C) may be associated with affinity for the Nav1.5 channel. Pref alkyl, halo(C-C)alkyl, hydroxy(C-C)alkyl, (C-C) erably compounds of the present invention demonstrate a alkoxy(C-C)alkyl, amino(C-C)alkyl, (C-C)alkylamino selectivity of 10-fold, more preferably 30-fold, most prefer (C-C)alkyl, di(C-C)alkylamino(C-C)alkyl, —CH2— ably 100-fold, for the Nav 1.7 channel when compared to C(O)R’, —CH C(O)OR, —CH C(O) N(R), their selectivity for the Nav1.5 channel whilst maintaining 35 S(O).R., and S(O)N(R): good potency for the Nav1.7 channel. In addition, the most X is absent, —O—, methylene, ethylene, methylene-O-, preferred compounds of the present invention may optionally or —O-methylene: also show selectivity for the Nav1.7 channel over Nav1.3, C is (C-Cs)cycloalkyl, Het', phenyl, or Het, each option whilst maintaining good potency for the Nav1.7 channel. ally Substituted on a ring carbon atom with one or more 40 Substituents selected from the group consisting of halo, cyano, hydroxy, (C-C)alkyl, halo(C-C)alkyl, (C-C) SUMMARY OF THE INVENTION alkoxy, halo(C-C)alkoxy, N(R), (R)N(C-C)alkyl, tri The invention therefore provides as Embodiment 1 a com fluoromethylthio, hydroxy(C-C)alkyl, (C-C)alkoxy(C- pound of the formula (I): C.)alkyl, -C(O)R. —C(O)CR, OC(O)R’, —C(O) N 45 (R), —CH C(O)R. —CH C(O)OR, CH, OC (O)R. —CH C(O) N(R), S(O).R.S(O)N(R), (C- Cs)cycloalkyl (C-C)alkyl, (C-C)cycloalkoxy, (C-C) (I) cycloalkylamino, (C-C)cycloalkylamino(C-C)alkyl, (C- Cs)cycloalkyl (C-C)alkylamino, (C-C)cycloalkyl (C-C) 50 alkylamino(C-C)alkyl, (C-C)cycloalkyl(C-C)alkoxy and D; and/or Het is optionally substituted on a ring nitrogen atom with a Substituent selected from the group consisting of hydroxy, (C-C)alkyl, halo(C-C)alkyl, amino(C-C)alkyl, (C-C) wherein 55 alkylamino(C-C)alkyl, di (C-C)alkylamino(C-C) Zis Het, optionally substituted on a ring carbonatom with alkyl, hydroxy(C-C)alkyl, (C-C)alkoxy(C-C)alkyl, one or more Substituents selected from the group consisting C(O)R’, C(O)OR, CH, C(O)R’, CH, C(O) of halo, cyano, (C-C)alkyl, halo(C-C)alkyl, (C-C) OR, CH, C(O) N(R), S(O).R., and S(O)N(R) alkoxy, halo(C-C)alkoxy, (C-C)cycloalkyl, (C-C)cy and D; cloalkyl (C-C)alkyl, (C-C)alkyl-S , amino, (C-C) 60 with the proviso that C is not 3,5-dioxo-4,5-dihydro-3H alkylamino, di(C-C)alkylamino, amino(C-C)alkyl, (C- 1.2.4 triazin-2-yl; C.)alkylamino(C-C)alkyl, and di(C-C)alkylamino(C- D is phenyl, benzyl, (C-Cs)cycloalkyl, or Het', each C.)alkyl; and/or Het is optionally substituted on a ring optionally Substituted on a carbon atom with one or more nitrogen atom with (C-C)alkyl, halo(C-C)alkyl and (C- Substituents independently selected from the group consist Cs)cycloalkyl; with the proviso that Z is not tetrazolyl: 65 ing of halo, cyano, hydroxy, (C-C)alkyl, halo(C-C)alkyl, Y',Y, Y and Y are each independently CH, CR' or N, (C-C)alkoxy, halo(C-C)alkoxy, amino, (C-C)alky provided that no more than two of Y',Y, Y- and Y are N: lamino, di(C-C)alkylamino, amino(C-C)alkyl, (C-C) US 8,907,101 B2 7 8 alkylamino(C-C)alkyl, di (C-C)alkylamino(C-C) As used herein the term alkoxy means an alicyclic, Satu alkyl, trifluoromethylthio, hydroxy(C-C)alkyl, (C-C) rated hydrocarbon chain of the formula OCH containing alkoxy(C-C)alkyl, -C(O)R. —C(O)OR, OC(O)R’, the requisite number of carbonatoms, which may be linear or —C(O) N(R), —CH C(O)R’, —CH C(O)CR, branched. Examples of alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, sec-butoxy and —CH, OC(O)R’, —CH C(O) N(R), S(O).R., and t-butoxy. S(O)N(R): Haloalkyl and haloalkoxy mean an alkyl or alkoxy group, Het' is a 3- to 8-membered, saturated or partially unsatur containing the requisite number of carbonatoms, Substituted ated monocyclic heterocyclic group comprising one or two or with one or more halo atoms as hereinbefore defined. three ring members selected from NR , —O , 10 The term “hydroxy' as used herein means an OH group. —C(O)— and -S(O) ; Specific examples of cycloalkyl include cyclopropyl. R is either the point of attachment to X or C to give cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, prefer ably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl each of which may be optionally substituted as specified. 15 Specific examples of Het' include oxiranyl, aziridinyl, oxetanyl, aZetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahy dropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, pip erazinyl, azepinyl, oxapinyl, oxazepinyl and diazepinyl (each optionally substituted as specified above). Specific examples of Het include pyrrolyl, furanyl, or R is selected from the group consisting of hydrogen, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, (C-C)alkyl, halo(C-C)alkyl, hydroxy(C-C)alkyl, (C- isothiazolyl, thiazolyl, triazolyloxadiazolyl, thiadiazolyl, tet C.)alkoxy(C-C)alkyl, —C(O)(C-C)alkyl, —C(O)C(C- razolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl C.)alkyl, —CH2—C(O)O(C-C)alkyl, —CH2—C(O)—N (optionally substituted as specified above). The structures of ((C-C)alkyl), S(O).R. S(O)N(R), and (C-Cs) 25 these groups are depicted below: cycloalkyl; p is 0, 1 or 2; and Het is a 5- or 6-membered aromatic heterocyclic group comprising either (a) 1 to 4 nitrogenatoms, (b) one oxygen or one Sulphur atom or (c) 1 oxygenatom or 1 Sulphur atom and 30 1 or 2 nitrogen atoms; pyrrole furan thio- pyrazole imida- isoxa or a tautomer thereof, or a pharmaceutically acceptable salt (pyrrolyl) (furanyl) phene (pyra- zole zole (thio- zolyl) (imida- (isoxa or solvate of the compound of formula (I), or its tautomer; phenyl) zolyl) zolyl 35 with the proviso that the compound of formula (I) is not the O S S O following specific compound: n N N N N N

\ N/ \ f \ N/ \, Nf \,N-N f \ N|| O N Ph oxazole isothia- thiazolyl 1,2,3- 1,3,4- 1-Oxa 40 (Oxa- zole (thia- triazole triazole 2,3- o1 N Ni- a NN zolyl) (isothia- zolyl) (1,2,3- (1,3,4- diazole zolyl) tria- tria- (1-Oxa O N O zolyl) zolyl) 2,3- diazolyl) O O O S S S 45 / 1. As used herein the term alkyl means an alicyclic, Saturated / hydrocarbon chain of the formula CH containing the S K S J S S A requisite number of carbon atoms, which may be linear or 1-Oxa- 1-Oxa- 1-Oxa- 1-thia- 1-thia- 1-thia branched. Examples of Such groups include methyl, ethyl, 2,4- 2.5- 3,4- 2,3- 2,4- 2.5- diazole diazole diazole diazole diazole diazole n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, tert-butyl, 50 (1-Oxa- (1-Oxa- (1-oxa- (1-thia- (1-thia- (1-thia pentyl, isoamyl and hexyl. Unless other wise specified the 2,4- 2.5- 3,4- 2,3- 2,4- 2.5- alkyl group contains from 1 to 6 carbon atoms. diazolyl) diazolyl) diazolyl) diazolyl) diazolyl) diazolyl) As used herein the term alkylene means a bivalent acyclic, H N N N N saturated hydrocarbon group of the formula CH2 containing 55 ( ( ) n SN s n the requisite number of carbonatoms, which may be linear or & J K || || branched. Examples of alkylene include methylene, 1,1-eth N-N N-N 2 21 2 4. ylene, 1.2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-pro 1-thia- tetra- pyridine pyrida- pyrimi- pyra pylene and 2.2-propylene. Unless otherwise specified the 3 4- zole (pyri- Zine dine Zine alkylene group contains from 1 to 6 carbon atoms. diazole (tetra- dinyl) (pyrida- (pyrimi- (pyra 60 (1-thia- zolyl) Zinyl) dinyl) py As used herein the term aryl means a phenyl ring or a 5- or 3,4- y y Zinyl) 6-membered aromatic heterocyclic group both of which can diazolyl) be optionally substituted with one or more substituents selected from the group consisting of halo, CN, halo(C-C) In the following embodiments of the invention, any group not alkyl, halo(C-C)alkoxy, and NO. 65 specifically defined has the same meaning as given for for As used herein the term halo means fluoro, chloro, bromo mula (I) above. In each case, where an embodiment covers a or iodo. compound where: US 8,907,101 B2 9 10 Z is tetrazolyl: either 2-thiazolyl or 4-thiazolyl each of which are either C is 3,5-dioxo-4,5-dihydro-3H-1.2.4 triazin-2-yl; or unsubstituted or monosubstituted on a ring carbonatom with a compound of formula halo, for example chloro; or Z is 1-thia-3,4-diazolyl which is unsubstituted; or Z is 1-thia-2,4-diazolyl which is unsubsti tuted. O N Ph In an alternative Embodiment (2.4), the invention provides o1 N Ni- 21 NN a compound of formula (I), or a pharmaceutically acceptable salt, Solvate or tautomer thereof, according to Embodiment 1, O N O wherein Z is 6-membered aromatic heterocyclic group com 10 prising 1 to 4 nitrogen atoms, and Z is optionally substituted as defined in Embodiment 1. In Embodiment (2.5), the invention provides a compound Such compounds are excluded. of formula (I), or a pharmaceutically acceptable salt, Solvate In Embodiment (2), the invention provides a compound of or tautomer thereof, according to Embodiment 1, wherein Zis formula (I), or a pharmaceutically acceptable salt, Solvate or 15 pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, more pref tautomer thereof, according to Embodiment 1, wherein Z is erably pyridinyl, pyridazinyl, or pyrimidinyl and Z is option Het, optionally substituted as defined in Embodiment 1, with ally substituted as defined in Embodiment 1. the proviso that Z is not tetrazolyl. In Embodiment (2.5a), the invention provides a compound In Embodiment (2a), the invention provides a compound of of formula (I), or a pharmaceutically acceptable salt, Solvate formula (I), or a pharmaceutically acceptable salt, Solvate or or tautomer thereof, according to Embodiment 1, wherein Zis tautomer thereof, according to Embodiment 1, wherein Z is pyridinyl, pyrazinyl, pyridaZinyl, or pyrimidinyl and Z is Het, optionally substituted as defined in Embodiment 1, with optionally Substituted on a ring carbon atom with halo, for the proviso that Z is not tetrazolyl or isoxazoyl. example chloro, or fluoro, (C-C)alkyl, for example methyl; In Embodiment (2.1), the invention provides a compound halo(C-C)alkyl, for example trifluoromethyl (C-C) of formula (I), or a pharmaceutically acceptable salt, Solvate 25 alkoxy, for example methoxy, or cyano. or tautomerthereof, according to Embodiment 1, wherein Zis In Embodiment (2.6) the invention provides a compound of a 5-membered aromatic heterocyclic group comprising either formula (I), or a pharmaceutically acceptable salt, Solvate or thiophenyl, or comprises either (a) 1 to 3 nitrogenatoms or (c) tautomer thereof, according to Embodiment 1, wherein Z is 1 oxygen atom or 1 Sulphur atom and 1 or 2 nitrogen atoms, pyrimidinyl, which is unsubstituted; or Z is pyridinyl which is and Z is optionally substituted as defined in Embodiment 1. 30 Substituted on a ring carbon with halo, for example fluoro; or In Embodiment (2.2), the invention provides a compound Z is pyridazinyl, which is unsubstituted. of formula (I), or a pharmaceutically acceptable salt, solvate In another Embodiment (2.7), the invention provides a or tautomerthereof, according to Embodiment 1, wherein Zis compound of formula (I), or a pharmaceutically acceptable thiophenyl, imidazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, salt, Solvate or tautomer thereof, according to Embodiment 1, 5-thiazolyl, 1-thia-3,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-2, 35 wherein Z is Het substituted on a ring nitrogen as defined in 4-diazolyl, 1-thia-2,3-diazolyl, 1,3,4-triazolyl, oxazolyl, Embodiment 1. Preferably Z is imidazolyl substituted on a pyrazolyl, 1-Oxa-2,5-diazolyl, or isoxazolyl, and Z is option ring nitrogen, more preferably Substituted on a ring nitrogen ally substituted as defined in Embodiment 1. with (C-C)alkyl, for example methyl. In Embodiment (2.2a), the invention provides a compound In Embodiment (3), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, Solvate or of formula (I), or a pharmaceutically acceptable salt, Solvate 40 tautomer thereof, according to any preceding Embodiment, or tautomerthereof, according to Embodiment 1, wherein Zis wherein Y and Y cannot both be N; more preferably, no imidazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, more than one of Y', Y, Y and Y is N. 1-thia-3,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-2,4-diazolyl, In Embodiment (3.1), the invention provides a compound 1-thia-2,3-diazolyl, 1.3,4-triazolyl, oxazolyl and Z is option of formula (I), or a pharmaceutically acceptable salt, Solvate ally substituted as defined in Embodiment 1. 45 or tautomer thereof, according to any preceding Embodi In Embodiment (2.2b), the invention provides a compound ment, wherein of formula (I), or a pharmaceutically acceptable salt, Solvate Y' is N, Y is CR', and Y and Y are each CH; or or tautomerthereof, according to Embodiment 1, wherein Zis Y is N, Y is CR', and Y and Y are each CH; or 2-thiazolyl, 4-thiazolyl, 1-thia-3,4-diazolyl or 1-thia-2,4-dia Y', Yi, Y and Y are each independently CH or CR', Zolyl and Z is optionally substituted as defined in Embodi 50 where preferably no more than two of Y', Y, Y and Y are ment 1. CR". In Embodiment (2.2c), the invention provides a compound In Embodiment (3.2), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, Solvate of formula (I), or a pharmaceutically acceptable salt, Solvate or tautomerthereof, according to Embodiment 1, wherein Zis or tautomer thereof, according to any preceding Embodi thiophenyl, imidazolyl, isothiazolyl, 2-thiazolyl, 4-thiazolyl, 55 ment, wherein 5-thiazolyl, 1-thia-3,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-2, Y', Y, Y and Y are each CH; or 4-diazolyl, 1-thia-2,3-diazolyl, 1,3,4-triazolyl, oxazolyl, Y' is CR', and Y.Y. and Y are each CH; or pyrazolyl, 1-Oxa-2,5-diazolyl, or isoxazolyl, and Z is either Y is CR" and Y', Yand Y are each CH; or unsubstituted or optionally Substituted on a ring carbonatom Y and Y are CR and Y and Y are CH; or with halo, for example bromo, chloro, fluoro or iodio; (C- 60 Y' and Y are CR' and Y and Y are CH; or C.)alkyl, for example methyl, ethyl or isopropyl: (C-C) Y and Y are CR and Y and Y are CH. alkoxy, for example methoxy or ethoxy; (C-C)alkyl-S—, In Embodiment (3.3), the invention provides a compound for example CHS ; or cyano; or optionally substituted on a of formula (I), or a pharmaceutically acceptable salt, Solvate ring nitrogen atom with (C-C)alkyl, for example methyl. or tautomer thereof, according to any preceding Embodi In Embodiment (2.3), the invention provides a compound 65 ment, wherein of formula (I), or a pharmaceutically acceptable salt, Solvate Y is CR, and Y, Y and Y are each CH; or or tautomerthereof, according to Embodiment 1, wherein Zis Y' and Y are CR' and Y and Y are CH. US 8,907,101 B2 11 12 In Embodiment (4), the invention provides a compound of wherein B is a 5-membered aromatic heterocyclic group formula (I), or a pharmaceutically acceptable salt, Solvate or comprising either (a) 1 to 3 nitrogen atoms, or (c) 1 oxygen tautomer thereof, according to any preceding Embodiment, atom or 1 Sulphur atom and 1 or 2 nitrogen atoms, more wherein each R" is independently selected from the group preferably where B is a 5-membered aromatic heterocyclic consisting of halo, cyano, (C-C)alkyl, halo(C-C)alkyl, group comprising either (a) 1 to 3 nitrogen atoms, or (c) 1 (C-C)alkoxy, —C(O)H, NH and —C(O)NH; more pref oxygen atom or 1 Sulphur atom and 1 or 2 nitrogenatoms but erably, each R" is independently selected from the group is not pyrazolyl, optionally substituted as defined in Embodi consisting of fluoro, chloro, bromo, iodo, cyano, methyl, ment 1. ethyl, trifluoromethyl, methoxy, —C(O)H, NH, and —C(O) In Embodiment (5c), the invention provides a compound of NH. 10 formula (I), or a pharmaceutically acceptable salt, Solvate or In Embodiment (4.1), the invention provides a compound tautomer thereof, according to any preceding Embodiment, of formula (I), or a pharmaceutically acceptable salt, Solvate wherein B is a 6-membered aromatic heterocyclic group or tautomer thereof, according to any preceding Embodi comprising 1 or 2 nitrogen atoms optionally Substituted as ment, whereinY' is N.Y. is CR', and Y and Y are each CH defined in Embodiment 1. and R' is independently selected from halo, for example 15 chloro; or cyano. In Embodiment (5.1), the invention provides a compound In Embodiment (4.2), the invention provides a compound of the formula (I), or a pharmaceutically acceptable salt, of formula (I), or a pharmaceutically acceptable salt, Solvate Solvate or tautomer thereof, according to any preceding or tautomer thereof, according to any preceding Embodi Embodiment, wherein B is phenyl, thiazolyl, thiadiazolyl, ment, wherein one ofY, Yi, YorY are CR', and the others pyrazolyl, triazolyl pyridinyl, pyrimidinyl, pyridazinyl or are each CH, and R' is independently selected from halo, for pyrazinyl, and wherein B is optionally substituted as defined example fluoro, chloro or iodo; cyano; (C-C)alkyl, for in Embodiment 1. example methyl or ethyl; halo(C-C)alkyl, for example trif In Embodiment (5.1a), the invention provides a compound luoromethyl, (C-C)alkoxy, for example methoxy; and of the formula (I), or a pharmaceutically acceptable salt, —C(O)NH2. 25 Solvate or tautomer thereof, according to any preceding In yet another alternative preferred embodiment (4.3), the Embodiment, wherein B is phenyl, thiazolyl, thiadiazolyl, invention provides a compound of formula (I), or a pharma triazolyl pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, ceutically acceptable salt, Solvate or tautomer thereof, and wherein B is optionally substituted as defined in Embodi according to any preceding Embodiment, whereinY' is CR', ment 1. and Y.Y. and Y are each CH and R' is cyano. 30 In a most preferred Embodiment (5.2), the invention pro In yet another alternative preferred embodiment (4.4), the vides a compound of the formula (I), or a pharmaceutically invention provides a compound of formula (I), or a pharma acceptable salt, solvate or tautomer thereof, according to any ceutically acceptable salt, Solvate or tautomer thereof, preceding Embodiment, wherein B is phenyl, optionally Sub according to any preceding Embodiment, wherein two of Y stituted as defined in Embodiment 1. Y.Y. and Y are CR' and the other two are CH and each R' 35 In Embodiment (5.3), the invention provides a compound is independently selected from halo, for example fluoro, of formula (I), or a pharmaceutically acceptable salt, Solvate chloro or bromo: cyano; and (C-C)alkyl, for example or tautomer thereof, according to any preceding Embodi methyl. ment, wherein B is unsubstituted; or is substituted on a ring In Embodiment (4.5), the invention provides a compound carbon atom with one or two substituents independently of formula (I), or a pharmaceutically acceptable salt, Solvate 40 selected from the group consisting of halo, cyano, (C-C) or tautomer thereof, according to any preceding Embodi alkyl, halo(C-C)alkyl, (C-C)alkoxy, halo(C-C)alkoxy, ment, whereinY' and Y are CR' and Y and Y are CH and cyano (C-C)alkyl, amino, (C-C)alkylamino, di(C-C) each R" is independently selected from halo, for example alkylamino, hydroxy(C-C)alkyl, (C-C)alkoxy(C-C) fluoro or chloro; or (C-C)alkyl, for example methyl. For alkyl, -C(O)OR, —C(O) N(R), —CH C(O) N example, both R" groups are fluoro. Alternatively one is 45 (R), and (C-Cs)cycloalkyl; and/or fluoro and the other chloro. Yet another alternative is where is Substituted on a ring nitrogen atom with one or two one R' group is fluoro and the other R' group is methyl. Substituents independently selected from the group consist In Embodiment (5), the invention provides a compound of ing of (C-C)alkyl, halo(C-C)alkyl, hydroxy(C-C)alkyl, formula (I), or a pharmaceutically acceptable salt, Solvate or CH, C(O)R’, or CHC(O)OR tautomer thereof, according to any preceding Embodiment, 50 In Embodiment (5.4), the invention provides a compound wherein B is selected from the group consisting of of formula (I), or a pharmaceutically acceptable salt, Solvate (i) phenyl: or tautomer thereof, according to any preceding Embodi (ii) 5-membered aromatic heterocyclic group comprising ment, wherein B is unsubstituted; or is substituted on a ring either (a) 1 to 3 nitrogen atoms, or (c) 1 oxygen atom or 1 carbon atom with one or two substituents selected from Sulphur atom and 1 or 2 nitrogen atoms; 55 cyano, methyl, ethyl, i-propyl. i-butyl, t-butyl, trifluorom (iii) 6-membered aromatic heterocyclic group comprising ethyl, 2.2.2-trifluoroethyl, C(CH),CN, methoxy, difluo 1 or 2 nitrogen atoms; romethoxy, trifluoromethoxy, hydroxymethyl, hydroxyethyl, and wherein B is optionally substituted as defined in hydroxypropyl, hydroxybutyl, methoxymethyl, bromo, Embodiment 1. chloro, fluoro, iodo, NH, -NH(CH), —N(CH), In Embodiment (5a), the invention provides a compound of 60 CH, C(O) NH, C(O) N(CH), —C(O)OCH formula (I), or a pharmaceutically acceptable salt, Solvate or and cyclopropyl; and/or tautomer thereof, according to any preceding Embodiment, is Substituted on a ring nitrogen atom with one or two wherein B is phenyl optionally substituted as defined in substituents selected from methyl, t-butyl, hydroxyethyl, Embodiment 1. —CHC(O)H, —CH2—C(O)O CHCH or 2.2.2-trifluo In Embodiment (5b), the invention provides a compound of 65 roethyl. formula (I), or a pharmaceutically acceptable salt, Solvate or In Embodiment (5.5), the invention provides a compound tautomer thereof, according to any preceding Embodiment, of formula (I), or a pharmaceutically acceptable salt, Solvate US 8,907,101 B2 13 14 or tautomer thereof, according to any preceding Embodi ment, wherein C is Het, attached to X, or directly to ring B if ment, wherein B is phenyl, which is unsubstituted; or X is absent, at a carbon atom and optionally Substituted as is Substituted on a ring carbon with one Substituent selected defined in Embodiment 1. from halo, for example fluoro, chloro, bromo, or iodo; cyano; In Embodiment (6.1a), the invention provides a compound (C-C)alkyl, for example methyl, ethyl, i-propyl, or i-butyl: 5 of formula (I), or a pharmaceutically acceptable salt, Solvate halo(C-C)alkyl, for example trifluoromethyl, (C-C) or tautomer thereof, according to any preceding Embodi alkoxy, for example methoxy; cyano(C-C)alkyl, for ment, wherein C is Het', attached to X, or directly to ring B if example C(CH)CN; halo(C-C)alkoxy, for example dif X is absent, at a carbon atom and optionally Substituted as luoromethoxy, or trifluoromethoxy; hydroxy(C-C)alkyl, defined in Embodiment 1. for example hydroxymethyl, hydroxyethyl, hydroxypropyl. 10 In Embodiment (6.2), the invention provides a compound or hydroxybutyl: (C-C)alkoxy(C-C)alkyl, for example of the formula (I), or a pharmaceutically acceptable salt, methoxymethyl; —C(O)OR, for example when R is (C- Solvate or tautomer thereof, according to any preceding C.)alkyl, for example methyl, to form —C(O)OCH: Embodiment, wherein C is a 5-membered aromatic hetero —C(O) N(R), for example when R is (C-C)alkyl, for 15 cyclic group comprising either (a) 1 to 4 nitrogen atoms, (b) example methyl, to form —C(O)—N(CH), and (C-Cs) one oxygen or one Sulphur atom or (c) 1 oxygen atom or 1 cycloalkyl, for example cyclopropyl; or Sulphur atom and 1 or 2 nitrogenatoms, for example furanyl. is Substituted on a ring carbon with two Substituents inde pyrazolyl; imidazolyl: 1,2,3-triazolyl: 1,3,4-triazolyl; tetra pendently selected from halo, for example fluoro, chloro or Zolyl; thiazolyl; isothiazolyl: oxazolyl; isoxazolyl; or 1-Oxa bromo; and (C-C)alkyl, for example methyl, to form, for 2,4-diazolyl, each optionally substituted as defined in example difluoro; dichloro; dibromo; fluoro, chloro; or Embodiment 1. chloro, methyl. In another even more preferred Embodiment (6.2a), the In Embodiment (5.6) the invention provides a compound of invention provides a compound of the formula (I), or a phar formula (I), or a pharmaceutically acceptable salt, Solvate or maceutically acceptable salt, Solvate or tautomer thereof, tautomer thereof, according to any preceding Embodiment, 25 according to any preceding Embodiment, wherein C is a wherein B is phenyl, which is substituted on a ring carbon 6-membered aromatic heterocyclic group comprising either with one substituent selected from halo, for example fluoro, (a) 1 to 4 nitrogenatoms, (b) one oxygen or one Sulphur atom or chloro; halo(C-C)alkyl, for example trifluoromethyl; or or (c) 1 oxygen atom or 1 Sulphur atom and 1 or 2 nitrogen halo (C-C)alkoxy, trifluoromethoxy; or atoms, for example pyridinyl, pyrazinyl, pyridazinyl, or pyri 30 midinyl, each optionally substituted as defined in Embodi is Substituted on a ring carbon with two Substituents, ment 1. selected from halo, for example fluoro, or chloro; halo(C- In yet another even more preferred Embodiment (6.2b), the C.)alkyl, for example trifluoromethyl; or halo(C-C)alkoxy, invention provides a compound of the formula (I), or a phar trifluoromethoxy. For example one substituent is fluoro and maceutically acceptable salt, Solvate or tautomer thereof, the other chloro. Alternatively one substituent is fluoro and 35 according to any preceding Embodiment, wherein C is a 3- to the other is trifluoromethyl. 8-membered, Saturated or partially unsaturated monocyclic In a preferred Embodiment (6), the invention provides a heterocyclic group comprising one or two ring members compound of formula (I), or a pharmaceutically acceptable selected from NR , —O , —C(O) , for example aze salt, Solvate or tautomer thereof, according to any preceding tidinyl; pyrrolidinyl, piperidinyl, oxetanyl; tetrahydropyra Embodiment, wherein C is (C-C)cycloalkyl, for example 40 nyl; pyrrolidonyl; imidazolidonyl: or morpholinyl, each cyclopropyl or cyclohexyl, optionally Substituted as defined optionally substituted as defined in Embodiment 1. in Embodiment 1. In yet further preferred Embodiment (6.3) the invention In Embodiment (6a), the invention provides a compound of provides a compound of the formula (I), or a pharmaceuti formula (I), or a pharmaceutically acceptable salt, Solvate or cally acceptable salt, Solvate or tautomerthereof, according to tautomer thereof, according to any preceding Embodiment, 45 any preceding Embodiment, wherein C is phenyl; cyclopro wherein the C ring, at the atom where it attaches to X, or pyl; cyclohexyl, pyrazolyl; furanyl, imidazolyl: 1,2,3-triaz directly to ring B if X is absent, is not further substituted olyl: 1,2,4-triazolyl: 1,3,4-triazolyl; tetrazolyl; thiazolyl: except that Such an atom may be substituted by hydrogen if isothiazolyl, oxazolyl; isoxazolyl: 1-oxa-2,4-diazolyl, chemically possible. pyridinyl; pyrazinyl; pyridazinyl; pyrimidinyl; azetidinyl: In Embodiment (6b), the invention provides a compound of 50 pyrrolidinyl, piperidinyl, oxetanyl; tetrahydropyranyl; pyr formula (I), or a pharmaceutically acceptable salt, Solvate or rolidonyl, imidazolidonyl; or morpholinyl, each optionally tautomer thereof, according to any preceding Embodiment, substituted as defined in Embodiment 1. wherein C is phenyl, optionally substituted as defined in In Embodiment (6.3a), the invention provides a compound Embodiment 1. of the formula (I), or a pharmaceutically acceptable salt, In Embodiment (6c), the invention provides a compound of 55 Solvate or tautomer thereof, according to any preceding formula (I), or a pharmaceutically acceptable salt, Solvate or Embodiment, wherein C is pyrazolyl; pyridinyl; pyridazinyl: tautomer thereof, according to any preceding Embodiment, pyrimidinyl; azetidinyl; piperidinyl; or tetrahydropyranyl: wherein C is Het', optionally substituted as defined in each optionally substituted as defined in Embodiment 1. Embodiment 1. In Embodiment (6.4) the invention provides a compound of In Embodiment (6d), the invention provides a compound of 60 the formula (I), or a pharmaceutically acceptable salt, Solvate formula (I), or a pharmaceutically acceptable salt, Solvate or or tautomer thereof, according to any preceding Embodi tautomer thereof, according to any preceding Embodiment, ment, wherein C is unsubstituted; or wherein C is Het, optionally substituted as defined in C is Substituted on a ring carbon atom with one or two Embodiment 1. Substituents selected from the group consisting of halo, In Embodiment (6.1), the invention provides a compound 65 cyano, hydroxy, (C-C)alkyl, halo(C-C)alkyl, (C-C) of formula (I), or a pharmaceutically acceptable salt, Solvate alkoxy, halo(C-C)alkoxy, (R)-amino, (R)-amino(C-C) or tautomer thereof, according to any preceding Embodi alkyl, hydroxy(C-C)alkyl, (C-C)alkoxy(C-C)alkyl, US 8,907,101 B2 15 16 —C(O)R’, -CH, O C(O)R.-C(O) NH, -C(O)— example methyl or t-butyl; and D, wherein D is (C-C) N(R), (C-Cs)cycloalkoxy, and D; and/or cycloalkyl, for example cyclopropyl, which is unsubstituted; when C is Het it is substituted on a ring nitrogenatom with and/or one Substituent selected from the group consisting of (C-C) which is Substituted on a ring nitrogen atom with one alkyl, halo(C-C)alkyl, di(C-C)alkylamino(C-C)alkyl, Substituent selected from (C-C)alkyl, for example methyl, hydroxy(C-C)alkyl, (C-C)alkoxy(C-C)alkyl, —C(O) ethyl or t-butyl; halo (C-C)alkyl, for example difluorom R. CH, C(O)O-R-CH C(O) NR; and D; and/ ethyl, trifluoromethyl, 2.2.2-trifluoroethyl, or 3,3,3-trifluoro O propyl, (C-C)alkoxy(C-C)alkyl, for example methoxy when C is Het', R is optionally selected from the group of ethyl, di(C-C)alkylamino(C-C)alkyl, for example 10 (CH.)N(CH3); C(O)R’, wherein R is (C-C)alkyl, for Substituents consisting of hydrogen, (C-C)alkyl, or—C(O) example t-butyl, -CH C(O)OR wherein R is indepen (C-C)alkyl. dently selected from hydrogen, or (C-C)alkyl, for example In Embodiment (6.5) the invention provides a compound of ethyl:—CH C(O) N(R), wherein both R are selected the formula (I), or a pharmaceutically acceptable salt, Solvate from hydrogen, or (C-C)alkyl, for example methyl; and D. or tautomer thereof, according to any preceding Embodi 15 for example phenyl, which is unsubstituted; benzyl, which is ment, wherein C is unsubstituted; or unsubstituted; (C-C)cycloalkyl, for example cyclopropylor C is Substituted on a ring carbon atom with one or two cyclobutyl: Het', for example azetidinyl which is attached to Substituents selected from the group consisting of chloro, the C ring via a carbon atom, more preferably via a carbon fluoro, cyano, hydroxy, methyl, ethyl, i-proyl, t-butyl, difluo atom at the 3 position and which azetidinyl is unsubstituted, romethyl, trifluoromethyl, methoxy, ethoxy, i-propoxy, trif or which is substituted on the Natom with (C-C)alkyl, for luoromethoxy, NH, N(CH), —CH-NH NH(cy example methyl, ethyl or isopropyl, or C(O)(C-C)alkyl, for clobutyl), —CHN-azetidinyl, —CHN-3,3- example C(O)CH; or piperidinyl which is unsubstituted, or difluoroazetidinyl, —CHN-3,3-dihydroxymethylazetidinyl, which is substituted on the Natom with (C-C)alkyl, for —CHN-3-hydroxypyrrolidinyl hydroxymethyl, hydroxy example methyl; or ethyl, methoxymethyl, -methoxyethyl, —C(O)CH, —C(O) 25 dioxidotetrahydro-3-thienyl which is unsubstituted; or tet OH, -CHC(O)OCH, -CHOC(O)CF, C(O) NH, rahydrofuranyl, which is unsubstituted. —C(O) N(CH), C(O) NH(t-butyl), C(O) NH(cy In Embodiment (6.7), the invention provides a compound clopropyl), —C(O)N-azetidinyl, —C(O)N-3-methylazetidi of formula (I), or a pharmaceutically acceptable salt, Solvate nyl cyclobutyloxy, and D, wherein D is cyclopropyl, cyclo or tautomer thereof, according to any preceding Embodi hexyl, aZetidinyl, morpholinyl and piperazinyl; and/or 30 ment, wherein C is pyrazolyl, which is unsubstituted, or which is substituted on a ring carbon atom with one substitu when C is Het, it is substituted on a ring nitrogen atom ent selected from (C-C)alkyl, for example methyl; or with one substituent selected from the group consisting of amino; or which is substituted on a ring nitrogen atom with hydroxy, methyl, ethyl, t-butyl, difluoromethyl, trifluorom one Substituent selected from (C-C)alkyl, for example ethyl, 2.2.2-trifluoroethyl, 3-fluoropropyl, (CH)N(CH), 35 methyl; or D, for example azetidinyl wherein R is hydrogen hydroxyethyl, methoxyethyl, —C(O)CH, —CH C(O) or (C-C)alkyl, for example methyl or ethyl. Preferably the O CHCH-CH C(O)OH, -CH C(O) N(CH), pyrazolyl is attached to X, or directly to ring B if X is absent, and D, wherein D is phenyl, benzyl, cyclopropyl, cyclobutyl, via a carbonatom, more preferably via a carbonatom at the 3 dioxidotetrahydro-3-thienyl, azetidinyl, N-methylazetidinyl, position. N-ethylazetidinyl, N-isopropylazetidinyl, tetrahydrafuranyl, 40 In Embodiment (6.8), the invention provides a compound piperidinyl, N-methylpiperidinyl; and/or of formula (I), or a pharmaceutically acceptable salt, Solvate when C is Het', R is either the point of attachment to X; or tautomer thereof, according to any preceding Embodi hydrogen, methyl or C(O)CH, C(O)OCH, C(O)OC(CH). ment, wherein C is pyridinyl, which is unsubstituted, or In an even more preferred Embodiment (6.6), invention which is substituted on a ring carbon atom with one substitu provides a compound of formula (I), or a pharmaceutically 45 ent selected from hydroxy; halo, for example fluoro or chloro; acceptable salt, Solvate or tautomer thereof, according to any cyano; (C-C)alkyl, for example methyl; halo(C-C)alkyl, preceding Embodiment, wherein C is pyrazolyl, which is for example trifluoromethyl; (C-C)alkoxy, for example preferably attached to X, or directly to ring B if X is absent, methoxy; N(R), wherein R is selected from hydrogen, or via a carbon atom, more preferably via the carbon at the 3 (C-C)alkyl, for example methyl, or (C-C)cycloalkyl, for position or the carbon at the 4 position and most preferably 50 example cyclobutyl, to give for example amino, N(CH), via the carbon at the 3 position. NH(cyclobutyl); N(R), (C-C)alkyl, for example N-azetidi In Embodiment (6.6a), invention provides a compound of nylmethyl, 3.3-difluoro-N-azetidinylmethyl; hydroxy(C- formula (I), or a pharmaceutically acceptable salt, Solvate or C.)alkyl, for example hydroxymethyl: C(O)N(R), for tautomer thereof, according to any preceding Embodiment, example C(O)N-azetidinyl: (C-C)cycloalkoxy, for example wherein C is pyrazolyl, which is unsubstituted, or 55 cyclobutoxy; and D, wherein D is Het', for example azetidi which is substituted on a ring carbonatom with one or two nyl, morpholinyl, or piperazinyl, all of which are unsubsti substituents independently selected from halo, for example tuted; or D is pyridinyl is Substituted on a ring nitrogen with fluoro, chloro; cyano; hydroxy, (C-C)alkyl, for example hydroxy. methyl; halo(C-C)alkyl, for example difluoromethyl or tri In Embodiment (6.9), the invention provides a compound fluoromethyl, (C-C)alkoxy, for example methoxy, ethoxy, 60 of formula (I), or a pharmaceutically acceptable salt, Solvate i-propoxy, methoxymethy, or methoxyethyl; amino; di(C- or tautomer thereof, according to any preceding Embodi C.)alkylamino, for example N(CH), hydroxy(C-C)alkyl, ment, wherein C is pyridinyl, which is substituted on a ring for example hydroxymethyl:—C(O)CR, wherein R is (C- carbon atom with one substituent selected from N(R), C.)alkyl, for example ethyl: —CH, O C(O)R’ wherein wherein R is selected from hydrogen, or (C-C)alkyl, for R’ is independently selected from halo(C-C)alkyl, for 65 example methyl, to give, for example amino, or N(CH), example trifluoromethyl; —C(O) N(R), wherein R is N(R)-(C-C)alkyl, wherein R is selected from hydrogen to independently selected from hydrogen, or (C-C)alkyl, for give, for example aminomethyl, or both R groups are US 8,907,101 B2 17 18 selected from (C-C)alkyl and are taken together with the N or tautomer thereof, according to any preceding Embodi to which they are attached to form a 4 membered ring to give, ment, wherein when B is phenyl, X is absent, and C is phenyl: for example, N-azetidinylmethyl, (C-C)cycloalkoxy, for (C-Cs)cycloalkyl, for example cyclopropyl: Het', for example cyclobutoxy; or D where D is Het', for example example, aZetidinyl, piperidinyl, oxetanyl, tetrahydropyra piperazinyl. 5 nyl, pyrrolidonyl, imidazolidonyl: phenyl: or Het, for In Embodiment (6.10), invention provides a compound of example furanyl, pyrazolyl, imidazolyl, 1.2.3-triazolyl, 1.2, formula (I), or a pharmaceutically acceptable salt, Solvate or 4-triazolyl, 1,3,4-triazolyl, tetrazolyl, thiazolyl, isothiazolyl, tautomer thereof, according to any preceding Embodiment, oxazolyl, isoxazolyl, 1-oxa-2,4-diazolyl pyridinyl, pyrazi wherein C is pyridazinyl, which is unsubstituted; or substi nyl, pyridazinyl, or pyrimidinyl. tuted on a ring carbon with halo, for example chloro. 10 In Embodiment (7.3), the invention provides a compound In Embodiment (6.11), invention provides a compound of of formula (I), or a pharmaceutically acceptable salt, Solvate formula (I), or a pharmaceutically acceptable salt, Solvate or or tautomer thereof, according to any preceding Embodi tautomer thereof, according to any preceding Embodiment, ment, wherein when B is phenyl, X is absent, and C is aze wherein C is azetidinyl, which is preferably attached to X via tidinyl, piperidinyl, tetrahydropyranyl pyrazolyl pyridinyl, a carbon atom, more preferably the carbon at the 3 position 15 pyridazinyl or pyrimidinyl. and R is selected from H or C(O)(C-C)alkyl, for example In Embodiment (7.4), the invention provides a compound —C(O)—CH, C(O)O(C-C)alkyl, for example —C(O) of formula (I), or a pharmaceutically acceptable salt, Solvate O CH. or tautomer thereof, according to any preceding Embodi In Embodiment (6.12), the invention provides a compound ment, wherein when B is phenyl, X is O, and C is phenyl; or of formula (I), or a pharmaceutically acceptable salt, Solvate Het, for example, pyridinyl. or tautomer thereof, according to any preceding Embodi In Embodiment (7.5), the invention provides a compound ment, wherein C is azetidinyl which is attached to X, or of formula (I), or a pharmaceutically acceptable salt, Solvate directly to ring B if X is absent, via a carbon atom, more or tautomer thereof, according to any preceding Embodi preferably the carbon at the 3 position and where R is ment, wherein when B is phenyl, X is CH, and C is (C-C) selected from H. 25 cycloalkyl, for example cyclopropyl; Het', for example, aze In Embodiment (6.13), the invention provides a compound tidinyl, morpholinyl, pyrrolidonyl, piperidinyl: or Het, for of formula (I), or a pharmaceutically acceptable salt, Solvate example, pyrazolyl, 1.3,4-triazolyl, imidazolyl, isoxazolyl, or tautomer thereof, according to any preceding Embodi or pyridinyl. ment, wherein C is piperidinyl, which is preferably attached In Embodiment (7.6), the invention provides a compound to X, or directly to ring B if X is absent, via a carbon atom, 30 of formula (I), or a pharmaceutically acceptable salt, Solvate more preferably the carbon at the 4 position, and which pip or tautomer thereof, according to any preceding Embodi eridinyl is unsubstituted, or which is substituted on a ring ment, wherein when B is phenyl, X is OCH, and C phenyl. carbon with two substituents selected from halo, for example In Embodiment (7.7), the invention provides a compound fluoro; or where R is selected from H., (C-C)alkyl, for of formula (I), or a pharmaceutically acceptable salt, Solvate example methyl, or C(O)C(C-C)alkyl, for example—C(O) 35 or tautomer thereof, according to any preceding Embodi O—C(CH). ment, wherein when B is pyrazolyl. X is absent, and Cphenyl: In Embodiment (6.14), the invention provides a compound (C-Cs)cycloalkyl, for example cyclohexyl; or Het, for of formula (I), or a pharmaceutically acceptable salt, Solvate example, pyridinyl. or tautomer thereof, according to any preceding Embodi In Embodiment (7.8), the invention provides a compound ment, wherein C is piperidinyl, which is attached to X, or 40 of formula (I), or a pharmaceutically acceptable salt, Solvate directly to ring B if X is absent, via a carbon atom at the 4 or tautomer thereof, according to any preceding Embodi position and which is unsubstituted. ment, wherein when B is pyrazolyl, X is CH, and Cisphenyl. In Embodiment (6.15), invention provides a compound of In Embodiment (7.9), the invention provides a compound formula (I), or a pharmaceutically acceptable salt, Solvate or of formula (I), or a pharmaceutically acceptable salt, Solvate tautomer thereof, according to any preceding Embodiment, 45 or tautomer thereof, according to any preceding Embodi wherein C is tetrahydropyranyl, which is preferably attached ment, wherein when B is thiazolyl, X is CH, and C is phenyl. to X, or directly to ring B if X is absent, via a carbon atom, In Embodiment (7.10), the invention provides a compound more preferably the carbon at the 4 position, and which tet of formula (I), or a pharmaceutically acceptable salt, Solvate rahydropyranyl is unsubstituted. or tautomer thereof, according to any preceding Embodi In Embodiment (6.16), the invention provides a compound 50 ment, wherein when B is pyridinyl, X is absent, and C is of formula (I), or a pharmaceutically acceptable salt, Solvate phenyl or Het, for example, pyrazolyl. or tautomer thereof, according to any preceding Embodi In Embodiment (7.11), the invention provides a compound ment, wherein C is pyrimidinyl, which is substituted on a ring of formula (I), or a pharmaceutically acceptable salt, Solvate carbon atom with one substituent selected from N(R), for or tautomer thereof, according to any preceding Embodi example amino; or D where D is Het', for example N-azetid 55 ment, wherein when B is pyridinyl, X is O, and C is phenyl. nyl, N-morpholinyl or N-piperazinyl, most preferably piper In Embodiment (7.12), the invention provides a compound azinyl wherein R is hydrogen. of formula (I), or a pharmaceutically acceptable salt, Solvate In Embodiment (7) the invention provides a compound of or tautomer thereof, according to any preceding Embodi formula (I), or a pharmaceutically acceptable salt, Solvate or ment, wherein when B is pyrimidnyl, X is absent, and C is tautomer thereof, according to any preceding Embodiment, 60 phenyl. wherein X is absent, —O—, methylene, or —O-methylene. In Embodiment (7.13), the invention provides a compound In Embodiment (7.1), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, Solvate of formula (I), or a pharmaceutically acceptable salt, Solvate or tautomer thereof, according to any preceding Embodi or tautomer thereof, according to any preceding Embodi ment, wherein when B is pyridazinyl, X is absent, and C is ment, wherein X is absent. 65 phenyl. In Embodiment (7.2), the invention provides a compound In Embodiment (7.14), the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, Solvate of formula (I), or a pharmaceutically acceptable salt, Solvate US 8,907,101 B2 19 20 or tautomer thereof, according to any preceding Embodi wherein Z. Y', Yi, Y.Y., X and Careas defined in any of ment, wherein when B is pyrazinyl, X is absent, and C is the preceding Embodiments; phenyl. each R" is independently selected from the group consist In Embodiment (8), the invention provides a compound of ing of halo, cyano, hydroxy, (C-C)alkyl, halo(C-C)alkyl, the formula (Ia) 5 (C-C)alkoxy, halo (C-C)alkoxy, cyano (C-C)alkyl, amino, (C-C)alkylamino, di(C-C)alkylamino, amino(C- C.)alkyl, (C-C)alkylamino(C-C)alkyl, di(C-C)alkyl (Ia) amino(C-C)alkyl, trifluoromethylthio. hydroxy(C-C) alkyl, (C-C)alkoxy(C-C)alkyl, -C(O)R’, —C(O)OR, 10 X -Y. \/S Z –OC(O)R’, C(O) N(R), —CH C(O)R’, —CH2— 1. 21 Yl N NN1 C(O)OR, CH, OC(O)R, CH, C(O) N(R), H S(O).R. S(O)N(R), (C-Cs)cycloalkyl, and (C-Cs)cy cloalkyl (C-C)alkyl, SAS --- and (R) 15 n is 0, 1 or 2. It will be appreciated that compounds of the formula (Ib) or a pharmaceutically acceptable salt, Solvate or tautomer are also embraced by formula (I) and that formula (Ib) is a thereof, preferred, subgroup of the formula (I). wherein Z. Y', Y.Y.Y,X and Careas defined in any of the In Embodiment (9.1), the invention provides a compound preceding Embodiments; of the formula (Ib) according to Embodiment 9, and C is a each R" is independently selected from the group consisting 5-membered aromatic heterocyclic group comprising either of halo, cyano, hydroxy, (C-C)alkyl, halo(C-C)alkyl, (C- (a) 1 to 4 nitrogenatoms, (b) one oxygen or one Sulphur atom C.)alkoxy, halo(C-C)alkoxy, cyano(C-C)alkyl, amino, or (c) 1 oxygen atom or 1 Sulphur atom and 1 or 2 nitrogen (C-C)alkylamino, di(C-C)alkylamino, amino(C-C) 25 atoms; optionally substituted as defined in Embodiment 1. alkyl, (C-C)alkylamino(C-C)alkyl, di(C-C)alkyl In Embodiment (9.2), the invention provides a compound amino(C-C)alkyl, trifluoromethylthio, hydroxy(C-C) of the formula (Ib) according to Embodiment 9, and each R' alkyl, (C-C)alkoxy(C-C)alkyl, -C(O)R. —C(O)CR, is independently selected from the group consisting of halo, –OC(O)R’, C(O) N(R), —CH C(O)R’, —CH cyano, (C-C)alkyl, halo(C-C)alkyl, (C-C)alkoxy, halo C(O)OR, CH, OC(O)R, CH, C(O) N(R), 30 (C-C)alkoxy, amino, (C-C)alkylamino, di(C-C)alky S(O).R. S(O)N(R), (C-Cs)cycloalkyl, and (C-Cs)cy lamino, hydroxy(C-C)alkyl, (C-C)alkoxy(C-C)alkyl, cloalkyl (C-C)alkyl: —C(O)CR, —C(O) N(R), —CH, C(O) N(R), and and (C-C)cycloalkyl. n is 0, 1 or 2. Specific preferred compounds according to the invention It will be appreciated that compounds of the formula (Ia) 35 are those listed in the Examples section below and the phar are also embraced by formula (I) and that formula (Ia) is a maceutically acceptable salts and Solvates thereof. preferred, subgroup of the formula (I). In Embodiment (8.1), the invention provides a compound DETAILED DESCRIPTION of the formula (Ia) according to Embodiment 8, and C is a 5-membered aromatic heterocyclic group comprising either 40 As used herein the term compounds of the invention (a) 1 to 4 nitrogenatoms, (b) one oxygen or one Sulphur atom means, unless otherwise stated, compounds of formula (I), or (c) 1 oxygen atom or 1 Sulphur atom and 1 or 2 nitrogen formula (Ia), formula (Ib), and compounds of Embodiment 1, atoms; optionally substituted as defined in Embodiment 1. Embodiment 2, Embodiment 2a, Embodiment 2.1, Embodi In Embodiment (8.2), the invention provides for a com ment 2.2, Embodiment 2.2a, Embodiment 2.2b, Embodiment pound of formula (Ia) according to Embodiment 8, and each 45 2.2c, Embodiment 2.3, Embodiment 2.4, Embodiment 2.5, R" is independently selected from the group consisting of Embodiment 2.5a, Embodiment 2.6, Embodiment 2.7, halo, cyano, (C-C)alkyl, halo (C-C)alkyl, (C-C)alkoxy, Embodiment 3, Embodiment 3.1, Embodiment 3.2, Embodi halo(C-C)alkoxy, amino, (C-C)alkylamino, di(C-C) ment 3.3, Embodiment 4, Embodiment 4.1, Embodiment 4.2, alkylamino, hydroxy(C-C)alkyl, (C-C)alkoxy(C-C) Embodiment 4.3, Embodiment 4.4, Embodiment 4.5, alkyl, -C(O)OR, C(O) N(R), —CH C(O) N 50 Embodiment 5, Embodiment 5a, Embodiment 5b, Embodi (R), and (Cs-Cs)cycloalkyl. ment 5c, Embodiment 5.1, Embodiment 5.1a, Embodiment In Embodiment (9), the invention provides a compound of 5.2. Embodiment 5.3, Embodiment 5.4, Embodiment 5.5, the formula (Ib) Embodiment 5.6, Embodiment 6, Embodiment 6a, Embodi ment 6b, Embodiment 6c, Embodiment 6d, Embodiment 6.1, 55 Embodiment 6.1a, Embodiment 6.2, Embodiment 6.2a, (Ib) Embodiment 6.2b, Embodiment 6.3, Embodiment 6.3a, O O Embodiment 6.4, Embodiment 6.5, Embodiment 6.6, \/ Embodiment 6.6a, Embodiment 6.7, Embodiment 6.8, 21 11's Sn - Z. Embodiment 6.9, Embodiment 6.10, Embodiment 6.11, n(R) l Y3 H 60 Embodiment 6.12, Embodiment 6.13, Embodiment 6.14, N O 41 Embodiment 6.15, Embodiment 6.16, Embodiment 7, Embodiment 7.1, Embodiment 7.2. Embodiment 7.3, X n Embodiment 7.4, Embodiment 7.5, Embodiment 7.6, Embodiment 7.7, Embodiment 7.8, Embodiment 7.9, 65 Embodiment 7.10, Embodiment 7.11, Embodiment 7.12, or a pharmaceutically acceptable salt, Solvate or tautomer Embodiment 7.13, Embodiment 7.14, Embodiment 8, thereof, Embodiment 8.1, Embodiment 8.2, Embodiment 9, Embodi US 8,907,101 B2 21 22 ment 9.1, and Embodiment 9.2. In each case, where the Y is NR, oxygen or sulphur atom; embodiment covers the compound according to the formula Y and Y are each independently selected from CR or below: nitrogen atoms; provided that Y.Y. and Y cannot all be nitrogen; and O each R" is independently selected from the group consist N | Ph ing of hydrogen, halo, cyano, (C-C)alkyl, halo (C-C) 1N Nii 21 NN alkyl, (C-C)alkoxy, halo(C-C)alkoxy, (C-C)cycloalkyl, o O S. O amino, (C-C)alkylamino and di(C-C)alkylamino; 10 tautomerism may occur to provide for example, a com pound of the formula (Id). it is excluded. Illustratively, when compounds of formula (Ic) comprise a Some compounds of the formula (I), (Ia) or (Ib), according nitrogen atom at Ya third tautomer, may also exist which is to any one of the preceding Embodiments, may exist in sev 15 represented below by formula (Ie) below: eral different tautomeric forms. Tautomerism, or tautomeric isomerism, occurs where structural isomers are interconvert ible via a low energy barrier. It can take the form of proton (Ie) H tautomerism, so called Valence tautomerism in compounds M which contain an aromatic moiety. In some compounds dif 5-N ferent tautomeric isomers may exist with respect to the posi V/ Y y tion of certain protecting groups or prodrug moieties. Illus -Y& \/ 2 M trative examples of such tautomeric forms are provided below 11 ns NN N but one of ordinary skill in the art would understand that many different tautomeric forms of Such compounds may be pos C-X-B Y3 sible and that the examples provided below are not exhaus 25 No 6 tive. Therefore, all references to compound of formula (I), (Ia) or (Ib), according to any one of the preceding Embodi Furthermore, when the compound of formula (I), (Ia) or ments, should be taken to include tautomers thereof, whether (Ib), according to any one of the preceding Embodiments, is illustrated or not. Furthermore, the illustrative examples pro vided below indicate situations where certain atoms are sub 30 a compound of the formula (If), as shown below, or a phar stituted with hydrogen. However, one of ordinary skill in the maceutically acceptable salt or solvate thereof, wherein: art would also understand that Such tautomeric forms may Y',Y,Y,Y, B, X and Care as defined in any one of the also exist when such atoms are Substituted by certain protect Embodiments above; ing groups or with prodrug Substitutents. As such the disclo Y.Y. Y' and Y''' are selected from CR, or a nitrogen sure herein is intended to also describe such alternative tau 35 atom in accordance with the definition of Z in Embodiment 1 tomeric forms. Furthermore, one of ordinary skill would above; and each R is independently selected from the group understand that certain intermediates used in the preparation consisting of hydrogen, halo, cyano, (C-C)alkyl, halo(C- of compounds capable of tautomerising are themselves C.)alkyl, (C-C)alkoxy, halo(C-C)alkoxy, (C-C)cy capable of existing in different tautomeric forms. cloalkyl, amino, (C-C)alkylamino and di(C-C)alky One such illustrative example is when the compound of 40 lamino; tautomerism may occur to provide for example, a formula (I), (Ia) or (Ib), according to any one of the preceding compound of the formula (Ig). Additionally, two other tau Embodiments, is a compound of the formula (Ic): tomers are possible represented by formulae (Ih) and (Ii). If Y' is a nitrogenatom then a compound of the formula (Ih) is possible and if Y is a nitrogen atom then a compound of Q p *s-Y \, 45 formula (II) is possible. Y2 \/ s/ 11'N, NN N H 9 C-X-B 2Y O O sen O No 1 50 (Ic) Y Y2 \/ N

C-X-B NorY3 No % 6 55 (If) O O rV. 11'N, \/n 4 N 9 C-X-B 2Y H O O sen O O Y4 60 y11 Y2N \/NN 2 r or a pharmaceutically acceptable salt or Solvate thereof, c-X-Bs, 2Y R4a wherein: 65 Y',Y,Y,Y, B, X and Careas defined in any one of the (Ig) Embodiments above; US 8,907,101 B2 23 24 -continued For a review of such complexes, see J Pharm Sci, 64 (8), Yg H 1269-1288 by Haleblian (August 1975). O O ys? N1 V/ Hereinafter all references to compounds of formula (I) -YS Sna 2Y' include references to Salts, Solvates and complexes thereof n N N and to Solvates and complexes of salts thereof. C-X-B 2Y The compounds of the invention include compounds of No Y4 formula (I) as hereinbefore defined, polymorphs, prodrugs (Ih) (including tautomeric forms of Such prodrugs), and isomers H Yg 10 thereof (including optical, geometric and tautomeric isomers) O O nN2 Ny10 as hereinafter defined and isotopically-labeled compounds of Y2 \/ 2 2J. formula (I). l N n 2 As stated, the invention includes all polymorphs of the C-X-B 2Y 15 compounds of formula (I) as hereinbefore defined. No Y4 Also within the scope of the invention are so-called pro drugs of the compounds of formula (I). Thus certain deriva tives of compounds of formula (I) which may have little or no All references to compounds of the invention, or to com pharmacological activity themselves can, when administered pounds of formulae (I), (Ia), and (Ib), should therefore be into or onto the body, be converted into compounds of for taken to include, where appropriate, the tautomeric isomers mula (I) having the desired activity, for example, by hydro of the compounds, as exemplified by formulae (Ic). (Id). (Ie), lytic cleavage. Such derivatives are referred to as prodrugs. (If). (Ig). (Ih), and (Ii) above. Further information on the use of prodrugs may be found in Pharmaceutically acceptable salts of the compounds of Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Sympo 25 sium Series (T Higuchi and W Stella) and Bioreversible formula (I) include the acid addition and base salts thereof. Carriers in Drug Design, Pergamon Press, 1987 (ed. E B Suitable acid addition salts are formed from acids which Roche, American Pharmaceutical Association). form non-toxic salts. Examples include the acetate, aspartate, Prodrugs in accordance with the invention can, for benzoate, besylate, bicarbonate/carbonate, bisulphate/sul example, be produced by replacing appropriate functional phate, borate, camsylate, citrate, edisylate, esylate, formate, 30 ities present in the compounds of formula (I) with certain fumarate, gluceptate, gluconate, glucuronate, hexafluoro moieties known to those skilled in the art as pro-moieties as phosphate, hibenzate, hydrochloride/chloride, hydrobro described, for example, in “Design of Prodrugs” by H Bund mide/bromide, hydroiodide/iodide, isothionate, lactate, gaard (Elsevier, 1985). malate, maleate, malonate, mesylate, methylsulphate, naph One skilled in the art would recognise that many different thylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, 35 pro-drug forms of compounds of the present invention are palmitate, pamoate, phosphate/hydrogen phosphate? dihydro possible. However, some illustrative examples of prodrugs in gen phosphate, Saccharate, Stearate. Succinate, tartrate, tosy accordance with the invention include: late and trifluoroacetate salts. Suitable base salts are formed from bases which form (i) where the compound of formula (I) contains a carboxy non-toxic salts. Examples include the aluminium, arginine, 40 lic acid functionality benZathine, calcium, choline, diethylamine, diolamine, gly (—COOH), an ester thereof, for example, replacement of cine, lysine, magnesium, meglumine, olamine, potassium, the hydrogen with (C-Cs)alkyl; Sodium, tromethamine and Zinc salts. (ii) where the compound of formula (I) contains an alcohol For a review on suitable salts, see “Handbook of Pharma functionality ( OH), an ether thereof, for example, replace ceutical Salts: Properties, Selection, and Use' by Stahl and 45 ment of the hydrogen with (C-C)alkanoyloxymethyl; and Wermuth (Wiley-VCH. Weinheim, Germany, 2002). A pharmaceutically acceptable salt of a compound of for (iii) where the compound of formula (I) contains a primary mula (I) may be readily prepared by mixing together solu or secondary amino functionality ( NH, or NHR where tions of the compound of formula (I) and the desired acid or RzH), an amide thereof, for example, replacement of one or base, as appropriate. The salt may precipitate from Solution 50 both hydrogens with (C-Co.)alkanoyl. and be collected by filtration or may be recovered by evapo A particularly useful prodrug of compounds of formula (I) ration of the solvent. The degree of ionisation in the salt may which have a general formula (Ic), is formed by replacement vary from completely ionised to almost non-ionised. of the hydrogen of the —NH-group of the sulphonamide The compounds of the invention may exist in both unsol moiety or the hydrogen of the NH-group of the 1,3-thiaz vated and solvated forms. The term solvate is used hereinto 55 olyl ring of such compounds is replaced by a prodrug moiety describe a molecular complex comprising the compound of (Prodrug) which is either —CHOP(=O)(OR), or -CHC the invention and one or more pharmaceutically acceptable (=O)R’ wherein R' is selected from the group consisting of solvent molecules, for example, ethanol. The term hydrate is hydrogen or (C-C)alkyl, for example —C(CH). Such employed when said solvent is water. compounds are prepared by reaction of the —NH-group of Included within the scope of the invention are complexes 60 the sulphonamide moiety or the NH-group of the 1,3- Such as clathrates, drug-host inclusion complexes wherein, in thiazolyl ring of the compounds of formula (Ic) with eitheran contrast to the aforementioned solvates, the drug and host are alkyl linked phosphate, such as an alkyl linked phosphoric present in Stoichiometric or non-stoichiometric amounts. acid oran alkyl linked phosphate ester, or with an alkyl linked Also included are complexes of the drug containing two or carboxylic acid group, such as an alkyl linked carboxylic acid more organic and/or inorganic components which may be in 65 or an alkyl linked carboxylic ester. Such prodrug compounds Stoichiometric or non-stoichiometric amounts. The resulting can generally be schematically represented as shown below complexes may be ionised, partially ionised, or non-ionised. by formula (Ic") or its tautomeric form (Id"): US 8,907,101 B2 25 26 wherein the counterion is optically active, for example, (Ic") D-lactate or L-lysine, or racemic, for example, DL-tartrate or -Y. DL-arginine. Q p \, Cis/trans isomers may be separated by conventional tech -Y. \/SS1's N niques well known to those skilled in the art, for example, chromatography and fractional crystallisation. r Conventional techniques for the preparation/isolation of C-x-Bs, 2Y Prodrug individual enantiomers include chiral synthesis from a suit Y6 (Id') able optically pure precursor or resolution of the racemate (or Q p \,, 10 the racemate of a salt orderivative) using, for example, chiral Y3 \/ high pressure liquid chromatography (HPLC) 11's 1n21 N Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for C-X-BN 2Y Prodrug 15 example, an alcohol, or, in the case where the compound of O formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting wherein C, X, B, Y.Y.Y.Y., Y, Y, Y7 are as defined diastereomeric mixture may be separated by chromatography above for compounds of formula (Ic) and Prodrug is a pro and/or fractional crystallization and one or both of the drug moiety as defined above. Phosphate prodrugs have been diastereoisomers converted to the corresponding pure enan generally described in, for example, Rautio, J., Kumpulainen, tiomer(s) by means well known to a skilled person. H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savol Chiral compounds of the invention (and chiral precursors ainen, J. Nat. Rev. Drug Discovery 2008, 7, 255. Carboxylic thereof) may be obtained in enantiomerically-enriched form acid and related ester prodrugs have been generally described using chromatography, typically HPLC, on an asymmetric in Calheiros, T.: Iley, J.; Lopes, F. Moreira, R. Bioorg. Med. 25 resin with a mobile phase consisting of a hydrocarbon, typi Chem. Lett. 1995, 5,937 and in Lopes. F.; Moreira, R.; Iley, J. cally heptane or hexane, containing from 0 to 50% isopro Bioorg. Med. Chem. 2000, 8,707. panol, typically from 2 to 20%, and from 0 to 5% of an When forming such prodrugs it is preferred that the hydro alkylamine, typically 0.1% diethylamine. Concentration of gen of the NH-group of the Sulphonamide moiety or the the eluate affords the enriched mixture. hydrogen of the NH-group of the 1,3-thiazolyl ring of such 30 Stereoisomeric conglomerates may be separated by con compounds is replaced by —CHOP(=O)(OR"), in particu ventional techniques known to those skilled in the art—see, lar wherein R' is hydrogen to give —CHOP(=O)(OH), for example, "Stereochemistry of Organic Compounds” by E or where R' is C(CH) to give —CHOP(=O)(OC L Eliel (Wiley, New York, 1994). (CH3)) – The present invention includes all pharmaceutically As such, in yet another embodiment, Embodiment 10, the 35 acceptable isotopically-labelled compounds of formula (I) invention provides for a prodrug of compounds of formula wherein one or more atoms are replaced by atoms having the (Ic") wherein the hydrogen of the NH-group of the sulpho same atomic number, but an atomic mass or mass number namide moiety or the hydrogen of the -NH-group of the different from the atomic mass or mass number usually found 1,3-thiazolyl ring of such compounds is replaced by either 40 in nature. CHOP(=O)(OR") or -CHC(=O)R’ wherein R' is Examples of isotopes suitable for inclusion in the com selected from the group consisting of hydrogen or (C-C) pounds of the invention include isotopes of hydrogen, such as alkyl, for example - C(CH), or a pharmaceutically accept Hand H, carbon, such as 'C, 'Cand C, chlorine, such as able salt, solvate or tautomer thereof. Cl, fluorine, such as 'F, iodine, such as 'I and 'I, Further examples of replacement groups in accordance 45 nitrogen, such as 'N and 'N, oxygen, such as 'O, ''O and with the foregoing examples and examples of other prodrug 'O, phosphorus, such as P. and sulphur, such as S. types may be found in the aforementioned references. Certain isotopically-labelled compounds of formula (I), As used herein, unless otherwise specified, references to for example, those incorporating a radioactive isotope, are formula (I) also encompass references to prodrugs, and salts, useful in drug and/or substrate tissue distribution studies. The solvates or tautomers thereof, such as those of Embodiment 50 radioactive isotopes tritium, i.e. H, and carbon-14, i.e. ''C, (10). and 'I are particularly useful for this purpose in view of Finally, certain compounds of formula (I) may themselves their ease of incorporation and ready means of detection. act as prodrugs of other compounds of formula (I). Substitution with heavier isotopes such as deuterium, i.e. Compounds of formula (I) containing one or more asym *H, may afford certain therapeutic advantages resulting from 55 greater metabolic stability, for example, increased in vivo metric carbon atoms can exist as two or more stereoisomers. half-life or reduced dosage requirements, and hence may be Where a compound of formula (I) contains an alkenyl or preferred in some circumstances. alkenylene group, geometric cis/trans (or Z/E) isomers are Substitution with positron emitting isotopes, such as 'C, possible. Where the compound contains, for example, a keto 'F, C and 'N, can be useful in Positron Emission Topog or oxime group or an aromatic moiety, tautomeric isomerism 60 raphy (PET) studies for examining substrate receptor occu (tautomerism) can occur. It follows that a single compound pancy. may exhibit more than one type of isomerism. Isotopically-labeled compounds of formula (I) can gener Included within the scope of the present invention are all ally be prepared by conventional techniques known to those stereoisomers, geometric isomers and tautomeric forms of skilled in the art or by processes analogous to those described the compounds of formula (I), including compounds exhib 65 in the accompanying Examples and Preparations using an iting more than one type of isomerism, and mixtures of one or appropriate isotopically-labeled reagents in place of the non more thereof. Also included are acid addition or base salts labeled reagent previously employed. US 8,907,101 B2 27 28 Pharmaceutically acceptable Solvates in accordance with different Subtypes according to differing pathophysiology, the invention include those wherein the solvent of crystalli including nociceptive, inflammatory and neuropathic pain. Zation may be isotopically Substituted, e.g. DO, de-acetone, Nociceptive pain is induced by tissue injury or by intense d-DMSO. stimuli with the potential to cause injury. Pain afferents are The compounds of formula (I), being Nav1.7 channel activated by transduction of stimuli by nociceptors at the site modulators, are potentially useful in the treatment of a range of injury and activate neurons in the spinal cord at the level of of disorders. The treatment of pain, particularly neuropathic, their termination. This is then relayed up the spinal tracts to nociceptive and inflammatory pain, is a preferred use. the brain where pain is perceived (Meyer et al., 1994, Text Physiological pain is an important protective mechanism book of Pain, 13-44). The activation of nociceptors activates 10 two types of afferent nerve fibres. Myelinated A-delta fibres designed to warn of danger from potentially injurious stimuli transmit rapidly and are responsible for sharp and stabbing from the external environment. The system operates through pain sensations, whilst unmyelinated C fibres transmit at a a specific set of primary sensory neurones and is activated by slower rate and convey a dull or aching pain. Moderate to noxious stimuli via peripheral transducing mechanisms (see severe acute nociceptive pain is a prominent feature of pain Millan, 1999, Prog. Neurobiol. 57, 1-164 for a review). 15 from central nervous system trauma, strains/sprains, burns, These sensory fibres are known as nociceptors and are char myocardial infarction and acute pancreatitis, post-operative acteristically Small diameter axons with slow conduction pain (pain following any type of Surgical procedure), post Velocities. Nociceptors encode the intensity, duration and traumatic pain, renal colic, cancer pain and back pain. Cancer quality of noxious stimulus and by virtue of their topographi pain may be chronic pain such as tumour related pain (e.g. cally organised projection to the spinal cord, the location of bone pain, headache, facial pain or visceral pain) or pain the stimulus. The nociceptors are found on nociceptive nerve associated with cancer therapy (e.g. postchemotherapy syn fibres of which there are two main types, A-delta fibres (my drome, chronic postSurgical pain syndrome or post radiation elinated) and C fibres (non-myelinated). The activity gener syndrome). Cancer pain may also occur in response to che ated by nociceptor input is transferred, after complex process motherapy, immunotherapy, hormonal therapy or radio ing in the dorsal horn, either directly, or via brain stem relay 25 therapy. Back pain may be due to herniated or ruptured inter nuclei, to the ventrobasal thalamus and then on to the cortex, vertabral discs or abnormalities of the lumber facet joints, where the sensation of pain is generated. sacroiliac joints, paraspinal muscles or the posterior longitu Pain may generally be classified as acute or chronic. Acute dinal ligament. Back pain may resolve naturally but in some pain begins Suddenly and is short-lived (usually twelve weeks patients, where it lasts over 12 weeks, it becomes a chronic or less). It is usually associated with a specific cause Such as 30 condition which can be particularly debilitating. a specific injury and is often sharp and severe. It is the kind of Neuropathic pain is currently defined as pain initiated or pain that can occur after specific injuries resulting from Sur caused by a primary lesion or dysfunction in the nervous gery, dental work, a strain or a sprain. Acute pain does not system. Nerve damage can be caused by trauma and disease generally result in any persistent psychological response. In and thus the term neuropathic pain encompasses many dis contrast, chronic pain is long-term pain, typically persisting 35 orders with diverse aetiologies. These include, but are not for more than three months and leading to significant psycho limited to, peripheral neuropathy, diabetic neuropathy, post logical and emotional problems. Common examples of herpetic neuralgia, trigeminal neuralgia, back pain, cancer chronic pain are neuropathic pain (e.g. painful diabetic neu neuropathy, HIV neuropathy, phantom limb pain, carpal tun ropathy, postherpetic neuralgia), carpal tunnel syndrome, nel syndrome, central post-stroke pain and pain associated back pain, headache, cancer pain, arthritic pain and chronic 40 with chronic alcoholism, hypothyroidism, uremia, multiple post-Surgical pain. Sclerosis, spinal cord injury, Parkinson's disease, epilepsy When a Substantial injury occurs to body tissue, via disease and vitamin deficiency. Neuropathic pain is pathological as it or trauma, the characteristics of nociceptor activation are has no protective role. It is often present well after the original altered and there is sensitisation in the periphery, locally cause has dissipated, commonly lasting for years, signifi around the injury and centrally where the nociceptors termi 45 cantly decreasing a patient’s quality of life (Woolf and Man nate. These effects lead to a heightened sensation of pain. In nion, 1999, Lancet, 353, 1959-1964). The symptoms of neu acute pain these mechanisms can be useful, in promoting ropathic pain are difficult to treat, as they are often protective behaviours which may better enable repair pro heterogeneous even between patients with the same disease cesses to take place. The normal expectation would be that (Woolf & Decosterd, 1999, Pain Supp., 6, S141-S147; Woolf sensitivity returns to normal once the injury has healed. How 50 and Mannion, 1999, Lancet, 353, 1959-1964). They include ever, in many chronic pain states, the hypersensitivity far spontaneous pain, which can be continuous, and paroxysmal outlasts the healing process and is often due to nervous sys or abnormal evoked pain, such as hyperalgesia (increased tem injury. This injury often leads to abnormalities in sensory sensitivity to a noxious stimulus) and allodynia (sensitivity to nerve fibres associated with maladaptationandaberrant activ a normally innocuous stimulus). ity (Woolf & Salter, 2000, Science, 288, 1765-1768). 55 The inflammatory process is a complex series of biochemi Clinical pain is present when discomfort and abnormal cal and cellular events, activated in response to tissue injury or sensitivity feature among the patient’s symptoms. Patients the presence of foreign Substances, which results in Swelling tend to be quite heterogeneous and may present with various and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56). pain symptoms. Such symptoms include: 1) spontaneous pain Arthritic pain is the most common inflammatory pain. Rheu which may be dull, burning, or stabbing; 2) exaggerated pain 60 matoid disease is one of the commonest chronic inflamma responses to noxious stimuli (hyperalgesia); and 3) pain pro tory conditions in developed countries and rheumatoid arthri duced by normally innocuous stimuli (allodynia—Meyer et tis is a common cause of disability. The exact aetiology of al., 1994, Textbook of Pain, 13-44). Although patients suffer rheumatoid arthritis is unknown, but current hypotheses Sug ing from various forms of acute and chronic pain may have gest that both genetic and microbiological factors may be similar symptoms, the underlying mechanisms may be dif 65 important (Grennan & Jayson, 1994, Textbook of Pain, 397 ferent and may, therefore, require different treatment strate 407). It has been estimated that almost 16 million Americans gies. Pain can also therefore be divided into a number of have symptomatic osteoarthritis (OA) or degenerative joint US 8,907,101 B2 29 30 disease, most of whom are over 60 years of age, and this is describe any ingredient other than the compound(s) of the expected to increase to 40 million as the age of the population invention. The choice of excipient will to a large extent increases, making this a public health problem of enormous depend on factors such as the particular mode of administra magnitude (Houge & Mersfelder, 2002, Ann Pharmacother. tion, the effect of the excipient on solubility and stability, and 36,679-686; McCarthy et al., 1994, Textbook of Pain, 387 5 the nature of the dosage form. 395). Most patients with osteoarthritis seek medical attention Pharmaceutical compositions suitable for the delivery of because of the associated pain. Arthritis has a significant compounds of the present invention and methods for their impact on psychosocial and physical function and is known to preparation will be readily apparent to those skilled in the art. be the leading cause of disability in later life. Ankylosing Such compositions and methods for their preparation may be spondylitis is also a rheumatic disease that causes arthritis of 10 the spine and Sacroiliac joints. It varies from intermittent found, for example, in Remington's Pharmaceutical Sci episodes of back pain that occur throughout life to a severe ences, 19th Edition (Mack Publishing Company, 1995). chronic disease that attacks the spine, peripheral joints and Oral Administration other body organs. The compounds of the invention may be administered Another type of inflammatory pain is visceral pain which 15 orally. Oral administration may involve Swallowing, so that includes pain associated with inflammatory bowel disease the compound enters the gastrointestinal tract, or buccal or (IBD). Visceral pain is pain associated with the viscera, which Sublingual administration may be employed by which the encompass the organs of the abdominal cavity. These organs compound enters the blood stream directly from the mouth. include the sex organs, spleen and part of the digestive sys Formulations suitable for oral administration include solid tem. Pain associated with the viscera can be divided into formulations such as tablets, capsules containing particulates, digestive visceral pain and non-digestive visceral pain. Com liquids, or powders, lozenges (including liquid-filled), chews, monly encountered gastrointestinal (GI) disorders that cause multi- and nano-particulates, gels, Solid solution, liposome, pain include functional bowel disorder (FBD) and inflamma films (including muco-adhesive), ovules, sprays and liquid tory bowel disease (IBD). These GI disorders include a wide formulations. range of disease states that are currently only moderately 25 Liquid formulations include Suspensions, solutions, syrups controlled, including, in respect of FBD, gastro-esophageal and elixirs. Such formulations may be employed as fillers in reflux, dyspepsia, irritable bowel syndrome (IBS) and func Soft or hard capsules and typically comprise a carrier, for tional abdominal pain syndrome (FAPS), and, in respect of example, water, ethanol, polyethylene glycol, propylene gly IBD, Crohn's disease, ileitis and ulcerative colitis, all of col, methylcellulose, or a suitable oil, and one or more emul which regularly produce visceral pain. Other types of visceral 30 Sifying agents and/or Suspending agents. Liquid formulations pain include the pain associated with dysmenorrhea, cystitis may also be prepared by the reconstitution of a solid, for and pancreatitis and pelvic pain. example, from a sachet. It should be noted that some types of pain have multiple The compounds of the invention may also be used in fast aetiologies and thus can be classified in more than one area, dissolving, fast-disintegrating dosage forms such as those e.g. back pain and cancer pain have both nociceptive and 35 described in Expert Opinion in Therapeutic Patents, 11 (6), neuropathic components. 981-986 by Liang and Chen (2001). Other types of pain include: For tablet dosage forms, depending on dose, the drug may pain resulting from musculo-skeletal disorders, including make up from 1 wt % to 80 wt % of the dosage form, more myalgia, fibromyalgia, spondylitis, sero-negative (non typically from 5 wt % to 60 wt % of the dosage form. In rheumatoid) arthropathies, non-articular rheumatism, 40 addition to the drug, tablets generally contain a disintegrant. dystrophinopathy, glycogenolysis, polymyositis and Examples of disintegrants include Sodium starch glycolate, pyomyositis; Sodium carboxymethyl cellulose, calcium carboxymethyl heart and vascular pain, including pain caused by angina, cellulose, croScarmellose sodium, crospovidone, polyvi myocardical infarction, mitral Stenosis, pericarditis, nylpyrrolidone, methyl cellulose, microcrystalline cellulose, Raynaud's phenomenon, Scleredoma and skeletal 45 lower alkyl-substituted hydroxypropyl cellulose, starch, muscle ischemia; pregelatinised starch and Sodium alginate. Generally, the dis head pain, such as migraine (including migraine with aura integrant will comprise from 1 wt % to 25 wt %, preferably and migraine without aura), cluster headache, tension from 5 wt % to 20 wt % of the dosage form. type headache mixed headache and headache associated Binders are generally used to impart cohesive qualities to a with vascular disorders; 50 tablet formulation. Suitable binders include microcrystalline erythermalgia; and cellulose, gelatin, Sugars, polyethylene glycol, natural and orofacial pain, including dental pain, otic pain, burning synthetic gums, polyvinylpyrrolidone, pregelatinised starch, mouth syndrome and temporomandibular myofascial hydroxypropyl cellulose and hydroxypropyl methylcellu pa1n. lose. Tablets may also contain diluents, such as lactose Compounds of the invention intended for pharmaceutical 55 (monohydrate, spray-dried monohydrate, anhydrous and the use may be administered as crystalline or amorphous prod like), mannitol, Xylitol, dextrose, Sucrose, Sorbitol, microc ucts. They may be obtained, for example, as solid plugs, rystalline cellulose, starch and dibasic calcium phosphate powders, or films by methods such as precipitation, crystal dihydrate. lization, freeze drying, spray drying, or evaporative drying. Tablets may also optionally comprise Surface active agents, Microwave or radio frequency drying may be used for this 60 Such as Sodium lauryl Sulfate and polysorbate 80, and glidants purpose. Such as silicon dioxide and talc. When present, Surface active They may be administered alone or in combination with agents may comprise from 0.2 wt % to 5 wt % of the tablet, one or more other compounds of the invention or in combi and glidants may comprise from 0.2 wt % to 1 wt % of the nation with one or more other drugs (or as any combination tablet. thereof). Generally, they will be administered as a formula 65 Tablets also generally contain lubricants such as magne tion in association with one or more pharmaceutically accept sium Stearate, calcium Stearate, Zinc Stearate, sodium Stearyl able excipients. The term “excipient' is used herein to fumarate, and mixtures of magnesium Stearate with sodium US 8,907,101 B2 31 32 lauryl Sulphate. Lubricants generally comprise from 0.25 wt mally. Typical formulations for this purpose include gels, % to 10 wt %, preferably from 0.5 wt % to 3 wt % of the tablet. hydrogels, lotions, solutions, creams, ointments, dusting Other possible ingredients include anti-oxidants, colou powders, dressings, foams, films, skin patches, wafers, rants, flavouring agents, preservatives and taste-masking implants, sponges, fibres, bandages and microemulsions. agents. 5 Liposomes may also be used. Typical carriers include alco Exemplary tablets contain up to about 80% drug, from hol, water, mineral oil, liquid petrolatum, white petrolatum, about 10 wt % to about 90 wt % binder, from about 0 wt % to glycerin, polyethylene glycol and propylene glycol. Penetra about 85 wt % diluent, from about 2 wt % to about 10 wt % tion enhancers may be incorporated—see, for example, J disintegrant, and from about 0.25 wt % to about 10 wt % Pharm Sci, 88 (10),955-958 by Finnin and Morgan (October lubricant. 10 Tablet blends may be compressed directly or by roller to 1999). form tablets. Tablet blends or portions of blends may alterna Other means of topical administration include delivery by tively be wet-, dry-, or melt-granulated, melt congealed, or electroporation, iontophoresis, phonophoresis, Sonophoresis extruded before tabletting. The final formulation may com and microneedle or needle-free (e.g. PowderjectTM, prise one or more layers and may be coated or uncoated; it 15 BiojectTM, etc.) injection. may even be encapsulated. Formulations for topical administration may beformulated The formulation of tablets is discussed in “Pharmaceutical to be immediate and/or modified release. Modified release Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. formulations include delayed-, Sustained-, pulsed-, con Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247 trolled-, targeted and programmed release. 6918-X). Inhaled/Intranasal Administration Solid formulations for oral administration may be formu The compounds of the invention can also be administered lated to be immediate and/or modified release. Modified intranasally or by inhalation, typically in the form of a dry release formulations include delayed-, Sustained-, pulsed powder (either alone, as a mixture, for example, in a dry blend controlled-, targeted and programmed release. with lactose, or as a mixed component particle, for example, Suitable modified release formulations for the purposes of 25 mixed with phospholipids, such as phosphatidylcholine) the invention are described in U.S. Pat. No. 6,106,864. Details from a dry powder inhaler or as an aerosol spray from a of other Suitable release technologies such as high energy pressurised container, pump, spray, atomiser (preferably an dispersions and osmotic and coated particles are to be found atomiser using electrohydrodynamics to produce a fine mist), in Verma et al., Pharmaceutical Technology On-line, 25(2), or nebuliser, with or without the use of a suitable propellant, 1-14 (2001). The use of chewing gum to achieve controlled 30 such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluo release is described in WOOO/35298. ropropane. For intranasal use, the powder may comprise a Parenteral Administration bioadhesive agent, for example, chitosan or cyclodextrin. The compounds of the invention may also be administered The pressurised container, pump, spray, atomizer, or nebu directly into the blood stream, into muscle, or into an internal liser contains a solution or Suspension of the compound(s) of organ. Suitable means for parenteral administration include 35 the invention comprising, for example, ethanol, aqueous etha intravenous, intraarterial, intraperitoneal, intrathecal, intra nol, or a suitable alternative agent for dispersing, solubilising, Ventricular, intraurethral, intrasternal, intracranial, intramus or extending release of the active, a propellant(s) as solvent cular and subcutaneous. Suitable devices for parenteral and an optional Surfactant, Such as Sorbitan trioleate, oleic administration include needle (including microneedle) injec acid, or an oligolactic acid. tors, needle-free injectors and infusion techniques. 40 Prior to use in a dry powder or Suspension formulation, the Parenteral formulations are typically aqueous solutions drug product is micronised to a size suitable for delivery by which may contain excipients such as salts, carbohydrates inhalation (typically less than 5 microns). This may be and buffering agents (preferably to a pH of from 3 to 9), but, achieved by any appropriate comminuting method, such as for some applications, they may be more Suitably formulated spiral jet milling, fluid bed jet milling, Supercritical fluid as a sterile non-aqueous solution or as a dried form to be used 45 processing to form nanoparticles, high pressure homogenisa in conjunction with a suitable vehicle Such as sterile, pyro tion, or spray drying. gen-free water. Capsules (made, for example, from gelatin or HPMC), The preparation of parenteral formulations under sterile blisters and cartridges for use in an inhaler or insufflator may conditions, for example, by lyophilisation, may readily be be formulated to contain a powder mix of the compound of accomplished using standard pharmaceutical techniques well 50 the invention, a Suitable powder base Such as lactose or starch known to those skilled in the art. and a performance modifier Such as 1-leucine, mannitol, or The solubility of compounds of formula (I) used in the magnesium Stearate. The lactose may be anhydrous or in the preparation of parenteral Solutions may be increased by the form of the monohydrate, preferably the latter. Other suitable use of appropriate formulation techniques, such as the incor excipients include dextran, glucose, maltose, Sorbitol, Xylitol, poration of Solubility-enhancing agents. 55 fructose, Sucrose and trehalose. Formulations for parenteral administration may be formu A Suitable solution formulation for use in anatomiser using lated to be immediate and/or modified release. Modified electrohydrodynamics to produce a fine mist may contain release formulations include delayed-, Sustained-, pulsed from 1 Jug to 20 mg of the compound of the invention per controlled-, targeted and programmed release. Thus com actuation and the actuation volume may vary from 1 Jul to 100 pounds of the invention may be formulated as a solid, semi 60 ul. A typical formulation may comprise a compound of for Solid, or thixotropic liquid for administration as an implanted mula (I), propylene glycol, sterile water, ethanol and sodium depot providing modified release of the active compound. chloride. Alternative solvents which may be used instead of Examples of Such formulations include drug-coated Stents propylene glycol include glycerol and polyethylene glycol. and PGLA microspheres. Suitable flavours, such as menthol and levomenthol, or Topical Administration 65 Sweeteners, such as Saccharin or saccharin Sodium, may be The compounds of the invention may also be administered added to those formulations of the invention intended for topically to the skin or mucosa, that is, dermally or transder inhaled/intranasal administration. US 8,907,101 B2 33 34 Formulations for inhaled/intranasal administration may be Thus the kit of the invention comprises two or more sepa formulated to be immediate and/or modified release using, for rate pharmaceutical compositions, at least one of which con example, poly(DL-lactic-coglycolic acid (PGLA). Modified tains a compound of formula (I) in accordance with the inven release formulations include delayed-, Sustained-, pulsed tion, and means for separately retaining said compositions, controlled-, targeted and programmed release. such as a container, divided bottle, or divided foil packet. An In the case of dry powder inhalers and aerosols, the dosage example of such a kit is the familiar blister pack used for the unit is determined by means of a valve which delivers a packaging of tablets, capsules and the like. metered amount. Units in accordance with the invention are The kit of the invention is particularly suitable for admin typically arranged to administer a metered dose or “puff istering different dosage forms, for example, oral and containing the compound of formula (I). The overall daily 10 parenteral, for administering the separate compositions at dose may be administered in a single dose or, more usually, as divided doses throughout the day. different dosage intervals, or for titrating the separate com Rectal/Intravaginal Administration positions against one another. To assist compliance, the kit The compounds of the invention may be administered rec typically comprises directions for administration and may be tally or vaginally, for example, in the form of a Suppository, 15 provided with a so-called memory aid. pessary, or enema. Cocoa butter is a traditional Suppository Dosage base, but various alternatives may be used as appropriate. For administration to human patients, the total daily dose Formulations for rectal/vaginal administration may befor of the compounds of the invention depends, of course, on the mulated to be immediate and/or modified release. Modified mode of administration. For example, oral administration release formulations include delayed-, Sustained-, pulsed may require a higher total daily dose, than an intravenous controlled-, targeted and programmed release. dose. The total daily dose may be administered in single or Ocular/Aural Administration divided doses. The compounds of the invention may also be administered For the avoidance of doubt, references herein to “treat directly to the eye or ear, typically in the form of drops of a ment' include references to curative, palliative and prophy micronised Suspension or solution in isotonic, pH-adjusted, 25 lactic treatment. sterile saline. Otherformulations suitable for ocular and aural Combinations administration include ointments, biodegradable (e.g. A Nav1.7 channel modulator may be usefully combined absorbable gel sponges, collagen) and non-biodegradable with another pharmacologically active compound, or with (e.g. silicone) implants, wafers, lenses and particulate or two or more other pharmacologically active compounds, par vesicular systems. Such as niosomes or liposomes. A polymer 30 ticularly in the treatment of pain. Such as crossed-linked polyacrylic acid, polyvinylalcohol, For example, a Nav1.7 channel modulator, particularly a hyaluronic acid, a cellulosic polymer, for example, hydrox compound of formula (I), or a pharmaceutically acceptable ypropylmethylcellulose, hydroxyethylcellulose, or methyl salt, solvate or tautomer thereof, as defined above, may be cellulose, or a heteropolysaccharide polymer, for example, administered simultaneously, sequentially or separately in gelangum, may be incorporated together with a preservative, 35 combination with one or more agents selected from: Such as benzalkonium chloride. Such formulations may also an alternative Nav1.7 channel modulator, for example one be delivered by iontophoresis. or more alternative compounds of the present invention, Formulations for ocular/aural administration may be for or alternatively those compounds disclosed in WO 2009/ mulated to be immediate and/or modified release. Modified O12242: release formulations include delayed-, Sustained-, pulsed 40 an alternative sodium channel modulator, Such as a Nav1.3 controlled-, targeted, or programmed release. modulator, for example those disclosed in WO 2008/ Other Technologies 118758; or a Nav1.8 modulator, for example those dis The compounds of the invention may be combined with closed in WO 2008/135826, more particularly N-6- soluble macromolecular entities, such as cyclodextrin and Amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl)-1- suitable derivatives thereof or polyethylene glycol-contain 45 methyl-1H-pyrazole-5-carboxamide: ing polymers, in order to improve their solubility, dissolution a compound which increases the levels of endocannabinoid rate, taste-masking, bioavailability and/or stability for use in Such as compounds with fatty acid amid hydrolase any of the aforementioned modes of administration. inhibitory (FAAH) activity, in particular those disclosed Drug-cyclodextrin complexes, for example, are found to be in WO 2008/047229, more particularly N-pyridazin-3- generally useful for most dosage forms and administration 50 yl-4-(3-5-(trifluoromethyl)pyridine-2-yl) routes. Both inclusion and non-inclusion complexes may be oxybenzylidene)piperidine-1-carboxamide: used. As an alternative to direct complexation with the drug, a compound which is an inhibitor of mPGES-1; the cyclodextrin may be used as an auxiliary additive, i.e. as an opioid analgesic, e.g. morphine, heroin, hydromor a carrier, diluent, or solubiliser. Most commonly used for phone, oxymorphone, levorphanol, levallorphan, these purposes are alpha-, beta- and gamma-cyclodextrins, 55 methadone, meperidine, fentanyl, cocaine, codeine, examples of which may be found in International Patent dihydrocodeine, oxycodone, hydrocodone, pro Applications Nos. WO 91/11 172, WO 94/02518 and WO poxyphene, nalmefene, nalorphine, naloxone, naltrex 98/55148. one, buprenorphine, butorphanol, nalbuphine or penta Kit-of-Parts Zocine; Inasmuch as it may desirable to administer a combination 60 a nonsteroidal antiinflammatory drug (NSAID), e.g. aspi of active compounds, for example, for the purpose of treating rin, diclofenac, diflusinal, etodolac, fenbufen, fenopro a particular disease or condition, it is within the scope of the fen, flufenisal, flurbiprofen, ibuprofen, indomethacin, present invention that two or more pharmaceutical composi ketoprofen, ketorolac, meclofenamic acid, mefenamic tions, at least one of which contains a compound in accor acid, meloxicam, nabumetone, naproxen, nimeSulide, dance with the invention, may conveniently be combined in 65 nitroflurbiprofen, olsalazine, Oxaprozin, phenylbuta the form of a kit suitable for coadministration of the compo Zone, piroXicam, Sulfasalazine, Sulindac, tolmetin or sitions. Zomepirac: US 8,907,101 B2 35 36 a barbiturate sedative, e.g. amobarbital, aprobarbital, but a 5-HT receptor agonist or antagonist, particularly a abarbital, butabital, mephobarbital, metharbital, metho 5-HT, agonist Such as eletriptan, Sumatriptan, hexital, pentobarbital, phenobartital, secobarbital, talb naratriptan, Zolmitriptan or rizatriptan; utal, theamylal or thiopental; a 5-HT2 receptor antagonist Such as R(+)-alpha-(2,3- a benzodiazepine having a sedative action, e.g. chlordiaz dimethoxy-phenyl)-1-2-(4-fluorophenylethyl)-4-pip epoxide, cloraZepate, diazepam, flurazepam, eridinemethanol (MDL-100907); lorazepam, oxazepam, temazepam or triazolam; a cholinergic (nicotinic) analgesic, such as ispronicline an H antagonist having a sedative action, e.g. diphenhy (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1- dramine, pyrilamine, promethazine, chlorpheniramine amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2- or chlorcyclizine; 10 chloropyridine (ABT-594) or nicotine; Tramadol(R); a sedative such as glutethimide, meprobamate, methaqua a PDEV inhibitor, such as 5-2-ethoxy-5-(4-methyl-1-pip lone or dichloralphenaZone; erazinyl-Sulphonyl)phenyl-1-methyl-3-n-propyl-1,6- a skeletal muscle relaxant, e.g. baclofen, carisoprodol, dihydro-7H-pyrazolo 4,3-dipyrimidin-7-one (sildena chlorZoxaZone, cyclobenzaprine, methocarbamol or 15 fil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6- orphrenadine; (3.4-methylenedioxyphenyl)-pyrazino 2', 1:6,1-pyrido an NMDA receptor antagonist, e.g. dextromethorphan 3,4-bindole-1,4-dione (IC-351 or tadalafil), 2-2- ((+)-3-hydroxy-N-methylmorphinan) or its metabolite ethoxy-5-(4-ethylpiperazin-1-yl-l-Sulphonyl)-phenyl dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ket 5-methyl-7-propyl-3H-imidazo[5.1-f1.2.4 triazin-4- amine, memantine, pyrroloquinoline quinine, cis-4- one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3- (phosphonomethyl)-2-piperidinecarboxylic acid, ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H budipine, EN-3231 (MorphiDex(R), a combination for pyrazolo 4.3-dipyrimidin-7-one, 5-(5-acetyl-2- mulation of morphine and dextromethorphan), topira propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3- mate, neramexane or perzinfotel including an NR2B aZetidinyl)-2,6-dihydro-7H-pyrazolo 4.3-dpyrimidin antagonist, e.g. ifenprodil, traxoprodil or (-)-(R)-6-2- 25 7-one, 5-2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl) 4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl-1-hy pyridin-3-yl)-3-ethyl-2-[2-methoxyethyl-2,6-dihydro droxyethyl-3,4-dihydro-2(1H)-quinolinone; 7H-pyrazolo 4,3-dipyrimidin-7-one, 4-(3-chloro-4- an alpha-adrenergic, e.g. doxazosin, tamsulosin, clonidine, methoxybenzyl)amino-2-(2S)-2-(hydroxymethyl) guanfacine, dexmetatomidine, modafinil, or 4-amino-6, pyrrolidin-1-yl)-N-(pyrimidin-2-ylmethyl)pyrimidine 7-dimethoxy-2-(5-methane-sulfonamido-1,2,3,4-tet 30 5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7- rahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline; dihydro-1H-pyrazolo 4,3-dipyrimidin-5-yl)-N-2-(1- a tricyclic antidepressant, e.g. desipramine, imipramine, methylpyrrolidin-2-yl)ethyl-4- amitriptyline or nortriptyline; propoxybenzenesulfonamide; an anticonvulsant, e.g. carbamazepine, lamotrigine, topi an alpha-2-delta ligand Such as gabapentin, pregabalin, ratmate or valproate; 35 3-methylgabapentin, (1C.3C.5C)(3-amino-methyl-bi a tachykinin (NK) antagonist, particularly an NK-3, NK-2 cyclo[3.2.0]hept-3-yl)-acetic acid, (3S.5R)-3-aminom or NK-1 antagonist, e.g. (O.R.9R)-7-3,5-bis(trifluorom ethyl-5-methyl-heptanoic acid, (3S.5R)-3-amino-5-me ethyl)benzyl-8,9,10,11-tetrahydro-9-methyl-5-(4-me thyl-heptanoic acid, (3S.5R)-3-amino-5-methyl thylphenyl)-7H-1,4-diazocino.2.1-g1.7-naphthyri octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, dine-6-13-dione (TAK-637), 5-(2R,3S)-2-[(1R)-1-3, 40 (2S,4S)-4-(3-fluorobenzyl)-proline, (1R,5R,6S)-6- 5-bis(trifluoromethyl)phenylethoxy-3-(4- (aminomethyl)bicyclo[3.2.0]hept-6-yl)acetic acid, fluorophenyl)-4-morpholinyl-methyl-1,2-dihydro 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4-oxa 3H-1,2,4-triazol-3-one (MK-869), aprepitant, diazol-5-one, C-1-(1H-tetrazol-5-ylmethyl)-cyclohep lanepitant, dapitant or 3-2-methoxy-5-(trifluo tyl-methylamine, (3S4S)-(1-aminomethyl-3,4-dim romethoxy)phenyl-methylamino-2-phenylpiperidine 45 ethyl-cyclopentyl)-acetic acid, (3S,5R)-3- (2S,3S); aminomethyl-5-methyl-octanoic acid, (3S.5R)-3- a muscarinic antagonist, e.g. oxybutynin, tolterodine, amino-5-methyl-nonanoic acid, (3S.5R)-3-amino-5- propiverine, tropsium chloride, darifenacin, Solifenacin, methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5- temiverine and ipratropium; dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5- a COX-2 selective inhibitor, e.g. celecoxib, rofecoxib, 50 dimethyl-octanoic acid; parecoxib, Valdecoxib, deracoxib, etoricoxib, or lumira a cannabinoid; coxib; metabotropic glutamate subtype 1 receptor (mGluR1) a coal-tar analgesic, in particular paracetamol; antagonist; a neuroleptic Such as droperidol, chlorpromazine, halo a serotonin reuptake inhibitor Such as Sertraline, Sertraline peridol, perphenazine, thioridazine, mesoridazine, trif 55 metabolite demethylsertraline, fluoxetine, norfluoxetine luoperazine, fluiphenazine, clozapine, olanzapine, ris (fluoxetine desmethyl metabolite), fluvoxamine, parox peridone, Ziprasidone, quetiapine, sertindole, etine, citalopram, citalopram metabolite desmethylcit aripiprazole, Sonepiprazole, blonanserin, illoperidone, allopram, escitalopram, d.l-fenfluramine, femoxetine, peroSpirone, raclopride, Zotepine, bifeprunoX, asenap ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefa ine, lurasidone, amisulpride, balaperidone, palindore, 60 Zodone, cericlamine and traZodone; eplivanserin, osanetant, rimonabant, meclinertant, a noradrenaline (norepinephrine) reuptake inhibitor, Such Miraxion(R) or sarizotan; as maprotiline, lofepramine, mirtazepine, oxaprotiline, a vanilloid receptoragonist (e.g. resinferatoxin) or antago feZolamine, tomoxetine, mianserin, buproprion, nist (e.g. capsaZepine); buproprion metabolite hydroxybuproprion, a beta-adrenergic Such as propranolol; 65 nomifensine and Viloxazine (Vivalan(R), especially a a local anaesthetic Such as mexiletine; Selective noradrenaline reuptake inhibitor Such as a corticosteroid Such as dexamethasone; reboxetine, in particular (S,S)-reboxetine; US 8,907,101 B2 37 38 a dual serotonin-noradrenaline reuptake inhibitor, such as It will be appreciated that the invention exists in a number venlafaxine, Venlafaxine metabolite O-desmethylven of different embodiments including: lafaxine, clomipramine, clomipramine metabolite des (i) a compound of formula (I) or a pharmaceutically accept methylclomipramine, dulloxetine, milnacipran and imi able salt, solvate or tautomer thereof; pramine; (ii) a process for the preparation of a compound of formula (I) an inducible nitric oxide synthase (iNOS) inhibitor such as or a pharmaceutically acceptable salt, Solvate or tautomer S-2-(1-iminoethyl)aminoethyl-L-homocysteine, thereof S-2-(1-iminoethyl)-aminoethyl-4,4-dioxo-L-cys (iii) a pharmaceutical composition including a compound of teine, S-2-(1-iminoethyl)aminoethyl-2-methyl-L- formula (I) or a pharmaceutically acceptable salt, Solvate cysteine, (2S,5Z)-2-amino-2-methyl-7-(1-iminoethyl) 10 or tautomer thereof, together with a pharmaceutically amino-5-heptenoic acid, 2-(1R,3S)-3-amino-4- acceptable excipient; hydroxy-1-(5-thiazolyl)-butylthio)-5-chloro-3- (iv) a pharmaceutical composition including a compound of pyridinecarbonitrile: 2-(1R,3S)-3-amino-4-hydroxy formula (I) or a pharmaceutically acceptable salt, Solvate 1-(5-thiazolyl)butylthiol-4-chlorobenzonitrile, (2S, or tautomer thereof, together with a pharmaceutically 4R)-2-amino-4-2-chloro-5-(trifluoromethyl)phenyl 15 acceptable excipient, for use in the treatment of a disease or thio)-5-thiazolebutanol, 2-(1R,3S)-3-amino-4- condition for which a Nav1.7 channel modulator is indi hydroxy-1-(5-thiazolyl)butylthio)-6- cated, particularly for the treatment of pain; (trifluoromethyl)-3 pyridinecarbonitrile, 2-(1R,3S)-3- (v) a compound of formula (I) or a pharmaceutically accept amino-4-hydroxy-1-(5-thiazolyl)butylthiol-5- able salt, Solvate or composition thereof, for use as a medi Cament, chlorobenzonitrile, N-4-2-(3-chlorobenzylamino) (vi) the use of a compound of formula (I) or of a pharmaceu ethylphenylthiophene-2-carboxamidine, O tically acceptable salt, Solvate or composition thereof, for guanidinoethyldisulfide; the manufacture of a medicament to treat a disease or an acetylcholinesterase inhibitor Such as donepezil; condition for which a Nav1.7 channel modulator is indi a prostaglandin E. Subtype 4 (EP4) antagonist Such as cated, particularly for the treatment of pain; N-(2-4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-cpy 25 (vii) a compound of formula (I) or of a pharmaceutically ridin-1-yl)phenylethylamino)-carbonyl-4-methyl acceptable salt, Solvate or composition thereof, for use in benzenesulfonamide or 4-(1S)-1-(5-chloro-2-(3- the treatment of a disease or condition for which a Nav1.7 fluorophenoxy)pyridin-3-yl)carbonyl)amino)ethyl channel modulator is indicated, particularly for use in the benzoic acid; treatment of pain; a leukotriene B4 antagonist; Such as 1-(3-biphenyl-4-ylm 30 (viii) a method of treating a disease or condition for which a ethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxy Nav1.7 channel modulator is indicated in a mammal, lic acid (CP-105696), 5-2-(2-Carboxyethyl)-3-6-(4- including a human being, including administering to said methoxyphenyl)-5E-hexenyloxyphenoxy-valeric acid mammal an effective amount of a compound of formula (I) (ONO-4057) or DPC-11870, or a pharmaceutically acceptable salt, Solvate or composi a 5-lipoxygenase inhibitor, Such as Zileuton, 6-(3-fluoro 35 tion thereof. 5-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phe All of the compounds of the formula (I) can be prepared by noxy-methyl-1-methyl-2-quinolone (ZD-2138), or 2.3, the procedures described in the general methods presented 5-trimethyl-6-(3-pyridylmethyl), 1,4-benzoquinone below or by the specific methods described in the Examples section and the Preparations section, or by routine modifica (CV-6504); tions thereof which can be made by employing the common a sodium channel blocker, Such as lidocaine; 40 general knowledge of one skilled in the art (see, for example, a 5-HT3 antagonist, such as ondansetron; Comprehensive Organic Chemistry, Ed Barton and 011 is, and the pharmaceutically acceptable salts and Solvates Elsevier; Comprehensive Organic Transformations: A guide thereof. to Functional Group preparations, Larock, John Wiley & Such combinations offer significant advantages, including Sons). The present invention also encompasses any one or synergistic activity, in therapy. 45 more of these processes for preparing the compounds of Inasmuch as it may desirable to administer a combination formula (I), in addition to any novel intermediates used of active compounds, for example, for the purpose of treating therein. a particular disease or condition, it is within the scope of the In the following general methods, Z. Y', Y, Y, Y, B, X, present invention that two or more pharmaceutical composi C and D are as previously defined for a compound of the tions, at least one of which contains a compound in accor 50 formula (I) unless otherwise stated. dance with the invention, may conveniently be combined in Compounds of the present invention can be prepared using the form of a kit suitable for coadministration of the compo readily available starting materials or known intermediates. sitions. The synthetic schemes set forth below provide exemplary Thus the kit of the invention comprises two or more sepa synthetic pathways for the preparation of compounds of the rate pharmaceutical compositions, at least one of which con 55 invention. tains a compound of formula (I) in accordance with the inven When preparing derivatives of formula (I) in accordance tion, and means for separately retaining said compositions, with the invention, it is open to a person skilled in the art to such as a container, divided bottle, or divided foil packet. An routinely select the best order of steps with which to synthe example of such a kit is the familiar blister pack used for the sise the intermediates, and to choose the form of the interme packaging of tablets, capsules and the like. 60 diate compounds which provides the best combination of The kit of the invention is particularly suitable for admin features for this purpose. Such features include the melting istering different dosage forms, for example, oral and point, solubility, processability and yield of the intermediate parenteral, for administering the separate compositions at form and the resulting ease with which the product may be different dosage intervals, or for titrating the separate com purified on isolation. positions against one another. To assist compliance, the kit 65 The skilled person may undertake the synthetic steps typically comprises directions for administration and may be described below in any suitable order in order to arrive at the provided with a so-called memory aid. compounds of formula (I). US 8,907,101 B2 39 40 According to a first process, compounds of formula (I) may be prepared from compounds of formula (VI) by the process illustrated in Scheme 1.

Scheme 1 ZCO2H H2NZ (VIII) (IX) N /6) HNRZ, (VII) (iii)

V/ V/ V/ (III) -YS \/ (IX) -YS Y 17 -YS Y 17 X OH 11 N1 NC, HNZ y11 n N y11 N N 1N1 2Y -->(i) || 2Y H (ii) - || 2Y Ra| (iv) - F Y4 F Y4 F Y4 (VI) (V) (IV) O O O O y11 N Y(N1 , y11 N Y%NN1 , C Nx1 B No ul 12Y l w C Nx1 B No l 12Y h (II) (I)

Wherein 35 ditions, for example lithium hexamethyldisilaZane, diazabi R" is a Suitable protecting group, preferably dimethoxy cyclo(2.2.2)octane, triethylamine, NaOH or pyridine. Pre benzyl, tert-butyloxycarbonyl, tert-butyl, methoxymethyl or ferred conditions comprise NaOH in 1,4-dioxane or pyridine ethoxyethyl. in dichloromethane at room temperature. Compounds of formula (VI) are either commercially avail Compounds of formula (II) can be prepared from com able or can be prepared according to Scheme 8. 40 pounds of formula (IV) according to reaction step (iv) by nucleophilic aromatic substitution reaction with a phenol (III) Compounds of formula (III) are either commercially avail under basic reaction conditions, for example potassium car able or can be prepared according to Scheme 11. bonate in DMF or DMSO, sodium hydride in NMP or DMF, Compounds of formula (VIII) and (IX) are commercially Sodium hydroxide or potassium hydroxide in 1,4-dioxane and available. 45 water or DMSO or potassium tert-butoxide in THF at from Compounds of formula (IV) can be prepared from com room temperature to 150° C. Preferred conditions comprise 2 pounds of formula (VI) and (VII) according to reaction step equivalents of potassium carbonate in DMF at 90° C. (iii) by displacement of a sulfonyl chloride with HNR'Z Compounds of formula (I) can be prepared from com under basic reaction conditions. Typical conditions comprise pounds of formula (II) according to reaction step (V) by Suit lithium hexamethyldisilaZane in THF from -78°C. to ambi 50 able deprotection methods under acidic conditions for ent temperature. example HCl, formic acid or trifluoroacetic acid. Preferred Alternatively, compounds of formula (IV) can be prepared methods comprise trifluoroacetic acid in dichloromethane or from compounds of formula (V) according to reaction step neat trifluoroacetic acid at a temperature of room temperature (ii) by introduction of a Suitable protecting group Such as 55 to 55° C. Alternatively, if the protecting group is dimethoxy tert-butyl or methoxymethyl or ethoxyethyl dimethoxyben benzyl, compounds of formula (I) can be prepared from com Zyl under basic reaction conditions or Mitsunobu conditions. pounds of formula (II) under basic conditions such as sodium Typical conditions comprise di-tert-butyldicarbonate and tri bicarbonate in ethanol/water at 80°C. or heating in an appro ethylamine in THF or chloromethyl methyl ether and diiso priate solvent such as ethanol or toluene at temperatures propylethylamine in methylene chloride or chloromethyl 60 exceeding 70° C. ethyl ether and diisopropylethylamine in methylene chloride Compounds of formula (VII) can be prepared from com or dimethoxybenzylalcohol, diisopropylazodicarboxylate pounds of formula (VIII) according to reaction step (vi) by and triphenylphosphine in THF. Curtius rearrangement through generation of an acyl azide Compounds of formula (V) can be prepared from com 65 using diphenylphosphoryl azide. Preferred conditions com pounds of formula (VI) according to reaction step (i) by prise diphenylphosphoryl azide and triethylamine with tert displacement of a Sulfonyl chloride under basic reaction con butanol in toluene at 90° C. US 8,907,101 B2 41 42 Alternatively compounds of formula (VII) may be pre Compounds of formula (XIII) are commercially available. pared from compounds of formula (IX) according to reaction step (vii) through the processes outlined for reaction step (ii) Compounds of formula (XII) can be prepared from com or by reductive amination with an aldehyde. Typical reaction pounds of formula (XIII) by nucleophilic aromatic substitu conditions comprise dimethoxybenzaldehyde in toluene at tion reaction according to process step (iv) as described above 110° C. followed by reduction with sodium borohydride. for Scheme 1. Preferred conditions comprise NaH in NMP at According to a second process, compounds of formula (I) OO C. may also be prepared from compounds of formula (V) by the Compounds of formula (XI) can be prepared from com process illustrated in Scheme 2. 10 pounds of formula (XII) by a reduction reaction according to process step (vii) for example hydrogenation, a suitable metal Scheme 2 reduction or use of sodium dithionite. Preferred conditions V / (III) 15 comprise calcium chloride or ammonium chloride in the pres Y2 S Z. y11Y n n1 1N1X OH ence of iron in ethanol/water. l Y3 h (iv) Compounds of formula (X) can be prepared from com F 41 pounds of formula (XI) according to process step (viii) by a (V) 20 Sandmeyer reaction. Typical conditions comprise sodium nitrite in HCl, acetic acid and water, followed by sulfur diox V / ide in acetic acid with copper chloride at 0°C. Y2 S Z. 11'N a1 Compounds of formula (I) can be prepared from com C B 3 25 pounds of formula (X) by reaction according to process step n1nX O Y 2Y H (i) by displacement of a sulfonyl chloride under basic reaction (I) conditions with compounds of formula (IX) as described above for Scheme 1. Compounds of formula (I) can be prepared from com- 30 Alternatively compounds of formula (I) can be prepared pounds of formula (V) by nucleophilic aromatic substitution from compounds of formula (X) by reaction according to reactionScheme according1 to process step (iv) as described above for process steps (iii)- - - and (V) by displacement of a Sulfonyl chlo According to a third process, compounds of formula (I) 35 ride under basic reaction conditions with compounds of for may also be prepared from compounds of formula (XIII) by mula (VII) followed by a suitable deprotection step as the process illustrated in Scheme 3. described above for Scheme 1.

Scheme 3 y1's-'2 CN-BN(III) 11&1N2 -s-N'-2 l 2Y X (iv) OH C B 2Y (vii)vii) C B 2Y (viii)viii F 41 Nx1 no 1 Nx1 no 11 (XIII) (XII) (XI) O O O O \/ (IX) \/ y11Y n n Cl H2NZ y11Y n n N 17 C B 2Y (i) C B 2Y H Nx1 No 41 Nx1 no 11 (X) (I)

HNRZ. (iii) III (VII) (v) V / -Y&Sr. Y 17 C Nx1 B No 412Y Ra US 8,907,101 B2 43 44 According to a fourth process, compounds of formula (I) (that can be deprotected at a later stage under Suitable condi may also be prepared from compounds of formula (X) by the tions to those skilled in the art). Typical conditions comprise process illustrated in Scheme 4. 7N NH in methanol and THF at room temperature. Scheme 4 Compounds of formula (I) can be prepared from com O O pounds of formula (XIV) according to reaction step (X) by \/ displacement of a Suitable leaving group on a heterocycle as described by Z under basic reaction conditions. Typical con ditions comprise potassium carbonate in DMF. 10 According to a fifth process, compounds of formula (I) may also be prepared from compounds of formula (X) by the process illustrated in Scheme 5.

Scheme 5

-continued Compounds of formula (XVI) can be prepared from com 45 pounds of formula (X) according to process step (xi) by (XV) displacement of a sulfonyl chloride with pentafluorophenol. ZLG Typical conditions comprise pentafluorophenol, or optionally a trichlorophenol intermediate, and triethylamine in dichlo 50 romethane at room temperature. Compounds of formula (I) can be prepared from com pounds of formula (XVI) by reaction according to process step (i) by displacement of a pentafluorophenyl ester under 55 basic reaction conditions with compounds of formula (IX) as described above for Scheme 1. Alternatively compound of formula (I) can be prepared from compounds of formula (XVI) by reaction according to 60 process steps (iii) and (v) by displacement of a pentafluo Wherein LG is a suitable leaving group such as Cl, Br, I. F. rophenyl ester under basic reaction conditions with com Compounds of formula (XV) are commercially available. pounds of formula (VII) followed by a suitable deprotection Compounds of formula (XIV) can be prepared from com step as described above for Scheme 1. pounds of formula (X) according to process step (ix) by 65 According to a sixth process, compounds of formula (I) displacement of a Sulfonyl chloride with ammonia or a pro may also be prepared from compounds of formula (IV) by the tected ammonium species such as dimethoxybenzylamine process illustrated in Scheme 6. US 8,907,101 B2 46

Scheme 6

(XVIII) Y (xii) to (v) C

Wherein

LG is a suitable leaving group as described in Scheme 4. 30 W can be an optionally substituted/ligated metal or boron group suitable for cross-coupling reactions such as a trialkyl Stannane, dihydroxyborane, dialkoxyborane or halozinc or a Suitable group for cross-coupling reactions, typically Br or I. 35 (XVIII) Compounds of formula (XVIII), (XXI) and (XX) are com (iv) mercially available or can be prepared according to Scheme 11. Compounds of formula (XVII) can be prepared from com pounds of formula (IV) according to process step (iv) by 40 nucleophilic aromatic Substitution reaction with compounds (xii) of formula (XVIII) as described in Scheme 1. Alternatively compounds of formula (XVII) can be pre pared from compounds of formula (IV) according to process 45 steps (xiii) and (iv) by nucleophilic aromatic substitution with TMS-ethanol, typical conditions comprise sodium hydride in DMF at 0°C., followed by nucleophilic aromatic substitution reaction with compounds of formula (XX) as described in Scheme 1. 50 Compounds of formula (I) may be prepared from com pounds of formula (XVII) according to process step (xii) and (v) by a cross-coupling reaction, with compounds of formula Wherein (XXI), in the presence of a suitable catalyst system, (e.g. 55 W can be an optionally substituted/ligated metal or boron palladium or nickel), and base. Typically Suzuki conditions group or a suitable group for cross-coupling reactions, typi are used, comprising 1.2-3 equivalents of boronic acid, base cally Br or I as described for Scheme 6. and 0.01-0.25 equivalents of a palladium catalyst with phos phine based ligands in an organic solvent at a temperature of Compounds of formula (XXII) can be prepared from com 60 pounds of formula (V) according to process step (iv) by from 50° C. to 100° C. Preferred conditions comprise boronic nucleophilic aromatic displacement reaction as described in acid, NaCO, and Pd(PPh) in DMF/water or DME/water at Scheme 1. 80°C. followed by a suitable deprotection step as described in Compounds of formula (I) can be prepared from com Scheme 1. pounds of formula (XXII) according to process step (xii) by a According to a seventh process, compounds of formula (I) 65 cross-coupling reaction, with compounds of formula (XXI). may also be prepared from compounds of formula (V) by the in the presence of a Suitable catalyst system as described in process illustrated in Scheme 7. Scheme 6. US 8,907,101 B2 47 48 According to an eighth process, compounds of formula Compounds of formula (XXVII) are commercially avail (VI) may also be prepared from compounds of formula able. (XXIII) by the process illustrated in Scheme 8. Compounds of formula (XXVI) can be prepared from compounds of formula (XXVII) by nucleophilic aromatic Scheme 8 Substitution reaction according to process step (iv) as described above for Scheme 1. F Y Compounds of formula (XXV) can be prepared from com N (xiv) pounds of formula (XXVI) by a palladium catalysed cross 3 coupling reaction with benzylmercaptain according to process F 2Y 10 step (Xvi). Typical conditions comprise benzylmercaptan, (XXIII) palladium dibenzylideneacetone and Xantphos in 1,4-dioxane and diisopropyl ether at reflux. Compounds of formula (X) can be prepared from com 15 pounds of formula (XXV) by an oxidation reaction according to process step (XV) as described for Scheme 8. According to a tenth process, compounds of formula (I) may also be prepared from compounds of formula (X) by the process illustrated in Scheme 10. 2O Compounds of formula (XXIII) are commercially avail able. Compounds of formula (XXIV) can be prepared from Scheme 10 compounds of formula (XXIII) according to process step O O (xiv) by nucleophilic aromatic substitution reaction with ben 25 Y2 \/ Zylmercaptan. Typical conditions comprise benzylmercaptain Y N1 No (i) He and cesium carbonate in DMSO at room temperature. U Compounds of formula (VI) can be prepared from com C B 2Y pounds of formula (XXIV) according to reaction step (XV), an Nx1 No Y4 l oxidation process in the presence of bleach. Preferred condi (X) HN V 30 tions comprise bleach and 4M HCl (aqueous) in dichlo (XXIX) romethane at 0°C. According to a ninth process, compounds of formula (X) O O may also be prepared from compounds of formula (XXVII) Y2 \/ by the process illustrated in Scheme 9. 1 N n 35 H (xvii)XW. C Nx1 B No Y42Y Scheme 9 (XXVIII) (III) O O Y2 W Y2 \/ Z. y11 N nN.1 N- He-^n- 40 H l 2Y (iv) C B 2Y Nx1 No Y4 (XXVII) (I) Y2 W 45

Wherein U and V are any suitable ring precursors such as N, NH. S. O etc. 50 Compounds of formula (XXIX) are commercially avail able. Compounds of formula (XXVIII) can be prepared accord ing to reaction step (i) by displacement of a Sulfonyl chloride (XXV) 55 with compounds of formula (XXIX) under basic reaction conditions as described in Scheme 1. Typical conditions com prise Sodium hydroxide in acetone and water at room tem perature.

60 Compounds of formula (I) can be prepared from com pounds of formula (XXVIII), a cyclisation reaction according to process step (Xvii). Typical conditions comprise heating at 120° C. in the presence of a suitable electrophile such as Wherein DMFDMA, trimethylorthoformate or glycoaldehyde. W can be an optionally substituted/ligated metal or boron 65 According to an eleventh process, compounds of formula group or a suitable group for cross-coupling reactions, typi (III) may also be prepared from compounds of formula cally Br or I as described for Scheme 6. (XXX) by the process illustrated in Scheme 11. US 8,907,101 B2 49 50 Wherein Scheme 11 LG is a Suitable leaving group as described in Scheme 4. R11 X NB1. OH 1N1X OH R" is described in Scheme 11 5 Compounds of formula (XXXI) can be prepared from (XXX) (III) compounds of formula (IV) according to process step (iv) by nucleophilic aromatic Substitution reaction with compounds Compounds of formula (XXX) are commercially available of formula (XXX) as described in Scheme 1. or can be synthesized from methods known to one skilled in the art. 10 Alternatively compounds of formula (XXXI) can be pre Compounds of formula (III) may be prepared from com pared from compounds of formula (IV) according to process pounds of formula (XXX) by the process illustrated in steps (xiii) and (iv) by nucleophilic aromatic substitution with Scheme 11. Where C is an aromatic heterocyclic group, com TMS-ethanol, typical conditions comprise sodium hydride in pounds of formula (III) can be formed from compounds of DMF at 0°C., followed by nucleophilic aromatic substitution 15 reaction with compounds of formula (XXXII) as described in formula (XXX) with R1 being a group such as a carboxylic Scheme 1. acid, ester, aldehyde, primary carboxamide, amine, hydra Zine, oxime, nitrile, hydroxylamine, acetyl, furan, dialky Compounds of formula (II) may be prepared from com laminoprop-2-ene-1-one, semicarbazone, diimine, alkyne or pounds of formula (XXXI) according to standard processes acid chloride using methods described in the literature. Such described in Scheme 11. literature is described and cited in textbooks such as: Het According to a thirteenth process, compounds of formula erocyclic Chemistry, J. A. Joule and K. Mills (Blackwell (I) may also be prepared from compounds of formula (V) by Science); Handbook of Heterocyclic Chemistry, A. R. the process illustrated in Scheme 13. Katritzky and A. F. Pozharskii (Pergamon); The Chemistry of Heterocycles. Structure, Reactions, Syntheses and Applica 25 tions, T. Eicher and S. Hauptmann (Wiley-VCH); Heterocy Schemer 13 clic Chemistry, T. L. Gilchrist (Addison Wesley Longman). Alternatively R1 can be an optionally substituted metal or (XXX) a boron group suitable for cross-coupling reactions such as a trialkylstannane, dihydroxyborane, dialkoxyborane or haloz 30 inc or a suitable group for cross-coupling reactions, typically Br, I or Cl. Typical Suzuki conditions comprise of 1.2-3 equivalents of boronic acid, base and 0.01-0.25 equivalents of a palladium catalyst with phosphine based ligands in an organic solvent at a temperature of from 50° C. to 100° C. 35 Typical Stille conditions are 1-1.5 eq Stannane, 2-3 eq cae sium fluoride, 0.01-0.25eq of a palladium catalyst and 0.1- He 0.25 eq copper (I) iodide. Scheme 12 According to a twelfth process, compounds of formula (II) 40 may also be prepared from compounds of formula (IV) by the process illustrated in Scheme 12.

Scheme 12

(iv) R1-X-B-LG (XXXII) US 8,907,101 B2 51 52 -continued The present invention also relates to novel intermediate O O compounds as defined above, all salts, Solvates and com Y2 \/ Z. plexes thereof and all solvates and complexes of salts thereof 1 n n N 1. H as defined hereinbefore for compounds of formula (I). The C B 2Y invention includes all polymorphs of the aforementioned spe Ya X 1 No Y4 cies and crystal habits thereof. EXAMPLES & PREPARATIONS

Compounds of formula (XXXI) can be prepared from 10 The following experimental details illustrate specifically compounds of formula (V) according to process step (iv) by how certain compounds of formula (I) may be prepared. All nucleophilic aromatic displacement reaction as described in examples, unless indicated as a reference example, are com Scheme 1. pounds of formula (I). Preparations are intermediates useful Compounds of formula (I) can be prepared from com in the synthesis of compounds of formula (I). pounds of formula (XXXI) according to processes described 15 "H Nuclear magnetic resonance (NMR) spectra were in all in Scheme 11. cases consistent with the proposed structures. Characteristic The methods described in Schemes 12 and 13 using chemical shifts (8) are given in parts-per-million downfield R1-X—B OH in a nucleophilic aromatic substitution reac from tetramethylsilane using conventional abbreviations for tion can also be used in place of C X—B OH to synthesise designation of major peaks: e.g. s. singlet; d, doublet, t, trip (I) by the methods described in Schemes 3, 4 and 5. let, q, quartet; m, multiplet; br, broad. According to a fourteenth process compounds of formula The mass spectra (m/z) were recorded using either electro (I) and (II) can be modified through further reaction of C to spray ionisation (ESI) or atmospheric pressure chemical ioni change the substitution on C when C is Het1, Het2 or Ar. As sation (APCI). When relevant, and unless stated otherwise, an example, when C contains a primary or secondary amino the m/z data provided are for isotopes 'F, C1 and Br. functionality, further Substitution can be made through a 25 The following abbreviations have been used for common simple alkyaltion or reductive alkylation procedure. Pre solvents: CDC1, deuterochloroform; d-DMSO, deu ferred conditions for the reductive alkylation include an alkyl terodimethylsulphoxide: CDOD, deuteromethanol; THF, aldhehyde, Sodium triacetoxyborohydride and acetic acid in tetrahydrofuran. Ammonia refers to a concentrated Solution tetrahydrofuran at room temperature. As a further example, of ammonia in water possessing a specific gravity of 0.88. when C is chloropyridyl, further substitution is possible 30 Where thin layer chromatography (TLC) has been used it through nucleophilic displacement by an amino or alkoxy refers to silica gel TLC using silica gel 60 F2s plates, R, is the functionality. distance traveled by a compound divided by the distance According to a fifteenth process compounds of formula traveled by the solvent front on a TLC plate. (III) when C is Het2 may be further modified to convert C into Where compounds are purified by HPLC the following a different Het2. As an example when C is furan, a Diels Alder 35 methods are used: with a reaction with an azadicarboxylate ester in the presence Preparative Reverse Phase HPLC Methods: of a Lewis acid catalyst Such as Zinc triflate yields a bicyclic a) Phenomenex 250x30 mm 15 micron C18 column. 40 adduct. Ester hydrolysis with for example an acid (such as mL/minutes. Gradient 85% A to 100% B Over 25 minutes. acetic acid) or a base (such as Sodium hydroxide) results in Solvent A: 7800 water/200 acetonitrile/8 trifluoroacetic acid. decarboxylation and dehydration to yield a pyridazine. 40 Solvent B: 7200 acetonitrile/800 water/8 trifluoroacetic acid, According to a sixteenth process: 254 nM UV detection. b) Phenomenex 100x21.2 mm 10 micron C18 column. 20 mL/minutes. Gradient 85% A to 100% B Over 25 minutes. Scheme 16 Solvent A: 7800 water/200 acetonitrile/8 trifluoroacetic acid. 45 Solvent B: 7200 acetonitrile/800 water/8 trifluoroacetic acid, O O 254 nM UV detection. -Y.2 H -Y. \/Sn Certain compounds of the Examples and Preparations were purified using Automated Preparative High Performance Liq N -e-(xviii) | n C uid Chromatography (HPLC). Reversed-phase HPLC condi F l Y 2Y F Y 2Y 50 tions were on FractionLynx systems. Samples were Submit ted dissolved in 1 mL of DMSO. Depending on the nature of (XXXII) the compounds and the results of a pre-analysis, the purifica tion was performed under either acidic conditions or basic compounds of formula (XXXII), which are commercially conditions at ambient temperature. Acidic runs were carried available or known in the literature, are typically treated with 55 out on a Sunfire Prep C18 OBD column (19x50mm, 5um), chlorosulfonic acid in chloroform at 0°C. with warming to basic runs were carried out on a Xterra Prep MS C18 (19x50 ambient temperature to provide compounds of formula (VI). mm, 5um), both from Waters. A flow rate of 18 mL/minutes Referring to the general methods above, it will be readily was used with mobile phase A: water+0.1% modifier (v/v) understood to the skilled person that where protecting groups and B: acetonitrile+0.1% modifier (v/v). For acidic runs the are present, these will be generally interchangeable with other 60 modifier was formic acid, for basic run the modifier was protecting groups of a similar nature, e.g. where a Sulfona diethylamine. A Waters 2525 binary LC pump supplied a mide is described as being protected with a tert-butyl or mobile phase with a composition of 5% B for 1 minutes then dimethoxybenzyl group, this may be readily interchanged ran from 5% to 98% Bover 6 minutes followed by a 2 minutes with any Suitable Sulfonamide protecting group. Suitable pro hold at 98% B. tecting groups are described in Protective Groups in Organic 65 Detection was achieved using a Waters 2487 dual wave Synthesis by T. Greene and P. Wuts (3rd edition, 1999, John length absorbance detector set at 225 nm followed in series by Wiley and Sons). a Polymer Labs PL-ELS 2100 detectoranda Waters ZQ2000 US 8,907,101 B2 53 54 4 way MUX mass spectrometer in parallel. The PL 2100 Temperature: 50 C ELSD was set at 30°C. with 1.6 L/minutes supply of Nitro Unless Otherwise Provided Herein: gen. The Waters ZQMS was tuned with the following param AcOH means acetic acid, eters: Boc means tert-butoxycarbonyl: (tert-butyloxycarbonyl) ES+ Cone voltage: 30 V Capillary: 3.20 kV WSCDI means 1-(3-dimethylaminopropyl)-3-ethylcarbodi ES- Cone voltage: -30 V Capillary: -3.00 kV imide hydrochloride; Desolvation gas: 600 L/hour CBZ means benzyloxycarbonyl: Source Temp: 120° C. CDI means N,N'-carbonyldiimidazole; Scan range 150-900 Da DABCO means 1,4-diazabicyclo[2.2.2]octane The fraction collection was triggered by both MS and 10 DCC means N,N'-dicyclohexylcarbodiimide: ELSD. DCM means dichloromethane; methylene chloride; Quality control analysis was performed using a LCMS DMAP means 4-dimethylaminopyridine; method orthogonal to the preparative method. Acidic runs DMB means dimethoxybenzyl: were carried out on a Sunfire C18 (4.6x50mm, 5um), basic DME means dimethoxylethane; runs were carried out on a Xterra C18 (4.6x50mm, 5um), 15 DMF means N,N-dimethylformamide: both from Waters. A flow rate of 1.5 mL/minutes was used DMFDMA means N,N-dimethylformamide dimethylacetal with mobile phase A: water+0.1% modifier (v/v) and B: DMSO means dimethyl sulphoxide: acetonitrile+0.1% modifier (v/v). For acidic runs the modifier EtN means triethylamine; was formic acid, for basic run the modifier was diethylamine. EtOH means ethanol A Waters 1525 binary LC pump ran a gradient elution from HBTU means O-benzotriazol-1-yl-N,N,N',N'-tetramethylu 5% to 95% B over 3 minutes followed by a 1 minutes hold at ronium hexafluorophosphate: 95% B. Detection was achieved using a Waters MUX UV HCl means hydrochloric acid; 2488 detector set at 225 nm followed in series by a Polymer HOAT means 1-hydroxy-7-azabenzotriazole; Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way HOBT means 1-hydroxybenzotriazole hydrate; MUX mass spectrometer in parallel. The PL 2100 ELSD was Hinig's base means N-ethyldiisopropylamine; set at 30° C. with 1.6 L/minutes supply of Nitrogen. The 25 KCO means potassium carbonate; Waters ZQ MS was tuned with the following parameters: KOH means potassium hydroxide: ES+ Cone voltage:25 V Capillary: 3.30 kV LiHMDS means lithium bis(trimethylsilyl)amide: ES- Cone voltage: -30 V Capillary: -2.50 kV Me means methyl; Desolvation gas: 800 L/hour NaH means sodium hydride; Source Temp: 150° C. 30 Na2CO means Sodium carbonate; Scan range 160-900 Da NaOH means sodium hydroxide: Unless otherwise noted, LCMS conditions were run NH means ammonia; according to one of the conditions given below: NMP means N-methylpyrrolidinone; 6 Minute LC-MS Gradient and Instrument Conditions Pd(PPh) means palladium tetrakis; Acid Run: 35 Pd(dba) means Tris(dilbenzylideneacetone)dipalladium; A: 0.1% formic acid in water TBTU means O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethy B: 0.1% formic acid in acetonitrile luronium tetrafluoroborate; Column: C18 phase Phenomenex Gemini 50x4.6 mm with 5 TFA means trifluoroacetic acid; micron particle size THF means tetrahydrofuran; and Gradient: 95-5% A over 3 min, 1 minutes hold, 1 ml/minutes TMS means trimethylsilyl. UV: 210 nm-450 nm DAD 40 Temperature: 50 C Example 1 2 Minute LC-MS Gradient and Instrument Conditions Acid Run: 3-cyano-4-(4-fluoro-2-(1-methyl-1H-pyrazol-5-yl) A: 0.1% formic acid in water phenoxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfona B: 0.1% formic acid in acetonitrile 45 mide Column: C18 phase Fortis Pace 20x2.1 mm with 3 micron particle size Gradient: 70-2%. A over 1.8 min, 0.2 minutes hold, 1.8 O 1\ ml/minutes 'V// l UV: 210 nm-450 nm DAD 50 NN Temperature: 75 C H C18 30 Minute Method LC-MS Gradient and Instrument Conditions A: 0.1% formic acid in H2O B: 0.1% formic acid in MeCN Column: Phenomenex C18 phase Gemini 150x4.6 mm with 5 55 micron particle size Gradient: 98-2%. A over 18 min, 2 minutes hold, 1 ml/minutes UV: 210 nm-450 nm DAD Method A Temperature: 50 C To a suspension of sodium hydride (60% dispersion in oil, Phenyl Hexyl 30 Minute Method LC-MS Gradient and 60 0.062 g) in N,N-dimethylformamide (5 mL) was added Instrument Conditions 4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation A: 10 mMammonium acetate in H2O 88A, 0.072 g, 0.00037 mol). This was stirred at room tem B: 10 mMammonium acetate in methanol perature for 10 minutes. To this mixture was added 3-cyano Column: Phenomenex Phenyl Hexyl 150x4.6 mm with 5 4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide micron particle size 65 (Preparation 65, 0.103 g, 0.000362 mol) and the resulting Gradient: 98-2%. A over 18 min, 2 minutes hold, 1 ml/minutes mixture was stirred for 3 hours. The reaction was quenched UV: 210 nm-450 nm DAD with 1 NHCl (aq) and extracted twice with ethyl acetate. The US 8,907,101 B2 55 56 combined organic layers were dried over Sodium Sulfate, Method C filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography using a gradient of To a suspension of sodium hydride (60% dispersion in oil, 0-10% methanol in CHCl to give the title compound as a 52 mg, 0.0013 mol) in DMF (1 mL) was added 2-(1-methyl white solid. LCMS Rt=1.50 minutes MS m/z 457.0 MH+ 5 1H-pyrazol-5-yl)phenol (Preparation 92A, 176 mg, 0.00101 mol) as a solution in DMF (1 mL) and the mixture was stirred Example 2 for 15 minutes. To this was added N-tert-butyl-3,4-difluoro N-thiazol-2-yl-benzenesulfonamide (Preparation 60, 350 2-fluoro-4-(2-(2-methylthiazol-4-yl)phenoxy)-N- mg, 0.00105 mol) as a solution in DMF (1 mL). The resulting (thiazol-2-yl)benzenesulfonamide) 10 orange solution was heated at 80°C. for 3 days. After cooling the reaction was diluted with ethyl acetate and washed with saturated aqueous NaHCO, water, and brine. The organic layer was dried over MgSO filtered, and concentrated in 15 vacuo. The crude product was purified by flash column chro matography using a 0-100% ethyl acetate in hexanes gradient to give a clear oil. This was dissolved intrifluoroacetic acid (3 mL, 0.04 mol) and heated to 50° C. for 24h. After cooling, the reaction was concentrated in vacuo and purified by flash column chromatography using a 0-10% methanol in CH2Cl2 4N gradient to give the title compound as a white solid. LCMS Rt=1.49 minutes MS m/z 430.9 MH+

Me 25 Example 4 Method B To a suspension of sodium hydride (60% dispersion in oil, 0.0260 g) in N,N-dimethylformamide (5 mL) was added 30 3-cyano-4-(4-isopropoxy-2-methylbiphenyl-2-yl) 2-(2-methylthiazol-4-yl)phenol (0.0830 g, 0.000434 mol). oxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide This was stirred at 20°C. for 10 minutes and then cooled to 5° C. in an ice water bath. To this mixture was added N-tert butyl-2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide (Preparation 62, 0.151 g, 0.000454 mol) and the reaction was 35 allowed to slowly warm to room temperature. After stirring for 16 hours, the reaction was quenched with water and extracted twice with ethyl acetate. The combined organic layers were dried over Sodium Sulphate, filtered, and concen trated in vacuo. The resulting residue was purified by flash 40 column chromatography. The purified product was dissolved in methylene chloride (15 mL) and treated with trifluoroace tic acid (5 mL, 0.06 mol). After stirring for 30 minutes, the reaction was concentrated in vacuo and the residue purified by flash column chromatography using a gradient of 0-5% 45 methanol in CHCl, providing the title compound as a white solid. LCMS Rt=1.54 minutes MS m/z 447.8 MH+ Example 3 50 3-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)phenoxy)- Method D N-(thiazol-2-yl)benzenesulfonamide To a solution of 4'-isopropoxy-2-methyl-biphenyl-2-ol (Preparation 37, 51 mg 0.212 mmol) and KOH (17.8 mg, 55 0.318 mmol) in DMSO (1 mL) was added 3-cyano-4-fluoro N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 30 mg, 0.11 mmol). The mixture was stirred at room temperature overnight followed by stirring at 60°C. for 24 h. 60 2N HCl (aq) (5 ml) was added to the reaction mixture fol lowed by extraction into tert-butyl methyal ether (10 ml). The organic layer was collected, dried (MgSO4) and concentrated in vacuo to afford the crude compound which was purified 65 using silica gel column chromatography (dichloromethane: methanol 95:5) to furnish the title compound. LCMS Rt=3.38 minutes MS m/z 507 MH+ US 8,907,101 B2 57 58 Example 5 to furnish the crude residue that was purified using prepara tive HPLC. LCMS Rt=2.29 minutes MS m/z. 417 MH+ 3-cyano-4-(5-fluoro-3'-isopropoxybiphenyl-2-yl) Example 95 oxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 4-(biphenyl-2-yloxy)-3-cyano-N-1,3-oxazol-2-ylben Zenesulfonamide

10 OW O 9Cy N

15 O

CN

Method G Method E Triethylamine (38 ul, 0.27 mmol) was added to oxazol-2- To a solution of 4-(2-bromo-4-fluoro-phenoxy)-3-cyano 25 ylamine (14 mg., 0.169 mmol) in THF (0.5 ml) and stirred for N-1,2,4thiadiazol-5-ylbenzenesulfonamide (Preparation 5 minutes. 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl 44, 72.6 mg, 0.15 mmol) in DMF (0.8 mL) was added 3-iso chloride (Preparation 55,50 mg, 0.14 mmol) in THF (0.5 ml) propoxyphenylboronic acid (40 mg, 0.225 mmol), palladium was then added slowly and the reaction stirred at room tem tetrakis triphenylphosphine (8.10 mg, 0.007 mmol) and a 2M perature overnight. Aqueous 2N HCl was added and the reac aqueous solution of sodium carbonate (0.225 mL, 0.45 30 tion extracted into ethyl acetate three times, the organic layer mmol). The reaction was heated to 100° C. overnight. After collected, dried (MgSO4), and concentrated in vacuo to fur cooling to room temperature, Saturated aqueous ammonium nish a crude residue that was purified using preparative chloride (3 mL) and dichloromethane (3 mL) was added and HPLC. LCMS Rt=3.17 minutes MS m/z 418 MH+ the organic extracted into dichloromethane (3x3 mL). The organic layer was concentrated in vacuo and the title com 35 Example 96 pound purified by preparative HPLC. LCMS Rt 2.46 min utes MS m/z 511 MH+ 4-(biphenyl-2-yloxy)-3-cyano-N-(3-methoxy-1,2,4- thiadiazol-5-yl)benzenesulfonamide Example 6 40 3-cyano-4-(2-cyclopropyl-4-fluorophenoxy)-N-12, -N. 4-thiadiazol-5-ylbenzenesulfonamide W X 45 H

Method H 55 NaOH (8 mg, 0.203 mmol) in water (0.25 ml) was added to 3-methoxy-1,2,4-thiadiazol-5-ylamine (27 mg, 0.203 mmol) in 1,4-dioxane (1.0 ml) and stirred at ambient tem Method F perature for 5 minutes. 4-(Biphenyl-2-yloxy)-3-cyano-ben To a solution of 2-cyclopropyl-4-fluorophenol Zenesulfonyl chloride (Preparation 55, 50 mg, 0.14 mmol) in (US2005245519, 60 mg, 0.4 mmol) and potassium carbonate 60 1,4-dioxane (0.5 ml) was added slowly and stirring continued (82.9 mg, 0.6 mmol) in DMF (1 ml) was added 3-cyano-4- at ambient temperature overnight. Aqueous HCl Solution fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Prepa (2M, 0.2 ml) was added, then saturated brine (2 ml), and the ration 65, 57 mg, 0.2 mmol). The reaction was heated to mixture extracted with ethyl acetate (3x2 ml). The combined 80-100° C. overnight. Saturated aqueous ammonium chloride organic layers were collected, dried (MgSO4), and concen and dichloromethane were added to the cooled reaction and 65 trated in vacuo to furnish a crude residue that was purified the organics extracted into dichloromethane (3x3 ml). The using preparative HPLC. organic layer was dried (MgSO4) and concentrated in vacuo LCMS Rt=2.49 min MS m/z 464.9 MH+ US 8,907,101 B2 59 60 Example 97 Example 99

4-(biphenyl-2-yloxy)-3-cyano-N-1,3-thiazol-4-yl 4-(biphenyl-2-yloxy)-3-cyano-N-isothiazol-4-ylben benzenesulfonamide Zenesulfonamide

O. O v 10 NŠs \/ M N

15

Method K Method I To a solution of isothiazol-4-ylamine (40 mg, 0.293 mmol) 4-(Biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride in pyridine (0.5 ml) and dichloromethane (0.5 ml) was added (Preparation 55, 50 mg, 0.14 mmol) in MeCN (0.5 ml) was 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonyl chloride added dropwise to thiazol-4-ylamine (20 mg, 0.15 mmol) and 25 (Preparation 55, 60 mg, 0.16 mmol) and the reaction stirred at DABCO (34 mg., 0.297 mmol) in MeCN (0.5 ml) and the room temperature overnight. 2N HCl was added and the heterogeneous mixture stirred together at 70° C. for 24 h. The reaction extracted into dichloromethane. The organic layer reaction was concentrated in vacuo and the residue was taken was collected, dried (MgSO4) and concentrated in vacuo to up in methanol (5 ml), passed through pad of charcoal and 30 furnish a crude residue that was purified using preparative CeliteTM, and washed with methanol. The filtrate was concen HPLC. trated in vacuo to afford a crude residue that was purified LCMS Rt=3.75 minutes MS m/z 434 MH+ using preparative HPLC. LCMS Rt=3.72 min MS m/z. 433.9 MH+ 35 Example 134 Example 98 N-(5-chloro-1,3-thiazol-2-yl)-3-cyano-4-(2-phenox yphenoxy)benzenesulfonamide 4-(biphenyl-2-yloxy)-3-cyano-N-(3-isopropyl-1,2,4- thiadiazol-5-yl)benzenesulfonamide 40 O 2O N yN C O H le N S 45 \-N S H S.1)N / O O O | Me 50 N

Method L 55 To a solution of N-(5-chloro-thiazol-2-yl)-3-cyano-4-fluo Method J robenzenesulfonamide (Preparation 52, 0.2 mmol, 63.5 mg) LiHMDS (1M solution in THF, 194 ul, 0.194 mmol) was and 2-phenoxyphenol (74 mg. 0.4 mmol) in THF (1 mL) was added to a stirred solution of 3-isopropyl-1,2,4thiadiazol added t-BuOK in THF (1 M, 0.6 mL). The reaction was 5-ylamine (28 mg, 0.194 mmol) in THF (0.5 ml). 4-(biphe 60 heated at 50° C. overnight. The reaction was cooled to room nyl-2-yloxy)-3-cyano-benzenesulfonic acid pentafluorophe temperature and poured into Saturated aqueous NHC1. The mixture was extracted thrice with CHCl and the combined nyl ester (Preparation 58, 50 mg, 0.097 mmol) was added and organic layer was dried over MgSO followed by evaporation the reaction was heated to 50° C. overnight. The reaction was in vacuo to obtain the crude residue which was purified using cooled and concentrated in vacuo before being purified using 65 preparative HPLC to afford the title compound. preparative HPLC. LCMS Rt=3.66 minutes MS m/z. 484 MCIH+, 486 LCMS Rt=3.88 min MS m/z 477 MH+ M7CIH+ US 8,907,101 B2 61 62 Example 170 ethyl acetate, washed with water and brine, dried over anhy drous sodium sulfate, filtered and was concentrated to give 4-4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy the crude product that was purified via automated flash chro 3-cyano-N-1,3-thiazol-2-ylbenzenesulfonamide matography (silica gel, 0% to 80% ethyl acetate in hexanes). 114 mg (66%) of the product was obtained as a white solid. LCMS Rt=1.80 minutes; MS m/z 548 MH+ H NMR (300 MHz, d-DMSO): & 1.46 (s, 9H), 6.73 (s, O O N N 1H), 6.92 (d. J–4.6 Hz, 1H), 7.14 (d. J=8.9 HZ, 1H), 7.34 (d. W{- ) 10 J–4.6 Hz, 1H), 7.38 (m, 2H), 7.61 (m, 2H), 8.10 (dd, J=8.9 & H 2.2 Hz, 1H), 8.28 (d. J=2.2 Hz, 1H), 12.95 (s, br. 1H). Library Protocol 1

15 O O N

\/NN O)S ArOH, NaH, DMSO -e- 700 C. 3-Cyano-4-fluoro-N-1,3-thiazol-2-ylbenzenesulfona F Me Me mide, (Preparation 46, 500 mg 0.00176 mol), 4-chloro-2-(1- Me methyl-1H-pyrazol-5-yl)phenol, (Preparation 89, 370 mg. F 0.00177 mol) and potassium carbonate (700 mg, 0.00287 mol) were stirred in dimethylformamide (5 mL) at 80°C. for 25 24 hours. The reaction mixture was cooled and partitioned O O N N between ethyl acetate (150 mL) and aqueous hydrochloric acid (80 mL of 2 molar), the organic layer was dried over WO)NN S TFADCM -e- anhydrous sodium sulphate, filtered and the solvents removed 30° C. in vacuo to give an orange Solid. The Solid was triturated with 30 ArO Me Me diethyl ether (20 mL) to give the title compound as an orange Me powder, (680 mg). F LCMS=1.40 minutes, MS m/z 472 (MCIH+ 'HNMR (d-DMSO): 83.73 (s.3H), 6.20 (d. 1H), 6.88 (d. 1H), 6.93 (d. 1H), 7.29 (d. 1H), 7.33 (d. 1H), 7.49 (d. 1H), 35 O O. N. N 7.66-7.71 (m, 2H), 7.87-7.91 (m, 1H), 8.10 (d. 1H). WC)NN S Example 279 H 4-4-(2-tertbutyl-5-trifluoromethyl-2H-pyrazol-3-yl)- 40 ArO phenoxy-3-cyano-N-thiazol-2-yl-benzenesulfona mide To a solution of the phenol (100 umol) in dimethylsulphox 45 ide (1 ml) was added NaH (60% dispersion in oil, 8 mg, 200 Me umol) and the reaction shaken at 30° C. for 1 hour. The reaction mixture was cooled to 5° C. and a solution of N-tert F sy. Me S butyl-3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide F \ ^ MMe OV/ O J) 50 (Preparation 60, 100 umol) in dimethylsulphoxide (100 ul) F e Sn-ss was added followed by continued shaking at 70° C. for 16 H hours. The crude product was purified by preparative HPLC to yield pure intermediate. 1 ml of a trifluoroacetic acid/ O dichloromethane solution (1:7) was added to the intermediate and the reaction shaken at 30°C. for 1 hour. The reaction was concentrated in vacuo to yield the desired product. The following further examples can be prepared analo Method M gously to the General Methods (as described above), and 3-Cyano-4-fluoro-N-(thiazol-2-yl)benzenesulfonamide 60 Methods A-M, as described for Examples 1-6, 95-99, 134, (Preparation 46, 89 mg, 0.31 mmol) was added to a mixture of and 279, and Library protocol 1, Substituting appropriate 4-(2-tert-butyl-5-trifluoromethyl-2H-pyrazol-3-yl)-phenol starting materials where necessary and making appropriate (Preparation 190, 89 mg, 0.31 mmol) and potassium carbon changes to experimental conditions informed by common ate (130 mg. 0.94 mmol) in N,N-dimethylformamide (2 mL, 65 general knowledge. Purification was performed either by 30 mmol). The reaction mixture was heated at 150° C. in the silica gel column chromatography, trituration or preparative microwave for 2 hours. The reaction mixture was diluted with HPLC.

US 8,907,101 B2 111 112 Example 587 Example 655 from above can be made as follows. To a solution of tert-butyl 4-(5-chloro-2-hydroxyphenyl)piperi 4-2-(6-Aminopyridin-3-yl)-4-fluorophenoxy-N-(5- dine-1-carboxylate (Preparation 231, 38 mg, 0.122 mmol) chloro-1,3-thiazol-2-yl)-3-cyanobenzenesulfonamide and potassium carbonate (50.6 mg, 0.366 mmol) in dimethyl sulfoxide (1 mL) was added tert-butyl (5-chloro-2,4-difluo 5 rophenyl)sulfonyl 1,3-thiazol-4-ylcarbamate (Preparation 453, 50 mg, 0.122 mmol). The mixture was stirred at room O O N N temperature for 16 hours before diluting with ethyl acetate (10 mL) and water (10 mL). The aqueous phase was acidified F N X to pH 4 with Saturated citric acid solution (aqueous) and H 10 extracted with ethyl acetate (3x10 mL). The combined organic layers were washed with Saturated aqueous sodium chloride solution (30 mL), dried over sodium sulphate, fil tered and concentrated in vacuo to afford tert-butyl 4-2-(4- 21 | {(tert-butoxycarbonyl)(1,3-thiazol-4-yl)aminosulfonyl 15 2-chloro-5-fluorophenoxy)-5-chlorophenylpiperidine-1- Ns carboxylate as a white foam. This was dissolved in dichlo romethane (1 mL), trifluoroacetic acid added (200 uL) and NH2 reaction stirred for 16 hours at room temperature before con centrating in vacuo. Purification by preparative HPLC Example 587 from above can be prepared as follows. N-(5- afforded the title compound. Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4-dimethoxyben LCMS Rt=1.05 minutes. MS m/z 502 (MCIH+ Zyl)-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide (Preparation 217, 100 mg, 0.146 mmol), 2-aminopyridine-5- Example 782 boronic acid pinacol ester (35.4 mg., 0.161 mmol), palladium 4-4-Chloro-2-(1H-pyrazol-4-yl)phenoxy-3-cyano (O) tetrakis(triphenylphoshine) (17.3 mg, 0.015 mmol) and 25 caesium carbonate (143 mg, 0.438 mmol) were charged to a N-1,3-thiazol-2-ylbenzenesulfonamide 25 ml round-bottomed flask and purged with nitrogen (x3). To this was added freshdegassed 1,4-dioxane (4 ml) and fresh degassed water (1 ml) and the vessel was heated to 60° C. and stirred for 16 hours. The solvent was removed in vacuo and 30 O O. N. N the residue was dissolved in methanol (2 ml) before loading C onto a ISOLUTETMSCX-2 cartridge (2g). The cartridge was washed with methanol (50 ml) followed by ammonia (2 M in methanol, 50 ml). The basic washes were concentrated in vacuo and the residue was dissolved in dichloromethane (10 35 ml). To this solution was added trifluoroacetic acid (1 ml) and the solution stirred at room temperature for 18 hours before concentrating in vacuo. The residue was dissolved in metha nol (2 ml) and loaded on to a ISOLUTETMPE-AX cartridge (5 g). The cartridge was washed with methanol (3 column Vol 40 umes) followed by formic acid (2% solution in methanol, 3 tert-Butyl 4-(5-chloro-2-hydroxyphenyl)-1H-pyrazole-1- column Volumes). The acidic washes were concentrated in carboxylate (Preparation 205,624 mg, 2.12 mmol), 3-cyano vacuo to afford a sticky yellow solid which was triturated in 4-fluoro-N-1,3-thiazol-2-ylbenzenesulfonamide (Prepara dichloromethane to afford the title compound as a white solid. tion 46, 500 mg, 1.76 mmol) and potassium carbonate (732 Yield 28 mg, 38%. 45 mg, 5.30 mmol) were stirred in dimethylsulphoxide (10 ml) LCMS Rt=2.04 minutes. MS m/z 502 (MCIH+ at 50° C. for 2 hours. The reaction was cooled to room tem 'HNMR (d-DMSO): 8 6.35 (bs, 2H), 6.45 (m, 1H), 6.75 perature and the mixture poured dropwise into hydrochloric (m. 1H), 7.32 (m, 1H), 7.48 (m, 3H), 7.55 (m. 1H), 7.9 (m, acid (2M aqueous, 100 ml). The mixture was stirred at room 1H), 8.0 (m, 1H), 8.1 (m, 1H). temperature for 18 hours. The precipitate was filtered and 50 suspended in methanol (10 ml). The mixture was treated with Example 655 hydrogen chloride (4M in dioxane, 2 ml). The mixture was then stirred at room temperature over for 60 hours. The mix 5-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2- ture was evaporated in vacuo. The residue was dissolved in fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide methanol (5 ml). The black Solution was passed through an ISOLUTETM SCX cartridge. The cartridge was eluted with 55 methanol (100 ml) followed by ammonia (2M in methanol). F o o N2\ S The dark ammonia Solution was evaporated in vacuo. The residue was dissolved in dichloromethane/methanol (95/5, 5 C Yus/ ml) and passed through a pad of silica. The Solution was H evaporated in vacuo. The residue was purified using a silica 60 gel column chromatography eluting with dichloromethane: O ethyl acetate (gradient 1:0 to 1:9, by volume). Concentration C in vacuo afforded the title compound as a white solid. Yield 427 mg, 53% LCMS Rt=2.26 minutes, MS m/z 458 (MCIH+ 65 N 'HNMR (d-DMSO): 8 6.87 (m, 2H), 7.28 (d. 1H), 7.32 H 7.41 (m, 3H), 7.87 (im, 3H), 8.12 (br. s. 1H), 8.23 (d. 1H), 12.83 (br. s. 1H), 13.08 (br. s. 1H). US 8,907,101 B2 113 114 Example 783 Example 785

3-cyano-4-2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluo N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-4-fluoro romethoxy)phenoxy-N-1,3-thiazol-2-ylbenzene 2-(1H-pyrazol-4-yl)phenoxybenzenesulfonamide Sulfonamide

O O N N 10 O O. N. N V/ y F W)-N H

15

N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-(4-fluoro-2-io 2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethoxy)phe dophenoxy)benzenesulfonamide (Preparation 240, 50 mg. nol (Preparation 533, 50.0 mg, 0.20 mmol) and 3-cyano-4- 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide (Preparation yl)-1H-pyrazole (27 mg, 0.14 mmol) palladium (O) tetrakis 46, 57 mg, 0.20 mmol) were used to prepare the title com 25 (triphenylphosphine) (10 mg, 0.009 mmol) and sodium car pound using Method F above. The product was purified by bonate (30 mg 0.28 mmol) were dissolved in flash column chromatography (SiO2) eluting with dichlo dimethylformamide:water (2:1, 1.5 ml) and heated to 90° C. romethane:ethyl acetate (gradient 8:2 to 2:8, by volume) to for 18 hours. The reaction was partitioned between ethyl afford the title compound, 98 mg, 97% yield. acetate and Saturated aqueous sodium chloride Solution. The LCMS Rt=1.47 minutes. MS m/z 522 MH+ 30 organic layer was separated, dried over Sodium Sulfate and evaporated in vacuo to afford a brown oil. Purification by "H NMR (400 MHz, CDC1): 83.86 (s.3H), 6.21 (d. 1H), preparative HPLC afforded the title compound. Yield 12.5 mg 6.58 (d. 1H), 6.66 (d. 1H), 7.10 (d. 1H), 7.24 (d. 1H), 7.33 (d. 30%. 1H), 7.36-7.42(m,2H), 7.91 (dd. 1H), 8.09 (d. 1H), 11.64 (br. LCMS=Rt 2.50 minutes. MS m/z 476 MCIH+ s, 1H) ppm. 35 'F NMR (376 MHz, CDC1): 8 -58.52 (s) ppm. Example 786 Example 784 N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-4-chloro 40 2-(1H-pyrazol-4-yl)phenoxybenzenesulfonamide 4-(2-azetidin-3-yl-4-chlorophenoxy)-5-chloro-N-(5- chloro-1,3-thiazol-2-yl)-2-fluorobenzenesulfonamide

45 F O C H C S-N

l )=n 50 O Sna C C

N H 55 The title compound was prepared according to the same 5-Chloro-N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4- method as that used for Example 785 above using 4-(4- dimethoxybenzyl)-2,4-difluorobenzenesulfonamide (Prepa chloro-2-iodophenoxy)-N-(5-chloro-1,3-thiazol-2-yl)-3-cy ration 655) and tert-butyl 3-(5-chloro-2-hydroxyphenyl)aze anobenzenesulfonamide (Preparation 219) and 4-(4.4.5.5- tidine-1-carboxylate (Preparation 237) were stirred in 60 tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole aS dichloromethane (2 ml) and trifluoroacetic acid (1 ml) to starting materials. Purification by preparative HPLC afforded prepare the title compound using Method Fabove but where the title compound. Yield 7.8 mg 17%. the N,N-dimethylformamide was replaced with dimethylsul LCMS=Rt 2.45 minutes. MS m/z 492 MCIH+ phoxide. The crude product was concentrated in vacuo and 65 'HNMR (400 MHz, CDC1): 86.63 (d. 1H), 6.8 (s, 1H), purified by preparative HPLC to afford the title compound. 7.05 (d. 1H), 7.22 (m. 1H), 7.60 (s, 1H), 7.80 (m,3H), 8.15 (s, LCMS Rt=2.47 minutes MS m/z 509 MCIH+ 1H) US 8,907,101 B2 115 116 Example 787 acetamide (Preparation 209, 239 mg, 0.661 mmol) and stirred for 30 minutes. To this was added tert-butyl 5-chloro-2,4- 4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-2,5- difluorophenylsulfonyl(thiazol-4-yl)carbamate (Preparation difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 453, 206 mg, 0.501 mmol) and stirred for 24 hours. After this time only a small amount of product was observed, so potas sium carbonate (40 mg, 0.3 mmol) was added and the reaction heated at 55° C. for 3 days. The reaction was cooled, diluted with ethyl acetate and the organic extract washed with water and Saturated aqueous Sodium chloride Solution, dried over magnesium Sulfate, filtered and concentrated in vacuo. Puri fication by automated flash column chromatography eluting with ethyl acetate:hexanes (gradient 0:1 to 1:0, by volume) afforded fully protected product. This residue was dissolved 15 in methanol (1 mL) and sodium carbonate solution (2 M aqueous, 0.08 mL, 0.2 mmol) and water (0.2 mL) added. The reaction was stirred at room temperature for 6 hours and then HN N heated at 55° C. for 16 hours before concentrating in vacuo and passing through a short silica gel column eluting with methanol:dichloromethane (gradient 0:1 to 1:9, by volume). A suspension of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro All product related fractions were combined, concentrated in N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation vacuo, dissolved in methanol (Saturated in gaseous hydrogen 647, 10 g, 22.45 mmol), 2-(2-aminopyridin-4-yl)-4-chlo chloride) and heated at 50° C. for 16 hours. Purification by rophenol (Preparation 258, 5g, 22.67 mmol) and potassium preparative HPLC afforded the title compound as a white carbonate (3.72 g, 26.94 mmol) in dimethyl sulfoxide (150 25 solid, 31 mg, 12% yield. mL) was stirred at room temperature for 2 hours. The reaction LCMS Rt=1.72 minutes. MS m/z 500 MCIH+ was partitioned between ethyl acetate (150 mL) and saturated "H NMR (300 MHz, d-DMSO): 8 6.85 (d. 1H), 7.11 (m, aqueous Sodium chloride solution (150 mL). The organic 1H), 7.24 (m. 1H), 7.41 (dd. 1H), 7.71 (m, 2H), 7.93 (d. 1H), layer was collected and concentrated in vacuo to afford an 8.93 (m. 1H), 11.45 (brs, 1H). orange residue. This was dissolved in dichloromethane (145 mL) and trifluoroacetic acid (8.48 mL) was added. The reac 30 Example 789 tion was stirred at room temperature for 24 hours before concentrating in vacuo to afford a pink residue. This was 2,5-difluoro-4-2-(1H-pyrazol-5-yl)-4-(trifluorom taken up in ethyl acetate (200 mL) to form a white slurry that ethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzene was washed with saturated sodium bicarbonate solution (200 Sulfonamide mL). Filtration yielded a white solid that was dried in vacuo, 35 slurried in water and hydrochloric acid (1 Naqueous solution, 1.05 eq) and extracted with ethyl acetate. The organic layer was collected and concentrated in vacuo to yield the title compound. LCMS Rt=1.92 minutes. MS m/z 496 MCIH+ 40 "H NMR (d-DMSO): 86.95 (m, 1H), 7.05 (s, 1H), 7.20 7.30 (m, 2H), 7.55 (d. 1H), 7.65 (s, 1H), 7.75 (m, 1H), 7.95 8.05 (m, 3H), 8.40 (s, 1H). Example 788 45 4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy 5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfona mide 50 A suspension of N-(2,4-dimethoxybenzyl)-2,5-difluoro-4- 2-iodo-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide (Preparation 363, 100 mg, 0.14 mmol), potassium carbonate (48 mg, 1.12 mmol) and 1-(ethoxymethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboro F V/ X 55 lan-2-yl)-1H-pyrazole (Preparation 337, 70 mg, 0.28 mmol) C n / in 1,4-dioxane (5 mL) and water (2 mL) was degassed and H palladium tetrakis (16 mg, 0.014 mmol) added before heating at 80°C. for 16 hours. Dicholoromethane (20 mL) and water O (10 mL) were added and the organics separated and evapo HN C 60 rated in vacuo to afford the crude product. Dicholoromethane 2 na (10 mL) and trifluoroacetic acid (5 mL) were added and the f reaction mixture was stirred at room temperature for 16 hours HN-N before concentrating in vacuo. Hydrochloric acid (4 M in 1,4-dioxane, 10 mL) was added and the reaction mixture was To a suspension of Sodium hydride (29 mg, 1.2 mmol) in 65 stirred for 16 hours before concentrating in vacuo. The resi dimethylformamide (1 mL) was added N-(1-tert-butyl-4-(5- due was purified by reverse phase chromatography to afford chloro-2-hydroxyphenyl)-1H-pyrazol-5-yl)-2.2.2-trifluoro the desired product, 6 mg, 9% yield. US 8,907,101 B2 117 118 LCMS Rt=4.23 minutes. MS m/z. 504 MH+ Example 792 "H NMR (CDOD): 88.05 (m, 1H), 8.30 (m, 1H), 8.70 (m, 1H), 8.95-9.10 (m, 3H), 9.70 (m, 2H). 4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy 3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide Example 790

2,5-difluoro-4-2-(1H-pyrazol-4-yl)-4-(trifluorom - N. ethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzene 10 Sulfonamide C YuH X

F F o O N1\ 15 F V/ N HN F Sn N s/ f N H HN-N

O To a solution of the N-1-tert-butyl-4-5-chloro-2-(2-cy N F ano-4-(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl) \ aminolsulfonylphenoxy)phenyl)-1H-pyrazol-5-yl)-2.2.2- N-N trifluoroacetamide (Preparation 419, 157 mg, 0.20 mmol) in H methanol (15 ml) was added hydrogen chloride (4M in 1,4- 25 dioxane, 3 ml). The resulting yellow solution was stirred and The title compound was prepared according to the same heated at 60° C. for 48 hours. The solvent removed in vacuo method as that used for Example 789 above using N-(2,4- to afford a pale yellow residue. The material was purified by dimethoxybenzyl)-2,5-difluoro-4-2-iodo-4-(trifluorom column chromatography (80 g silica gel column) eluting with ethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 30 methanol:dichloromethane (5:95, by volume) to afford the (Preparation 363) and the boronic ester tert-butyl 4-(4.4.5.5- title compound as a yellow oily solid, 56 mg, 59% yield. tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-car LCMS Rt 3.09 minutes. MS m/z, 474 (MCIH+ boxylate. Purification using reverse phase chromatography "H NMR (CDOD): 8 6.64-6.70 (m. 1H), 7.19-7.22 (m, afforded the title compound. 1H), 7.31-7.38 (m, 1H), 7.50 (br-s, 1H), 7.64 (br-s, 1H), LCMS Rt=3.98 minutes. MS m/z. 504 MH+ 35 7.86-7.90 (m, 2H), 8.10 (s, 1H). "H NMR (CDOD): 88.30 (m, 1H), 8.60 (m, 1H), 8.85 (m, 1H), 9.05 (m, 1H), 9.35-9.45 (m, 3H), 10.65 (s, 1H). Example 793

Example 791 40 3-cyano-4-2-(1H-pyrazol-5-yl)-4-(trifluo romethoxy)phenoxy-N-1,2,4-thiadiazol-5-ylbenze 4-(4-chloro-2-(1H-pyrazol-4-yl)phenoxy)-3-cyano nesulfonamide N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 45

N N1\ OV/ O $1 \ 'W' Y 50 n S C n S? H H

O

21 55

HN-N

The title compound was prepared from 4-(4-chloro-2-io 3-cyano-N-(1,2,4-thiadiazol-5-yl)-4-2-iodo-4-(trifluo dophenoxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzene 60 romethoxy)phenoxybenzenesulfonamide (Preparation 760, sulfonamide (Preparation 355) and (4.4.5.5-tetramethyl-1,3, 500 mg. 0.88 mmol), 1-(ethoxymethyl)-5-(4.4.5.5-tetram 2-dioxaborolan-2-yl)-1H-pyrazole using Method E above ethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Preparation with microwave irradiation for 1 hour at 85°C. 337, 600 mg, 1.4 mmol), palladium (O) tetrakis triph enylphosphine (78 mg, 0.067 mmol) and sodium carbonate LCMS Rt=3.24 minutes MS m/z 457 (MCIH 65 (420 mg, 3.963 mmol) were dissolved in a mixture of water (4 HNMR (400 MHz, d-DMSO): 8 6.85 (d. 1H), 7.30-7.40 mL) and 1,4-dioxane (12 mL) and heated to 85°C. under N (m. 2H), 7.95 (m, 2H), 8.00 (s. 2H), 8.25 (s, 1H), 8.45 (s, 1H) for 7 hours. Further 1-(ethoxymethyl)-5-(4.4.5.5-tetram US 8,907,101 B2 119 120 ethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg 0.23 Example 795 mmol) and palladium (0) tetrakis triphenylphosphine (10 mg. 0.008 mmol) were added and the reaction stirred at 85°C. 3-cyano-4-2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluo under N for 18 hours. The reaction was quenched by the romethoxy)phenoxy-N-1,2,4-thiadiazol-5-ylbenze addition of ethyl acetate (20 mL) and Saturated aqueous brine solution (20 mL). The organic layer was collected, dried over nesulfonamide Sodium Sulphate and concentrated in vacuo before purifica tion using silica gel column chromatography (dichlo romethane:methanol:acetic acid V/v/v 100:0:0 to 95:5:0.5) to V/ -\ afford a white solid. This was dissolved in 4M HCl in 1,4- 10 : - s/ dioxane (5 mL) and stirred at room temperature for 4 hours H before concentration in vacuo and purification using silica gel column chromatography (V/v/v dichloromethane:methanol: acetic acid 100:0:0 to 90:10:1 to afford a residue that was triturated in dichloromethane (5 mL) to afford 210 mg of the 15 title compound as a white solid as the HCl salt. LCMS Rt=1.56 minutes. MS m/z. 509 MH+ "H NMR (d-DMSO): 8 6.55 (s, 1H), 6.85 (d. 1H), 7.45 The title compound was prepared from 3-cyano-N-(2,4- 7.50 (m, 2H), 7.75 (s, 1H), 7.90-8.00 (m, 2H), 8.25 (s, 1H), dimethoxybenzyl)-4-2-iodo-4-(trifluoromethoxy)phe 8.45 (s, 1H) noxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Prepa ration 497) and 1-methyl-1H-pyrazole-5-boronic acid Example 794 pinacol ester using Method E above. Purification afforded the title compound. 4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy 25 LCMS Rt=3.96 minutes. MS m/z 523 MH+ 5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzene 'HNMR (CDC1): 83.9 (s.3H), 6.25 (m, 1H), 6.7 (m. 1H), Sulfonamide 7.3-7.45 (m, 3H), 7.9 (m. 1H), 8.05 (m, 3H).

30 Example 796 O O N1\ V/ N C 5-chloro-4-(4-chloro-2-piperidin-4-ylphenoxy)-2- {ul fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide H

F O o N1\ HN C C \ uly N N d 40 O Dimethyl sulfoxide (5.0 mL) was added to a flask contain C ing N-1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H-pyra Zol-5-yl)-2.2.2-trifluoroacetamide (Preparation 209, 0.100 g, 45 0.000276 mol), 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-dif N luoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Prepara H tion 333, 0.116 g., 0.000251 mol) and potassium carbonate (0.104 g., 0.000753 mol) and the reaction mixture was stirred To a solution of tert-butyl 4-(5-chloro-2-hydroxyphenyl) at room temperature under nitrogen for 16 hours. The reaction 50 piperidine-1-carboxylate (Preparation 231, 0.500 g, 0.0014 mixture was poured into water (50.0 mL) and the aqueous mol) and potassium carbonate (0.579 g, 0.00419 mol) in extracted with ethyl acetate (4x30.0 mL). The combined dimethyl sulfoxide (5.0 mL) was added 5-chloro-N-(2,4- organics were washed with Saturated aqueous sodium chlo dimethoxybenzyl)-2,4-difluoro-N-1,2,4-thiadiazol-5-ylben ride solution (30 mL), dried over magnesium sulfate, filtered Zenesulfonamide (Preparation333, 0.644g, 0.0014 mol). The and concentrated in vacuo. The residue was dissolved in 55 mixture was stirred at room temperature under nitrogen for methanol (5.0 mL) and hydrochloric acid (4M in 1,4-diox 1.5 hours before diluting with ethyl acetate (10.0 mL) and ane, 5.0 mL, 0.020 mol) and stirred at 100°C. under nitrogen water (10.0 mL). The aqueous layer was extracted with ethyl for 16 hours. The mixture was concentrated in vacuo and the acetate (3x10.0 mL). The combined organic extracts were residue was purified by reverse phase chromatography elut washed with saturated aqueous sodium chloride solution (30 ing with water:acetonitrile:trifluoroacetic acid (gradient 60 mL), dried over sodium sulfate, filtered and concentrated in 95:5:0.1 to 30:70:0.1, by volume) to afford a colourless gum. vacuo. The residue was purified by column chromatography This was triturated with heptane to afford the title compound (40 g silica gel column) eluting with ethyl acetate: heptane (gradient 0:1 to 35:65, by volume) to afford 1.03 g of tert as a white powder, 0.030g, 22% yield. butyl 4-5-chloro-2-(2-chloro-4-(2,4-dimethoxybenzyl)(1, LCMS Rt=3.40 minutes. MS m/z 501 (MCICIH+ 2,4-thiadiazol-5-yl)aminosulfonyl-5-fluorophenoxy)phe 'HNMR (400 MHz, d-DMSO): 8 6.75 (m. 1H), 7.2 (m, 65 nylpiperidine-1-carboxylate as a white solid. This material 1H), 7.35 (m, 1H), 7.55 (s, 1H), 7.65 (m, 1H), 7.85 (m, 1H), was dissolved in dichloromethane (5.0 mL), trifluoroacetic 8.4 (s, 1H). acid (1.0 mL) added and reaction stirred for 16 hours at room US 8,907,101 B2 121 122 temperature under nitrogen. Methanol (5.0 mL) was added to 5-chloro-4-4-chloro-2-(2-cyanopyridin-4-yl)phenoxy afford a white precipitate. This suspension mixture was fil N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,2,4-thiadiazol-5-yl tered through a CeliteTM pad and washed with methanol. The benzenesulfonamide (Preparation 340, 0.04 g., 0.00006 mol) filtrate was concentrated in vacuo and the residue was diluted was partially dissolved in methanol (5.0 mL) and 1,4-dioxane with methanol (2.0 mL), dichloromethane (2.0 mL) and satu (5.0 mL). The solution was passed through an H-CubeTM at rated aqueous sodium bicarbonate (4.0 mL) and stirred for 1 70° C. with Raney nickel catalyst (30 mm cartridge) 3 times hour at room temperature to afford a white solid. The suspen eluting with methanol to get complete conversion. Concen sion was filtered and the solid washed with water and diethyl tration in vacuo afforded the title compound as a colourless ether. The collected solid was recrystallised from hot aceto solid, 0.004 g, 10% yield. nitrile and ethanol (1:1 V/v) to afford the title compound as a white solid, 0.1929 mg, 27% yield. LCMS Rt=1.13 minutes. MS m/z 527.0 MCIH+ 'HNMR (400 MHz, d-DMSO): & 1.83 (m, 2H), 1.95 (m, H NMR (400 MHz, CDOD): 84.11 (s. 2H), 6.52 (m. 1H), 2H), 3.02 (m, 3H), 3.33 (d. 2H), 6.90 (d. 1H), 7.00 (dd. 1H), 6.97 (m 1H), 7.24 (m, 1H), 7.55 (m, 4H), 7.85 (s1H), 8.59 (m, 7.33 (m, 2H), 7.85 (d. 1H), 7.90 (s, 1H), 8.29 (br. s. 2H) 1H) Anal. Calcd for CH,ClFN.O.S.0.12CH: C, 45.41: H, 3.51; N, 11.01. Found: C, 45.19; H, 3.49; N, 11.02. 15 Example 799 Example 797 3-cyano-4-2-(5-methyl-1H-pyrazol-4-yl)-4-(trifluo 3-Cyano-4-2-(tetrahydro-2H-pyran-4-yl)-4-(trifluo romethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzene romethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzene Sulfonamide Sulfonamide

F o, o N1\ 25 F O. H. F \/ uly F N F NN S H F \, NS X N O O 30 Me 2 CN f N-N H

3-cyano-4-2-(5-methyl-1-trity1-1H-pyrazol-4-yl)-4-(trif 35 luoromethyl)phenoxy-N-1,2,4-thiadiazol-5-ylbenzene sulfonamide (Preparation 428, 345 mg, 0.46 mmol) was dis To a suspension of zinc dust (458 mg, 7.00 mmol) and solved in 4N HCl in 1,4-dioxane (5 ml) and stirred at room lithium chloride (212 mg, 5.00 mmol) in tetrahydrofuran was temperature for 3 hours before concentrating in vacuo. The residue obtained was purified using an ISCOTM (12 g SiO2) added dibromoethane (0.043 mL, 0.50 mmol) under nitrogen. eluting with methanol:dichloromethane (gradient 0:1 to 1:9. 40 The mixture was heated at 70° C. for 10 minutes before by volume). The purified compound was triturated with cooling and adding chlorotrimethlsilane (0.013 mL, 0.10 dichloromethane (10 mL) to afford the title compound as a mmol). The reaction mixture was stirred for 1 hour then white solid (148 mg, 34% isolated as the hydrochloride 4-iodotetrahydro-2H-pyran (1060 mg, 5.00 mmol) was added salt). and stirring continued for 18 hours. This mixture was added to LCMS Rt=1.84 minutes. MS m/z. 507 MH+ 45 "H NMR (400 MHz, d-DMSO): 8 2.25 (s, 3H), 6.85 (d. a pre-stirred (10 minutes) Suspension of 3-cyano-N-(2,4- 1H), 7.50 (d. 1H), 7.60 (d. 1H), 7.80 (s. 2H), 7.90 (d. 1H), 8.20 dimethoxybenzyl)-4-2-iodo-4-(trifluoromethyl)phenoxy (s, 1H), 8.45 (s, 1H). N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 429, 11 mg, 0.3 mmol), palladium(II) acetate (6.7 mg, 0.03 Example 798 50 mmol) and dicyclohexyl(2,6'-dimethoxybiphenyl-2-yl) 4-2-[2-(aminomethyl)pyridin-4-yl)-4-chlorophe phosphine (24.6 mg, 0.06 mmol) in tetrahydrofuran (0.5 mL). noxy-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylben The reaction mixture was stirred at room temperature for 2 Zenesulfonamide hours before pouring into saturated aqueous ammonium chlo 55 ride solution (10 mL). The aqueous layer was extracted with ethyl acetate (3x10 mL). The combined organic layers were F dried over magnesium sulfate and concentrated in vacuo to C obtain a residue that was purified using an ISCOTM system SN N eluting with heptane:ethyl acetate (1:0 to 4:6, by volume). 60 The residue was dissolved in dichloromethane (3 mL) and O trifluoroacetic acid (3 mL) was added. After stirring for 1 hour at room temperature, methanol (20 mL) was added and the 21 C resulting precipitate was filtered and the filtrate concentrated in vacuo. The crude material was purified using preparative HN N N HPLC to afford the title compound. LCMS Rt=2.51 minutes. MS m/z. 509 MH US 8,907,101 B2 123 124 Example 800 luoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Prepara tion 688, 270 mg, 0.321 mmol) was dissolved in 5-Chloro-2-fluoro-N-(5-fluoropyridin-2-yl)-4-2- dichloromethane (15 ml) and N.N.N',N'-tetramethylnaphtha piperidin-4-yl-4-(trifluoromethyl)phenoxybenzene lene-1,8-diamine (85 mg, 0.40 mmol) was added followed by Sulfonamide 1-chloroethyl chloroformate (0.07 ml, 0.65 mmol) and the solution was stirred at room temperature for 4 hours. The Solution was concentrated in vacuo and the residue was par titioned between ethyl acetate (40 ml) and 1 Maqueous citric F acid solution (20 ml), the ethyl acetate was washed with F F o o 21 10 F \/ water, dried over anhydrous Sodium Sulphate, evaporated and F NN s the solvents removed in vacuo to give an oil. The oil was H dissolved in methanol (15 ml) and refluxed for 5 hours. Some of the methanol was removed in vacuo to leave about 5 ml, the O precipitated solid was removed by filtration and the filtrate was adsorbed onto silica gel (5 g) and dried prior to purifica C tion by column chromatography on silica gel using 10-25% V/v methanol (containing 10% V/v 0.880 aqueous ammonia) N in dichloromethane. This afforded the title compound as a H pinkish solid, 80 mg. LCMS Rt=1.10 minutes, m/z =525 (MCIH+: 527 A mixture of tert-butyl 4-2-hydroxy-5-(trifluoromethyl) M7CIH+ phenylpiperidine-1-carboxylate (Preparation 317, 51 mg, 'HNMR (d-DMSO): 83.20 (brs, 3H), 4.22-4.28 (m, 4H), 0.15 mmol), 5-chloro-2,4-difluoro-N-(5-fluoropyridin-2-yl)- 5.14-5.21 (m. 1H), 6.45 (d. 1H), 7.03-7.09 (m. 1H), 7.23 (d. 25 1H), 7.52-7.61 (m, 3H), 7.72 (d. 1H), 7.89 (s, 1H), 8.75 (brs, N-(methoxymethyl)benzenesulfonamide (Preparation 349, 1H) 50 mg, 0.1 mmol) and potassium carbonate (28 mg, 0.20 CHN analysis. Required for mono hydrate: C, 44.24; H, mmol) in anhydrous dimethylsulfoxide (2 mL) was heated at 3.16: N, 15.48. Found: C, 44.33/44.19; H, 3.22/3.22: N, 50° C. for 30 minutes. The reaction mixture was cooled to 15.66/15.68; room temperature and diluted with ethyl acetate and water. The layers were separated and the aqueous layer extracted 30 Example 801 with ethyl acetate. The combined extracts were washed with saturated aqueous Sodium chloride solution, water, dried over Trifluoroacetic Acid Salt magnesium Sulfate and concentrated in vacuo to afford the title compound as a light yellow thick oil, which was used in 4-2-(1-AZetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophe the next step without further purification. The residue was 35 noxy-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzene diluted with dichloromethane (2 mL), trifluoroacetic acid Sulfonamide (210 ul, 2.7 mmol) was added and solution stirred at room temperature for 18 hours. The reaction solution was concen trated in vacuo and purified by preparative HPLC to afford the title compound as a white powder, 55.3 mg (as the trifluoro 40

acetic acid salt) LCMS Rt=1.54 minutes. MS m/z 548 MCIH+ "H NMR (CDOD): 8 1.94-2.32 (m, 5H), 3.09-3.28 (m, 2H), 3.47-3.63 (m, 2H), 6.97-7.31 (m, 3H), 7.72-7.55 (m, 2H), 7.74 (s, 1H), 8.12 (m. 1H), 8.21 (m, 1H) 45 Example 801 4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophe noxy-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzene 50 Sulfonamide An alternative method to the trifluoroacetic acid salt of Example 801 is provided below: Tert-butyl 3-5-5-chloro-2-(4-(2,4-dimethoxybenzyl) 55 (1,2,4-thiadiazol-5-yl)aminosulfonyl)-2,5-difluorophe F o O N1\ noxy)phenyl)-1H-pyrazol-1-yl)azetidine-1-carboxylate, V/ | N (Preparation 850, 145.47 g., 0.1455 mol) was dissolved in Sn s/ dichloromethane (1450 mL) and then trifluoroacetic acid (354.7 mL, 4.69 mol) was added slowly over 30 minutes. The 60 pink mixture was stirred at room temperature for 2 hours and then methanol (1450 mL) was added to give a white precipi tate. The solid was filtered off and the filtrate was concen trated in vacuo to give an oil. The oil was dissolved in a small volume of methanol and tert-butylmethyl ether was added 65 very slowly with stirring to give an oily dispersion which 4-(4-chloro-2-1-1-(diphenylmethyl)azetidin-3-yl)-1H would not crystallize. The solvents were removed in vacuo pyrazol-5-yl)phenoxy)-N-(2,4-dimethoxybenzyl)-2,5-dif and the residue was dissolved in methanol and evaporated, US 8,907,101 B2 125 126 this was repeated a further two times to give a foam. The foam room temperature for 100 minutes before filtration and drying was triturated with tert-butylmethyl ether, filtered off and in vacuo to provide sodium salt of the title compound as a dried to give the title compound as the trifluoroacetate salt cream coloured solid (9.6 g). which was a pale yellow powder, (120g). 'FNMR (d-DMSO): 8 -60.5 ppm (s). HPLC Rt=2.22 minutes 'HNMR (CDOD) 84.50-4.55 (m, 4H), 5.19-5.28 (m. 1H), 'HNMR (d-DMSO): 87.22 (d. 1H), 7.43 (d. 1H), 7.80 6.39 (d. 1H), 6.76-6.82 (m, 1H), 7.27 (d. 1H), 7.54 (d. 1H), 8.00 (m, 4H), 8.04 (s, 1H), 8.13 (s, 1H), 9.28 (s, 1H), 9.45 (s, 7.60-7.64 (m. 1H), 7.68-7.74 (m, 2H), 8.24 (s, 1H). 1H).

Example 802 10 Example 803 3-cyano-4-2-pyridazin-4-yl-4-(trifluoromethyl)phe 4-2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy noxy-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzene Sulfonamide 15

O O 1N F O O $1\ F Y N usS V/ N H C Sn N S/ H

O

25 HN N C

N-NH To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-2- pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,2,4-thia 30 The title compound was prepared from N-1-tert-Butyl-4- diazol-5-ylbenzenesulfonamide, (Preparation 711, 59.7 mg, (5-chloro-2-hydroxyphenyl)-1H-pyrazol-3-yl)-2.2.2-trifluo 0.091 mmol) in dichloromethane (3 mL) was added trifluo roacetamide (Preparation 209) and 5-chloro-N-(2,4- roacetic acid (0.33 mL) The mixture was stirred overnight at dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2- room temperature under nitrogen. The reaction mixture was ylbenzenesulfonamide (Preparation 247) using Method B concentrated in vacuo. The purple residue was partitioned 35 above with the exception that heating at 55° C. in HCl (gas) between dichloromethane (10 mL) and water (10 mL). The saturated methanol for 16 hours was used to remove the aqueous layer was extracted with dichloromethane (3x10 protecting groups. Purification by preparative HPLC afforded mL) and the combined organic layers were washed with Satu the title compound. rated aqueous sodium chloride solution (10 mL), dried over LCMS Rt=1.61 minutes anhydrous sodium sulfate, filtered and the solvent removed in 40 vacuo to afford a brown solid (30.7 mg, 67%). MS m/z 503 M7CIHI+, 501 (MCIH+ LCMS Rt=3.81 minutes, MS m/z 505 MH+ 'HNMR (d-DMSO): 84.50 (brs, 2H), 6.89 (m, 1H), 7.21 'HNMR (d-DMSO): 8 7.28 (m. 1H), 7.56 (m, 1H), 7.91 (m. 1H), 7.37 (m. 1H), 7.66 (m. 1H), 7.70 (m, 1H), 7.89 (m, (m. 1H), 7.98 (m. 1H), 8.02 (m. 1H), 8.18 (m, 1H), 8.27 (m, 1H), 8.81 (d. 1H). 1H), 8.44 (s, 1H), 9.31 (m, 1H), 9.45 (m. 1H). 45 Method 2 Example 804 The sodium salt of Example 802 can also be prepared as follows. To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-2- 4-4-chloro-5-fluoro-2-(1H-pyrazol-4-yl)phenoxy pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,2,4-thia 50 3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide diazol-5-ylbenzenesulfonamide, (Preparation 711, 18.2 g, 0.028 mol) in dichloromethane (182 mL) was added trifluo roacetic acid (91 mL) dropwise over 3 minutes. The mixture was stirred for 45 minutes before addition of water (200 mL) O O s.v. and methanol (200 mL). The resulting slurry was stirred at 55 room temperature for 18 hours before filtration through a C short pad of silica (9 cm diameterx2 cm deep). The filtrate YJ-2 was concentrated in vacuo to remove organics before addition of a saturated aqueous solution of sodium bicarbonate (91 mL) and dichloromethane (150 mL) with vigourous stirring 60 for 30 minutes. The aqueous layer was extracted with methyl CN ethyl ketone (3x100 mL) and solid sodium bicarbonate (20g) added to improve separation of aqueous/organic layers. The combined organic extracts were washed with brine (150 mL), dried over sodium sulfate before addition of toluene (180 mL) 65 and concentration/drying in vacuo at 50° C. The resulting To a solution of tert-butyl 4-5-chloro-2-(2-cyano-4-(2, pale orange Solid (14.7 g) was slurried in water (120 mL) at 4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)aminosulfo US 8,907,101 B2 127 128 nylphenoxy)-4-fluorophenyl)-1H-pyrazole-1-carboxylate Example 806 (Preparation 728, 190 mg, 0.26 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.3 mL, 3.65 mmol) and 5-Chloro-2-fluoro-4-4-fluoro-2-1-(1-methylazeti the reaction mixture was left to stir at room temperature for 16 din-3-yl)-1H-pyrazol-5-yl)phenoxy-N-1,2,4-thia hours. The reaction was quenched by addition of water (10 diazol-5-ylbenzenesulfonamide mL) and the resulting mixture left to stir for 20 minutes. Then the layers were separated, the organic phase was washed with saturated aqueous Sodium chloride Solution (5 mL), dried N over anhydrous magnesium Sulphate, filtered and concen F O O 1 \ trated in vacuo. The crude oil was purified using ISCOTM (5g 10 Y% cartridge) 1-20% v/v gradient of methanol in dichlo NN N romethane as the eluent. The title compound was obtained as H a white solid (61 mg. 50%). LCMS Rt=4.51 minutes, MS m/z 477 (MCIH+ 15 Me NN C 'HNMR (d-DMSO): 8 6.95 (m, 1H), 7.10 (m. 1H), 7.55 (m. 1H), 7.80-8.01 (m, 2H), 8.10 (m, 2H), 13.0 (brs, 1H). The title compound was prepared by analogy with Example 807 below using 4-2-(1-azetidin-3-yl-1H-pyrazol Example 805 5-yl)-4-fluorophenoxy-5-chloro-2-fluoro-N-1,2,4-thiadia Zol-5-ylbenzenesulfonamide (Example 810, 45 mg, 0.08 mmol). 2,5-difluoro-4-2-pyridazin-4-yl-4-(trifluoromethyl) 25 Yield 14.5 mg 34%. phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfona LCMS Rt=2.49 minutes, m/z 539 MCIH+ mide TLCRf-0.5 (methyl isobutyl ketone:acetic acid:water 2:1: 1) 'HNMR (d-DMSO): 8 2.94 (s, 3H), 4.13-4.58 (m, 4H), 30 5.20 (m. 1H), 6.43 (s, 1H), 6.81 (d. 1H), 7.26-7.34 (m. 1H), N 7.39-7.48 (m, 2H), 7.67-7.74 (m, 2H), 7.91 (s, 1H) F F F OV/ O $1 \ Example 807 Sn S. F N N H 5-Chloro-2-fluoro-4-4-fluoro-2-1-(1-methylazeti 35 din-3-yl)-1H-pyrazol-5-yl)phenoxy-N-1,3-thiazol O 4-ylbenzenesulfonamide

21 F S Nnn 40 F O O Yu)YC The mixture of N-(2,4-dimethoxybenzyl)-2,4,5-trifluoro H N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 647, 44 mg., 0.10 mmol), 2-pyridazin-4-yl-4-(trifluorom 45 ethyl)phenol (Preparation 712, 34 mg., 0.10 mmol), and Me NN C potassium carbonate (55 mg, 0.40 mmol) in N,N-dimethyl formamide (1.0 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into aqueous 2 M hydrochloric acid solution (5.0 ml) and filtered to give a solid. 50 4-2-(1-AZetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophe The solid was dissolved in dichloromethane (1.0 ml) and noxy-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfona trifluoroacetic acid (1.0 ml) was added to the solution. The mide (Example 808, 29 mg, 0.052 mmol) was stirred in resulting solution was stirred for 16 hours. Methanol (5.0 ml) dichloromethane (2 ml), methanol (0.2 ml), aqueous formal was added to the reaction mixture and filtered off polymeric dehyde (0.015 ml of 37% wt/vol) added and the reaction Solid. The filtrate was concentrated in vacuo to give a residue. 55 stirred at room temperature for a further 30 minutes. Sodium The residue was passed through a 5 g SCXTM column with 1:1 triacetoxyborohydride (37 mg, 0.172 mmol) was added and dichloromethane:methanol solution and then 1:0.75:0.25 the solution stirred for 3 hours. The solvents were removed in dichloromethane:methanol:7N ammonia solution in metha vacuo and the residue dissolved in ethyl acetate and extracted nol. The filtrate was concentrated in vacuo and purified by with Saturated aqueous sodium hydrogencarbonate Solution 60 (2x10 ml) and brine (2x10 ml). The organic layer was sepa HPLC. Yield 7.3 mg, 14%. rated, dried over sodium sulphate, filtered and evaporated to give a solid. The compound was purified using preparative LCMS Rt=2.44 minutes MS m/z 516 MH+ HPLC to afford the title compound. Yield 15.9 mg 57%. LCMS Rt=2.38 minutes, m/z 538 MCIH+ 'HNMR (400 MHz, CDOD): 8 7.25 (m, 1H), 7.30 (d-d, 65 'HNMR (CDOD): 8 4.25 (m, 4H), 5.25 (m. 1H), 6.34 (s, 1H), 7.80-7.85 (m, 2H), 8.00 (d. 1H), 8.05 (d-d. 1H), 8.25 (s, 1H), 6.92 (d. 1H) 7.08 (s, 1H), 7.45 (m,3H), 7.66 (s, 1H), 7.79 1H), 9.30 (d. 1H), 9.50 (s, 1H) (d. 1H), 8.92 (s, 1H), 9.17 (brs, 1H), 11.32 (brs, 1H). US 8,907,101 B2 129 130 Example 808 NMR (d-DMSO) 83.31 (bs, 2H)4.04-4.14 (m, 4H), 5.05 5.14 (m, 1H), 6.30 (s, 1H), 6.38 (bs, 1H), 6.86 (d. 1H), 7.43 (d. 4-2-(1-AZetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophe 1H), 7.61 (m, 2H), 7.68 (m, 1H), 7.84 (m. 1H), 8.01 (s, 1H), noxy-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzene 8.67 (s, 1H). 5 Sulfonamide Example 810 4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-fluorophe noxy-5-chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylben 10 Zenesulfonamide

N F O O S

15 C WNN NX H

C The title compound was prepared by analogy with Example 809, below, from tert-butyl {5-chloro-4-(2-1-1- (diphenylmethyl)azetidin-3-yl)-1H-pyrazol-5-yl)-4-fluo rophenoxy)-2-fluorophenylsulfonyl-1,3-thiazol-4-ylcar bamate (Preparation 683, 140 mg, 0.177 mmol). Yield 42 mg 25 The title compound was prepared by analogy with 42%. Example 809, above, from 5-chloro-N-(2,4-dimethoxyben LCMS Rt=1.04 minutes, m/z 524 MCIH+ Zyl)-4-(2-1-1-(diphenylmethyl)azetidin-3-yl)-1H-pyrazol HNMR (CDOD): 84.25 (m, 4H), 5.25 (m, 1H), 6.34 (s, 5-yl)-4-fluorophenoxy)-2-fluoro-N-1,2,4-thiadiazol-5-yl 1H), 6.92 (d. 1H) 7.08 (s, 1H), 7.45 (m,3H), 7.66 (s, 1H), 7.79 benzenesulfonamide (Preparation 681, 500 mg, 0.594 (d. 1H), 8.92 (s, 1H), 9.17 (brs, 1H), 11.32 (brs, 1H). 30 mmol). Final purification was achieved by Suspending the solid in methanol and the mixture filtered through CeliteTM (insoluble purple solid discarded). The colourless filtrate was Example 809 evaporated and the residue triturated with diethyl ether and the off-white solid filtered off and dried at 60°C. in vacuo to give the title compound. Yield 113 mg 34%. 4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophe 35 LCMS Rt=1.10 minutes, m/z 525 (MCIH+ noxy-3-cyano-N-1,3-thiazol-4-ylbenzenesulfona 'HNMR (d-DMSO): 84.27 (m, 4H), 5.23 (m. 1H), 6.40 (s, mide 1H), 6.92 (d. 1H) 7.34 (m, 1H), 7.45 (m, 2H), 7.69 (s, 1H), 7.79 (d. 1H), 8.35 (s, 1H), 8.72 (brs, 1H), 9.10 (brs, 1H). 'FNMR (d-DMSO) & 74.39 (s.3F) 106.9 (s, 1F) 116.7 (s, 40 1F). TLCRf-0.5 (methyl isobutyl ketone:acetic acid:water 2:1: 1) Example 811 45 4-4-Chloro-2-1-(1-methylazetidin-3-yl)-1H-pyra zol-5-yl)phenoxy-2,5-difluoro-N-1,2,4-thiadiazol 5-ylbenzenesulfonamide

50 tert-butyl ({4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4- F s-N chlorophenoxy-3-cyanophenylsulfonyl) 1,3-thiazol-4-yl V/ y carbamate (Preparation 679, 200 mg, 0.326 mmol) was n s stirred in 4M hydrogen chloride solution in 1,4-dioxan (10 55 H ml) at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between methyl-t-butyl ether (80 ml) and water (40 ml). The F aqueous layer was neutralized to pH7 by adding sodium hydrogen carbonate and was then concentrated in vacuo. The 60 crude product was purified by column chromatography on silica gel using dichloromethane:methanol:0.880 aqueous ammonia, 90:10:1 to 70:30:3. This gave a buff powder (65 4-2-(1-azetidin-3-yl-1H-pyrazol-5-yl)-4-chlorophe mg) which was triturated with methyl tert-butyl ether to give noxy-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfona the title compound as a buff powder, 55 mg. 65 mide (Example 801, 54 mg., 0.1 mmol) was stirred with LCMS Rt=1.26 minutes, m/z 513 MCIH+; 515 dichloromethane (2 mL) methanol (0.2 mL) and 37% w/v. M7CIH+ aqueous formaldehyde solution (0.025 mL, 0.34 mmol) at US 8,907,101 B2 131 132 room temperature for 15 minutes. Sodium triacetoxyborohy An alternative method of preparing Example 811 is as dride (68 mg 0.32 mmol) was added at the reaction stirred at follows: 4-2-(1-AZetidin-3-yl-1H-pyrazol-5-yl)-4-chlo room temperature for 18 hours. 37% wt/volaqueous formal rophenoxy-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzene dehyde solution (0.025 mL, 0.34 mmol) was added and the sulfonamide trifluoroacetate salt, (Example 801, 110.45 g, reaction stirred for 15 minutes then sodium triacetoxyboro 5 0.1558 mol) was dissolved in dichloromethane (1050 mL) hydride (68 mg, 0.32 mmol) was added at the reaction stirred and methanol (110.45 mL). Acetic acid (17.86 mL, 2.73 mol) at room temperature for 3 hours. The mixture was evaporated was added followed by aqueous formaldehyde solution and the residue dissolved in ethyl acetate (20 mL) and washed (58.54 mL of 37 wt % in water, 0.779 mol), stirred at room with Saturated aqueous sodium bicarbonate solution (2x10 temperature for 30 minutes. The solution was then cooled in ml) and Saturated aqueous sodium chloride solution (2x10 10 an ice bath and sodium triacetoxyborohydride (82.56 g. ml). The organic layer was separated, dried over sodium 0.3895 mol) was added, stirred whilst warming to room tem sulphate, filtered and evaporated to give a solid. The solid was perature over 1.5 hours. Aqueous formaldehyde Solution suspended in methyl isobutyl ketone:acetic acid: water 2:1:1 (29.27 mL of 37 wt % in water, 0.3895 mol) was added, and eluted through a silica column (5 g) with methyl isobutyl stirred for 30 minutes then sodium triacetoxyborohydride ketone:acetic acid:water 2:1:1. The appropriate fractions 15 (82.56 g., 0.3895 mol) was added and stirred at room tempera were combined and concentrated in vacuo to give a film. This ture for 1.5 hours. The reaction was quenched by adding was scratched with ethyl acetate then diethyl ether and dried water (552.25 mL) and stirred for 30 minutes then 0.880 in vacuo to give the title compound as a white solid. Yield 30 aqueous ammonia Solution (100 mL) was added in two equal mg. 54%. portions and stirred for a further 30 minutes. The resulting LCMS Rt=1.11 minutes, m/z 539 MCIH+ solid was filtered off and dried to give the crude title com 'HNMR (d-DMSO): 8 2.80 (s.3H), 4.10 (m 2H)4.24 (m pound as a white solid, (135 g). The crude product was Sus 2H)5.05 (m 1H)6.43 (d 1H)7.07 (m. 1H) 722 (d 1H) 7.57 (m, pended in ethanol (405 mL) and heated to reflux for 1 hour 3H) 7.69 (s1H) 7.89 (s, 1H), then water (405 mL) was added and the resulting slurry was TLC Rf-0.5 (methyl isobutyl ketone:acetic acid:water 2:1: stirred at 90° C. for 30 minutes before being allowed to cool 1) 25 to 35° C. The solid was filtered off and dried to give the title compound as a white solid, (67.5 g). Example 811 HPLC Rt=2.43 minutes Sodium Salt LCMS Rt=2.11 minutes, m/z =539 MCIH+ 'HNMR (d-DMSO) & 2.96 (s, 3H), 428-4.35 (m, 2H), 4-4-Chloro-2-1-(1-methylazetidin-3-yl)-1H-pyra 30 4.42-4.51 (m, 2H), 5.11-5.21 (m, 1H), 6.47 (d. 1H), 7.04-7.10 zol-5-yl)phenoxy-2,5-difluoro-N-1,2,4-thiadiazol (m. 1H), 7.24-7.26 (m, 1H), 7.55-7.62 (m, 3H), 7.73 (d. 1H), 5-ylbenzenesulfonamide sodium salt 7.92 (s, 1H). The sodium salt of Example 811 was prepared as follows: 4-4-Chloro-2-1-(1-methylazetidin-3-yl)-1H-pyrazol-5- 35 Example 812 ylphenoxy-2,5-difluoro-N-1,2,4-thiadiazol-5-ylbenzene sulfonamide, (Example 811, 35.0 g, 0.06494 mol) was sus 4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-5- pended in water (210 mL) and a solution of sodium hydroxide chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfona (2.47 g., 0.06169 mol) in water (210 mL) was added dropwise mide over 10 minutes. The resulting cloudy solution was filtered 40 and the water removed in vacuo to give a white foam. The foam was triturated with tert-butylmethyl ether and the white solid filtered off and dried to give the title compound as a F o o 21 SN white powder, (28.85g). C \/ N 'HNMR (d-DMSO) & 2.27 (s, 3H), 3.29-3.35 (m, 2H), 45 NN N 3.54-3.59 (m, 2H), 4.70-4.79 (m, 1H), 6.34 (d. 1H), 7.04-7.10 H (m. 1H), 7.18-7.21 (d. 1H), 7.49 (d. 1H), 7.53-7.60 (m, 3H), 7.90 (s, 1H). O Example 811 C 50 21 4-4-Chloro-2-1-(1-methylazetidin-3-yl)-1H-pyra Sa zol-5-yl)phenoxy-2,5-difluoro-N-1,2,4-thiadiazol HN N 5-ylbenzenesulfonamide The title compound was prepared by analogy with the method used for Example 813 below using 5-chloro-N- (ethoxymethyl)-2,4-difluoro-N-pyrimidin-4-ylbenzene O O N1\ sulfonamide, 5-chloro-N-(4E)-1-(ethoxymethyl)pyrimidin V/ N 4(1H)-ylidene-2,4-difluorobenzenesulfonamide and 5-chloro-N-(4E)-1-(ethoxymethyl)pyrimidin-4(1H)- {ulH 60 ylidene-2,4-difluorobenzenesulfonamide, (Preparation 719) used as a mixture of three regioisomers and 2-(2-aminopyri din-4-yl)-4-chlorophenol (Preparation 721). LCMS Rt=1.39 minutes, MS m/z 506 MH+ 65 'HNMR (d-DMSO): 8 6.90-7.02 (m, 2H), 7.05 (s, 1H), 7.21-7.29 (m, 2H), 7.66 (dd. 1H), 7.77 (d. 1H), 7.90-8.30 (m, 4H), 8.62 (s, 1H). US 8,907,101 B2 133 134 Example 813 Example 814 5-chloro-4-4-chloro-2-(1-methyl-1H-pyrazol-5-yl) 4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-5- phenoxy-2-fluoro-N-pyrimidin-4-ylbenzenesulfona chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzene mide Sulfonamide

F O O S ~\ F o o 21y 10 V/ N C Sn N S/ \/NN s J H H O

15 C C 21 Sa N NH2

A suspension of 5-chloro-N-(ethoxymethyl)-2,4-difluoro The title compound was prepared from 2-(2-aminopyridin N-pyrimidin-4-ylbenzenesulfonamide and 5-chloro-N- 4-yl)-4-chlorophenol, (Preparation 721) and 5-chloro-N-(2, (4E)-1-(ethoxymethyl)pyrimidin-4(1H)-ylidene-2,4-dif 4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-yl luorobenzenesulfonamide and 5-chloro-N-(4E)-1- benzenesulfonamide (Preparation 247) using a method (ethoxymethyl)pyrimidin-4(1H)-ylidene-2,4- 25 analogous to that used in Preparation 669. Purification by difluorobenzenesulfonamide (Preparation 719) used as a semi-preparative HPLC using 15-100% MeOH/HO yielded mixture of three regioisomers, (64 mg., 0.18 mmol), 4-chloro the title compound. 2-(1-methyl-1H-pyrazol-5-yl)phenol (Preparation 89) (37 LCMS Rt=1.47 minutes, MS m/z 512 MH+ mg, 0.18 mmol) and potassium carbonate (37 mg, 0.26 mmol) 'HNMR (d-DMSO): 8 6.96 (m, 1H), 7.04 (m, 1H), 7.23 in dimethylsulfoxide (1 mL) was stirred at room temperature 30 (m. 2H), 7.60 (m, 1H), 7.73 (d. 1H), 7.91 (m, 2H), 8.83 (m, for 19 hours then diluted with ethyl acetate (30 mL), washed 1H). Yet further examples of the present invention were pre with 1M aqueous sodium hydroxide, water, saturated aque pared, again using methods analogous to the General ous Sodium chloride solution, dried over anhydrous sodium Schemes described above, Library Protocols 1 and 2 Sulfate and concentrated in vacuo. The residue was taken up in described above, and Methods A-M as described for trifluoroacetic acid (1 mL) and stirred for 3 hours then con 35 Examples 1-6, 95-99, 134, 170, and 279 above, or any of the centrated in vacuo. The residue was purified by reverse phase other fully written up experimental conditions provided, sub HPLC to give 29 mg (27%) of the desired product as a white stituting appropriate starting materials where necessary and solid. making appropriate changes to experimental conditions LCMS Rt=1.67 minutes MS m/z. 494 MH+ informed by the schemes and conditions provided and com HNMR (d-DMSO): 83.77 (s, 3H), 6.33 (d. 1H), 6.96 40 mon general knowledge. Purification was performed either 7.02 (m, 2H), 7.32 (d. 1H), 7.41 (d. 1H), 7.55-7.65 (m, 2H), by silica gel column chromatography, trituration or prepara 7.96 (d. 1H), 8.25 (d. 1H), 8.60 (s, 1H). tive HPLC.

MS miz Eg Unless otherwise No Name stated 815 4-3'-(azetidin-1-ylmethyl)-5-iodobiphenyl-2-yl)oxy-3-cyano- 630 MH+ N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 816 5-chloro-4-(4-chloro-2-(5-methyl-1H-pyrazol-4-yl)phenoxy-2- 500 (MCIH+ fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 817 5-chloro-4-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy-2- 514 MCIH+ fluoro-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide 818 4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-3-cyano-N- 485 MH+ 1,3,4-thiadiazol-2-ylbenzenesulfonamide 819 5-chloro-4-4-chloro-2-1-(2-methoxyethyl)-1H-pyrazol-3- 544 (MCIH+ yl)phenoxy-2-fluoro-N-1,3,4-thiadiazol-2- ylbenzenesulfonamide 820 4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-2,5-difluoro-N- 496 (MH)+ 1,3,4-thiadiazol-2-ylbenzenesulfonamide 821 4-4-chloro-2-(1H-pyrazol-4-yl)phenoxy-2,5-difluoro-N-1,3,4- 470 (MCIH+ thiadiazol-2-ylbenzenesulfonamide 822 4-3'-(azetidin-1-ylmethyl)-5-chlorobiphenyl-2-yl)oxy-5- 565 (MCIH+ chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide 823 4-3'-(azetidin-1-ylcarbonyl)-5-chlorobiphenyl-2-yl)oxy-5- 579 MCIH+ chloro-2-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide 824 5-chloro-4-(5-chloro-3'-(3-hydroxyazetidin-1- 595 (MCIH+ yl)carbonylbiphenyl-2-yloxy)-2-fluoro-N-1,2,4-thiadiazol-5- ylbenzenesulfonamide 825 4-(4-chloro-2-(tetrahydro-2H-pyran-4-yl)phenoxy-3-fluoro-N- 470 (MCIH+ 1,2,4-thiadiazol-5-ylbenzenesulfonamide

US 8,907,101 B2 147 148 Example 878 A solution of lithium hexamethyldisilazide (1.0 M in tet rahydrofuran, 272 uL, 0.272 mmol) was added to a solution of 3-cyano-4-2-pyridaZin-4-yl-4-(trifluoromethoxy) tert-butyl 4-(4-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)pip phenoxy-N-1,2,4-thiadiazol-5-ylbenzenesulfona erazine-1-carboxylate (Preparation 853, 100.0 mg, 0.2180 mide mmol) in N,N-dimethylformamide (3 mL, 40 mmol). After stirring 5 minutes, tert-butyl (2,4,5-trifluorophenyl)sulfo nyl 1,3-thiazol-4-ylcarbamate (Preparation 854, 72 mg, 0.18 O O S1 N mmol) was added as a solid. The reaction mixture was stirred V/ ) at ambient temperature. After 2 hours, the reaction mixture F O n s 10 was diluted with water, neutralized with Saturated aqueous F H ammonium chloride, and extracted with ethyl acetate (3x). F The combined organic layers were washed with brine, dried O over sodium Sulfate, filtered, and concentrated onto diatoma ceous earth. The residue was purified by automated flash 21 | 15 chromatography (24 g SiO2, hexanes to ethyl acetate) to N afford the intermediate. N LC/MS Rt=1.96 minutes, MS m/z. 764 MCIH+ s 'HNMR (d-DMSO): 89.11 (d. 1H),8.10 (d. 1H), 7.98 (m, 1H), 7.91 (d. 1H), 7.72 (d. 1H), 7.62 (m, 1H), 7.40 (d. 1H), Example 878 from above can be prepared as follows. 7.12 (m, 1H), 6.93 (brs, 1H), 6.76 (m. 1H), 3.48 (m, 4H), 3.40 2-pyridazin-4-yl-4-(trifluoromethoxy)phenol (Preparation (m, 4H), 1.41 (s, 9H), 1.22 (s.9H). Trifluoroacetic acid (500 888, 1.03 g, 4.02 mmol) was taken up in dimethyl sulfoxide uL.7 mmol) was added to a solution of tert-butyl 4-4-2-(4- (50 mL, 600 mmol) and potassium carbonate (1.03 g, 7.45 {(tert-butoxycarbonyl)(1,3-thiazol-4-yl)aminosulfonyl-2, mmol) added, followed by 3-cyano-N-(2,4-dimethoxyben 5-difluorophenoxy)-5-chlorophenylpyridin-2- Zyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide yl)piperazine-1-carboxylate in 5 mL of methylene chloride. (Preparation 68, 1.74 g. 4.00 mmol). The reaction mixture 25 After stirring 3 hours at ambient temperature, the reaction was stirred at 23°C. for 18 hours. The reaction mixture was mixture was concentrated in vacuo. The residue was taken up diluted with water and extracted two times with ethyl ether. in 2 mL of dimethyl sulfoxide, filtered through a plug of The combined organic phase was washed Successively with cotton, and purified by reverse-phase HPLC. The product water and brine. The organic phase was dried over magne containing fractions were concentrated in vacuo, and the sium sulfate, then treated with activated carbon and filtered 30 residual solution was diluted with water and lyophilized to through a pad of diatomaceous earth. The solvent was afford an off white powder (85.0 mg, 83%). removed in vacuo. The residue was dissolved in methylene LC/MS Rt–1.43 minutes, MS m/z 564 MCIH+ chloride (100 mL, 2000 mmol) and trifluoroacetic acid (2.0 H NMR (d-DMSO): 8 11.42 (s, 1H), 8.91 (d. 1H), 8.13 mL, 26 mmol) was added. The solution was stirred for 2 hours (d. 1H), 7.75 (m, 1H), 7.68 (d. 1H), 7.57 (m, 1H), 7.31 (d. 1H), then concentrated in vacuo. The residue was purified by col 35 7.13 (m. 1H), 7.06 (d. 1H), 7.01 (brs, 1H), 6.82 (m, 1H), 3.72 umn chromatography (40 g silica gel column, 0 to 10% (m, 4H), 3.18 (m, 4H). methanol in dichloromethane gradient elution). The product fractions were combined and concentrated in vacuo to a resi Example 1023 due. The residue was triturated with ethyl ether and the solid collected by filtration. Vacuum drying gave 1.35 g of product 40 2.5-Difluoro-4-2-1-(1-methylazetidin-3-yl)-1H as a white solid. pyrazol-5-yl)-4-(trifluoromethyl)phenoxy-N-1,3- LCMS Rt=1.67 min, MS m/z 521 MH+ thiazol-4-ylbenzenesulfonamide 'HNMR (300 MHz, d-DMSO): 8 7.14 (d. 1H), 7.57 (d. 1H), 7.68 (m. 1H), 7.85 (dd. 1H), 7.89 (d. 1H), 7.98 (dd. 1H), 8.25 (d. 1H), 8.49 (s, 1H), 9.29 (dd. 1H), 9.40 (dd. 1H). 45

S Example 1022 F O O 4-4-Chloro-2-[2-(dimethylamino)pyridin-4-ylphe Y{ noxy-3-cyano-N-1,2,4-thiadiazol-5-ylbenzene H Sulfonamide 50

F

F S O. O 55

C Y N X H 2-1-(1-Methylazetidin-3-yl)-1H-pyrazol-5-yl)-4-(trifluo romethyl)phenol, (Preparation 855, 137 mg, 0.00046 mol) O was dissolved in acetonitrile (10 mL) and treated with potas 60 sium tert-butoxide (57 mg, 0.0005 mol) and stirred under 21 F nitrogen for 30 minutes. Tert-butyl 1.3-thiazol-4-yl(2,4,5- trifluorophenyl)sulfonylcarbamate, (Preparation 297, 182 N mg, 0.00046 mol) was added and the solution stirred for 2 r N 65 hours. Water (0.2 mL) was added and the solution evaporated. itsu The residue was suspended in water and extracted with ethyl acetate (1x20 mL). The organic layer was separated and US 8,907,101 B2 149 150 washed with brine (2x20 mL). The organic layer was sepa 1H), 7.11 (d. 1H), 7.53 (d. 1H), 7.63 (d. 1H), 7.72-7.77 (m, rated, dried over anhydrous sodium sulphate, filtered and 2H), 7.89 (dd. 1H), 8.14 (d. 1H), 8.92 (d. 1H). evaporated to give a foam. The foam was purified using an ISCOTM Companion (4 g. silica gel, eluting with dichlo Example 1025 romethane:acetic acid 99.5:0.5 to dichloromethane:methano l:acetic acid 95:5:0.5). The appropriate fractions were evapo 4-4-Chloro-2-[2-(cyclobutyloxy)pyridin-4-ylphe rated to give a film. The film was triturated with diethyl ether noxy-3-cyano-N-1,2,4-thiadiazol-5-yl benzene to give the title compound as a white Solid (11 mg). Sulfonamide LCMS Rt=1.19 minutes, MS m/z =572 MH+ 10 TLC dichloromethane:methanol:acetic acid 95:5:0.5, Rf-0.5 C HNMR (CDC1) & 3.15 (s, 3H)4.24-4.34 (m, 2H)4.83 15 4.87(m,2H)5.41-5.49 (m, 1H) 6.42 (s, 1H)6.47 (s, 1H) 6.82 SN N (d. 1H) 7.27 (s, 1H) 7.61 (d. 1H) 7.67 (s, 1H) 7.77 (s, 1H) 7.91-795 (m. 1H) 8.21 (s, 1H).

Example 1024

4-4-Chloro-2-1-(1-ethylazetidin-3-yl)-1H-pyrazol 5-yl)phenoxy-3-cyano-N-1,3-thiazol-4-ylbenzene 25 4-(4-chloro-2-[2-(cyclobutyloxy)pyridin-4-yl)phenoxy}- Sulfonamide 3-cyano-N-(2,4-dimethoxybenzyl)-N-1,2,4-thiadiazol-5-yl benzenesulfonamide, (Preparation 861, 40 mg 0.000058 mol) was dissolved in dichloromethane (1 mL) and cooled to 0°C. Trifluoroacetic acid (0.2 mL, 0.00261 mol) was added 30 and the reaction stirred for 1 hour warming slowly to room temperature. The solvent was removed in vacuo and the resi due redissolved in dichloromethane (1 mL). Once again the Solvent was removed in vacuo to give a purple residue (154 mg). The material was suspended in methanol (3 mL) and filtered through CeliteTM. The solvent was removed in vacuo to obtain the title compound as an off white solid (15.5 mg). LCMS Rt=1.83 minutes, MS m/z =540 MCIH+ 'HNMR (CDOD) & 1.62-1.74 (m. 1H), 1.79-1.88 (m. 1H), 40 2.04-2.14 (m, 2H), 2.38–2.45 (m, 2H), 5.03-5.11 (m, 1H), To a suspension of 4-2-(1-azetidin-3-yl-1H-pyrazol-5- 6.87-6.90 (m, 2H), 7.08-7.09 (m, 1H), 7.33 (d. 1H), 7.57-7.60 yl)-4-chlorophenoxy-3-cyano-N-1,3-thiazol-4-ylbenzene (dd. 1H), 7.63 (d. 1H), 7.93 (dd. 1H), 8.07-8.09 (m, 1H), 8.12 sulfonamide, Example 809 (500mg 0.000797 mol) in metha (d. 1H), 8.20 (s, 1H). 45 nol (4 mL) and dichloromethane (4 mL) was added Example 1026 triethylamine (161 mg, 0.00159 mol) and the reaction cooled to 0°C. in an ice/water bath. To the suspension was added 4-4-Chloro-2-[2-(dimethylamino)pyridin-4-ylphe sodium triacetoxyborohydride (422 mg, 0.00199 mol) and noxy-3-cyano-N-1,2,4-thiadiazol-5-ylbenzene the reaction was then stirred at 0°C. for 10 minutes. Acetal 50 Sulfonamide dehyde (105 mg, 0.00239 mol) was added dropwise and the reaction stirred at 0° C. for 1.5 hours. The solvent was removed in vacuo to give an orange oil which was partitioned between dichloromethane (25 mL) and water (25 mL). The 55 O O S1 N organic layer was separated and the aqueous layer was V/ extracted with dichloromethane (2x20 mL). The combined C S n N S. N organic layers were washed with Saturated aqueous sodium H chloride solution (20 mL) and filtered through a phase sepa O rator. The solvent was removed in vacuo to give a pink solid 60 which was triturated in hot ethyl acetate (10.0 mL), allowed to cool to room temperature and then filtered to give the title 21 | N compound as a white solid, (431 mg). Me N a. N N LCMS Rt=1.95 minutes, MS m/z =541 MH+ 65 HNMR (d-DMSO) & 1.11 (t,3H), 3.26 (q, 2H), 4.16 (brs, 2H), 4.42 (brs., 2H), 5.14 (brs., 1H), 6.30 (d. 1H), 6.99 (d. US 8,907,101 B2 151 152 3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzene washed with water (200 mL), dried over MgSO and concen sulfonamide (Preparation 65, 40 mg, 0.14 mmol), 4-chloro trated in vacuo to approximately 100 mL whereby a precipi 2-2-(dimethylamino)pyridin-4-yl)phenol (Preparation 865, tate was observed. This mixture was allowed to cool for 18 35.0 mg, 0.141 mmol) and potassium carbonate (58 mg, 0.42 hours and the resulting solid filtered and washed with cold mmol) in dimethylsulfoxide (1 mL. 20 mmol) was stirred at ethyl acetate (10 mL) and dried in vacuo at 60° C. to provide 150° C. for 16 hours. The reaction mixture was cooled to the title compound as a sand coloured crystalline solid (17.5 ambient temperature and poured into Saturated aqueous g) containing 8.2% by weight ethyl acetate Solvate. ammonium chloride. The aqueous layer was extracted with LCMS Rt=1.58 minutes. MS m/z 532 (MCIH+ ethyl acetate (3x). The combined organic layers were washed 10 with brine, dried over sodium sulfate, filtered, and concen 'HNMR (d-DMSO): 8 7.30 (d. 1H), 7.50 (d. 1H), 7.83 trated in vacuo. The residue was taken up in methylene chlo 7.85 (m. 1H), 7.92-7.98 (m, 2H), 8.08-8.13 (m, 1H), 8.81 (s, ride, concentrated onto diatomaceous earth, and purified by 1H), 9.32 (d. 1H), 9.51 (s, 1H). automated flash chromatography (12 gSiO, hexanes to 20% 15 Microanalysis: CHCIF.N.O.S.0.55 EtOAc required methanol in ethyl acetate). The product-containing fractions C, 43.91; H, 2.48: N, 12.08; C1, 6.13%. Found C, 43.90; H, were concentrated in vacuo then lyophilized from water and 2.42: N, 12.04; C1, 6.14%. minimal acetonitrile to afford the product as a light yellow powder (40 mg, 60%). LC/MS Rt=1.40 minutes, MS m/z 513 MCIH+ "H NMR (d-DMSO): 88.03 (m. 2H), 7.94 (s, 1H), 7.86 Example 1028 (m. 1H), 7.68 (d. 1H), 7.60 (m. 1H), 7.41 (d. 1H), 6.89 (d. 1H), 6.60 (m, 2H), 2.95 (s, 6H). 4-2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl) 25 phenoxy-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2- Example 1027 ylbenzenesulfonamide 5-Chloro-2-fluoro-4-2-pyridazin-4-yl-4-(trifluorom ethyl)phenoxy-N-1,3,4-thiadiazol-2-ylbenzene Sulfonamide 30 F F s1\ F V /n usN y H F F O O N1 N F W . ) 35 O F NN S HN C H 2 N \ O N-NH 40 C 21 To a solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2- Nin fluoro-4-2-3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra N zol-4-yl)-4-(trifluoromethyl)phenoxy-N-1,3,4-thiadiazol 45 2-ylbenzenesulfonamide (Preparation 867, 3.20 g, 4.00 To a stirred solution of 5-Chloro-N-(2,4-dimethoxyben mmol) in ethanol (200 mL) was added saturated aqueous Zyl)-2-fluoro-4-(2-pyridazin-4-yl-4-(trifluoromethyl)phe ammonium chloride solution (50 mL) and iron (5.66 g. 101 noxy-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Prepa mmol). The reaction solution was heated at 80° C. for 15 ration 900, 30.3 g, 44.4 mmol) in 1,4-dioxane (250 mL) at 50 minutes. The solution was cooled, filtered and adjusted to room temperature was added a 4M solution of HCl in 1,4- pH=9 with saturated aqueous sodium bicarbonate solution. dioxane (300 mL) dropwise over 30 minutes. The resulting The mixture was filtered and then concentrated to remove Suspension was left to stir at room temperature for 3 hours most of the ethanol. The resulting slurry was extracted with before concentration in vacuo. The residue was azeotroped dichloromethane (3x). The organic extracts were combined, with diethyl ether (3x300 mL) followed by a diethyl ether 55 trituration (200 mL) to provide crude material as a fawn dried over anhydrous magnesium Sulfate, filtered, and con coloured solid. This material was suspended in methanol (200 centrated. This provided the aminopyrazole as a yellow foam. mL) and filtered through Celite, washed with methanol (400 To this was added an HCl (g) saturated methanol solution mL) and the resulting filtrate concentrated in vacuo to give a (200 mL) and the mixture heated at 60°C. for two hours. The sand coloured solid. This material was suspended in water 60 reaction solution was cooled, concentrated, and purified by (100 mL) and treated with 880 ammonia (60 mL) portionwise automated flash column chromatography using a 0-10% until pH 9-10 was achieved. The resulting solution was methanol/dichloromethane gradient. Additional purification washed with diethyl ether (3x75 mL) and the aqueous layer by prep HPLC provided the TFA salt. The resulting white acidified to pH-5 with citric acid. The mixture was then 65 solid was redissolved in a HCl(g) saturated methanol solution extracted with ethyl acetate (3x200 mL) and brine (100 mL) and concentrated (3x) in order to isolate the HCl salt of the added to aid separation. The combined organic layers were title compound (1.20 g, 53%) as a white solid. US 8,907,101 B2 153 154 LC/MS Rt=1.67 minutes white solid with 1.5 eq of HCl present (30.3 g, 70%) via MS m/z 535 (MCIH+ trituration with dichloromethane. 'HNMR (d-DMSO): 87.25(d. 1H), 7.32 (d. 1H), 7.73 (m, LC/MS Rt=1.73 minutes MS m/z 534 MCIH+

1H), 7.53 (m, 1H), 7.61 (m. 1H), 7.93 (d. 1H), 7.97 (s, 1H), Example 1029 8.91 (d. 1H).

4-2-(3-amino-1H-pyrazol-4-yl)-4-(trifluoromethyl) 10 Example 1030 phenoxy-5-chloro-2-fluoro-N-1,3-thiazol-4-ylben Zenesulfonamide 4-4-Chloro-2-(2-piperazin-1-ylpyrimidin-4-yl)phe 15 noxy-3-cyano-N-1,2,4-thiadiazol-5-ylbenzene Sulfonamide F F F V / X F n / 2O N H O O S1 N

V/ O Sn-ss C H HN N 25 \ N-NH

To a solution of tert-butyl (5-chloro-2-fluoro-4-2-3-ni 30 tro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-(trif luoromethyl)phenoxyphenyl)sulfonyl 1.3-thiazol-4-ylcar bamate (Preparation 872, 55 g, 74 mmol) in ethanol (800 mL) was added Saturated aqueous ammonium chloride Solution (200 mL, 3000 mmol) and iron (65 g, 1200 mmol). The 35 3-Cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzene reaction solution was heated at 80°C. for two hours at which sulfonamide (Preparation 65, 43.6 mg, 0.154 mmol), tert point iron (10g, 185 mmol) was added and the mixture heated butyl 4-4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl)pip for an additional hour. The solution was cooled, filtered and 40 erazine-1-carboxylate (Preparation 873, 50.0 mg, 0.128 adjusted to pH=9 with saturated aqueous sodium bicarbonate mmol) and potassium carbonate (53 mg, 0.38 mmol) in dim solution. The mixture was filtered and then concentrated to ethylsulfoxide (1 mL, 10 mmol) was stirred at 100° C. for 16 remove most of the ethanol. The resulting slurry was hours. The reaction mixture was cooled to ambient tempera extracted with dichloromethane (4x). The organic extracts 45 ture and poured into Saturated aqueous ammonium chloride. were combined, dried over anhydrous magnesium Sulfate, The aqueous layer was extracted with ethyl acetate (3x). The filtered, and concentrated to provide the free amine as an combined organic layers were washed with brine, dried over orange oil. Purification by manual flash column chromatog sodium sulfate, filtered, and concentrated in vacuo to afford raphy using 40% then 75% ethyl acetate/hexanes and a 5x31 50 the crude intermediate, tert-butyl 4-4-(5-chloro-2-(2-cyano cm column provided a mix of Boc protected Sulphonamide 4-(1,2,4-thiadiazol-5-ylamino)sulfonylphenoxyphenyl) and non-Boc protected Sulphonamide free amine as an orange pyrimidin-2-yl)piperazine-1-carboxylate, as a yellow solid. Trifluoroacetic acid (300 uL, 4 mmol) was added to a solution oil. To this mixture was added an HCl (g) saturated methanol of tert-butyl 4-4-(5-chloro-2-(2-cyano-4-(1,2,4-thiadiazol solution (400 mL) and the mixture heated at 60° C. for 7 55 hours. The reaction Solution was cooled and concentrated to 5-ylamino)sulfonylphenoxyphenyl)pyrimidin-2-yl)pip give a white solid. The solid was redissolved in methanol, erazine-1-carboxylate (83 mg, 0.154 mmol) in methylene heated to reflux and ethyl acetate added until just before a chloride (2.9 mL, 46 mmol). After 1 hour, the reaction mix precipitate formed. It was then cooled, washed with ethyl 60 ture was concentrated in vacuo. The residue was purified by acetate and dichloromethane to provide the title compound as reverse-phase HPLC to afford the product as a white solid a white Solid. This was repeated until no more clean product (trifluoroacetic acid salt, 36 mg, 51%).O was obtained. The impure filtrate was purified by prep HPLC, LC/MS Rt=1.52 minutes, MS m/z 555 MCIH+ the product fractions concentrated and the TFA salt 65 H NMR (d-DMSO): 8 8.49 (d. 1H), 8.38 (s, 1H), 8.23 (d. exchanged for an HCl salt. All product was combined, dis- 1H), 7.97 (m, 2H), 7.72 (m, 1H), 7.49 (d. 1H), 7.04 (d. 1H), Solved in methanol, filtered, concentrated and isolated as a 6.99 (d. 1H), 3.73 (m, 4H), 3.08 (m, 4H). US 8,907,101 B2 155 156 Example 1031 Example 1033 4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-5- 3-Cyano-4-2-1-(1-ethylazetidin-3-yl)-1H-pyrazol chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfona 5-yl)-4-(trifluoromethyl)phenoxy-N-1,2,4-thiadia mide Zol-5-ylbenzenesulfonamide

F o o N1 N VW 10 V/ C Sn S {ul N H H

O 15 21 C

N HN N 4-2-(1-AZetidin-3-yl-1H-pyrazol-5-yl)-4-(trifluorom 4-2-(2-aminopyridin-4-yl)-4-chlorophenoxy-5-chloro ethyl)phenoxy-3-cyano-N-1,2,4-thiadiazol-5-ylbenzene 2-fluoro-N-(methoxymethyl)-N-pyridazin-3-ylbenzene sulfonamide, (Preparation 881, 2.90 g, 0.00529 mol) was Sulfonamide and 4-2-(2-aminopyridin-4-yl)-4-chlorophe dissolved in acetic acid (6 mL) with warming and then dichlo noxy-5-chloro-2-fluoro-N-(3E)-2-(methoxymethyl) romethane (50 ml) was added. The solution was stirred under pyridazin-3(2H)-ylidenebenzenesulfonamide, (Preparation 25 nitrogen and cooled in an ice/acetone bath. Sodium triac 875, 93 mg, 0.17 mmol) in trifluoroacetic acid (1 mL, 10 etoxyborohydride (5.0 g, 0.0236 mol) was added, stirred with mmol) was stirred for 24 hours. The reaction mixture was cooling for 15 minutes and then a solution of acetaldehyde concentrated and the residue was taken in methanol (1 mL. 20 (1.2 mL, 0.021 mol) in dichloromethane (10 mL) was added mmol) and 2 M of hydrogen chloride in water (1 mL, 2 dropwise over 45 minutes. The reaction mixture was stirred mmol). After stirring for two days, the reaction mixture was 30 with cooling for 1 hour and then allowed to warm to room concentrated and the residue liophilized from acetonitrile temperature and stirred for a further 45 minutes. LCMS indi water to give 76 mg of product as a hydrochloride salt. cated that a small amount of starting material remained so the LCMS Rt=1.36 min MS m/z 506 MH+ mixture was cooled again in ice and a further portion of "H NMR (300 MHz, d-DMSO): 86.99 (dd. 1H), 7.12 (d. sodium triacetoxyborohydride (0.50 g, 0.00236 mol) was 35 added, followed by acetaldehyde (0.10 mL, 0.00178 mol). 1H), 7.21 (d. 1H), 7.24 (s, 1H), 7.62 (dd. 1H), 7.73 (d. 1H), The reaction mixture was stirred whilst warming to room 7.78 (dd. 1H), 7.96-8.02 (m,3H),8.17 (bs, 2H), 8.40 (dd. 1H), temperature over 1 hour. Water (5.0 mL) was added to quench 13.8 (bs, 1H). the reaction and the mixture was stirred at room temperature Example 1032 for 15 minutes and the solvents were then removed in vacuo. 40 The residue was partitioned between ethyl acetate (150 mL) 4-2-[2-(AZetidin-1-ylmethyl)pyridin-4-yl)-4-chlo and water (50 mL) with 0.880 aqueous ammonia (20 mL) rophenoxy-2,5-difluoro-N-1,3-thiazol-4-ylbenzene added. The organic layer was washed with water (2x50 mL), Sulfonamide dried over anhydrous sodium sulphate, filtered and the sol vents removed in vacuo to give the crude product as a pale 45 yellow foam (2.30 g). A further batch was obtained by re extracting the combined aqueous layers with ethylacetate (80 F O O S mL) to give a pale yellow foam (700 mg). The two batches were combined and re-crystallized from ethyl acetate (25 C \Sn ( 2) mL) to give the title compound as a white powder (1.84 g). N N 50 300 mg of this material was re-crystallized from water?etha nol to give the pure title compound (215 mg). O LCMS Rt=11.40 minutes, MS m/z 576 MH+ F 'HNMR (d-DMSO) & 1.09 (t, 3H), 3.32 (brm, 2H), 4,23 21 4.49 (brm, 4H), 5.13 (m, 1H), 6.47 (s, 1H), 7.05 (d. 1H), 7.53 55 (d. 1H), 7.73 (s, 1H), 7.88-8.00 (m, 4H), 8.04 (d. 1H). \\ 1 The remaining material (1.53 g, 0.00266 mol) was added to N a solution sodium hydroxide (97 mg 0.00243 mol) in water (15 mL) and warmed to give a slightly cloudy solution which tert-Butyl (4-2-[2-(azetidin-1-ylmethyl)pyridin-4-yl)-4- was filtered whilst still hot and the water was then removed in chlorophenoxy-2,5-difluorophenyl)sulfonyl) 1,3-thiazol-4- 60 vacuo to give a gum. The gum was treated with tert-butylm ylcarbamate, (Preparation 878, 0.325 g, 0.0005 mol) was ethylether (50 mL) for 3 days and then the solvent was dissolved in dichloromethane (3 mL) then 4 molar hydrogen removed in vacuo to give the Sodium salt of the title com chloride in 1,4-dioxane (3 mL) was added. The reaction was pound as a foam (1.20 g). stirred at room temperature for 18 hours. The reaction was LCMS Rt=1.28 minutes, MS m/z =576 MH+ concentrated in vacuo and the crude product purified by pre 65 'HNMR (d-DMSO) & 0.85 (t, 3H), 2.41 (q, 2H), 3.24 (m, parative HPLC to give the title compound. 2H), 3.52 (m, 2H), 4.74 (m. 1H), 6.33 (s, 1H), 7.07 (d. 1H), LCMS Rt=1.07 minutes, MS m/z =549 MCIH+ 748-7.56 (m, 2H), 7.81-8.03 (m, 5H). US 8,907,101 B2 157 158 Example 1034 3-Cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4- thiadiazol-5-yl)benzenesulfonamide (Preparation 68, 59 mg, 5-Chloro-2-fluoro-4-5-fluoro-2-pyridazin-4-yl-4- 0.14 mmol) was added to a mixture of 5-fluoro-2-pyridazin (trifluoromethyl)phenoxy-N-1,3,4-thiadiazol-2- 4-yl-4-(trifluoromethyl)phenol (Preparation 884, mg, 0.14 ylbenzenesulfonamide mmol) and potassium carbonate (22 mg, 0.16 mmol) in dim ethyl sulfoxide (2 mL, 30 mmol). The reaction mixture was stirred at ambient temperature. After 3 hours the reaction F F F o o $1\ mixture was diluted with water and Saturated aqueous ammo F \/ us N nium chloride and extracted with ethyl acetate (3x). The F SS1'sN N 10 H combined organic layers were washed with water then brine, dried over Sodium sulfate, filtered, and concentrated in vacuo. O The residue was taken up in methylene chloride, concentrated onto diatomaceous earth, and purified by automated flash 21 C 15 chromatography (12 g SiO2, hexanes to ethyl acetate) to afford the intermediate as a glass (63 mg, 69%). LC/MS Rt=1.88 minutes, MS m/z 673 MH+ Trifluoroacetic acid (500 uL, 6 mmol) was added to a 5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3, solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-5-fluoro 4-thiadiazol-2-ylbenzenesulfonamide (Preparation 247, 63 2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N-1,2,4-thia mg, 0.14 mmol) was added to a mixture of 5-fluoro-2-py diazol-5-ylbenzenesulfonamide (63 mg) in methylene chlo ridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 884, mg, ride (5 mL, 70 mmol). After stirring 20 minutes, the reaction 0.14 mmol) and potassium carbonate (22 mg, 0.16 mmol) in mixture was concentrated onto diatomaceous earth and puri dimethyl sulfoxide (2 mL, 30 mmol). The reaction mixture fied by automated flash chromatography (12 g SiO2, methyl was stirred at ambient temperature. After 3 hours the reaction 25 mixture was diluted with water and Saturated aqueous ammo ene chloride to 9:1 methylene chloride-methanol) to afford nium chloride and extracted with ethyl acetate (3x). The the product as a light yellow solid (38 mg, 54%). combined organic layers were washed with water then brine, LC/MS Rt=1.66 minutes, MS m/z 523 MH+ dried over Sodium sulfate, filtered, and concentrated in vacuo. H NMR (d-DMSO): 89.45 (m, 1H), 9.31 (m. 1H), 8.48 The residue was taken up in methylene chloride, concentrated 30 onto diatomaceous earth, and purified by automated flash (s, 1H), 8.30 (d. 1H), 8.23 (d. 1H), 8.04 (m. 1H), 7.90 (m, 1H), chromatography (12 g SiO, hexanes to ethyl acetate) to 7.75 (d. 1H), 7.44 (d. 1H). afford the intermediate 5-chloro-N-(2,4-dimethoxybenzyl)- 2-fluoro-4-5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl) Example 1036 phenoxy-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide as a glass (22 mg, 23%). 35 LC/MS Rt=1.88 minutes, MS m/z 700 MCIH+ 4-2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy Trifluoroacetic acid (500 uL, 6 mmol) was added to a 5-chloro-2-fluoro-N-pyrimidin-4-ylbenzenesulfona solution of 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4- mide 5-fluoro-2-pyridazin-4-yl-4-(trifluoromethyl)phenoxy-N- 1,3,4-thiadiazol-2-ylbenzenesulfonamide (22 mg) in methyl 40 ene chloride (5 mL, 70 mmol). After stirring 20 min, the reaction mixture was concentrated onto diatomaceous earth and purified by automated flash chromatography (4g SiO2, methylene chloride to 9:1 methylene chloride-methanol) to afford the product as a tan solid (6 mg, 9%). 45 C S LC/MS Rt=1.72 minutes, MS m/z 550 MCIH+ "H NMR (d-DMSO): 8 9.50 (m. 1H), 9.33 (m, 1H), 8.83 (s, 1H), 8.16 (d. 1H), 7.95 (m, 2H), 7.62 (d. 1H), 7.52 (d. 1H).

Example 1035 50 C 3-Cyano-4-5-fluoro-2-pyridazin-4-yl-4-(trifluorom ethyl)phenoxy-N-1,2,4-thiodiazol-5-ylbenzene Sulfonamide

55 4-2-3-amino-1-(tetrahydro-2H-pyran-2-yl)-1H-pyra N zol-4-yl)-4-chlorophenoxy-5-chloro-2-fluoro-N-(meth F F O O S1 oxymethyl)-N-pyrimidin-4-ylbenzenesulfonamide (Prepara Sn S. tion 887, 58 mg, 0.093 mmol) in methanol (1 mL, 20 mmol) F YJ)N N H and 2 M of hydrogen chloride in water (1 mL, 2 mmol) was 60 heated at 60° C. for 2 hours then concentrated. The residue O was liophilized from acetonitrile-water to give 50 mg of a white solid. 21 | LCMS Rt=1.64 min, MS m/Z. 495 MH+ N N 'HNMR (d-DMSO): 8 6.93 (m, 2H), 7.18 (d. 1H), 7.46 s (dd. 1H), 7.72 (d. 1H), 7.97 (m, 2H), 8.21 (d. 1H), 8.58 (s, 1H). US 8,907,101 B2 159 160 Example 1037 chloro-2-fluoro-N-(3E)-2-(methoxymethyl)pyridazin-3 (2H)-ylidene benzenesulfonamide (Preparation 891). 2-fluoro-5-methyl-4-2-pyridazin-4-yl-4-(trifluo LCMS Rt=1.62 min, MS m/Z. 495 MH+ romethoxy)phenoxy-N-1,3,4-thiadiazol-2-ylbenze 'HNMR (d-DMSO): 8 6.94 (d. 1H), 7.17 (d. 1H), 7.44 nesulfonamide 5 (dd. 1H), 7.71 (d. 1H), 7.76 (dd. 1H), 7.97 (m, 3H), 8.38 (dd, 1H). F O O S ~\ V/ N Example 1039 F O Sn S/ N 10 (2Z)-2-(4-4-Chloro-2-(1-methyl-1H-pyrazol-5- Dr H F yl)phenoxy-3-cyanophenyl)sulfonyl)iminol-1,3- O thiazol-3(2H)-yl)methyl dihydrogen phosphate

Me 21 15 O O \/ HO NinN - 2-pyridazin-4-yl-4-(trifluoromethoxy)phenol (Preparation O S usu OH 888, 30 mg, 0.12 mmol) was taken up in dimethylsulfoxide (1 mL, 20 mmol) and potassium carbonate (30 mg, 0.22 mmol) added, followed by N-(2,4-dimethoxybenzyl)-2,4-difluoro 5-methyl-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 889, 51.7 mg, 0.117 mmol). The reaction was heated at 60° C. for 72 hours. The reaction was cooled and 25 Di-tert-butyl (2Z)-2-(4-4-chloro-2-(1-methyl-1H diluted with 1N HC1. The resulting precipitate was collected pyrazol-5-yl)phenoxy-3-cyanophenylsulfonyl)iminol-1,3- by filtration. The solid was dissolved in methylene chloride thiazol-3(2H)-yl)methyl phosphate, (Example 1040,250 mg. (1.0 mL, 16 mmol) and dried over magnesium sulfate. The 0.00036 mol) was dissolved in ethyl acetate (10 mL) and then solution was then treated with trifluoroacetic acid (45 uL. trifluoroacetic acid (1 mL) was added. The solution was 0.58 mmol) and stirred for 2 hours. The reaction mixture was 30 stirred at room temperature for 3 hours, then a further portion concentrated in vacuo. The residue was purified by reverse of trifluoroacetic acid (2 mL) was added and stirred at room phase HPLC. Product fractions were combined and the sol temperature for 18 hours. The solvents were removed in vent removed in vacuo to give a residue. The product was vacuo and the residue was partitioned between tert-butylm purified a second time by column chromatography (4 g silica ethyl ether (30 mL) and water (40 mL) and a few drops of gel column, 0 to 10% methanol in methylene chloride gradi 35 aqueous sodium hydroxide Solution (2 molar). The aqueous layer was then acidified to pH1-2 with aqueous hydrochloric ent elution). Product fractions were combined and concen acid (2 molar) to give a sticky cream precipitate which was trated in vacuo to give 11.2 mg of colorless glass. dissolved in a mixture of dichloromethane, ethanol and LCMS Rt=1.67 min, MS m/z 528 MH+ methanol. This organic layer was dried over anhydrous 'HNMR (300 MHz, d-DMSO): 8 2.20 (s, 3H), 6.94 (d. sodium sulphate, filtered and the solvents removed in vacuo 1H), 7.23 (d. 1H), 7.54 (m. 1H), 7.75 (d. 1H), 7.81 (d. 1H), 40 to give the crude product which was triturated with ethyl 7.90 (dd. 1H), 8.78 (s, 1H), 9.29 (dd. 1H), 9.45 (dd. 1H). acetate to give the title compound as a buff powder, (85 mg). Example 1038 MS m/z =582 (MCIH+ 'HNMR (d-DMSO) & 3.73 (s.3H), 5.60 (d. 2H), 6.22 (d. 4-2-(3-amino-1H-pyrazol-4-yl)-4-chlorophenoxy 45 1H), 6.90-6.96 (m, 2H), 7.34 (s, 1H), 7.41 (d. 1H), 7.47-7.51 5-chloro-2-fluoro-N-pyridazin-3-ylbenzenesulfona (m. 1H), 7.66-7.71 (m, 2H), 7.92-7.97 (m. 1H), 8.18 (d. 1H). mide Example 1040

N 50 Di-tert-butyl (2Z)-2-(4-4-chloro-2-(1-methyl-1H F o o N1 pyrazol-5-yl)phenoxy-3-cyanophenylsulfonyl) imino-1,3-thiazol-3(2H)-yl)methyl phosphate C \/NN N H 55 O Me Me HN N C O O X. \/ / M N-NH NN lso The title compound was prepared according to the proce - JhO 4 dure in Example 1036 using 4-2-3-amino-1-(tetrahydro S N €1. 2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-chlorophenoxy-5- \-/ Me chloro-2-fluoro-N-(methoxymethyl)-N-pyridazin-3- 65 ylbenzenesulfonamide and 4-2-3-amino-1-(tetrahydro 2H-pyran-2-yl)-1H-pyrazol-4-yl)-4-chlorophenoxy-5- US 8,907,101 B2 161 162 4-4-Chloro-2-(1-methyl-1H-pyrazol-5-yl)phenoxy-3- Preparation 37 cyano-N-1,3-thiazol-2-ylbenzenesulfonamide, (Example 170, 200 mg 0.000424 mol), di-tert-butyl chloromethyl 4-isopropoxy-2-methylbiphenyl-2-ol phosphate (J. Med. Chem. 51 (2008) p1111-1114, supple mentary data) (160 mg, 0.000619 mol) and cesium carbonate (420 mg 0.00129 mol) were stirred in dimethylformamide (2 mL) at 60° C. for 18 hours. The mixture was cooled then Me Me partitioned between tert-butylmethyl ether (80 mL) and water (40 mL), the organic layer was dried over anhydrous sodium M-( sulphate, filtered and the solvent removed in vacuo to give the 10 title compound as a pale yellow gum, (250mg). LCMS=1.63 minutes, MS m/z =694 MCIH+ HO 'HNMR (CDC1) & 1.42 (s.9H), 1.51 (s.9H), 3.87 (s.3H), 5.68 (d. 2H), 6.21 (s, 1H), 6.50 (d. 1H), 6.66 (d. 1H), 7.13 (d. 15 2-Iodophenol (1.54 g, 7.00 mmol) was combined with 1H), 7.23 (d. 1H), 7.39 (s, 1H), 7.46 (s, 1H), 7.48-7.53 (m, 2-(4-isopropoxy-2-methyl-phenyl)-4.4.5.5-tetramethyl-1,3, 1H), 7.94-7.99 (m, 1H), 8.15 (s, 1H). 2dioxaborolane (Preparation 38, 2.00 g, 7.24 mmol), cesium carbonate (4.56 g. 13.99 mmol) and palladium tetrakis(triph enylphosphine) (0.24g, 0.21 mmol) in 1,2-dimethoxyethane PREPARATIONS (40 mL). The reaction mixture was heated to reflux for 18 hours. The reaction mixture was cooled to room temperature The following Preparations illustrate the preparation of and then acidified with a 1 N aqueous HCl solution. The certain intermediates used to prepare the Examples above. organics were extracted 3 times with diethylether. The 25 organic layers were combined, washed with brine, dried over Preparation 14 magnesium Sulphate and concentrated in vacuo. The residue was purified by column chromatography using as eluant a mixture heptane/ethyl acetate to afford 543 mg (31% yield) of (2,4-dimethoxy-benzyl)-1,2,4thiadiazol-5-yl 4-isopropoxy-2-methylbiphenyl-2-ol as a pale yellow oil. amine/N-(2,4-dimethoxybenzyl)-1,2,4-thiadiazol-5- 30 MS m/z 243 MH+ amine 'HNMR (CDC1): & 1.37 (d. 6H), 2.12 (s, 3H), 4.56-4.62 (m. 1H), 6.80 (dd. 1H), 6.85 (d. 1H), 6.93-7.01 (m, 2H), 7.10-7.14 (m, 2H), 7.23-7.28 (m, 1H).

35 Preparation 38 2-(4-isopropoxy-2-methyl-phenyl)-4.4.5.5-tetram ethyl-1,3,2dioxaborolane

40

Me O Me N P O A mixture of 5-amino-1,2,4-thiadiazole (1 g; 9.89 mmol) Me 45 O Me and 2,4-dimethoxybenzaldehyde (1.81 g; 10.9 mmol) in tolu Me ene (30 ml) was refluxed under Dean and Stark conditions for Me Me 2 hours. The reaction mixture was evaporated, the residue taken up in methanol (25 ml), NaBH (600 mg: 15.9 mmol) In a flame-dried flask under nitrogen, 3-methyl-4-(4.4.5.5- added carefully in Small portions (vigorous effervescence 50 tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (see after each addition), and the reaction was left stirring over WO2007092751A, 2.30 g, 9.82 mmol) was dissolved in dim night at ambient temperature. Aqueous HCl (2M, 1 ml) was ethylformamide (40 mL). Sodium hydride 60% dispersion in added followed by aqueous NaOH (2M, 10 ml). The bulk of mineral oil (0.48g, 12 mmol) was added to the mixture. The the methanol was evaporated, water (20 ml) added and reaction mixture was stirred at room temperature under nitro extracted with ethyl acetate (2x30 ml). The combined organic 55 gen for 30 minutes. 2-Iodopropane (2.55g, 15.00 mmol) was was washed brine (20 ml), dried, and evaporated. The residue added and the reaction mixture was stirred at 70° C. for 18 was purified by silica gel column chromatography (ISCOTM hours. The reaction mixture was quenched with water. The column 120 g; ethyl acetate:heptane 25:75 to 60:40) to fur organics were extracted 3 times with diethylether. The nish a semi-solid residue that was re-evaporated from hep 60 organic layers were combined, dried over magnesium Sul tane. 2-3 ml tBuOMe was added, then 2-3 ml heptane, the phate and concentrated in vacuo. The residue was purified by solid filtered off, washed with heptane and dried to afford 1.22 column chromatography, using as eluant a mixture of hep g of the title compound. tane/ethyl acetate, to afford 2.02 g (73% yield) of 2-(4-iso 'HNMR (d-DMSO): 83.73 (s.3H), 3.78 (s.3H), 4.36 (d. propoxy-2-methyl-phenyl)-4.4.5.5-tetramethyl-1,3,2diox J=5.46 Hz, 2H), 6.47 (dd, J=8.58, 2.34 Hz, 1H), 6.56 (d. 65 aborolane as a yellow oil. MS m/Z 277 MH+ J=2.34 Hz, 1H), 7.15 (d. J=8.19 Hz, 1H), 7.88 (s, 1H), 8.65 HNMR (CDC1): 1-132 (m. 18H), 2.50 (s.3H), 4.50-4.60 (br. S., 1H) (m. 1H), 6.67-6.69 (m, 2H), 7.69 (d. 1H). US 8,907,101 B2 163 164 Preparation 42 (50 ml) was added over approx 20 minutes at room tempera ture. The reaction was stirred at this temperature for 2 days 4-(4-fluorophenyl)-2-(methylamino)pyrimidin-5-ol before decanting the Supernatant and concentrating in vacuo to furnish a dark oil. 2M HCl (200 ml) was added and the N mixture triturated until solidification occurred. A brick red -Ns solid was filtered off, washed with water and dried to furnish N 21.5g of the title product. "HNMR (d-DMSO): 86.9 (d. 1H), 2 O 7.3 (m. 1H), 7.6 (m. 1H), 8.15 (m, 1H), 8.3 (d. 1H), 12.9 (br 10 s1H). LCMS Rt=2.34 min MS m/z 284 MH+. Preparation 50 3-cyano-4-(2-iodo-phenoxy)-N-1,2,4thiadiazol-5- yl-benzenesulfonamide F 15 (2-Amino-1,3-oxazol-5-yl)(4-fluorophenyl)methanone O N (US2005032859, 1 g, 4.85 mmol) and 40% methyl amine VNS e water in excess (50 mL) were combined in tert-butanol (50 mL). The mixture was stirred at 50° C. under nitrogen for 2 \, IXN hours. The mixture was concentrated in vacuo. The residue O was filtered through a pad of silica gel using neat ethylacetate as eluant. The Solution was concentrated in vacuo to afford I | 0.73 g (66%) of 4-(4-fluorophenyl)-2-(methylamino)pyrimi N din-5-ol as a crystalline brown solid. MS m/z, 220M+ "H NMR CDC1/CDOD: & 2.94 (s, 3H), 6.90-720 (m, 25 To a solution of 2-iodophenol (6.0 mmol. 1320 mg) and 2H), 7.95 (s, 1H), 8.00-8.30 (m, 2H). KCO (10.5 mmol. 1450 mg) in DMF (15.0 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfona Preparation 44 mide (Preparation 65, 4.5 mmol. 1280 mg). The reaction 30 mixture was heated at 80° C. for 24 hours. The reaction was 4-(2-bromo-4-fluoro-phenoxy)-3-cyano-N-12.4 cooled to room temperature and the mixture was poured into thiadiazol-5-ylbenzenesulfonamide 1 Naqueous HCl (100 mL) to obtain a white solid. The afforded solid was washed with heptane and the solid was 1\ dried in vacuo to furnish 1.932 g of the title compound. n ul 35 LCMS Rt=1.67 minutes MS m/z, 485 MH+ N S 'HNMR (d-DMSO): 86.78 (d. 1H), 7.14-7.22 (m. 1H), 7.39-7.44 (m. 1H), 7.52-7.58 (m, 1H), 799-8.05 (m, 2H), 8.33 (d. 1H), 8.52 (s, 1H). Br 40 Preparation 51 N 3-cyano-4-(2-bromo-6-methyl-phenoxy)-N-12.4 Prepared according to the process of Preparation 51, using thiadiazol-5-yl-benzenesulfonamide 2-bromo-4-fluorophenol and 3-cyano-4-fluoro-N-(1,2,4- thiadiazol-5-yl)benzenesulfonamide (Preparation 65). 45 LCMS Rt=3.01 min MS m/z 284 MH+ HNMR (d- DMSO): 86.8 (m. 1H), 7.4 (m, 1H), 7.6 (m, 1H), 7.8 (m, 1H), O H 8.0 (m. 1H), 8.3 (m. 1H), 8.5 (s, 1H). Me \-N 2N Preparation 46 50 Y, NX 3-cyano-4-fluoro-N-(thiazol-2-yl)benzenesulfona O mide Br | O. O. N. N N W ) 55 - To a solution of 2-bromo-6-methylphenol (6.0 mmol. 1120 H mg) and KCO (10.5 mmol. 1450 mg) in DMF (15.0 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benze 60 nesulfonamide (Preparation 65, 4.5 mmol. 1280 mg). The reaction mixture was heated at 80° C. After stirring for over night at 80°C., the reaction was cooled to room temperature N and poured into 1 Naqueous HCl (100 mL) to precipitate To 2-aminothiazole (12.55g, 125.3 mmol) was added pyri which was filtered to obtain solid. The solid was washed with dine (46 ml) and dichloromethane (75 mL) and the mixture 65 water (100 mL) and heptane (100 mL) and the solid was dried stirred to give a solution. A solution of 3-cyano-4-fluoroben under vacuum to furnish the title compound. LCMS Rt=3.05 Zenesulfonyl chloride (25 g, 114 mmol) in dichloromethane minutes MS m/z 451 M(79Br)H+, 453 M(81Br)H+ US 8,907,101 B2 165 166 'HNMR (d-DMSO): 8 2.17 (s.3H), 6.70 (d. 1H), 7.25-7.31 tane 10/90 to 20/80) to furnish 4.58 g of the title compound. (m. 1H), 7.44-7.48 (m, 1H), 7.64-7.69(m, 1H), 8.01 (dd. 1H), 'HNMR (CDC1): 86.7 (m, 1H), 7.2-7.6 (m, 9H), 7.85 (m, 8.34 (d. 1H), 8.52 (s, 1H). 1H), 8.15 (m, 1H). Preparation 52 Preparation 56 N-(5-chloro-thiazol-2-yl)-3-cyano-4-fluorobenzene Sulfonamide 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-benzonitrile 10

O H V -N S VO N.O)—a 15

N

To a stirred mixture of 2-amino-5-chlorothiazole-hydro chloride (3.76 g. 22.0 mmol) in dichloromethane (20 ml) was added pyridine (8.09 ml, 100 mmol). 3-cyano-4-fluoroben 25 To a stirred mixture of 2-(biphenyl-2-yloxy)-5-bromo Zenesulfonyl chloride (4.39 g, 20 mmol) dissolved in dichlo benzonitrile (Preparation 57, 10.1 g, 288 mmol), Pd dba romethane (5 mL) and was added to the reaction mixture (1.32 g, 1.44 mmol), and Xantphos (1.67 g, 2.88 mmol) in dropwise at room temperature. After stirring for 48 hours at diisopropylether (10 ml) and 1,4-dioxane (100 ml) was added room temperature, 1 NHCl (100 mL) was poured into the benzyl mercaptain (3.58 g. 288 mmol) and the reaction heated reaction and the mixture was extracted with dichlo 30 at gentle reflux for 4 to 5 hours, then stirred at ambient romethane/methanol (v/v=95/5, 100 ml) three times. The col temperature for 30 hours. The reaction mixture was evapo lected organic layer was evaporated in vacuo and dried over rated and the residue purified using silica gel column chro MgSO to obtain the crude residue. The crude residue was matography, eluting with dichloromethane/heptane (30/70, washed with dichloromethane (10 mL) and filtered to afford then 50/50, then 60/40), to furnish 6.08 gm pale yellow solid pale yellow solid as the title compound. LCMS Rt=1.39 min 35 utes MS m/z. 318 (MCIH+, 320 M7CIH+ HNMR (d- as the title compound. LCMS Rt=1.88 minutes MS m/z 394 DMSO): 8 7.59 (s, 1H), 7.66-7.73 (m, 1H), 8.15-8.21 (m, MH+ HNMR(CDC1): 83.93 (s. 2H) 6.46 (d. J=8.58 Hz, 1H), 8.33-8.37 (m, 1H). 1H) 7.06-7.18 (m, 4H) 7.21-7.30 (m, 4H) 7.31-743 (m, 5H) 7.45-7.55 (m,3H) Preparation 55 40 Preparation 57 4-(biphenyl-2-yloxy)-3-cyanobenzenesulfonyl chloride 2-(biphenyl-2-yloxy)-5-bromo-benzonitrile 45

Br

55

A mixture of 5-benzylsulfamyl-2-(biphenyl-2-yloxy)-ben A suspension of 5-bromo-2-fluorobenzonitrile (6.48 g. Zonitrile (Preparation 56, 6.06 g. 15.4 mmol), dichlo 60 32.4 mmol), 2-phenylphenol (5.79 g, 34 mmol) and potas romethane and aq. HCl was stirred vigorously with cooling sium carbonate (4.92 g, 35.6 mmol) in DMF (50 ml) was (ice bath). Sodium hypochlorite was added dropwise over 30 heated at 70° C. for 3 hours. The reaction was cooled and minutes and stirring continued with cooling for 1 hour. The quenched by the addition of water (200 ml) followed by layers were separated, the aqueous extracted with dichlo extraction with thBuOMe. The organic layer was dried romethane (2x100 ml), and the organic collected, dried 65 (MgSO) and concentrated in vacuo. The residue was purified (MgSO) and concentrated in vacuo. The residue was purified using silica gel column chromatography (ethyl acetate:Hep using silica gel column chromatography (ethyl acetate:Hep tane 5:95 to 15:85) to furnish 10.1 g of the desired compound. US 8,907,101 B2 167 168 LCMS Rt=1.78 min MS m/z 349 M+HNMR (d-DMSO): ran (500 mL) was added 4-dimethylaminopyridine (22g, 0.18 8 6.6 (m, 1H), 7.2-7.6 (m, 9H), 7.65 (m. 1H), 8.0 (m. 1H). mol) and di-tert-butyldicarbonate (200 g, 0.9 mol) and the mixture was heated to 50° C. for 4 days. The di-tert-butyldi Preparation 58 carbonate was added portionwise every few hours, usually in conjunction with a precipitate that would form and then go 4-(biphenyl-2-yloxy)-3-cyano-benzenesulfonic acid back into solution after the addition. After cooling to room pentafluorophenol ester temperature the reaction was concentrated and absorbed onto silica geland purified by flash column chromatography (ethyl acetate:Hexanes 0-100% ethyl acetate). This provided the 10 two products in a 4:1 A:B ratio. F A=N-tert-butyl-3,4-difluoro-N-thiadiazol-2-yl-benzene F F Sulfonamide: LCMS Rt=1.66 minutes MS m/z 333 MH+ H NMR N V/ Šs S 15 (CDC1) & 8.02 (m. 1H), 7.89 (m, 1H), 7.73 (d. 1H), 7.45 (d. No F 1H), 7.33 (m, 1H), 1.43 (s.9H). B=N-3-tert-butyl-3H-thiazol-(2Z)-ylidene-3,4-difluo F O robenzenesulfonamide: LCMS Rt=1.51 minutes MS m/z 333 MH+ H NMR (CDC1) & 7.69 (m, 2H), 7.20 (m. 1H), 7.07 (d. 1H), 6.42 (d. 1H), 1.57 (s, 9H). Preparation 61 A solution of 4-(biphenyl-2-yloxy)-3-cyano-benzene sulfonyl chloride (Preparation 55, 500 mg, 1.35 mmol) in 25 dichloromethane (5 ml) was added slowly to pentafluorophe 3,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide nol (249 mg, 1.35 mmol) and Et-N (137 mg, 1.35 mmol) in dichloromethane (5 ml) and stirring continued overnight at ambient temperature. The reaction was concentrated in vacuo 30 and purified using silica gel column chromatography (dichlo romethane?heptane 40/60, then 60/40, then 80/20, then dichloromethane) to furnish the title compound. LCMS Rt=1.92 minutes "H NMR (400 MHz. CDC1,) & (ppm): 6.69 (d. J=8.98 Hz, 1H) 7.21-7.30 (m, 2H) 7.31-7.38 35 (m. 2H) 7.43-7.53 (m, 4H) 7.53-7.58 (m. 1H) 7.79 (dd, J=8.98, 2.34 Hz, 1H) 8.06 (d. J=2.34 Hz, 1H) 'F NMR (376 MHz, CDC1) & (ppm): 160.82 (t, J=19.50 Hz) -154.87 (t, J=21.80 Hz)-151.09 (d. J=17.21 Hz) To a slurry of 2-aminothiazole (23.88 g., 0.2384 mol) in Preparation 60 40 methylene chloride (150 mL) and pyridine (38.0 mL, 0.470 mol) was added dropwise a solution of 3,4-difluorobenzene N-tert-butyl-3,4-difluoro-N-(thiazol-2-yl)benzene sulphonyl chloride (25.0g, 0.118 mol) in 10 mL of methylene sulfonamide and N-3-tert-butyl-3H-thiazol-(2Z)- chloride. After stirring for 48 hours the reaction was diluted ylidene-3,4-difluorobenzenesulfonamide or (Z) N with more dichloromethane and extracted with 1N HC1. The (3-tert-butylthiazol-2(3H)-ylidene)-3,4- 45 organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chro difluorobenzenesulfonamide matography to give 3,4-difluoro-N-(thiazol-2-yl)benzene sulfonamide as a white solid. LCMS Rt=1.24 minutes MS m/z 277 MH+ 50 Q p N {-S Preparation 62 N-tert-butyl-2,4-difluoro-(N-thiazol-2-yl)benzene F 1. 55 sulfonamide and N-3-tert-butyl-3H-thiazol-(2Z)- Me ylidene-2,4-difluorobenzenesulfonamide F Q p N Yell 60 Q p N MAMe Me

F 65 F 1. To a solution of 3,4-difluoro-N-(thiazol-2-yl)benzene Me sulfonamide (Preparation 61, 50 g, 0.2 mol) in tetrahydrofu US 8,907,101 B2 169 170 -continued (8.25 g, 0.0376 mol) was added and the reaction was allowed to stir for 3 hours at 20° C. After this time, the reaction was Q p N poured into 150 mL of 1N HC1. This solution was extracted with ethyl acetate (3x50 mL). The combined organics were Cels 5 dried over sodium sulfate, filtered and concentrated to give the title compound as a brown solid. LCMS Rt=1.22 minutes F MAMe Me MS m/z 283 MH+H NMR (d-DMSO)88.54 (s, 1H), 8.39 To a solution of 2,4-difluoro-N-(thiazol-2-yl)benzene (dd. 1H), 8.19 (m, 1H), 7.71 (m, 1H). sulfonamide (Preparation 63, 11.3 g, 0.04.09 mol) in tetrahy 10 drofuran (200 mL) was added 4-dimethylaminopyridine (5.0 Preparation 68 g, 0.041 mol) and di-tert-butyldicarbonate (26.8g, 0.123 mol) and heated to 40°C. for 3 days. The di-tert-butyldicarbonate 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2, was added portion-wise every few hours, usually in conjunc 4-thiadiazol-5-yl)benzenesulfonamide tion with a precipitate that would form and then go back into 15 Solution after the addition. After cooling to room temperature s-N the reaction was concentrated and absorbed onto silica gel V A” y and purified by flash column chromatography. This provided n s the two products in a 5.5:1 A:B ratio. A=N-tert-butyl-2,4-difluoro-N-thiadiazol-2-yl-benzene Sulfonamide: LCMS Rt=1.92 minutes MS m/z 333 MH+ H NMR (CDC1) & 8.03 (m. 1H), 7.67 (d. 1H), 7.42 (d. 1H), 6.96 (m, MeO OMe 2H), 1.49 (s.9H). N B=N-3-tert-butyl-3H-thiazol-(2Z)-ylidene-2,4-difluo 25 (2,4-Dimethoxy-benzyl)-(1,2,4)thiadiazol-5-yl-amine robenzenesulfonamide: (Preparation 14, 8.010 g, 0.03200 mol) was dissolved in LCMS Rt=1.54 minutes MS m/z 333 MH+ H NMR tetrahydrofuran (100 mL, 1.3 mol) and cooled to -78°C. 1.0 (CDC1) & 8.07 (m. 1H), 7.12 (d. 1H), 6.95 (m, 2H), 6.47 (d. M of Lithium hexamethyldisilazide in tetrahydrofuran (35.2 1H), 1.70 (s, 9H). mL) was added dropwise to the reaction mixture. The cooling 30 bath was removed and the reaction was allowed to stir for 30 Preparation 63 minutes. The reaction was cooled back to -78° C. and a solution of 3-cyano-4-fluorobenzenesulfonyl chloride (7.028 2,4-difluoro-N-(thiazol-2-yl)benzenesulfonamide g, 0.03200 mol) in tetrahydrofuran (80 mL, 0.99 mol) was added dropwise to the reaction. The reaction was allowed to 35 stir for 30 minutes at -78°C. The reaction was poured into saturated aqueous ammonium chloride. The aqueous phase N H was extracted with ethyl acetate (three times). The combined organic phase was washed twice with 10% citric acid solu F tion, water and brine. The organic phase was dried over mag 40 nesium Sulfate and evaporated to a residue. The residue was To a slurry of 2-aminothiazole (15.08 g., 0.1506 mol) in purified by column chromatography (120g silica gel column, methylene chloride (100 mL) and pyridine (24 mL, 0.30 mol) Hexanes to ethyl acetate gradient elution). Product fractions was added dropwise over 20 minutes a solution of 2,4-difluo were combined and evaporated to a residue. The residue was robenzenesulfonyl chloride (10 mL, 0.07 mol) in 10 mL of triturated with 10% t-butyl methyl ether in hexanes and the methylene chloride. After stirring at room temperature for 48 45 resulting off-white solid collected by filtration and rinsed hours the reaction was concentrated and purified by flash with hexanes. Vacuum drying gave 3.58 g of the title com column chromatography eluting with hexane/ethyl acetate. pound. LCMS Rt=1.66 minutes MS m/z 457 M Na+. MS LCMS Rt=1.21 minutes MS m/z 277 MH+ m/z 151 MH+2,4-Dimethoxybenzyl 'H NMR (d-DMSO) Preparation 65 & 8.44 (s, 1H) 8.33 (dd. 1H), 8.25 (m, 1H), 7.72 (t, 1H), 7.03 50 (d. 1H), 6.43 (m, 2H), 5.23 (s. 2H), 3.73 (s.3H), 3.64 (s.3H). 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzene Preparation 72 Sulfonamide thiazole-4-yl-carbamic acid tert-butyl ester O O S1 \ V/ 55 S n N s H H F N 60 N Sodium hydroxide (5.08 g., 0.127 mol) was dissolved in water (60 mL) and 1,4-1,4-dioxane (300 mL). 1,2,4-Thiadia 65 Thiazole-4-carboxylic acid (6.46g, 50.0 mmol) was slur Zol-5-amine (10g, 0.1 mol) was added and the reaction stirred ried in tert-butyl alcohol (280 mL. 2900 mmol). Triethy for 5 minutes. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride lamine (7.68 mL, 55.1 mmol) and diphenylphosphonic azide US 8,907,101 B2 171 172 (11.9 mL, 55.1 mmol) were added and the reaction was reaction was concentrated in vacuo and the residue purified heated at reflux for 18 hours. The reaction was evaporated to by flash column chromatography eluting with 0-100% hex a residue. The residue was dissolved in ethyl acetate and ane/ethyl acetate gradient. Two regioisomeric products in a washed with water, 5% citric acid (aqueous), water, Saturated 1:4 A:B ratio were obtained with the major being the less aqueous sodium bicarbonate and brine. The organic phase 5 polar and the minor being more polar. was dried over magnesium sulfate and evaporated to a resi A=4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol due. The residue was purified by silica gel chromatography LCMS Rt=1.43 minutes MS m/z. 209 MH+ (80 g ISCOTM column, hexanes to ethyl acetate gradient elu 1H NMR (CDC1,) & 7.65 (d. 1H), 7.34 (dd. 1H), 7.22 (d. tion). Product fractions were combined and evaporated to a 1H), 6.99 (d. 1H), 6.40 (d. 1H), 5.52 (m, 1H), 2.96 (s, 3H). residue. The residue was triturated with 20% methyl t-butyl 10 B=4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenol ether in hexanes. The solid was collected by filtration. LCMS Rt=1.58 minutes MS m/z. 209 MH+ Vacuum drying gave 6.48g of product as a white solid. LCMS 1H NMR (CDC1) & 10.85 (s, 1H), 7.54 (d. 1H), 7.44 (d. Rt=1.46 minutes MS m/z 201 MH+ 1H), 7.17 (dd. 1H), 7.00 (d. 1H), 6.61 (d. 1H), 3.98 (s.3H). Preparation 88 15 Preparation 92 4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenol and 2-(1-methyl-1H-pyrazol-5-yl)phenol and 2-(1-me 4-fluoro-2-(1-methyl-1H-pyrazol-3-yl)phenol thyl-1H-pyrazol-3-yl)phenol

25 OH

30 To a suspension of 6-fluorochromone (2.01 g, 0.0122 mol) in ethanol (40 mL) was added methylhydrazine sulfate (1.91 g, 0.0132 mol) and triethylamine (2.2 mL, 0.016 mol). The reaction was heated to reflux for 18 hours. After cooling, the Prepared by the process described by J. Catalan et. al in reaction was concentrated in vacuo and the residue purified JACS, 1992, 114, 503.9. Two regioisomeric products in a 1:1 by flash column chromatography eluting with hexane/ethyl 35 A:B ratio were obtained. acetate. Two regioisomeric products in a 1:2 A:B ratio were A=2-(1-methyl-1H-pyrazol-5-yl)phenol obtained with the major being the less polar and the minor LCMS Rt=1.31 minutes MS m/z 175 MH+ being more polar. H NMR (CDC1) & 7.62 (d. 1H), 7.39 (m. 1H), 7.26 (dd, A=4-fluoro-2-(1-methyl-1H-pyrazol-5-yl)phenol 40 1H), 7.06 (m, 2H), 6.39 (d. 1H), 6.34 (m, 1H), 3.83 (s.3H). LCMS Rt=1.28 minutes MS m/Z 193 MH+ B=2-(1-methyl-1H-pyrazol-3-yl)phenol 1H NMR (CDC1) & 7.54 (d. 1H), 7.07-6.91 (m, 4H), 6.33 LCMS Rt=1.45 minutes MS m/z 175 MH+ (d. 1H), 3.78 (s.3H). H NMR (CDC1) & 10.94 (s, 1H), 7.62 (dd. 1H), 7.42 (d. B-4-fluoro-2-(1-methyl-1H-pyrazol-3-yl)phenol 1H), 7.25 (m. 1H), 7.08 (dd. 1H), 6.95 (m. 1H), 6.64 (d. 1H), LCMS Rt=1.43 minutes MS m/Z 193 MH+ 45 3.98 (s.3H). 1H NMR (CDC1,) & 10.64 (s, 1H), 7.44 (d. 1H), 7.27 (dd. 1H), 6.97 (m, 2H), 6.59 (d. 1H), 3.99 (s.3H). Preparation 190 Preparation 89 4-(2-tert-butyl-5-trifluoromethyl-2H-pyrazol-3-yl)- phenol 4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenol and 50 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)phenol

55

60 OH A mixture of 4,4,4-trifluoro-1-(4-hydroxyphenyl)butane To a suspension of 6-chlorochromone (2.00 g, 0.01 11 mol) 1,3-dione (500 mg, 0.002 mol) and tert-butylhydrazine in ethanol (35 mL) was added methylhydrazine sulfate (1.85 65 hydrochloride (270 mg 0.0022 mol) in ethanol (12 mL, 0.21 g, 0.0128 mol) and triethylamine (2.0 mL, 0.014 mol). The mol) was heated at 150° C. in microwave for 1 h. Solvent was reaction was heated to reflux for 18 hours. After cooling, the removed and the residue was purified via automated flash US 8,907,101 B2 173 174 chromatography (silica gel, 0% to 30% ethyl acetate in hex cooling bath was removed and the reaction warmed to room anes) to give the product as an off-white solid (0.36 g. 60%). temperature, stirred for a further 5 minutes then cooled back LCMS Rt=1.75 minutes to -70° C. 3-Cyano-4-fluorobenzenesulfonyl chloride (2.54 MS m/z 285 MH+ g, 11.6 mmol) in tetrahydrofuran (10 ml) was added dropwise keeping the temperature below -60° C. and the reaction mix Preparation 205 ture was warmed to room temperature. Saturated aqueous ammonium chloride solution (50 ml) was added followed by tert-Butyl 4-(5-chloro-2-hydroxyphenyl)-1H-pyra water to dissolve the solid which had precipitated out. The Zole-1-carboxylate aqueous layer was extracted with ethyl acetate (50 ml) and the 10 organic extracts dried over magnesium Sulphate and deco lourising charcoal, filtered through CeliteTM and the filtrate evaporated in vacuo. The resulting gum was purified using a C short column (silica gel, 150 g) eluting with ethyl acetate: heptane (1:1, by Volume) affording a gum which was tritu 15 rated with tert-butyl ether, filtered, washed with heptane and OH dried in vacuo to give the title compound as a buff solid, 2.84 g, 57% yield. LCMS Rt=4.65 minutes. MS m/z. 468 (S 'HNMR (CDC1): 83.68 (s.3H), 3.80 (s.3H), 4.99 (s.2H), N-N 6.34 (d. 1H), 6.39 (dd. 1H), 7.12 (d. 1H), 7.28 (s, 1H), 7.31 (t, 1H), 7.98 (dd. 1H),8.05 (m. 1H). 'FNMR (CDC1): 8 -98.51 X- Me (m. 1F) O yu Me Preparation 208 25 5-Chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2- A suspension of 4-chloro-2-iodophenol (200 mg. 0.78 amine mmol) and potassium carbonate (434 mg., 3.14 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was degassed and heated for 1 hour at 50° C. tert-Butyl 4-(4,4,5,5-tetramethyl 30 1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (347 mg, 1.18 mmol) and palladium (O) tetrakis(triph enylphoshine) (91 mg 0.08 mmol) were added and the mix ture heated at 50° C. for 5 hours. Dichloromethane (20 ml) O)- and water (10 ml) were added and the organics separated and 35 evaporated in vacuo. The residue was purified by column O O chromatography (silica gel) eluting with ethyl acetate:hep tane (2:8 to 1:0, by volume) to afford the title product as a Me Me white solid, 155 mg. 66% yield. LCMS Rt 3.03 minutes. MS m/z 195 (MCl( BOC)H+ 40 Nitrogen was bubbled through a suspension of 2-amino-5- 'HNMR (d-DMSO): 81.60 (s.9H), 6.90 (m. 1H), 7.15 (m, chlorothiazole hydrochloride (25.0 g, 146 mmol) in dichlo 1H), 7.80 (m. 1H), 8.40 (m, 1H), 8.65 (m. 1H), 10.40 (s, 1H). romethane (1000 ml) for 10 minutes before the addition of piperidine (13.0 g, 15.0 ml, 150 mmol) via syringe. 2,4- Preparation 207 Dimethoxybenzaldehyde (22.1 g, 133 mmol) was added fol 45 lowed by freshly dried 3 A molecular sieves (ca. 40 g). The N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4- mixture was stirred at 45° C. under nitrogen for 16 hours. dimethoxybenzyl)-4-fluorobenzenesulfonamide Upon cooling to room temperature the mixture was filtered through a pad of CeliteTM, washing with dichloromethane (2000 ml) before concentrating in vacuo to give a yellow 50 solid, 58.2g. This residue was dissolved in methanol (1250 ml) and sodium borohydride (13.0 g, 340 mmol) was added portionwise. Upon complete addition the mixture was heated to 50° C. for 30 minutes before cooling to room temperature and stirring under nitrogen for 16 hours. The solvent was 55 concentrated in vacuo and the residue partitioned between ethyl acetate (300 ml) and water (500 ml). The layers were separated and the aqueous was extracted with ethyl acetate (3x300 ml). The combined organics were washed with water (300 ml), saturated aqueous sodium chloride solution (300 60 ml), dried over magnesium Sulphate, filtered and concen trated in vacuo to give a red-brown Solid, 41.6 g. This residue Under an atmosphere of nitrogen, 5-chloro-N-(2,4- was dissolved in ethyl acetate and passed through a plug of dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208, 3.0 silica. Concentration in vacuo afforded a red-brown solid, g 10.5 mmol) was dissolved in tetrahydrofuran (20 ml) and 39.3 g, which was subsequently triturated with diethyl ether cooled to -70° C. Lithium hexamethyldisilazane (1 M in 65 (ca. 500 ml) and stirred for 60 hours. The solid was filtered tetrahydrofuran, 12.6 ml, 12.6 mmol) was added dropwise, and air-dried to give the title compound as a white Solid, 12.1 keeping the temperature below -60° C. After 5 minutes, the g, 32% yield. The mother liquor was concentrated in vacuo to US 8,907,101 B2 175 176 give a brown solid, 25 g, which was stirred in diethyl ether: Preparation 210 heptane (2:3, 500 ml). The solid material was filtered and air-dried to give the title compound as an off-white solid, 13.2 g, 35% yield. (5-Chloro-2-methoxy-phenyl)acetonitrile 'HNMR (d-DMSO): 83.65 (s.3H), 3.75 (s.3H), 4.2 (m, 2H), 6.4 (m. 1H), 6.5 (s, 1H), 6.9 (s, 1H), 7.1 (m. 1H), 7.9 (m, 1H). C Preparation 209 10 N-1-tert-butyl-4-(5-chloro-2-hydroxyphenyl)-1H pyrazol-5-yl)-2.2.2-trifluoroacetamide

15 C To a solution of methyl 5-chloro-2-methoxybenzoate (25.4 g, 127 mmol) in ether (200 ml), cooled in an ice water bath, F OH was added dropwise lithium tetrahydroaluminate (1 M in F H N diethyl ether, 110 ml, 110 mmol). After 2 hours the reaction F 21 f was quenched with water and then acidified to pH 3 with hydrochloric acid (6 M aqueous solution). The layers were O N-N separated and the organic layer dried over magnesium sulfate, 25 filtered and concentrated in vacuo to give a white solid. The 16 Me solid was dissolved dichloromethane (200 ml) and treated Me with thionyl chloride (25 ml, 340 mmol). After heating at reflux for 2 hours, the reaction was cooled to room tempera To a solution of (5-chloro-2-methoxy-phenyl)acetonitrile ture and water added. The layers were separated and the (Preparation 210, 2.154g, 11.86 mmol) in ethyl formate (20 aqueous layer extracted with dichloromethane (2x50 ml). ml) was added sodium (605 mg, 26.3 mmol). The reaction The combined organics were dried over magnesium sulfate, was heated at a gentle reflux for 16 hours. After cooling to filtered and concentrated in vacuo to give an orange solid. room temperature, water and dichloromethane were added This solid was dissolved dimethyl sulphoxide (175 ml), and the solution adjusted to pH 3 with hydrochloric acid (6 M sodium cyanide (12.75g, 260.2 mmol) added and solution aqueous solution). The layers were separated and the aqueous 35 heated to 80° C. for 3 hours. After cooling to room tempera layer extracted with dichloromethane (2x50 ml). The com ture, water was added and a solid formed that was filtered and bined organics were washed with Saturated aqueous sodium washed with water to provide the title compound as an off chloride Solution, dried over magnesium Sulphate, filtered white solid, 20.8 g., 91% yield. and evaporated in vacuo. Purification by flash column chro LCMS Rt 1.55 minutes. matography eluting with ethyl acetate:hexanes (gradient 0:1 40 to 1:1, by volume) gave a white solid which was dissolved in HNMR (CDC1): 83.70 (s. 2H), 3.90 (s.3H), 6.84 (d. 1H), ethanol (50 ml), tert-butylhydrazine hydrochloride (1.77 g. 7.30 (m, 1H), 7.39 (m, 1H). 14.2 mmol) added and solution heated to reflux for 24 hours. The reaction was cooled and evaporated in vacuo to give a Preparation 211 brown oil. This oil was dissolved in dichloromethane (50 ml) 45 and triethylamine (4.2 ml, 30 mmol) and trifluoroacetic anhy dride (4.2 ml, 30 mmol) were added. After stirring for 16 tert-Butyl 4-(5-fluoro-2-hydroxyphenyl)pyridin-2- hours, the reaction was washed with potassium hydrogen ylcarbamate sulphate (1 Naqueous solution), sodium bicarbonate (1 N aqueous solution) and Saturated aqueous sodium chloride 50 Solution. The organic layer was separated, dried over magne sium Sulphate, filtered and concentrated in vacuo to give a F brown oil. This oil was dissolved in dichloromethane (20 ml) and cooled over an ice water bath before the addition of boron tribromide (1 M in dichloromethane, 22 ml, 22 mmol). After 55 OH stirring for 45 minutes the reaction was added to ice water. The layers were separated and the aqueous layer washed with 21 O Me dichloromethane (2x20 ml). The combined organics were dried over magnesium sulfate, filtered and concentrated in N N O Me vacuo to give a brown oil. 60 H Me Purification by flash column chromatography eluting with ethyl acetate:hexane (gradient 0:1 to 1:0, by volume) to afford the title compound as a brown oil that solidified to a tan solid 4-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) upon standing, 2.82 g. 66% yield. phenol (Preparation 212, 0.082g, 0.000386 mol), tert-butyl LCMS Rt 1.61 minutes. MS m/z. 362 MH+ 65 (4-chloropyridin-2-yl)carbamate (0.0588 g., 0.000257 mol), HNMR (CDC1): & 1.69 (s.9H), 6.87 (im, 1H), 7.16 (m, anhydrous sodium carbonate (0.070 g., 0.000660 mol) and 2H), 7.64 (s, 1H), 8.74 (s, 1H). palladium (O) tetrakis(triphenylphosphine) (0.029 mg, US 8,907,101 B2 177 178 0.000025 mol) were suspended in 1,4-dioxane (3.0 ml) and bonate (363 mg, 2.63 mmol) in dimethylsulphoxide (20 ml) water (1.0 ml). The suspension was stirred at 85°C. for 16 were stirred at room temperature under nitrogen for 18 hours. hours before cooling to room temperature. The reaction was The reaction mixture was poured into water (50 ml) and diluted with ethyl acetate (10 ml) and organic phase was extracted with ethyl acetate (3x30 ml). The combined organ washed with Saturated aqueous sodium bicarbonate Solution ics were washed with Saturated aqueous Sodium chloride (2x10.0 ml), dried over sodium sulphate, filtered and concen solution (30 ml), dried over magnesium sulfate, filtered and trated in vacuo. Purification by ISCOTM (12 gSiO) eluting concentrated in vacuo to give the title compound as an off with ethyl acetate: heptane (gradient 0:1 to 3:7, by volume) white solid, 670 mg, quantitative yield. afforded the title compound as a solid, 41 mg, 54%. LCMS R, 3.50 minutes. LCMS Rt=1.40 minutes MS m/z. 303 MH+ 10 'HNMR (d-DMSO): 83.6 (s.3H), 3.7 (s.3H), 4.9 (s. 2H), "H NMR (400 MHz, d-DMSO): & 1.45 (s, 9H), 6.95 (m, 6.4 (m, 2H), 6.8 (m. 1H), 7.0 (m, 1H), -7.4 (m, 2H), 7.55 (s, 1H), 7.05 (m. 1H), 7.15 (m, 1H), 7.20 (d. 1H), 8.00 (s, 1H), 1H), 7.9 (m, 1H), 8.0 (m, 1H), 8.35 (m. 1H). 8.25 (d. 1H), 9.65 (s, 1H), 9.75 (s, 1H) Preparation 218 Preparation 212 15 4-Fluoro-2-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan 4-Fluoro-2-iodophenol 2-yl)phenol

F

OH OH 25

B O1 Yo N-Iodosuccinimide (10g, 45.0 mmol) and 4-fluoro-phenol (5.00 g, 40.0 mmol) were suspended in acetic acid (39 ml, 649.0 mmol) and stirred for 5 minutes before addition of - is. 30 Me Me concentrated sulphuric acid (0.79 ml, 13.4 mmol). The reac tion mixture was stirred for 18 hours at room temperature before diluting with water (100 ml). The aqueous layer was To a suspension of (5-fluoro-2-hydroxyphenyl)boronic extracted with dichloromethane (2x30 ml). The combined acid (1.000 g, 0.00641 mol) in toluene (3.0 ml) was added organic extracts were washed with sodium thiosulphate solu pinacol (0.875 g, 0.0074.04 mol). This was heated to reflux 35 tion (20% aqueous, wit:V), water, dried over sodium sulfate, using a Dean-Starkapparatus for 24 hours before concentrat filtered and concentrated in vacuo. The crude residue was ing in vacuo. The residue was suspended intert-butyl-methyl purified by column chromatography (silica gel) eluting with ether (10.0 ml) and organic layer was washed with saturated aqueous sodium chloride solution (2x10.0 ml), dried over toluene to afford the title compound as an off white solid, 4.5 40 g, 40% yield. Sodium Sulphate, filtered and concentrated in vacuo to afford LCMS Rt=1.33 minutes. MS m/Z 237 MH) the title compound as a translucent oil, 1.4g, 92% yield. H NMR (400 MHz, CDC1) 8: 5.22 (s, 1H), 6.99 (m, 2H), 'HNMR (CDC1): & 1.35 (s, 12H), 6.80 (dd. 1H), 7.05 (dt, 7.42 (dd. 1H) ppm. 1H), 7.35 (dd. 1H), 7.60 (s, 1H). Preparation 219 Preparation 217 45 N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4- 4-(4-Chloro-2-iodophenoxy)-N-(5-chloro-1,3-thia dimethoxybenzyl)-4-(4-fluoro-2-iodophenoxy)ben Zol-2-yl)-3-cyanobenzenesulfonamide Zenesulfonamide 50 O O N N C

55

I | N I O Ol 60 M e To a stirred suspension of 4-chloro-2-iodophenol (305 mg. 1.20 mmol) and potassium carbonate (207 mg, 1.5 mmol) in N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-N-(2,4- dimethyl sulphoxide (5.0 ml) was added N-(5-chloro-1,3- dimethoxybenzyl)-4-fluorobenzenesulfonamide (Prepara 65 thiazol-2-yl)-3-cyano-N-(2,4-dimethoxybenzyl)-4-fluo tion 207, 410 mg. 0.876 mmol), 2-iodo-4-fluorophenol robenzenesulfonamide (Preparation 207, 468 mg, 1.00 (Preparation 218, 229 mg 0.964 mmol) and potassium car mmol). Suspension stirred at room temperature for 18 hours. US 8,907,101 B2 179 180 The reaction mixture was poured into ethyl acetate (20 ml) ethyl phenol (8.02 g, 49.5 mmol) and, after 5 minutes, con and Saturated aqueous ammonium chloride Solution (20 ml) centrated sulphuric acid (0.87 ml, 14.8 mmol). The pale and the aqueous layer extracted with ethyl acetate (3x20 ml). brown/red Suspension was stirred at room temperature under Combined organic layers were dried over magnesium sulfate nitrogen for 48 hours before diluting with water and extract and concentrated in vacuo. The crude residue was dissolved 5 ing with dichloromethane. The organic extract was washed in dichloromethane (5 ml), trifluoroacetic acid (5 ml) was with water, Saturated aqueous sodium thiosulphate solution, added and the reaction mixture was stirred at room tempera water, dried over magnesium Sulphate before decolourising ture for 2 hours. The solvent was concentrated in vacuo and charcoal added. The suspension was left to stand for 10 min purified by ISCOTM preparative system eluting with dichlo utes before filtering through a short pad of silica gel eluting romethane:ethyl acetate (gradient 1:0 to 6:4, by volume) to 10 with dichloromethane. The solvent was evaporated in vacuo afford the title compound as a solid, 396 mg, 72% yield. to give an oil which was purified by flash column chromatog LCMS Rt 3.43 minutes. MS m/z 552 MCIH" raphy on silica eluting with dichloromethane to give the title 'HNMR (d-DMSO): 8 6.86 (d. 1H), 7.43 (d. 1H), 7.55 (s, compound as a pale yellow oil, 9.017 g. 63% yield. 1H), 7.62 (dd. 1H), 7.99 (dd. 1H), 8.09 (d. 1H), 8.29 (d. 1H). LCMS Rt=1.53 minutes. MS m/z 287 MH) 15 H NMR (400 MHz, CDC1): 8 5.79 (brs, 1H), 7.05 (d. Preparation 221 1H), 7.51 (dd. 1H), 7.93 (d. 1H) ppm. Method 2 (2E)-3-(Dimethylamino)-1-(5-fluoro-2-hydroxyphe Preparation 224 can also be prepared as follows. nyl)prop-2-en-1-one N-iodosuccinimide (69.5 g., 0.309 moles) was suspended in acetic acid (257 mL) and cooled to 0°C. 4-Trifluorometh ylphenol (50.0 g, 0.310 moles) was added followed by sul phuric acid (5.44 mL) dropwise over 5 minutes. The orange brown Suspension was stirred whist warming slowly to room 25 temperature over 18 hours. A further portion of N-iodosuc cinimide (2.5g, 0.011 moles) was added and the mixture was OH stirred at room temperature for 24 hours. The reaction was quenched by adding water (150 mL) and extracted with dichloromethane (2x100 mL). The combined organics were 30 washed with a saturated aqueous solution of sodium met abisulphite (2x50 mL) and then with saturated aqueous sodium chloride solution (50 mL). The organics were dried over anhydrous magnesium Sulphate, filtered and the solvents removed in vacuo to give the crude title product as a light 35 yellow oil. This batch was combined with the products from To a solution of 4-fluoro-2-hydroxyacetophenone (13.0 g, two further identical reactions and purified by distillation in 84.4 mmol) in isopropanol (150 ml), was added dimethylfor vacuo. The product was collected boiling at approximately mamide dimethylacetal (20.1 g, 169 mmol). The resulting 45° C. at 2 mBar to give the title compound as a pink-orange yellow solution was heated at 45°C. without stirring for 18 semi-solid (216 g). hours before cooling to room temperature. The resulting crys 40 LCMS Rt=2.89 minutes. MS m/z.287 M-H talline yellow solid was isolated by filtration and washed with 'HNMR (CDC1): 85.62 (brs, 1H), 7.03 (d. 1H), 7.51 (d. a minimum of cold isopropanol. The filtrate concentrated in 1H), 7.92 (s, 1H). vacuo to 30 ml and the resulting yellow solution cooled to 5° C., resulting in precipitation of a further batch of yellow solid. Preparation 226 The solid was isolated by filtration, washing with a minimum of cold isopropanol and combined with the original batch to 45 2-Iodo-4-(trifluoromethoxy)phenol afford the title compound, 17.0 g, 96% yield. LCMS Rt 2.02 minutes. 'HNMR (CDC1): 8 2.97 (s, 3H), 3.20 (s, 3H), 5.64 (m, 1H), 6.86 (m. 1H), 7.07 (m, 1H), 7.36 (m, 1H), 7.91 (m. 1H). F F 50 is Preparation 224 O 2-Iodo-4-(trifluoromethyl)phenol

55 OH

To a suspension of N-iodosuccinimide (6.95g, 31 mmol) in 60 glacial acetic acid (2 ml) was added 4-trifluoromethoxyphe nol (4.0 ml, 31 mmol) and, after 5 minutes, concentrated OH sulphuric acid (0.5 ml, 9 mmol). The pale brown suspension was stirred at room temperature under nitrogen for 48 hours before diluting with water and extracting with dichlo 65 romethane. Organic extract was washed with water, Saturated To a suspension of N-iodosuccinimide (11.10 g, 49.5 aqueous Sodium thiosulphate solution, water, dried over mag mmol) in glacial acetic acid (40 ml) was added 4-trifluorom nesium Sulfate and decolourising charcoal added. The result US 8,907,101 B2 181 182 ing suspension was left to stand for 30 minutes before filtering in vacuo. The resulting crystals were washed with diethyl through a short pad of silica gel eluting with dichlo ether and dried in vacuo to give the title compound as white romethane. The solvent was evaporated in vacuo to give the crystals, 53 g, 97% yield. title compound as an oil, 8.78 g., 94% yield. LCMS (7.5 minute acid run) ESI m/z 212 MCIHI* Rt LCMS Rt=1.51 minutes. MS m/z. 303 MH 2.25 minutes. "H NMR (400 MHz, CDC1): 85.49 (brs, 1H), 6.99 (d. 'HNMR (d-DMSO): & 1.80 (m, 4H), 3.10 (m, 3H), 3.35 1H), 7.15 (dd. 1H), 7.55 (d. 1H) ppm. (m. 2H), 6.84 (d. 1H), 7.02 (m, 1H), 7.11 (m. 1H), 8.30 (brs, 1H), 8.62 (brs, 1H), 9.80 (s, 1H). Preparation 231 10 Preparation 233 tert-Butyl 4-(5-chloro-2-hydroxyphenyl)piperidine 1-carboxylate 4-(5-Chloro-2-methoxyphenyl)piperidine

15 C C

OH

N H 25 A solution of benzyl 4-(5-chloro-2-methoxyphenyl)piperi dine-1-carboxylate (Preparation 234, 73 g, 0.2 mol) in con centrated hydrochloric acid (200 ml) was refluxed with stir 30 ring for 2 hours before concentrating in vacuo. Water (100 To a Suspension of 4-chloro-2-piperidin-4-ylphenolhydro ml), sodium hydroxide (10 Maqueous solution, 20 ml) and bromide (Preparation 232, 100 mg, 0.342 mmol) and N-ethyl chloroform (200 ml) were added to the residue. The aqueous N-isopropylpropan-2-amine (65.5ul, 0.376 mmol) in dichlo layer was extracted with chloroform (2x200 ml). The com romethane (5 ml) at 0°C. was added dropwise a solution of bined organic layers were washed with water (200 ml), satu di-tert-butyl dicarbonate (82.9 mg, 0.376 mmol) in dichlo 35 rated aqueous sodium chloride solution (200 ml), dried over romethane (1 ml). The resulting mixture was warmed to room sodium sulphate, filtered through silica gel (100 g, 40/63 um) temperature and stirred for 16 hours. Water (1 ml) was added and evaporated in vacuo to afford the title compound as white and stirred for 5 minutes before filtering through a phase crystals, 40 g, 89% yield. separating cartridge. The organics were evaporated in vacuo to afford the title compound as a pale cream solid, 110 mg. 40 Preparation 234 100% yield. LCMS Rt 1.64 minutes. MS m/z. 310 MH Benzyl 4-(5-chloro-2-methoxyphenyl)piperidine-1-car 'HNMR (CDC1): 8 1.51 (m, 9H), 1.61 (m, 2H), 1.82 (d. boxylate 2H), 2.83 (t, 2H), 3.0 (m. 1H), 4.25 (d. 2H), 6.69 (d. 1H), 7.04 45 (dd. 1H), 7.10 (d. 1H). C Preparation 232 Me 4-Chloro-2-piperidin-4-ylphenol hydrobromide O1 50

C N 55 OH es

60 N HBr To a solution of tert-butyl 4-(5-chloro-2-methoxyphenyl)- To 4-(5-chloro-2-methoxyphenyl)piperidine (Preparation 4-hydroxypiperidine-1-carboxylate (Preparation 235, 90 g, 233, 40 g, 0.177 mol) was added hydrogen bromide (48% in 65 0.263 mol) in 1,4-dioxane (200 ml) was added hydrogen water, 100 ml) and refluxed for 24 hours before concentrating chloride (4M in dioxane, 150 ml, 0.6 mol) under argon. The in vacuo. 1,4-Dioxane was added and solution concentrated mixture was stirred for 24 hours and evaporated in vacuo. US 8,907,101 B2 183 184 Diethyl ether was added before concentrating in vacuo. Water ous, 160 ml), sodium sulphate (300 g) and hexane (500 ml). (300 ml) and diethyl ether (500 ml) were added to this residue The mixture was stirred for 10 hours. The organic layer was before the addition of sodium carbonate (32 g, 0.3 mol) under decanted, filtered through silica gel (300 g, 63/100 um) wash vigorous stirring. Mixture cooled over an ice bath before the ing with ethyl acetate:hexane (4.6, by volume, 2x400 ml). dropwise addition of benzyl chlorocarbonate (43 ml, 0.3 The filtrate was evaporated in vacuo and the residue recrys mol). The bath was removed and the mixture stirred for 1 tallized from ethyl acetate:hexane to afford the title com hour. The aqueous layer was extracted with ether (2x200 ml). pound as white crystals, 100 g, 39% yield. The combined organic layers were washed with water (200 ml), Saturated aqueous sodium chloride solution (200 ml), Preparation 237 dried over sodium sulfate, filtered through silica gel (100 g, 10 40/63 um) and evaporated in vacuo. 1,4-Dioxane was added tert-Butyl 3-(5-chloro-2-hydroxyphenyl)azetidine-1- and concentrated in vacuo before diluting with dichlo carboxylate romethane (300 ml). Triethylsilane (132 ml, 0.828 mol) and trifluoroacetic acid (96 ml, 1.24 mol) were added under argon C and the mixture was stirred for 20 hours before concentrating 15 in vacuo. To this residue were added Saturated aqueous potas sium carbonate solution to basify the solution to pH10. Water OH (200 ml) was added and the aqueous layer was extracted with diethyl ether. The combined organic fractions were washed with water (2x200 ml), saturated aqueous sodium chloride solution (200 ml), dried over sodium sulphate, filtered N through silica gel (100 g, 40/63 um) and evaporated in vacuo. 1,4-dioxane was added to this residue before concentrating in vacuo. To a solution of this residue in tetrahydrofuran (300 es ml), cooled over an ice bath in an atmosphere of argon, was 25 added borane (1 M in tetrahydrofuran, 260 ml). The mixture 1. Me was stirred at room temperature for 2 hours before cooling Me over an ice bathin argon and adding acetic acid (260 ml). The mixture was stirred for 24 hours before evaporating in vacuo. To a solution oftert-Butyl 3-(2-tert-butyl (dimethyl)silyl To this residue were added Saturated aqueous potassium car 30 oxy-5-chlorophenyl)azetidine-1-carboxylate (Preparation bonate solution to basify the solution to pH 10. Water (200 238, 3.1 g, 7.79 mmol) in tetrahydrofuran (80 ml) was added ml) was added and the aqueous layer was extracted with tetramethylammonium fluoride (1.0 g, 10.74 mmol). The diethyl ether. The organic fractions were washed with water mixture was stirred at room temperature for 18 hours before (2x200 ml), saturated aqueous sodium chloride solution (200 concentrating in vacuo. The residue was partitioned between ml), dried over sodium sulfate and evaporated in vacuo. The 35 tert-butyl methyl ether (100 ml) and aqueous sodium hydrox residue was purified on silica gel (500 g. 60/100 um) eluting ide Solution. The organics were dried over sodium sulfate, with carbon tetrachloride:ethyl acetate (gradient 1:0 to 10:1, filtered and evaporated in vacuo to give a reddish brown oil, by Volume) to give the title compound as a yellow oil, 73 g, 2.33 g. This was purified by column chromatography (100 g 77% yield. of silica) eluting with heptane:ethyl acetate (6:4, by volume) 40 to afford the title compound as a reddish brown gum, 850 mg. Preparation 235 38% yield. tert-Butyl 4-(5-chloro-2-methoxyphenyl)-4-hydrox LCMS Rt 1.52 minutes. MS m/z 282 (MCIH. ypiperidine-1-carboxylate 'HNMR (CDC1): 81.44 (s, 9H), 3.93 (m. 1H), 4.04 (m, 45 2H), 4.28 (m, 2H), 6.72 (d. 1H), 7.05 (m, 2H). C Preparation 238 tert-Butyl 3-(2-tert-butyl (dimethyl)silyloxy-5- OH 50 chlorophenyl)azetidine-1-carboxylate

C

55 y O1 Si Me Me Me Me To a stirred solution of 2-bromo-4-chloroanisole (164 g. 0.74 mol) in tetrahydrofuran (1 L), cooled at -70° C. and 60 under an atmosphere of argon, was added butyl lithium (2.7M in heptane, 280 ml) over a period of 1 hour. The mixture was stirred for 30 minutes, maintaining the temperature at -70° C., before the addition of N-boc-4-piperidone (145 g, 0.73 mol) in tetrahydrofuran (250 ml) over a period of 1 hour. The 65 reaction temperature was warmed to -40° C. over 2 hours before the addition of sodium hydrogen sulphate (5M aque US 8,907,101 B2 185 186 Zinc powder (700 mg, 10.7 mmol) was suspended in N.N- To a solution of N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4- dimethylformamide (20 ml) under nitrogen. 1,2-dibromoet fluorobenzenesulfonamide (Preparation 52, 100 mg, 0.32 hane (120 ul) was added and suspension heated to 60° C. for mmol) and potassium carbonate (109 mg. 0.8 mmol) in dim 10 minutes before cooling to room temperature. Chlorotrim ethylformamide (3 ml) was added 4-fluoro-2-iodophenol ethylsilane (180 ul) was added and the mixture heated to 60° (Preparation 218, 0.32 mmol) and the reaction heated at 80° C. for 10 minutes then cooled to room temperature. tert-Butyl C. for 24 hours. The solution was added dropwise into rapidly 3-iodoazetidine-1-carboxylate (3.0 g, 10.6 mmol) was added stirring hydrochloric acid (2M aqueous solution). The fine with a slight exotherm observed. The mixture was stirred at dark precipitate was filtered and dried in vacuo to afford the room temperature for 1 hour before the addition of tert-butyl title product as a brown solid, 100 mg, 59% yield. (4-chloro-2-iodophenoxy)dimethylsilane (Preparation 239, 10 LCMS Rt 1.59 minutes. (ESI) m/z 536 MCIHI. 2.2g, 5.97 mmol) followed immediately by tri-2-furylphos 'HNMR (d-DMSO): 86.81 (d. 1H), 7.46 (m, 2H), 7.57 (s, phine (250 mg, 1.08 mmol) and (1E.4E)-1,5-diphenylpenta 1H), 7.92 (m, 1H),8.00 (m. 1H), 8.29 (s.1H), 13.03 (brs, 1H). 1,4-dien-3-one-palladium (2:1) (300 mg, 0.52 mmol). The Preparation 247 mixture was stirred at room temperature for 30 minutes then 15 heated at 70° C. for 5 hours before concentration in vacuo. 5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N- The residue was partitioned between ethyl acetate (100 ml) 1,3,4-thiadiazol-2-ylbenzenesulfonamide and aqueous sodium carbonate solution (50 ml). The organic extract was dried over Sodium Sulphate, filtered and evapo rated in vacuo to afford the title compound as a brown oil, 3.2 9. F O o $1\ LCMS Rt 1.68 minutes. MS m/z 795 (MCIH+ V/ N Sn N / Preparation 239 N N tert-Butyl (4-chloro-2-iodophenoxy)dimethylsilane 25 C C Me Me Me Me No O1 VSi / M e o1 30 Me To a solution of N-(2,4-dimethoxybenzyl)-1,3,4-thiadia Me Zol-2-amine (Preparation 248,899 mg, 3.58 mmol) in tet rahydrofuran (6.0 mL), cooled to -78°C., was added lithium To a solution of 4-chloro-2-iodophenol (1.587 g. 6.238 hexamethyldisilazide (1.0 M in tetrahydrofuran, 4.3 mL) mmol) in dichloromethane (10 ml) was added 1H-imidazole 35 dropwise. The reaction was stirred for 35 minutes at room (1.01 g, 14.3 mmol) followed by a solution of tert-butyl temperature, cooled to -78°C. before the dropwise addition (chloro)dimethylsilane (2.63 ml, 13.7 mmol) in dichlo of 5-chloro-2,4-difluorobenzenesulfonyl chloride (850 mg. romethane (10 ml) dropwise. The resulting white suspension 0.0034 mol). The reaction mixture was stirred at -78°C. for was stirred for 16 hours at room temperature before concen 1 hour then at room temperature for 4 hours. The reaction trating in vacuo. The residue was diluted with ethyl acetate 40 mixture was poured into Saturated aqueous ammonium chlo (20 ml) and water (20 ml). The aqueous phase was acidified ride solution and extracted with dichloromethane. The com with hydrochloric acid (2 Maqueous solution) and extracted bined organic layers were washed with Saturated aqueous with ethyl acetate. The combined organic layers were washed Sodium chloride solution, dried over magnesium sulfate, fil with hydrochloric acid (2 M aqueous Solution), Saturated tered and concentrated in vacuo. The residue was purified by aqueous sodium chloride Solution, dried over Sodium Sulfate, 45 automated flash chromatography eluting with ethyl acetate: filtered and concentrated in vacuo. The residue was purified hexanes (gradient 0:1 to 1:0, by volume) to afford the title by column chromatography (40 g silica gel column) eluting compound as a white solid, 1.16 g, 73% yield. with ethyl acetate:heptane (gradient 0:1 to 3:7, by volume) to LCMS Rt=1.76 minutes. MS m/z 484 (MCINa+ afford the title compound as pale yellow oil, 2.2g, 95% yield. 'HNMR (CDC1): 8 3.71 (s, 3H), 3.78 (s, 3H), 5.35 (m, 50 2H), 6.26 (m, 1H), 6.38 (m. 1H), 6.99 (m. 1H), 7.27 (m, 1H), 'HNMR (CDC1): 8 0.28 (s, 6H), 1.07 (s.9H), 6.74 (d. 1H), 7.83 (m. 1H), 8.87 (im, 1H). 7.18 (dd. 1H), 7.74 (dd). Method 2 Preparation 240 Preparation 247 can also be prepared as follows. N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-(4-fluoro 55 (Preparation 248, 203.4 g. 0.809 moles) was dissolved in 2-iodophenoxy)benzenesulfonamide 2-methyltetrahydrofuran (1.63 L) and the yellow suspension was cooled to -38°C. to -45° C. Lithium bis(trimethylsilyl) O O N N amide (890 mL of 1 molar solution in tetrahydrofuran, 0.890 F y)- moles) was added slowly over 15 minutes keeping the tem N 60 perature between -38° C. and -45° C. to give an orange H Suspension. This orange Suspension was stirred at -38°C. to -45° C. for 45 minutes and then a solution of 5-chloro-2,4- difluorobenzenesulfonyl chloride, (200 g, 0.809 moles) in 2-methyltetrahydrofuran (407 mL) was added slowly over 20 65 minutes keeping the temperature between -38°C. and -45° C. to give an orange Suspension. The mixture was stirred whist warming to 15° C. over 1 hour. The reaction was US 8,907,101 B2 187 188 quenched by adding a solution of ammonium chloride (203.4 'HNMR (d-DMSO): 83.75 (s.3H), 3.80 (s.3H), 4.37 (d. g, 3.80 moles) in water (1.02 L) and stirred vigorously for 5 2H), 6.49 (m. 1H), 6.58 (s, 1H), 7.19 (d. 1H), 7.97 (m. 1H), minutes. The stirring was stopped and the phases allowed to 8.59 (s, 1H). separate. The lower layer was removed and the organic layer was washed with water (813.6 mL). The organic layer was Preparation 250 concentrated in vacuo to give an orange solid which was triturated with isopropyl acetate (1.22 L) to give the title tert-Butyl (3-cyano-4-fluorophenyl)sulfonyl 1,3- compound as a yellow-orange solid (218.6 g). thiazol-4-ylcarbamate LC Rt=1.76 minutes. MS m/z 484 (MCINa+ Me 'HNMR (CDC1): 8 3.71 (s, 3H), 3.78 (s, 3H), 5.35 (m, 10 2H), 6.26 (m, 1H), 6.38 (m. 1H), 6.99 (m. 1H), 7.27 (m, 1H), 7.83 (m. 1H), 8.87 (im, 1H). s Preparation 248 15 N-(2,4-Dimethoxybenzyl)-1,3,4-thiadiazol-2-amine

HN us.N To a stirred solution of tert-butyl 1.3-thiazol-4-ylcarbam ate (Preparation 72, 0.500 g, 0.002497 mol) in tetrahydrofu ran (10.0 mL) was added lithium 1,1,1,3,3,3-hexamethyldisi Men O O1 25 lazan-2-ide (1.0 M solution in tetrahydrofuran, 2.50 mL. 0.0025 mol) at 0°C. under nitrogen. After stirring for 1 hour To a solution of 2-amino-1,3,4-thiadiazole (3.05 g, 0.0302 at 0° C. the reaction mixture was cooled to -78° C. and mol) and 2,4-dimethoxy-benzaldehyde (4.55g, 0.0274 mol) 3-cyano-4-fluorobenzenesulfonyl chloride (0.453 g, in dichloromethane (125 mL) was added chlorotriisopro 0.002063 mol) in tetrahydrofuran (5.0 mL) was added. The poxytitanium (16 mL, 0.067 mol) portionwise over 5 min 30 mixture was warmed to room temperature for 16 hours. Satu utes. After stirring for 1 hour, sodium triacetoxyborohydride rated aqueous ammonium chloride solution (20.0 mL) was (11.72 g, 0.05530 mol) was added portion wise and stirred for added and the aqueous layer was extracted with ethyl acetate 24 hours. The reaction was quenched with Saturated aqueous (3x20.0 mL). Combined organic layers were dried over sodium bicarbonate solution and adjusted to pH 9 with Sodium Sulfate and concentrated in vacuo. This crude residue sodium hydroxide (6 Naqueous solution) and extracted with 35 was purified using ISCOTM (12 g SiO) eluting with ethyl dichloromethane. The combined organic extracts were dried acetate:dichloromethane (gradient 0:1 to 3:7, by volume) to over magnesium sulfate, filtered and concentrated in vacuo. afford the title compound as a white solid, 426 mg, 54% yield. The residue was purified by flash column chromatography LCMS Rt=1.53 minutes MS m/z 284 MH(-Boc)+ eluting with methanol:dichloromethane (gradient 0:1 to 1:9. 40 "H NMR (400 MHz, d-DMSO): & 1.25 (s, 9H), 7.90 (t, by volume) to afford the title compound as a white solid, 590 1H), 8.15 (s, 1H), 8.40 (m, 1H), 8.55 (d. 1H), 9.15 (s, 1H) mg, 45% yield. Preparation 255 LCMS Rt=1.36 minutes. MS m/z 252 MNa+ 'HNMR (CDC1): 8 3.86 (s, 3H), 3.90 (s, 3H), 4.49 (m, tert-Butyl 4-(4-chloro-2-iodophenoxy)-3-cy 2H), 6.08 (brs, 1H), 6.47 (m, 2H), 7.27 (m, 1H), 8.39 (s, 1H). 45 anophenylsulfonyl-1,3-thiazol-4-ylcarbamate Method 2 Preparation 248 can also be prepared as follows. S 2,4-Dimethoxybenzaldehyde (771.37 g. 4.64 moles) was added to a suspension of 2-amino-1,3,4-thiadiazole (391.2g, C W N 2 3.87 moles) in Xylene (5.87 L) and heated to reflux. Dean 50 Starkapparatus was used to remove the water and the reaction was stirred overnight. After cooling to room temperature, the reaction was further cooled to 5° C. and diluted with 2-me Clu-O thyltetrahydrofuran (2.93 L). Sodium tetrahydroborate I CN -K Me (73.17g, 1.93 moles) was added as a single portion. Methanol 55 (782.8 mL) was then added slowly over 30 minutes, main To a suspension of potassium carbonate (0.0549 g, taining the temperature below 15° C. After a further 30 min 0.000397 mol) in N,N-dimethylformamide (3.0 mL) was utes water (1 L) was added followed by saturated aqueous added tert-butyl (3-cyano-4-fluorophenyl)sulfonyl 1,3-thia Sodium hydrogencarbonate Solution (1 L) and the mixture zol-4-ylcarbamate (Preparation 250, 0.1004 g., 0.000167 stirred at room temperature overnight. The biphasic mixture 60 mol) and stirred at room temperature under nitrogen for 10 was diluted with 2-methyltetrahydrofuran and heated to 43° minutes. 4-chloro-2-iodophenol (0.067g, 0.000263 mol) was C. to aid dissolution. The layers were separated and the added and stirred at room temperature for 16 hours. The organic layer washed with water (3 L) before concentrating in reaction was diluted with ethyl acetate (10.0 mL). The vacuo. The resulting Solid was slurried in heptanes (2.5 L). organic phase was washed Saturated aqueous sodium chloride homogenised, filtered, washed with tert-butylmethyl ether 65 solution (2x10.0 mL), dried over sodium sulfate, filtered and and dried to afford 715 g of the title compound. concentrated in vacuo to afford the title compound as a yellow LC Rt=1.36 minutes. MS m/z 252 MNa+ oil, 162 mg, 100% yield. US 8,907,101 B2 189 190 LCMS Rt=1.78 minutes MS m/z 618 MCIH+ crude residue was purified by column chromatography elut "H NMR (400 MHz, d-DMSO): & 1.25 (s, 9H), 7.00 (d. ing with ethyl acetate:hexane (gradient 1:19 to 3:17, by vol 1H), 7.50 (d. 1H), 7.65 (d. 1H), 7.90 (s, 1H),8.10 (s, 1H), 8.20 ume) to afford the title compound as white solid, 37 g. 64% (d. 1H), 8.55 (s, 1H), 9.15 (s, 1H) yield. 5 LCMS Rt=3.46 minutes MS m/z 395 MH+ Preparation 258 H NMR (400 MHz, CDC1): & 1.35 (s.9H), 7.07-7.13 (m, 1H), 7.52 (s, 1H), 8.00-8.06 (m, 1H), 8.78 (s, 1H). 2-(2-aminopyridin-4-yl)-4-chlorophenol Preparation 301 C 10 3-Cyano-4-fluoro-N-(5-fluoropyridin-2-yl)benzene Sulfonamide OH F O O 21 N 15 YNN usN 2 H N NH2 A suspension of 2-amino-4-chloropyridine (13 g, 101.12 mmol), (5-chloro-2-hydroxy)benzeneboronic acid (20.9 g, 121 mmol), tetrakis triphenylphosphine palladium (11.7 g. | 10.1 mmol) and sodium carbonate (42.9 g, 404 mmol) in N water (120 mL) and 1,4-dioxane (360 mL) was heated to 90° 3-Cyano-4-fluorobenzenesulfonyl chloride (5 g, 20 C. under nitrogen for 24 hours. The reaction was cooled, 25 mmol), 5-fluoropyridin-2-amine (3.37 g. 30 mmol) and pyri concentrated in vacuo and the residue was extracted into ethyl dine (4.87 mL, 60 mmol) in dichloromethane (100 mL) were acetate (500 mL) before filtration. The filtrate was washed stirred at room temperature for 2 hours before concentrating with 2N HCl (aqueous, 500 mL) and water (700 mL). The in vacuo. The residue was triturated in hydrochloric acid (2 N combined aqueous layer was basified with Saturated aqueous aqueous solution, 100 mL) for 16 hours. The precipitate was sodium bicarbonate solution (1500 mL) before extracting 30 filtered to afford the title compound as a pale pink solid, 6.1 g. into ethyl acetate twice (2x800 mL). The organic layer was LCMS Rt=2.61 minutes, MS m/z 296 MH+. dried over sodium sulphate and concentrated in vacuo. The "H NMR (400 MHz, d-DMSO): 6 ppm 7.12 (dd. 1H), residue was purified using silica gel column chromatography 7.62-7.79 (m, 2H), 8.19 (d. 1H), 8.24-8.32 (m. 1H), 8.45 (dd. (2-12% methanol in dichloromethane) to afford the title com 1H), 11.42 (br. s., 1H). pound as a yellow solid, 11.13 g, 50%. 35 LCMS Rt=1.58 minutes. MS m/z 221 (MCIH+ Preparation 317 'HNMR (400 MHz, d-DMSO): 85.80 (brs, 2H), 6.60(m, 2H), 6.95 (m, 1H), 7.20 (m. 1H), 7.90 (m. 1H), 9.95 (m, 1H). tert-Butyl 4-2-hydroxy-5-(trifluoromethyl)phenyl piperidine-1-carboxylate Preparation 297 40 F tert-Butyl 1.3-thiazol-4-yl(2,4,5-trifluorophenyl) F Sulfonylcarbamate F F N2\ W S 45 OH n N -N/ F es 50 N F Me Me Me es To a solution of tert-butyl 1.3-thiazol-4-ylcarbamate 1. Me (Preparation 72, 28.94g, 144.55 mmol) in anhydrous tetrahy 55 Me drofuran (600 ml), cooled to -70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1 M in Boron tribromide (1 M in dichloromethane, 2.8 mL) was tetrahydrofuran, 144.55 ml, 144.55 mmol) dropwise. The added to a solution of tert-butyl 4-2-methoxy-5-(trifluorom reaction mixture was warmed to room temperature and stirred ethyl)phenylpiperidine-1-carboxylate (Preparation 318, 503 for 1 hour before cooling -70° C. 2,4,5-trifluoro benzene 60 mg, 1.40 mmol) in dichloromethane (2 mL) at 0° C. and sulfonyl chloride (40 g, 173.46 mmol) in tetrahydrofuran (80 stirred for 1 hour at 0°C. and then at room temperature for 1 ml) was added dropwise and then the reaction mixture was hour. The reaction mixture was quenched with cold water and slowly warmed to room temperature and stirred for 2 hours. basified to pH 9 with saturated aqueous sodium bicarbonate The reaction mixture was quenched with Saturated aqueous Solution. The aqueous layer was extracted with ethyl acetate ammonium chloride solution and extracted with ethylacetate. 65 and organic extracts dried over Sodium sulfate, filtered and Organic layer was washed with water and Saturated aqueous concentrated in vacuo to afford the intermediate as a light Sodium chloride solution before concentrating in vacuo. The yellow solid. US 8,907,101 B2 191 192 LCMS Rt=1.23 minutes MS m/Z 246 MH+ A suspension of 2-bromo-1-methoxy-4-(trifluoromethyl) To the above crude intermediate (270 mg, 1.1 mmol) in benzene (825 mg, 3.23 mmol), tert-butyl 4-(4,4,5,5-tetram acetonitrile (2.8 mL) was added di-tert-butyldicarbonate (240 ethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H)- mg, 1.1 mmol) and stirred 18 hours at room temperature carboxylate (1.00 g, 3.23 mmol), potassium carbonate (1.34 before concentrating in vacuo. The residue was purified via g, 9.697 mmol) and 1,1'-bis(diphenylphosphino)ferrocene automated flash chromatography eluting with ethyl acetate: hexanes (gradient 2:8 to 1:0, by volume) to afford the title dichloro-palladium(II) complex with dichloromethane (1:1) compound as a white solid, 127 mg. (158 mg, 0.193 mmol) in N,N-dimethylformamide (19 mL) LCMS Rt=1.90 minutes MS m/Z 246 MH+ was purged with argon. After 30 minutes, the reaction mixture 10 was heated at 90° C. and stirred for 22 hours before cooling to Preparation 318 room temperature and filtering through CeliteTM, washing with ethyl acetate. The filtrate was concentrated in vacuo to tert-Butyl 4-2-methoxy-5-(trifluoromethyl)phenyl -quarter and partitioned between water (100 mL) and ethyl piperidine-1-carboxylate 15 acetate (75 mL). The aqueous layer was extracted with ethyl acetate (2x75 mL). Combined organic layers were washed with water, aqueous lithium chloride Solution, Saturated aque ous sodium chloride solution, dried over sodium sulfate, fil tered and concentrated in vacuo. The residue was purified by automated flash chromatography (24 g silica gel) eluting with hexanes:ethyl acetate (gradient 1:0 to 3:1, by volume) to afford the title compound as a clear oil, 1.1 g. LCMS Rt=1.71 minutes MS m/z 258 MH+ 25 Preparation 322

N-(5-Chloro-1,3-thiazol-2-yl)-4-(4-cyano-2-iodophe es 30 noxy)-2,5-difluorobenzenesulfonamide 1. Me Me tert-Butyl 4-2-methoxy-5-(trifluoromethyl)phenyl-3,6- 35 F O O. N. N dihydropyridine-1 (2H)-carboxylate (Preparation 319, 512 NC W{- )- C mg, 1.43 mmol) was hydrogenated for 16 hours over palla H dium (10 wt.% on activated carbon, 10 mg, 0.009 mmol) at a pressure of 40 psi. The reaction mixture was filtered through CeliteTM and concentrated in vacuo to afford the title com 40 pound as a white solid, 503 mg. LCMS Rt=2.03 minutes MS m/z. 260 MH+ Preparation 319 To a suspension of potassium carbonate (0.068g, 0.000492 45 mol) and N-(5-chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxy tert-Butyl 4-2-methoxy-5-(trifluoromethyl)phenyl benzyl)-2,4,5-trifluorobenzenesulfonamide (Preparation 3,6-dihydropyridine-1 (2H)-carboxylate 334, 0.200 g, 0.000418 mol) in dimethylsulfoxide (3.0 mL) was added 4-hydroxy-3-iodobenzonitrile (Preparation 342, 0.108 g., 0.000441 mol) and was stirred at 65° C. under nitro 50 gen for 16 hours. The reaction was diluted with ethyl acetate (10.0 mL). The organic phase was washed with saturated aqueous sodium chloride solution (2x10.0 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude 55 was dissolved in dichloromethane (1.5 mL), treated with trifluoroacetic acid (1.5 mL) and stirred at room temperature under nitrogen for 16 hours. Reaction was concentrated in vacuo and residue dissolved in ethyl acetate (10.0 mL). The organic extract was washed with Saturated aqueous sodium N 60 bicarbonate solution (2x10.0 mL), dried over sodium sul phate, filtered and concentrated in vacuo. The resulting resi due was purified using ISCOTM (12 g SiO) eluting with es methanol:dichloromethane (gradient 0:1 to 1:39, by volume) to afford the title compound as an orange solid, 165 mg, 35% 1. Me 65 Me yield. LCMS Rt=1.60 minutes. MS m/z 552 MCIH+ US 8,907,101 B2 193 194 Preparation 333 H NMR (400 MHz, CDC1): 83.70 (s.3H), 3.75 (s, 3H), 5.15 (s.2H), 6.18 (d. 1H), 6.35 (m. 1H), 6.87(m, 1H), 7.20 (d. 5-Chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N- 1H), 7.77 (m, 1H), 8.22 (s, 1H) 1,2,4-thiadiazol-5-ylbenzenesulfonamide Preparation 337 1-(Ethoxymethyl)-5-(4.4.5.5-tetramethyl-1,3,2-diox aborolan-2-yl)-1H-pyrazole F O,\/ O N| N N {ul 10

F

C 15 O O k J. To a solution of (N-(2,4-dimethoxybenzyl)-1,2,4-thiadia 1-> N Zol-5-amine (Preparation 14, 40.6 g., 0.1619 mol) in anhy N= drous tetrahydrofuran (600. mL), cooled to -70° C., under nitrogen was added lithium 1,1,1,3,3,3-hexamethyldisilaZan Butyl lithium (2.5M in hexanes, 32.4 mL, 0.0811 mol) was 2-ide (1 M in tetrahydrofuran, 161.9 mL, 0.161.9 mol) drop added slowly via Syringe to a solution of 1-(ethoxymethyl)- wise. The reaction mixture was warmed to room temperature 25 1H-pyrazole (Preparation338, 9.3g, 0.074 mol) in anhydrous and stirred for 1 hour before cooling to -70° C. A solution of tetrahydrofuran (100.0 mL) at 0°C. and stirred under nitro 5-chloro-2,4-difluorobenzenesulfonyl chloride (40 g, 0.1619 gen for 15 minutes and then at room temperature for 30 mol) in tetrahydrofuran (200.0 mL) was added dropwise. minutes. The mixture was cooled to -78° C. and 2-isopro After complete addition, the reaction mixture was gradually poxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (16.5 mL, warmed to room temperature and stirred for 1 hour. Reaction 30 0.0811 mol) was added via syringe. The mixture was warmed mixture was quenched with Saturated aqueous ammonium to room temperature and stirred under nitrogen for 60 hours. chloride solution and extracted with ethyl acetate. Organic Saturated aqueous ammonium chloride solution (50.0 mL) layer was washed with water and Saturated aqueous sodium was added followed by water (150.0 mL). The mixture was chloride solution. Crude residue was purified by column poured into tert-butylmethylether (200.0 mL) and the bipha chromatography eluting with ethyl acetate:hexane (gradient 35 sic mixture stirred vigorously for 30 minutes. The aqueous 1:19 to 3:17, by volume) to afford the title compound as a layer was acidified to pH 6 with hydrochloric acid (6.0 M white Solid, 46 g. aqueous solution) and extracted with tert-butylmethylether LCMS Rt=3.88 minutes. MS m/z 462 (MCIH+ (3x200.0 mL). The combined organics were washed with "H NMR (400 MHz, CDC1): 83.66 (s.3H), 3.74 (s.3H), saturated aqueous sodium chloride solution (100.0 mL) and 5.34 (s. 2H), 6.14-6.15 (m, 2H), 6.34 (dd. 1H), 6.86 (t, 1H), 40 7.19 (d. 1H), 7.73 (t, 1H), 8.21 (s, 1H) then stirred with activated charcoal (1 g) for 30 minutes. Magnesium sulphate was added and the mixture filtered Preparation 334 through a pad of CeliteTM, washing with tert-butylmethyl ether (1 L). Concentration in vacuo afforded the title com N-(5-Chloro-1,3-thiazol-2-yl)-N-(2,4-dimethoxyben pound as a brown oil, 14.5 g., 78% yield. Zyl)-2,4,5-trifluorobenzenesulfonamide 45 H NMR (400 MHz, CDC1): 8 1.14 (t, 3H) 1.34 (s, 12H) 3.52 (q, 2H) 5.71 (s. 2H)6.78 (d. 1H) 7.58 (d. 1H). Preparation 338 F OV/ {-O N y–c.N 50 1-(Ethoxymethyl)-1H-pyrazole

F 55 1-> N F NR O f Me Me To a mixture of pyrazole (10g, 0.150 mol) and potassium 60 carbonate (22.3 g, 0.162 mol) in acetone (200.0 mL), cooled Prepared according to Preparation 333 using 5-chloro-N- to 0°C. under nitrogen, was added chloromethyl ethyl ether (2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation (15.0 mL, 0.162 mol) via syringe over a period of 20 minutes. 208) and 2,4,5-trifluorobenzenesulfonyl chloride. Purifica The reaction was stirred for 30 minutes at 0°C. and then for tion using ISCOTM (12 g SiO) eluting with ethyl acetate: 2 hours at room temperature. The mixture was filtered, wash heptane (gradient 0:1 to 3:7, by volume) afforded the title 65 ing the solid with acetone (200.0 mL). The filtrate was care compound as an orange Solid. fully concentrated in vacuo (at 400 mbar). The crude material LCMS Rt=1.80 minutes. MS m/z 479 MCIH+ was purified by flash column chromatography eluting with US 8,907,101 B2 195 196 pentane:diethylether (1:1, by volume) to afford the title com sodium chloride solution (20.0 mL) was added to the reaction pound as a colourless oil, 9.3 g, 50% yield. resulting in the formation of a white precipitate. This was H NMR (400 MHz, CDC1): 8 1.18 (t, 3H)3.54 (q, 2H) filtered and washed with water (20.0 mL) and heptane (20.0 5.47 (s. 2H) 6.35 (t, 1H) 7.57 (d. 1H) 7.59 (d. 1H). mL) before being dried in vacuo for 2 hours to afford the title compound as a white solid, 0.67 g. 100% yield. Preparation 339 LCMS Rt=3.87 minutes. MS m/z 694.0 (MCIH+ "H NMR (400 MHz, d-DMSO): 83.58 (s, 3H), 3.66 (s, 4-(5-Chloro-2-hydroxyphenyl)pyridine-2-carboni 3H), 5.20 (s. 2H), 6.20 (m, 1H), 6.40 (m. 1H), 7.05 (m, 2H), trile 7.22 (m, 1H), 7.65 (m, 2H), 7.82 (d. 1H), 7.85 (dd. 1H), 8.20 10 (dd. 1H), 8.42 (d. 1H), 8.77 (dd. 1H) Preparation 341 C 4-(Difluoromethoxy)-2-iodophenol 15 OH F F 21 N 2. s

OH (5-Chloro-2-hydroxyphenyl)boronic acid (2.0 g, 0.012 mol), 4-chloropyridine-2-carbonitrile (1.61 g, 0.012 mol), 25 (1,1'-bis(diphenylphosphino) ferrocene)dichloropalladium (II) (0.424 g., 0.00058 mol) and sodium carbonate (3.7 g. To a suspension of N-iodosuccinimide (1.12 g, 0.005 mol) 0.035 mol) in 1,4-dioxane (20.0 mL) and deionised water (1.0 in acetic acid (15.0 mL) was added 4-(difluoromethoxy)phe mL) were degassed with nitrogen (x3) before heating at 100° nol (0.8 g., 0.005 mol) under nitrogen. Sulfuric acid (0.147g, C. for 18 hours under nitrogen. The reaction was cooled and 30 0.0015 mol) was added and the resulting dark brown suspen hydrochloric acid (2.0 M aqueous solution, 30.0 mL) added. sion was stirred at room temperature for 4 hours before the Reaction was filtered, washing with ethyl acetate (50.0 mL). addition of N-iodosuccinimide (0.6 g., 0.0025 mol). The mix The organic layer was concentrated in vacuo and purified by ture was stirred for 16 hours before diluting with citric acid flash column chromatography on the ISCOTM (40 g SiO2) (1.0 M aqueous solution, 20.0 mL) and water (20.0 mL). The eluting with ethyl acetate:heptane (gradient 0:1 to 7:3, by 35 aqueous layer was extracted with dichloromethane (2x30.0 volume) to afford the title compound as a yellow solid, 0.23g. mL). Combined organic layers were dried over sodium Sul 8.6% yield. phate, filtered and concentrated in vacuo to afford a dark purple oil. This was concentrated in vacuo from toluene LCMS Rt=1.42 minutes. MS m/z 231.0 MCIH+ (3x20.0 mL) to afford a brown oil. The aqueous layer was "H NMR (400 MHz, d-DMSO): 8 7.01 (d. 1H), 7.33 (dd, 40 concentrated in vacuo. Both organic and aqueous crude resi 1H), 7.54 (d. 1H), 7.97 (dd. 1H), 8.23 (m. 1H), 8.74 (m, 1H) dues were purified by flash column chromatography on the Preparation 340 ISCOTM (40 g SiO) eluting with ethyl acetate: heptane (gra dient 0:1 to 1:1, by volume) to afford the title compound as a 5-Chloro-4-4-chloro-2-(2-cyanopyridin-4-yl)phe yellow oil, 0.604g, 42% yield. noxy-N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,2,4- 45 LCMS Rt=1.44 minutes. MS m/z 285.0 MH thiadiazol-5-ylbenzenesulfonamide H NMR (400 MHz, CDC1): 8 6.40 (t, 1H), 6.97 (d. 1H), 7.07 (dd. 1H), 7.46 (d. 1H) Preparation 342 50 F O O N M S-N 4-Hydroxy-3-iodobenzonitrile C SS -Q \ N

O 55 NC

C 21 O N vil O 2 N vil 60 4-Hydroxy-3-iodobenzonitrile was prepared by the Prepared according to Preparation 255 using 4-(5-chloro method analogous to Preparation 341 above using N-io 2-hydroxyphenyl)pyridine-2-carbonitrile (Preparation 339, dosuccinimide, acetic acid, Sulfuric acid and 4-Hydroxyben 0.23 g, 0.001 mol) and 5-chloro-N-(2,4-dimethoxybenzyl)- 65 Zonitrile. Purified by ISCOTM (80 g SiO) eluting with ethyl 2,4-difluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide acetate:heptane (gradient 0:1 to 3:7, by volume) to yield the (Preparation 333, 461 mg, 0.998 mmol). Saturated aqueous title compound.