HK1209736B - N-substituted benzamides and methods of use thereof - Google Patents

Description

N-substituted benzamides and methods of use thereof

Priority of invention

This application claims priority from U.S. provisional patent application No. 61/668951 filed on 7/6/2012. The entire contents of this provisional application are hereby incorporated by reference in their entirety.

Technical Field

The present invention relates to organic compounds useful for therapy and/or prophylaxis in mammals, and in particular to inhibitors of sodium channels (e.g., nav1.7) useful for the treatment of sodium channel-mediated diseases or conditions, such as pain and other diseases and conditions associated with the modulation of sodium channels.

Voltage gated sodium channels, which trigger action potentials in nerves, muscles and other electrically stimulated cells, transmembrane proteins are an essential component of normal sensation, emotion, thought and movement (cotterall, w.a., Nature (2001), volume 409, page 988-. These channels are composed of highly processed alpha subunits associated with helper beta subunits. The pore-forming alpha subunit is sufficient for channel function, but the kinetic and voltage-dependent part of the channel gate is modified by the beta subunit (Goldin et al, Neuron (2000), Vol.28, p. 365-. Electrophysiological recording, biochemical purification, and molecular cloning have identified ten different sodium channel alpha subunits and four beta subunits (Yu, f.h. et al, sci.stke (2004), 253; and Yu, f.h. et al, Neurosci. (2003),20: 7577-85).

When voltage depolarized across the excitable cell plasma membrane (voltage-dependent gating), the hallmarks of sodium channels include rapid activation and inactivation and efficient and selective conduction of sodium ions through conductance pores inherent to the protein structure (Sato, C. et al, Nature (2001),409: 1047-. At negative membrane potentials or hyperpolarized membrane potentials, the sodium channel is closed. Following membrane depolarization, sodium channels rapidly open and then inactivate. Channels conduct current only in the open state and, once deactivated, have to return to the resting state, membrane hyperpolarization is favoured before they reopen (stimulated). Different sodium channel subtypes vary in their voltage ranges of activation and inactivation as well as their kinetics of activation and inactivation.

The protein family of sodium channels has been extensively studied and shown to be involved in many important bodily functions. Studies in this area have identified variants of the alpha subunit that produce major changes in channel function and activity that may ultimately lead to major pathophysiological afflictions. Members of this protein family are designated nav1.x, where x ═ 1 to 9. Nav1.1 and nav1.2 are highly expressed in the brain (Raymond, c.k. et al, j.biol.chem. (2004),279(44):46234-41) and are important for normal brain function. Some loss-of-function mutations in nav1.1 in humans lead to epilepsy, apparently because many of these channels are expressed in inhibitory neurons (Yu, f.h. et al, Nat Neurosci (2006),9(9), 1142-9). Thus, blocking nav1.1 in the CNS may produce adverse effects, as it may produce hyperexcitability. However, nav1.1 is also expressed in the peripheral nervous system and blockade may gain analgesic activity.

Nav1.3 is expressed primarily in the central nervous system of the fetus. It is expressed at very low levels in the peripheral nervous system or not at all, but after damage to the nervous system, it is up-regulated in the dorsal horn sensory neurons of rats (Hains, b.d., et al, j.neurosci, (2003),23(26): 8881-92). Thus, after nerve damage, it is an inducible target for the treatment of pain.

Nav1.4 is expressed primarily in skeletal muscle (Raymond, c.k. et al, op.cit.). Mutations in this gene have been shown to have profound effects on muscle function, including paralysis (Tamaoka a., intern. med. (2003), (9): 769-70).

Nav1.5 is expressed primarily in cardiac myocytes (Raymond, c.k. et al, op.cit.), including the atria, ventricles, sinoatrial node, atrioventricular node, and the purkinje fibers of the heart. The rapid rise in cardiac action potential and the rapid conduction of pulses through cardiac tissue is due to the turn-on of nav 1.5. Abnormalities in nav1.5 function can lead to the formation of a variety of arrhythmias. Mutations in human nav1.5 result in a variety of arrhythmia syndromes, including, for example, long QT3(LQT3), Brugada Syndrome (BS), hereditary cardiac conduction defects, sudden death syndrome (SUNDS), and Sudden Infant Death Syndrome (SIDS) (Liu, h. et al, am.j. pharmacogenomics (2003),3(3): 173-9). Sodium channel blocker therapy has been widely used to treat cardiac arrhythmias.

Nav1.6 is a widely distributed voltage gated sodium channel found throughout the central and peripheral nervous systems. It is expressed at high density in the Langerhans (Ranvier) node with medullary neurons (Caldwell, J.H. et al, Proc. Natl. Acad. Sci. USA (2000),97(10): 5616-20).

Nav1.7 is a tetrodotoxin sensitive voltage gated sodium channel encoded by gene SCN 9A. Human NaV1.7 was first cloned from neuroendocrine cells (Klugbauer, N. et al, 1995EMBO J.,14(6):1084-90.), rat NaV1.7 from the pheochromocytoma PC12 cell line (Toledo-Aral, J.J. et al, Proc. Natl. Acad. Sci. USA (1997),94: 1527-1532) and from the rat dorsal root ganglion (Sangameswaran, L. et al, (1997), J.biol. chem.,272(23): 14805-9). Nav1.7 is expressed primarily in the peripheral nervous system, particularly nociceptors and olfactory neurons, as well as sympathetic neurons. Inhibition or blocking of nav1.7 has been shown to produce analgesic activity. Knock-out of nav1.7 expression in a subset of predominantly painful sensory neurons results in resistance to inflammatory pain (Nassar et al, op. cit.). Similarly, loss of function mutations in humans results in congenital analgesia (CIP) in which the individual is resistant to both inflammatory and neuropathic pain (Cox, J.J. et al, Nature (2006); 444: 894-. In contrast, gain-of-function mutations in nav1.7 have been established in two human inheritable pain conditions, primary erythromelalgia and familial rectal pain (Yang, y, et al, j.med.genet. (2004),41(3): 171-4). In addition, the single nucleotide polymorphism (R1150W) that has very slight effects on the time and voltage dependence of channel gating has a large effect on pain perception (Estacion, M. et al, 2009.Ann Neurol 66: 862-6; Reimann, F. et al, Proc NatlAcad Sci U S A (2010),107: 5148-53). About 10% of patients with multiple pain patients have alleles that confer greater sensitivity to pain and are therefore more likely to respond to blockade by nav 1.7. Because nav1.7 is expressed in both sensory and sympathetic neurons, it is expected that enhanced pain perception will be accompanied by cardiovascular abnormalities such as hypertension, but no correlation has been reported. Thus, both CIP mutations and SNP analysis indicate that human pain responses are more sensitive to changes in nav1.7 current than to interference with autonomic nerve function.

Nav1.8 is expressed primarily in sensory ganglia of the peripheral nervous system, such as the dorsal root ganglia (Raymond, c.k. et al, op.cit.). There were no identified human mutations to nav1.8 that produced an altered pain response. NaV1.8 differs from NaV of most neurons because it is insensitive to blockade by tetrodotoxin. Thus, separation of the current can be performed by tetrodotoxin through this channel. These studies have shown that the majority of total sodium current in some dorsal root ganglion neurons is NaV1.8(Blair, N.T. et al, J Neurosci (2002),22: 10277-90). Knock-down of NaV1.8 in rats has been achieved by using antisense DNA or small interfering RNA and an almost complete reversal of neuropathic Pain in models of spinal nerve ligation and chronic compressive injury (Dong, X.W. et al, Neuroscience (2007),146: 812-21; Lai J. et al. Pain (2002),95: 143-52). Therefore, based on the limited tissue distribution of this NaV isoform and the analgesic activity produced by knockdown channel expression, NaV1.8 is considered to be a promising target for analgesics.

NaV1.9 is also a tetrodotoxin insensitive sodium channel that is expressed primarily in dorsal root ganglion neurons (Dib-Hajj, S.D. et al (see Dib-Hajj, S.D. et al, Proc. Natl. Acad. Sci. USA (1998),95(15):8963-8) which is also expressed in enteric neurons, particularly the intestinal muscle plexus (Rugiero, F. et al, J Neurosci (2003),23: 2715-25). the limited tissue distribution of this NaV isoform suggests that it may be a useful target for analgesics (Lai, J. et al, op. cit.; Wood, J.N. et al, 2006 op. cit; Chung, J.M. et al, op. cit.). knock-out VNa1.9 results in resistance to some forms of inflammatory pain (Amaya, F. et al, Neurosci. J., Acosu. 26, Priest. 52, Natl S.A 2005-B.T, ProlA 102: 14).

This closely related family of proteins has long been recognized as a target for therapeutic intervention. Sodium channels are targeted by a variety of pharmacological agents. These include neurotoxins, antiarrhythmics, anticonvulsants, and local anesthetics (England, S. et al, Future Med Chem (2010),2: 775-90; Termin, A. et al, Annual Reports in medical Chemistry (2008),43: 43-60). All current pharmacological agents that act on sodium channels have receptor sites on the alpha subunit. Neurotoxins of at least six different receptor sites have been identified as well as local anesthetics and related drugs for one receptor site (cestele, s. et al, Biochimie (2000), vol 82, page 883-892).

Small molecule sodium channel blockers or local anesthetics and related antiepileptic and antiarrhythmic drugs interact with overlapping receptor sites located in the lumen of the pores of the sodium channel (Catterall, w.a., Neuron (2000),26: 13-25). Amino acid residues in the S6 segment from at least the three-quarter domain contribute to this complex drug receptor site, with the IVS6 segment playing a major role. These regions are highly conserved and therefore most sodium channel blockers known to date interact with all channel subtypes of similar potency. However, sodium channel blockers may have been generated that have a therapeutic selectivity and an adequate therapeutic window for treating epilepsy (e.g., lamotrigine, phenytoin, and carbamazepine) and certain arrhythmias (e.g., lidocaine, tocainide, and mexiletine). However, the potency and therapeutic index of these blockers is not optimal and these compounds have limited availability in a variety of therapeutic areas where sodium channel blockers would be ideally suitable.

Sodium channel blockers have been shown to be useful in the treatment of pain, including acute, chronic, inflammatory and/or neuropathic pain (see, e.g., Wood, j.n. et al, j.neurobiol. (2004),61(1), 55-71. preclinical evidence shows that sodium channel blockers can inhibit neuronal firing of peripheral and central neurons, and via this mechanism they are thought to be useful in alleviating pain. in some cases, abnormal or ectopic firing can originate from injured or otherwise sensitized neurons. Carrageenan) promotes pain-related behavior and is associated with increased expression of sodium channel subunits (Gould et al Brain res., (1999),824(2): 296-99; black et al, Pain (2004),108(3): 237-47). Thus, changes in the expression level or distribution of sodium channels can have a major impact on neuronal excitability and pain-related behavior.

Controlled infusion of lidocaine, a known sodium channel blocker, indicates that the drug is effective for neuropathic pain, but has a narrow therapeutic index. Similarly, an orally available local anesthetic, mexiletine, has dose-limiting side effects (Wallace, M.S. et al, Reg. Anesth. pain Med. (2000),25: 459-67). The main focus of drug discovery targeting voltage gated sodium channels has been on strategies for improving therapeutic index. One major strategy is to identify selective sodium channel blockers aimed at preferentially blocking nav1.7, nav1.8, nav1.9 and/or nav 1.3. These are sodium channel isoforms that are preferentially expressed in sensory neurons and are unlikely to be involved in generating any dose-limiting side effects. For example, the presence of blockade of nav1.5 would be of proarrhythmic concern, making sodium channel blocker selectivity for nav1.5 considered highly desirable. Furthermore, almost 700 mutations in the SCN1A gene encoding nav1.1 have been identified in patients with Severe Myoclonic Epilepsy (SMEI) in infants, making it the most common mutant gene in human epilepsy. Half of these mutations result in protein truncation (Meisler, M.H., et al, The Journal of Physiology (2010),588: 1841-8). Therefore, sodium channel blocker to NaV1.1 selectivity is also desirable.

In addition to strategies for identifying selective sodium channel blockers, there are ongoing strategies for identifying therapeutic agents for treating neuropathic pain. There has been some degree of success in treating neuropathic pain conditions through the use of drugs that were originally approved as anticonvulsants, such as gabapentin, and, more recently, pregabalin. However, drug therapy for neuropathic pain often has limited success for a variety of reasons: sedation, particularly the first development of anticonvulsant or antidepressant drugs, addiction or tachyphylaxis, particularly opiates, or lack of efficacy, particularly NSAIDs and anti-inflammatory agents. Accordingly, there remains a great need to explore new forms of treatment for neuropathic pain including, but not limited to, post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chronic lumbar pain, phantom limb pain and pain due to cancer and chemotherapy, chronic pelvic pain, complex regional pain syndrome and associated neuropathic pain.

There are a limited number of effective sodium channel blockers currently used in the clinic for the treatment of pain with minimal adverse side effects. There is also an unmet need for a drug that effectively treats neuropathic pain and other sodium channels associated with pathological conditions and that does not contain the adverse side effects of blocking sodium channels that are not implicated in nociception. The present invention provides methods that meet the needs of these standards.

Summary of The Invention

One aspect of the present invention provides novel compounds. In a first embodiment of such compounds (embodiment 1; abbreviated "E1"), the invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein in formula I:

R¹is selected from-NR^1AR^1B、-X^1R-NR^1AR^1B、-X^1R-OR^1A5-10 membered heteroaryl ring containing 1 to 4 nitrogen atoms and containing 1 to 3A 4-10 membered C-linked heterocycloalkyl group of a nitrogen atom; r^1AAnd R^1BEach independently selected from hydrogen and C_1-8Alkyl, -C (═ Y)¹)OR^R1C、-C(＝Y¹)R^R1C、-C(＝Y¹)N(R^R1C)₂、-(X^1R)_0-1R^xAnd C_1-8An alkoxy group; or R^1AAnd R^1BOptionally combine to form a 4-10 membered heterocyclic ring optionally containing 1 to 3 additional heteroatoms selected from N, O and S as ring vertices; r^R1CIs selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl, benzyl, and 5-6 membered heteroaryl; x^1RIndependently selected from C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene, wherein X^1ROptionally substituted with one or more groups selected from oxo and thioxo; y is¹Independently is O or S; r^xIndependently selected from 6-10 membered aryl, 5-10 membered heteroaryl, C_3-8Cycloalkyl and C_2-7A heterocycloalkyl group; and wherein R¹Optionally further substituted by 1 to 5 substituents independently selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl- (X)^1R)_0-1-、C_3-8Heterocycloalkyl- (X)^1R)_0-16-to 10-membered aryl- (X)^1R)_0-1-, 5-10 membered heteroaryl- (X)^1R)_0-1-、F、Cl、Br、I、-CN、-NO₂、-(X^1R)_0-1NR^R1aR^R1b、-(X^1R)_0-1OR^R1a、-(X^1R)_0-1SR^R1a、-(X^1R)_0-1N(R^R1a)C(＝Y¹)OR^R1c、-(X^1R)_0-1OC(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)C(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1C(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)C(＝O)R^R1b、-(X^1R)_0-1C(＝O)OR^R1a、-(X^1R)_0-1OC(＝O)R^R1a、-(X^1R)_0-1-P(＝O)(OR^R1a)(OR^R1b)、-(X^1R)_0-1S(O)_1-2R^R1c、-(X^1R)_0-1S(O)_1-2N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)S(O)_1-2N(R^R1a)(R^R1b) And- (X)^1R)_0-1N(R^R1a)S(O)_1-2(R^R1c) Substituted with the substituent(s); r^R1aAnd R^R1bEach independently selected from hydrogen and C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; or R^R1aAnd R^R1bTogether with the nitrogen to which they are attached form a morpholino, piperidino or piperazino ring, wherein said ring is optionally substituted with one or more substituents independently selected from C_1-8Alkyl, halo, hydroxy, C_1-8Alkylamino radical, C_1-8Dialkylamino radical, C_1-8Haloalkyl and C_1-8A hydroxyalkyl group; r^R1cIs selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group;

R^Nis hydrogen, C_1-4Alkyl or C_1-4A haloalkyl group;

D¹is N or C (R)^D1)；

D³Is N or C (R)^D3)；

R^D1、R^D2、R^D3And R^D4Each independently selected from H, F, Cl, Br, I, -CN, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl and a 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from F, Cl, Br, I, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent substitution of alkoxy;

l is selected from C_1-4Alkylene radical, C_2-4Alkenylene radical, C_2-4Alkynylene and C_1-4A linker of heteroalkylene, wherein L is optionally substituted with 1 to 3 substituents independently selected from ═ O, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Acyl substituent substitution;

the subscript m represents an integer of 0 or 1;

X¹and X²Each independently selected from the group consisting of absent, -O-, -S-, -S (O) -, -S (O)₂- - -N (H) - -and- -N (R)^x1) -, wherein R^x1Is C_1-8Alkyl radical, C_1-8Acyl or-S (O)₂(C_1-8Alkyl), and wherein if said subscript m is 0, then X¹Or X²One of which is absent;

the subscript n is an integer of from 0 to 5;

ring a represents a 6-10 membered aryl or 5-10 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S;

R^Aindependently at each occurrence, selected from H, C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl- (X)^RA)_0-1、C_3-8Halocycloalkyl- (X)^RA)_0-1、C_1-8Cyanoalkyl, C_1-8Hydroxyalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl, F, Cl, Br, I, -CN, -NO₂、C_2-9Heterocycloalkyl- (X)^RA)_0-1-、C_6-10Aryl radical- (X)^RA)_0-1-, 5-6 membered heteroaryl- (X)^RA)_0-1-、-(X^RA)_{0- 1}NR^A1R^A2、-(X^RA)_0-1OR^A1、-(X^RA)_0-1SR^A1、-(X^RA)_0-1N(R^A1)C(＝O)OR^A3、-(X^RA)_0-1OC(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)C(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1C(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)C(＝O)R^A2、-(X^RA)_0-1C(＝O)R^A1、-(X^RA)_0-1C(＝O)OR^A1、-(X^RA)_0-1OC(＝O)R^A1、-P(＝O)(OR^A1)(OR^A2)、-(X^RA)_0-1S(O)_1-2R^A3、-(X^RA)_0-1S(O)_1-2N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)S(O)_1-2N(R^A1)(R^A2) And- (X)^RA)_{0- 1}N(R^A1)S(O)_1-2(R^A3) (ii) a Each X^RAIndependently selected from C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene, said C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene is optionally substituted with one or more groups selected from oxo and thioxo; r^A1And R^A2Independently selected from hydrogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Hydroxyalkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; or R^A1And R^A2Together with the nitrogen to which they are attached form a morpholino, piperidino or piperazino ring, optionally substituted with one or more C_1-8Alkyl, halo, hydroxy, C_1-8Haloalkyl and C_1-8Hydroxyalkyl substitution; r^A3Is selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; wherein R is^AOptionally further substituted with 1 to 5 substituents independently selected from F, Cl, Br, I, -NH₂、-OH、-CN、-NO₂Oxo (═ O), C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4haloalkyl-C (═ O) -, C_1-4haloalkyl-S (O)_0-2-、C_1-4haloalkyl-C (═ O) n (h) -, C_1-4Haloalkyl-n (h) -C (═ O) -, (haloalkyl)₂N-C(＝O)-、C_1-4haloalkyl-OC (═ O) n (h) -, C_1-4haloalkyl-OC (═ O) n (h) -, haloalkyl-n (h) -C (═ O) O-, (haloalkyl)₂N-C(＝O)O-、C_1-4Alkylamino radical, C_1-4Dialkylamino radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_2-5Heterocycloalkoxy and tetralin substituents.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula I or any embodiment thereof and a pharmaceutically acceptable excipient.

In another aspect of the invention, the invention provides methods for treating diseases and conditions in a mammal by administering to a mammal in need thereof a therapeutically effective compound of formula I or embodiments thereof.

In another aspect of the invention, the invention provides a method of reducing the ion flow through voltage-dependent sodium channels in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or an embodiment thereof.

In another aspect of the invention, the invention provides a method of treating pruritus or cancer in an ion flux by voltage-dependent sodium channels in a mammal comprising administering to a mammal in need thereof a compound of formula I or an embodiment thereof.

In another aspect of the invention, the invention provides a method of treating or treating, but not preventing, pain in a mammal comprising administering to a mammal in need thereof a compound of formula I or an embodiment thereof.

In another aspect of the present invention, the present invention provides a method for the treatment or prevention of pain, depression, cardiovascular diseases, respiratory diseases and psychiatric diseases or a combination thereof, comprising administering an effective amount of a compound of formula I or an embodiment thereof.

In another aspect, the present invention provides compounds of formula I, or pharmaceutically acceptable salts thereof, for use as medicaments for the treatment of diseases and conditions selected from pain, depression, cardiovascular diseases, respiratory diseases and psychiatric diseases or combinations thereof, comprising administering an effective amount of a compound of formula I, or embodiments thereof.

In another aspect, the present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diseases and conditions selected from pain, depression, cardiovascular disease, respiratory disease and psychiatric disease, or a combination thereof, comprising administering an effective amount of a compound of formula I, or an embodiment thereof.

In another aspect, the present invention provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for use in pharmaceutical therapy.

Detailed Description

Definition of

As used herein, the term "alkyl" by itself or as part of another substituent means (unless otherwise specified) a straight or branched chain hydrocarbon group (i.e., C) having the specified number of carbon atoms_1-8Meaning one to eight carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds. Examples of such unsaturated alkyl groups include ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2, 4-pentadienyl, 3- (1, 4-pentadienyl), ethynyl, 1-and 3-propynyl, 3-butynyl, and higher homologs and isomers. The terms "cycloalkyl", "carbocyclic" or "carbocycle" refer to a hydrocarbon ring system having a total number of 3 to 10 ring atoms (e.g., 3-10 membered cycloalkyl is cycloalkyl having 3 to 10 ring atoms, or C_3-10Cycloalkyl is cycloalkyl having 3 to 10 carbon ring atoms) and is fully saturated or has no more than one double bond between ring vertices for 3-5 membered cycloalkyl and fully saturated or has no more than two double bonds between ring vertices for 6 membered cycloalkyl or larger. As used herein, "cycloalkyl," "carbocyclic," or "carbocycle" also means bicyclic, polycyclic, and spirocyclic hydrocarbon ring systems, such as, for example, bicyclo [2.2.1]Heptane, pinane, bicyclo [2.2.2]Octane, adamantane, norbornene, spiro C_5-12Alkanes, and the like. As used herein, the terms "alkenyl," "alkynyl," "cycloalkyl," "carbocycle," and "carbocyclic" are intended to include mono-and polyhalogenated variants thereof.

The term "heteroalkyl," by itself or in combination with another term, means (unless otherwise stated)Further stated) a stable straight or branched chain hydrocarbyl group consisting of the stated number of carbon atoms and one to three heteroatoms selected from O, N, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatoms O, N and S can be placed at any internal position of the heteroalkyl group. The heteroatom Si may be placed anywhere in the heteroalkyl group, including where the alkyl group is attached to the remainder of the molecule. "heteroalkyl" may contain up to three units of unsaturation and also includes mono-and polyhalogenated variants or combinations thereof. Examples include-CH₂-CH₂-O-CH₃、-CH₂-CH₂-O-CF₃、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-CH₂-S-CH₂-CH₃、-S(O)-CH₃、-CH₂-CH₂-S(O)₂-CH₃、-CH＝CH-O-CH₃、-Si(CH₃)₃、-CH₂-CH＝N-OCH₃and-CH ═ N (CH)₃)-CH₃. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃and-CH₂-O-Si(CH₃)₃。

The term "heterocycloalkyl," "heterocyclic," or "heterocycle" refers to a saturated or partially unsaturated ring system group having 3-10 ring atoms that collectively contain one to five heteroatoms selected from N, O and S as ring atoms (e.g., a 3-10 membered heterocycloalkyl is a heterocycloalkyl having 3-10 ring atoms, C_2-9Heterocycloalkyl is a heterocycloalkyl having 3-10 ring atoms, where 2-9 ring atoms are carbon), wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. Unless otherwise indicated, "heterocycloalkyl," "heterocyclic," or "heterocycle" may be a monocyclic, bicyclic, spiro, or polycyclic ring system. The terms "heterocycloalkyl," "heterocyclic," and "heterocycle" also include polycyclic ring systems wherein at least one ring is a saturated or partially unsaturated ring containing from one to five heteroatoms selected from N, O and S as defined above; such polycyclic ring systems may also be within polycyclic ring systemsComprising a fused aromatic, fused heteroaromatic or fused carbocyclic ring as defined herein. "heterocycloalkyl," "heterocyclic," or "heterocycle" may be substituted with one or more oxo or thioxo groups. Non-limiting examples of "heterocycloalkyl," "heterocyclic," or "heterocycle" include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2, 4(1H,3H) -dione, 1, 4-dioxane, morpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone (pyrone), tetrahydrofuran, tetrahydrothiophene (tetrahydrothiophene), quinuclidine, tropane (tropane), 2-azaspiro [3.3]Heptane, (1R,5S) -3-azabicyclo [3.2.1]Octane, (1s,4s) -2-azabicyclo [2.2.2]Octane, (1R,4R) -2-oxa-5-azabicyclo [2.2.2]Octane, indolin-2-one, 1H-pyrrolo [3,2-c]Pyridin-2 (3H) -one, and the like. A "heterocycloalkyl," "heterocyclic," or "heterocyclic" group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms. "heterocycloalkyl," "heterocyclic," or "heterocycle" may include mono-and polyhalogenated variants thereof.

The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane (including branched alkanes), such as through a-CH₂CH₂CH₂CH₂-and-CH (CH)₂)CH₂CH₂Examples are given. Generally, alkyl (or alkylene) groups will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. "alkenylene" and "alkynylene" refer to unsaturated forms of "alkylene" having double and triple bonds, respectively. "alkylene," "alkenylene," and "alkynylene" are also intended to include mono-and polyhalogenated variants.

The term "heteroalkylene" by itself or as part of another substituent means a divalent saturated or unsaturated or polyunsaturated radical derived from heteroalkyl, e.g., through-CH₂-CH₂-S-CH₂CH₂-and-CH₂-S-CH₂-CH₂-NH-CH₂-、-O-CH₂-CH＝CH-、-CH₂-CH＝C(H)CH₂-O-CH₂-and-S-CH₂C.ident.C-is exemplified. For heteroalkylene groups, heteroatoms can also occupy one or both ends of the chain terminus (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). The term "heteroalkylene" is also intended to include mono-and polyhalogenated variants.

The terms "alkoxy," "alkylamino" and "alkylthio" are used in their conventional sense and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom ("oxy"), an amino ("amino") or a thio group, and also include mono-and polyhalogenated variants thereof. In addition, for dialkylamino groups, the alkyl moieties can be the same or different.

The term "halo" or "halogen," by itself or as part of another substituent, means (unless otherwise specified) a fluorine, chlorine, bromine, or iodine atom. The term "(halo) alkyl" is intended to include both "alkyl" and "haloalkyl" substituents. Additionally, the term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C_1-4Haloalkyl "is intended to include trifluoromethyl, 2,2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, and the like.

The term "aryl" means (unless otherwise specified) a polyunsaturated, typically aromatic, hydrocarbon ring group that can be monocyclic or polycyclic (up to tricyclic) fused together and having the specified number of aryl ring atoms. The term includes polycyclic ring systems in which at least one ring is polyunsaturated. The term "heteroaryl" refers to an aryl ring containing one to five heteroatoms selected from N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. The heteroaryl group may be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl groups, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl (pyridinyl), triazinyl, quinolyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl (phthalazinyl), benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuranyl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidyl, pyrazolopyrimidinyl, imidazopyridine, benzothiazolyl (benzothiazolyl), benzofuranyl, benzothienyl, indolyl, quinolinyl, isoquinolinyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furanyl, thienyl, and the like. Optional substituents for each of the above-indicated aryl and heteroaryl ring systems may be selected from acceptable substituents described further below.

The term "C_1-8Hydroxyalkyl "includes alkyl substituted with one or more (e.g., 1,2,3, or 4) hydroxy groups.

The term "C_3-8cycloalkyl-C_1-8Alkyl "includes a substituent substituted by one or more (e.g. 1,2,3 or 4) C_3-8Cycloalkyl-substituted alkyl.

The term "C_3-8Halocycloalkyl "includes C substituted with one or more (e.g., 1,2,3, or 4) halo groups_3-8A cycloalkyl group.

The term "C_1-8Cyanoalkyl "includes alkyl substituted with one or more (e.g., 1,2,3, or 4) cyano groups.

The term "C_3-8cycloalkyl-C_1-8Alkoxy "includes a group consisting of one or more (e.g., 1,2,3, or 4) C_3-8Cycloalkyl-substituted alkoxy.

The term "oxo" means double-bonded oxygen (═ O), and the term "thio" means double-bonded sulfur (═ S).

The above terms (e.g., "alkyl," "aryl," and "heteroaryl"), in some embodiments, will include both substituted and unsubstituted forms of the indicated group. Preferred substituents for each type of group are provided below.

Substituents for alkyl groups (including those groups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl, cycloalkyl, and heterocycloalkyl) can be a variety of groups including, but not limited to, halogen, -OR ', -NR' R ', -SR', -SiR 'R', -OC (O) R ', -C (O) R', -CO₂R'、-CONR'R″、-OC(O)NR'R″、-NR″C(O)R'、-NR″'C(O)NR'R″、-NR″C(O)₂R'、-NHC(NH₂)＝NH、-NR′C(NH₂)＝NH、-NHC(NH₂)＝NR'、-NR″'C(NR'R″)＝N-CN、-NR″'C(NR'R″)＝NOR'、-NHC(NH₂)＝NR',-S(O)R'、-S(O)₂R'、-S(O)₂NR'R″、-NR'S(O)₂R″、-NR″'S(O)₂NR'R″、-CN、-NO₂、-(CH₂)_1-4-OR'、-(CH₂)_1-4-NR'R″、-(CH₂)_1-4-SR'、-(CH₂)_1-4-SiR'R″R″'、-(CH₂)_1-4-OC(O)R'、-(CH₂)_1-4-C(O)R'、-(CH₂)_1-4-CO₂R'、-(CH₂)_1-4CONR ' R ", ranges in value from zero to (2m ' +1), where m ' is the total number of carbon atoms in such groups. R ', R ' and R ' are each independently designated to include, inter alia, hydrogen, unsubstituted C_1-6Alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C_1-6Alkyl radical, C_1-6Alkoxy or C_1-6Thioalkoxy or unsubstituted aryl-C_1-4Alkyl, unsubstituted heteroaryl, substituted heteroaryl groups. When R 'and R' are attached to the same nitrogen atom, they may combine with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR' R "is intended to include 1-pyrrolidinyl and 4-morpholinyl. Other substituents for alkyl (including heteroalkyl, alkylene) include, for example, ═ O, ═ NR ', ═ N-OR ', ═ N-CN, ═ NH, where R ' includes substituents as described above.

Similarly, substituents for aryl and heteroaryl groupsAre variable and are typically selected from the group consisting of, but not limited to, halogen, -OR ', -OC (O) R', -NR 'R', -SR ', -R', -CN, -NO₂、-CO₂R'、-CONR'R″、-C(O)R'、-OC(O)NR'R″、-NR″C(O)R'、-NR″C(O)₂R'、-NR'C(O)NR″R″'、-NHC(NH₂)＝NH、-NR'C(NH₂)＝NH、-NHC(NH₂)＝NR'、-S(O)R'、-S(O)₂R'、-S(O)₂NR'R″、-NR'S(O)₂R″、-N₃perfluoro-C_1-4Alkoxy and perfluoro-C_1-4Alkyl, - (CH)₂)_1-4-OR'、-(CH₂)_1-4-NR'R''、-(CH₂)_1-4-SR'、-(CH₂)_1-4-SiR'R″R″'、-(CH₂)_1-4-OC(O)R'、-(CH₂)_1-4-C(O)R'、-(CH₂)_1-4-CO₂R'、-(CH₂)_1-4CONR' R ", ranging in value from zero to the total number of open valences on the aromatic ring system; and wherein R ', R ' and R ' are independently selected from hydrogen, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) -C_1-4Alkyl and unsubstituted aryloxy-C_1-4An alkyl group. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether from 1-4 carbon atoms. When the substituent for the aryl or heteroaryl group contains an alkylene linker (e.g., - (CH)₂)_1-4-NR' R "), the alkylene linker also comprises a halo variant. For example, when used as part of a substituent, the linker "- (CH)₂)_1-4- "is intended to include difluoromethylene, 1, 2-difluoroethylene, and the like.

As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

As used herein, the term "chiral" refers to a molecule having the non-overlapping nature of mirror image partners, while the term "achiral" refers to a molecule whose mirror image partners can overlap.

As used herein, the term "stereoisomer" refers to compounds having the same chemical composition but differing with respect to the spatial arrangement of the atoms or groups.

As used herein, wavy lines intersecting bonds in chemical structure ""indicates the point of attachment of a bond, whose wavy bond in the chemical structure intersects the rest of the molecule.

The term "C-linked" as used herein means that the group described by the term is attached to the remainder of the molecule through a ring carbon atom.

The term "N-linked" as used herein means that the group described by the term is attached to the remainder of the molecule through a ring nitrogen atom.

"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics, and reactivities. Mixtures of diastereomers can be separated under high resolution analytical procedures such as electrophoresis and chromatography.

"enantiomer" refers to a stereoisomer of two compounds that are non-overlapping mirror images of each other.

The definitions and conventions of stereochemistry used herein follow the definitions and conventions of S.P. Parker, eds, McGraw-HillDirectionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, as mixtures thereof, e.g., racemic mixtures, are contemplated to form part of the invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to denote the rotational labels of the plane polarized light of the compound, where (-) or 1 means that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures. A50: 50 enantiomeric mixture is referred to as a racemic mixture or racemate, and can be produced without stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species which are optically inactive.

As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversion via proton migration, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions through recombination of some of the bonding electrons.

As used herein, the term "solvate" refers to the association or complexation of one or more solvent molecules with a compound of the present invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex where the solvent molecule is water.

As used herein, the term "protecting group" refers to a substituent that is typically used to block or protect a particular functional group on a compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in a compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-Butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl groups. "carboxy-protecting group" refers to a substituent of a carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenethylsulfonyl, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfinyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl, and the like. For a general description of protecting Groups and their use, see p.g.m.wuts and t.w.greene, Greene's Protective Groups in Organic Synthesis, 4 th edition, Wiley-Interscience, New York, 2006.

As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cattle, pigs, and sheep.

As used herein, the term "pharmaceutically acceptable salt" is intended to include salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese salts, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, naturally occurring amines, and the like), such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral forms of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like. Also included are Salts of amino acids such as arginine and the like, and Salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge, s.m. et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science,1977,66, 1-19). Certain specific compounds of the invention contain both basic and acidic functional groups that allow the compounds to be converted into base addition salts or acid addition salts.

The neutral form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention the salts are equivalent to the parent form of the compound.

In addition to salt forms, the present invention provides compounds in prodrug form. As used herein, the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Alternatively, prodrugs can be converted to the compounds of the present invention by chemical or biochemical means in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir containing a suitable enzyme or chemical agent.

Prodrugs of the invention include compounds in which an amino acid residue or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues is covalently linked through an amide or ester bond to a free amino, hydroxyl, or carboxylic acid group of a compound of the invention. Amino residues include, but are not limited to, the 20 naturally occurring amino acids commonly designated by the three letter symbols and also include phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, desmosine (demosine), isodesmosine, gamma-carboxyglutamic acid, hippuric acid, octahydroindole-2-carboxylic acid, statine, 1,2,3, 4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, p-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone, and tert-butylglycine.

Other types of prodrugs are also contemplated. For example, the free carboxyl groups of the compounds of the invention may be derivatized as amides or alkyl esters. As another example, compounds of the invention containing a free hydroxyl group may be derivatized into prodrugs by converting the hydroxyl group to a group such as, but not limited to, phosphate, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl, as outlined in Fleisher, D.et al, (1996) Improved organic Drug Delivery, solvent limits over come by the use of modified Advanced Drug Delivery Reviews,19: 115. Also included are carbamate prodrugs of hydroxy and amino groups, such as those that are carbonate prodrugs, sulfonates and sulfates of hydroxy groups. Derivatization of the hydroxyl group with (acyloxy) methyl and (acyloxy) ethyl ethers is also contemplated, where the acyl group may be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine, and carboxylic acid functional groups, or where the acyl group is an amino acid ester as described above. Prodrugs of this type are described in j.med.chem., (1996),39: 10. More specific examples include the use of compounds such as (C)_1-6) Alkanoyloxymethyl (alkyloxymethyl), 1- ((C)_1-6) Alkanoyloxy) ethyl, 1-methyl-1- ((C)_1-6) Alkanoyloxy) ethyl group, (C)_1-6) Alkoxycarbonyloxymethyl, N- (C)_1-6) Alkoxycarbonylaminomethyl, succinyl, (C)_1-6) Alkanoyl, α -amino (C)_1-4) Alkanoyl, arylacyl, and α -aminoacyl or α -aminoacyl- α -aminoacyl for replacing a hydrogen atom of an alcohol group, wherein each α -aminoacyl is independently selected from a naturally occurring L-amino acid, P (O) (OH)₂、-P(O)(O(C_1-6) Alkyl radical)₂Or a glycosyl (the radical resulting from the removal of the hydroxyl group of the hemiacetal form of the carbohydrate).

Other examples of prodrug derivatives are described, for example, in a) Design of Prodrugs, edited by H.Bundgaard, (Elsevier,1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K.Widder et al (Academic Press, 1985); b) a Textbook of Drug Design and Development, edited by Krogsgaard-La rsen and H.Bundgaard, Chapter 5 "Design and Application of Prodrugs," H.Bundgaard, pp.113 and 191 (1991); c) bundgaard, advanced Drug delivery reviews, 8: 1-38 (1992); d) bundgaard et al, Journal of Pharmaceutical Sciences, 77:285 (1988); and e) N.Kakeya et al, chem.pharm.Bull., 32:692(1984), each of which is specifically incorporated herein by reference.

In addition, the present invention provides metabolites of the compounds of the present invention. As used herein, "metabolite" refers to a product produced by the in vivo metabolism of a specified compound or salt thereof. Such products can be produced by, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc., of the administered compound.

Metabolites are typically identified by: preparation of a radiolabel for a compound of the invention (e.g.,¹⁴c or³H) Isotopes, which are administered parenterally in detectable doses (e.g., greater than about 0.5mg/kg) to animals such as rats, mice, guinea pigs, monkeys, or to humans, allow metabolism for a sufficient time (typically about 30 seconds to 30 hours) and isolate their conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by using antibodies capable of binding to the epitope that survives in the metabolite). Metabolite structure is analyzed in a conventional manner, e.g., by mass spectrometry: (MS), liquid chromatography/mass spectrometry (LC/MS), or Nuclear Magnetic Resonance (NMR) analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites may be used in diagnostic assays for therapeutic dosages of the compounds of the present invention, as long as they are not found in vivo.

Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent to the uses contemplated by the present invention and are intended to be within the scope of the present invention.

Certain compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers and individual isomers (e.g., individual enantiomers) are intended to be encompassed within the scope of the present invention.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the invention also includes isotopically-labeled variants of the invention, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated as being within the scope of the compounds of the invention and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as²H(“D”)、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³²P、³³P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. certain isotopically-labeled compounds of the present invention (e.g., with³H or¹⁴C-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritiated (i.e. by tritiation)³H) Isotopes and carbon-14 (i.e.¹⁴C) Isotopes are useful because they are easy to prepare and detect. In addition, via heavier isotopes such as deuterium (i.e.²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., prolonged in vivo half-life or reduced dosage requirements), and may therefore be preferred in some circumstances. Such as¹⁵O、¹³N、¹¹C and¹⁸positron emitting isotopes of F are useful in Positron Emission Tomography (PET) studies to examine stromal receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

The terms "treat" and "treatment" refer to therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of a disease or disorder, stabilized (i.e., not worsening) disease or disorder state, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. "treatment" may also mean prolonging survival compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder, as well as those susceptible to or to prevent the disease or disorder.

The phrase "therapeutically effective amount" or "effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, disorder, or condition, (ii) reduces, ameliorates, or eliminates one or more symptoms of the particular disease, disorder, or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, disorder, or condition described herein. For cancer treatment, efficacy can be measured, for example, by assessing time to disease progression (TTP) and/or determining Response Rate (RR).

The term "bioavailability" refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term indicating a measure of time (rate) and the total amount (degree) of drug that reaches the systemic circulation from the dosage form administered.

A. Compound (I)

In a first aspect, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein in formula I:

R¹is selected from-NR^1AR^1B、-X^1R-NR^1AR^1B、-X^1R-OR^1AA 5-10 membered heteroaryl ring comprising 1 to 4 nitrogen atoms and a 4-10 membered C-linked heterocycloalkyl comprising 1 to 3 nitrogen atoms; r^1AAnd R^1BEach independently selected from hydrogen and C_1-8Alkyl, -C (═ Y)¹)OR^R1C、-C(＝Y¹)R^R1C、-C(＝Y¹)N(R^R1C)₂、-(X^1R)_0-1R^xAnd C_1-8An alkoxy group; or R^1AAnd R^1BOptionally combine to form a 4-10 membered heterocyclic ring optionally containing 1 to 3 additional heteroatoms selected from N, O and S as ring vertices; r^R1CIs selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl, benzyl, and 5-6 membered heteroaryl; x^1RIndependently selected from C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene, wherein X^1ROptionally substituted by one or more groups selected from oxo and thioxoSubstitution; y is¹Independently is O or S; r^xIndependently selected from 6-10 membered aryl, 5-10 membered heteroaryl, C_3-8Cycloalkyl and C_2-7A heterocycloalkyl group; and wherein R¹Optionally further substituted by 1 to 5 substituents independently selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl- (X)^1R)_0-1-、C_3-8Heterocycloalkyl- (X)^1R)_0-16-to 10-membered aryl- (X)^1R)_0-1-, 5-10 membered heteroaryl- (X)^1R)_0-1-、F、Cl、Br、I、-CN、-NO₂、-(X^1R)_0-1NR^R1aR^R1b、-(X^1R)_0-1OR^R1a、-(X^1R)_0-1SR^R1a、-(X^1R)_0-1N(R^R1a)C(＝Y¹)OR^R1c、-(X^1R)_0-1OC(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)C(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1C(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)C(＝O)R^R1b、-(X^1R)_0-1C(＝O)OR^R1a、-(X^1R)_0-1OC(＝O)R^R1a、-(X^1R)_0-1-P(＝O)(OR^R1a)(OR^R1b)、-(X^1R)_0-1S(O)_1-2R^R1c、-(X^1R)_0-1S(O)_1-2N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)S(O)_1-2N(R^R1a)(R^R1b) And- (X)^1R)_0-1N(R^R1a)S(O)_1-2(R^R1c) Substituted with the substituent(s); r^R1aAnd R^R1bEach independently selected from hydrogen and C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; or R^R1aAnd R^R1bTogether with the nitrogen to which they are attached form a morpholino, piperidino or piperazino ring, wherein said ring is optionally substituted with one or more substituents independently selected from C_1-8Alkyl, halo, hydroxy, C_1-8Alkylamino radical, C_1-8Dialkylamino radical, C_1-8Haloalkyl and C_1-8A hydroxyalkyl group; r^R1cIs selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group;

R^Nis hydrogen, C_1-4Alkyl or C_1-4A haloalkyl group;

D¹is N or C (R)^D1)；

D³Is N or C (R)^D3)；

R^D1、R^D2、R^D3And R^D4Each independently selected from H, F, Cl, Br, I, -CN, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl and a 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from F, Cl, Br, I, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent substitution of alkoxy;

l is selected from C_1-4Alkylene radical, C_2-4Alkenylene radical, C_2-4AlkynyleneRadical and C_1-4A linker of heteroalkylene, wherein L is optionally substituted with 1 to 3 substituents independently selected from ═ O, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Acyl substituent substitution;

the subscript m represents an integer of 0 or 1;

X¹and X²Each independently selected from the group consisting of absent, -O-, -S-, -S (O) -, -S (O)₂- - -N (H) - -and- -N (R)^x1) -, wherein R^x1Is C_1-8Alkyl radical, C_1-8Acyl or-S (O)₂(C_1-8Alkyl), and wherein if said subscript m is 0, then X¹Or X²One of which is absent;

the subscript n is an integer of from 0 to 5;

ring a represents a 6-10 membered aryl or 5-10 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S;

R^Aindependently at each occurrence, selected from H, C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl- (X)^RA)_0-1、C_3-8Halocycloalkyl- (X)^RA)_0-1、C_1-8Cyanoalkyl, C_1-8Hydroxyalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl, F, Cl, Br, I, -CN, -NO₂、C_2-9Heterocycloalkyl- (X)^RA)_0-1-、C_6-10Aryl radical- (X)^RA)_0-1-, 5-6 membered heteroaryl- (X)^RA)_0-1-、-(X^RA)_{0- 1}NR^A1R^A2、-(X^RA)_0-1OR^A1、-(X^RA)_0-1SR^A1、-(X^RA)_0-1N(R^A1)C(＝O)OR^A3、-(X^RA)_0-1OC(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)C(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1C(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)C(＝O)R^A2、-(X^RA)_0-1C(＝O)R^A1、-(X^RA)_0-1C(＝O)OR^A1、-(X^RA)_0-1OC(＝O)R^A1、-P(＝O)(OR^A1)(OR^A2)、-(X^RA)_0-1S(O)_1-2R^A3、-(X^RA)_0-1S(O)_1-2N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)S(O)_1-2N(R^A1)(R^A2) And- (X)^RA)_{0- 1}N(R^A1)S(O)_1-2(R^A3) (ii) a Each X^RAIndependently selected from C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene, said C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene is optionally substituted with one or more groups selected from oxo and thioxo; r^A1And R^A2Independently selected from hydrogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Hydroxyalkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; or R^A1And R^A2Together with the nitrogen to which they are attached form a morpholino, piperidino or piperazino ring, optionally substituted with one or more C_1-8Alkyl, halo, hydroxy, C_1-8Haloalkyl and C_1-8Hydroxyalkyl substitution; r^A3Is selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; wherein R is^AOptionally further substituted with 1 to 5 substituents independently selected from F, Cl, Br, I, -NH₂、-OH、-CN、-NO₂Oxo (═ O), C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4haloalkyl-C (═ O) -, C_1-4haloalkyl-S (O)_0-2-、C_1-4haloalkyl-C (═ O) n (h) -, C_1-4Haloalkyl-n (h) -C (═ O) -, (haloalkyl)₂N-C(＝O)-、C_1-4haloalkyl-OC (═ O) n (h) -, C_1-4haloalkyl-OC (═ O) n (h) -, haloalkyl-n (h) -C (═ O) O-, (haloalkyl)₂N-C(＝O)O-、C_1-4Alkylamino radical, C_1-4Dialkylamino radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_2-5Heterocycloalkoxy and tetralin substituents.

In another embodiment, in the compounds of formula I, R^D1、R^D2、R^D3And R^D4Each independently selected from H, F, Cl and-CN.

In another embodiment, in the compounds of formula I, R^D1、R^D2、R^D3And R^D4Is a 5-6 membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O and S, wherein the 5-6 membered heteroaryl group is further optionally substituted with 1 to 3 heteroatoms independently selected from F, Cl, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent of alkoxy.

In another embodiment, in the compounds of formula I, R^D1、R^D2、R^D3And R^D4Is independently selected from H, F and Cl, or R^D1、R^D2、R^D3And R^D4Is a 5-6 membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O and S, wherein the 5-6 membered heteroaryl group is further optionally substituted with 1 to 3 heteroatoms independently selectedFrom F, Cl, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent of alkoxy.

In another embodiment, in the compounds of formula I, R^D1、R^D2、R^D3And R^D4Is a 5-6 membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O and S, wherein the 5-6 membered heteroaryl group is further optionally substituted with 1 to 3 heteroatoms independently selected from F, Cl, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent of alkoxy.

In another embodiment, in the compounds of formula I, R^D1、R^D2、R^D3And R^D4Independently selected from H, F, Cl, -CN, -CF₃And pyridyl, wherein said pyridyl is further optionally substituted with 1 to 3 substituents selected from the group consisting of F, Cl, -CN, and C_1-4Substituent of alkoxy.

In another embodiment, in the compounds of formula I, D is¹Is C (R)^D1) And D³Is C (R)^D3)。

In another embodiment, in the compounds of formula I, D is¹Is N and D³Is C (R)^D3)。

In another embodiment, in the compounds of formula I, D is¹Is C (R)^D1) And D³Is N.

In another embodiment, in the compounds of formula I, D is¹And D³Each is N.

In another embodiment, the compound of formula I is a compound of formula Ia:

wherein D¹Is CH or N.

In another embodiment, the compound of formula Ia is a compound of formula Ib

In another embodiment, in the compounds of formula I, R^D2、R^D3And R^D4Each of one or more of (A) and (B) is independently selected from F, Cl, -CN, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl and a 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from F, Cl, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent substitution of alkoxy; and the remaining R^D2、R^D3And R^D4Each is H.

In another embodiment, in the compounds of formula I, R^D2、R^D3And R^D4Two or more of (A) are each independently selected from F, Cl, -CN, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl and a 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from F, Cl, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent substitution of alkoxy; and the remaining R^D2、R^D3And R^D4Is H.

In another embodiment, in the compounds of formula I, the A ring is 6-10 membered aryl.

In another embodiment, in the compounds of formula I, the a ring is phenyl.

In another embodiment, in the compounds of formula I, the a ring is 5-6 membered heteroaryl.

In another embodiment, in the compounds of formula I, the a ring is pyridinyl.

In another embodiment, in the compounds of formula I, wherein n is 2 or 3.

In another embodiment, the compound of formula I is a compound of formula Ic:

wherein D¹Is CH or N; and E is C (R)^A) Or N.

In another embodiment, the compound of formula I is a compound of formula Id:

wherein D¹Is CH or N; and E is C (R)^A) Or N.

In another embodiment, the compound of formula I is a compound of formula Ie:

wherein D¹Is CH or N; and E is C (R)^A) Or N. .

In another embodiment, the compound of formula I is a compound of formula If:

wherein; d¹Is CH or N; and E is C (R)^A) Or N.

In another embodiment, in the compounds of formula I, R¹Selected from: -NH₂、-NH(CH₃)、-N(CH₃)₂、

In another embodiment, in the compounds of formula I, R¹Selected from:

in another embodiment, in the compounds of formula I, X¹is-O-or-N (H) -; x²Is absent; subscript m is 1; and- (L) -is selected from C_1-4Alkylene radical, C_2-4Alkenylene or C_2-4Alkynylene and is optionally substituted.

In another embodiment, in the compounds of formula I, X¹is-O-or-N (H) -; x²Is absent; subscript m is 1; and- (L) -is selected from-CH₂-、–C(＝O)-、–C(H)(CH₃)-、–CH₂-CH₂-、–CH₂-C(H)(CH₃)-、–C(H)(CH₃)-C(H₂)-、–CH₂CH₂CH₂-、–CH₂-C(H)(CH₃)-CH₂-or-CH₂CH₂CH₂CH₂-。

In another embodiment, in the compounds of formula I, X¹is-O-; subscript m is 1 and- (L) -is-CH₂-or-CH₂-CH₂-。

In another embodiment, in the compounds of formula I, X¹Is absent; x²is-O-or-N (H) -; subscript m is 1; and areAnd- (L) -is selected from-C (H)₂-、–C(＝O)-、–C(H)(CH₃)-、–CH₂-CH₂-、–CH₂-C(H)(CH₃)-、–C(H)(CH₃)-C(H₂)-、–CH₂CH₂CH₂-、–CH₂-C(H)(CH₃)-CH₂-or-CH₂CH₂CH₂CH₂-。

In another embodiment, in the compounds of formula I, X¹And X²Is absent; subscript m is 1; and- (L) -is selected from-C (H)₂-、–C(＝O)-、–C(H)(CH₃)-、–CH₂-CH₂-、–CH₂-C(H)(CH₃)-、–C(H)(CH₃)-C(H₂)-、–CH₂CH₂CH₂-、–CH₂-C(H)(CH₃)-CH₂-or-CH₂CH₂CH₂CH₂-。

In another embodiment, in the compounds of formula I, X¹And X²Is absent; subscript m is 1; and- (L) -is optionally substituted C_1-4A heteroalkylene group.

In another embodiment, in the compounds of formula I, m is 0; x¹Selected from-O-and-N (H) -; and X²Is absent.

In another embodiment, in the compounds of formula I, R^AIs selected from C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-5Cycloalkyl, 3-5 membered heterocycloalkyl, C_1-4Haloalkoxy, C_3-5Halocycloalkyl, F, Cl, Br, I, -OH, -NH₂、-CN、-NO₂、C_1-4Alkoxy, -C (═ O) -N (R)^A1)(R^A2) and-N (R)^A1)(R^A2)。

In another embodiment, in the compounds of formula I, R^AIs selected from C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-5Cycloalkyl radical, C_1-4Haloalkoxy, C_3-5HalogenatedCycloalkyl radicals F, Cl and C_1-4An alkoxy group.

In another embodiment, in the compounds of formula I, R^AIs methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, ethyl, pentafluoroethyl, cyclopropyl, -F, Cl, -OH, -NH₂or-CN.

In another embodiment, in the compounds of formula I, R^ASelected from the group consisting of trifluoromethyl, pentafluoroethoxy, ethyl, isopropyl, 2-fluoroethoxy, fluoromethyl, 3-difluorocyclobutyl, cyclobutyl, isopropyl, F, Cl, isopropoxy, trifluoromethoxy, and cyclopropyl.

In another embodiment, in the compounds of formula I, R^ASelected from H, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-5Cycloalkyl, 3-to 5-membered heterocycloalkyl, C_1-4Haloalkoxy, C_3-5Halocycloalkyl, F, Cl, Br, I, -OH, -NH₂、-CN、-NO₂、C_1-4Alkoxy, -C (═ O) -N (R)^A1)(R^A2) and-N (R)^A1)(R^A2)。

In another embodiment, in the compounds of formula I, R^ASelected from H, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-5Cycloalkyl radical, C_1-4Haloalkoxy, C_3-5Halocycloalkyl radicals F, Cl and C_1-4An alkoxy group.

In another embodiment, in the compounds of formula I, R^AIs H, methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, ethyl, pentafluoroethyl, cyclopropyl, -F, Cl, -OH, -NH₂or-CN.

In another embodiment, in the compounds of formula I, R^ASelected from the group consisting of H, trifluoromethyl, pentafluoroethoxy, ethyl, isopropyl, 2-fluoroethoxy, fluoromethyl, 3-difluorocyclobutyl, cyclobutyl, isopropyl, F, Cl, isopropoxy, trifluoromethoxy, and cyclopropyl.

In another embodimentIn embodiments, in the compounds of formula I, at least one R^AIs selected from C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-5Cycloalkyl radical, C_2-4Heterocycloalkyl radical, C_1-4Haloalkoxy, C_3-5Halocycloalkyl, F, Cl, Br, I, -OH, -NH₂、-CN、-NO₂、C_1-4Alkoxy, -C (═ O) -N (R)^A1)(R^A2) and-N (R)^A1)(R^A2)。

In another embodiment, in the compounds of formula I, at least one R^AIs selected from C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-5Cycloalkyl radical, C_1-4Haloalkoxy, C_3-5Halocycloalkyl radicals F, Cl and C_1-4An alkoxy group.

In another embodiment, in the compounds of formula I, at least one R^ASelected from the group consisting of methyl, trifluoromethyl, difluoromethyl, monofluoromethyl, ethyl, pentafluoroethyl, cyclopropyl, -F, Cl, -OH, -NH₂and-CN.

In another embodiment, in the compounds of formula I, at least one R^ASelected from the group consisting of trifluoromethyl, pentafluoroethoxy, ethyl, isopropyl, 2-fluoroethoxy, fluoromethyl, 3-difluorocyclobutyl, cyclobutyl, isopropyl, F, Cl, isopropoxy, trifluoromethoxy, and cyclopropyl.

In another embodiment, in the compounds of formula I, each R is^AIndependently selected from C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8Halocycloalkyl radicals F, Cl, - (X)^RA)_0-1OR^A1And- (X)^RA)_0-1NR^A1R^A2。

In another embodiment, in the compounds of formula I, each R is^AIndependently selected from fluoro, chloro, trifluoromethyl, fluoromethyl, pentafluoroethoxy, trifluoromethoxy, cyclopropyl, cyclobutyl, 2-difluorocyclobutyl, 2-methylpropoxy and piperidino.

In another embodiment, in the compounds of formula I, the group:

selected from:

in another embodiment, the compound of formula I is selected from the compounds listed in table 1 herein (below), or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein in formula I:

R¹is selected from-NR^1AR^1B、-X^1R-NR^1AR^1B、-X^1R-OR^1AA 5-10 membered heteroaryl ring comprising 1 to 4 nitrogen atoms and a 4-10 membered C-linked heterocycloalkyl comprising 1 to 3 nitrogen atoms; r^1AAnd R^1BEach independently selected from hydrogen and C_1-8Alkyl, -C (═ Y)¹)OR^R1C、-C(＝Y¹)R^R1C、-C(＝Y¹)N(R^R1C)₂、-(X^1R)_0-1R^xAnd C_1-8An alkoxy group; or R^1AAnd R^1BOptionally combine to form a 4-10 membered heterocyclic ring optionally containing 1 to 3 additional heteroatoms selected from N, O and S as ring vertices; r^R1CIs selected from C_1-8Alkyl radical, C_1-8HalogenatedAlkyl radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl, benzyl, and 5-6 membered heteroaryl; x^1RIndependently selected from C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene, wherein X^1ROptionally substituted with one or more groups selected from oxo and thioxo; y is¹Independently is O or S; r^xIndependently selected from 6-10 membered aryl, 5-10 membered heteroaryl, C_3-8Cycloalkyl and C_2-7A heterocycloalkyl group; and wherein R¹Optionally further substituted by 1 to 5 substituents independently selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl- (X)^1R)_0-1-、C_3-8Heterocycloalkyl- (X)^1R)_0-16-to 10-membered aryl- (X)^1R)_0-1-, 5-10 membered heteroaryl- (X)^1R)_0-1-、F、Cl、Br、I、-CN、-NO₂、-(X^1R)_0-1NR^R1aR^R1b、-(X^1R)_0-1OR^R1a、-(X^1R)_0-1SR^R1a、-(X^1R)_0-1N(R^R1a)C(＝Y¹)OR^R1c、-(X^1R)_0-1OC(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)C(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1C(＝O)N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)C(＝O)R^R1b、-(X^1R)_0-1C(＝O)OR^R1a、-(X^1R)_0-1OC(＝O)R^R1a、-(X^1R)_0-1-P(＝O)(OR^R1a)(OR^R1b)、-(X^1R)_0-1S(O)_1-2R^R1c、-(X^1R)_0-1S(O)_1-2N(R^R1a)(R^R1b)、-(X^1R)_0-1N(R^R1a)S(O)_1-2N(R^R1a)(R^R1b) And- (X)^1R)_0-1N(R^R1a)S(O)_1-2(R^R1c) Substituted with the substituent(s); r^R1aAnd R^R1bEach independently selected from hydrogen、C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; or R^R1aAnd R^R1bTogether with the nitrogen to which they are attached form a morpholino, piperidino or piperazino ring, wherein said ring is optionally substituted with one or more substituents independently selected from C_1-8Alkyl, halo, hydroxy, C_1-8Alkylamino radical, C_1-8Dialkylamino radical, C_1-8Haloalkyl and C_1-8A hydroxyalkyl group; r^R1cIs selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group;

R^Nis hydrogen, C_1-4Alkyl or C_1-4A haloalkyl group;

D¹is N or C (R)^D1)；

D³Is N or C (R)^D3)；

R^D1、R^D2、R^D3And R^D4Each independently selected from H, F, Cl, Br, I, -CN, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl and containing 1 to 3 hetero atoms chosen from N, O and S5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is further optionally substituted by 1 to 3 substituents selected from F, Cl, Br, I, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent of alkoxy and said C_2-7Heterocycloalkyl is further optionally substituted with 1 to 3 substituents selected from F and-OH;

l is selected from C_1-4Alkylene radical, C_2-4Alkenylene radical, C_2-4Alkynylene and C_1-4A linker of heteroalkylene, wherein L is optionally substituted with 1 to 3 substituents independently selected from ═ O, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Acyl substituent substitution;

the subscript m represents an integer of 0 or 1;

X¹and X²Each independently selected from the group consisting of absent, -O-, -S-, -S (O) -, -S (O)₂- - -N (H) - -and- -N (R)^x1) -, wherein R^x1Is C_1-8Alkyl radical, C_1-8Acyl or-S (O)₂(C_1-8Alkyl), and wherein if said subscript m is 0, then X¹Or X²One of which is absent;

the subscript n is an integer of from 0 to 5;

ring a represents a 6-10 membered aryl or 5-10 membered heteroaryl group containing 1 to 3 heteroatoms selected from N, O and S;

R^Aindependently at each occurrence, selected from H, C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl- (X)^RA)_0-1、C_3-8Halocycloalkyl- (X)^RA)_0-1、C_1-8Cyanoalkyl, C_1-8Hydroxyalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl, F, Cl, Br, I, -CN, -NO₂、C_2-9Heterocycloalkyl- (X)^RA)_0-1-、C_6-10Aryl radical- (X)^RA)_0-1-, 5-6 membered heteroaryl- (X)^RA)_0-1-、-(X^RA)_{0- 1}NR^A1R^A2、-(X^RA)_0-1OR^A1、-(X^RA)_0-1SR^A1、-(X^RA)_0-1N(R^A1)C(＝O)OR^A3、-(X^RA)_0-1OC(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)C(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1C(＝O)N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)C(＝O)R^A2、-(X^RA)_0-1C(＝O)R^A1、-(X^RA)_0-1C(＝O)OR^A1、-(X^RA)_0-1OC(＝O)R^A1、-P(＝O)(OR^A1)(OR^A2)、-(X^RA)_0-1S(O)_1-2R^A3、-(X^RA)_0-1S(O)_1-2N(R^A1)(R^A2)、-(X^RA)_0-1N(R^A1)S(O)_1-2N(R^A1)(R^A2) And- (X)^RA)_{0- 1}N(R^A1)S(O)_1-2(R^A3) (ii) a Each X^RAIndependently selected from C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene, said C_1-4Alkylene radical, C_1-4Heteroalkylene group, C_2-4Alkenylene and C_2-4Alkynylene is optionally substituted with one or more groups selected from oxo and thioxo; r^A1And R^A2Independently selected from hydrogen, C_1-8Alkyl radical, C_1-8Haloalkyl, C_1-8Hydroxyalkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; or R^A1And R^A2Together with the nitrogen to which they are attached form a morpholino, piperidino or piperazino ringOptionally substituted by one or more C_1-8Alkyl, halo, hydroxy, C_1-8Haloalkyl and C_1-8Hydroxyalkyl substitution; r^A3Is selected from C_1-8Alkyl radical, C_1-8Haloalkyl, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-8Alkyl radical, C_3-8cycloalkyl-C_1-8Alkoxy, tetralin, phenyl-C_1-8Alkyl, phenyl-C_1-8Alkoxy, 5-6 membered heteroaryl-C_1-8Alkyl, 5-6 membered heteroaryl-C_1-8Alkoxy, 3-7 membered heterocycloalkyl-C_1-8Alkyl, 3-7 membered heterocycloalkyl-C_1-8An alkoxy group; wherein R is^AOptionally further substituted with 1 to 5 substituents independently selected from F, Cl, Br, I, -NH₂、-OH、-CN、-NO₂Oxo (═ O), C_1-4Alkyl radical, C_1-4Haloalkyl, C_1-4Alkoxy radical, C_1-4haloalkyl-C (═ O) -, C_1-4haloalkyl-S (O)_0-2-、C_1-4haloalkyl-C (═ O) n (h) -, C_1-4Haloalkyl-n (h) -C (═ O) -, (haloalkyl)₂N-C(＝O)-、C_1-4haloalkyl-OC (═ O) n (h) -, C_1-4haloalkyl-OC (═ O) n (h) -, haloalkyl-n (h) -C (═ O) O-, (haloalkyl)₂N-C(＝O)O-、C_1-4Alkylamino radical, C_1-4Dialkylamino radical, C_3-6Cycloalkyl radical, C_3-6Cycloalkoxy, C_2-5Heterocycloalkoxy and tetralin substituents.

In another embodiment, in the compounds of formula I, R^D1、R^D2、R^D3And R^D4Independently selected from H, F, Cl, -CN, C_2-8Alkenyl radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from F, Cl, Br, I, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent of alkoxy and said C_2-7Heterocycloalkyl is further optionally substituted with 1 to 3 substituents selected from F and-OH.

In another embodiment, in the compounds of formula I, R^D1、R^D2、R^D3And R^D4Independently selected from H, F, Cl, -CN, vinyl, cyclopropyl, oxetanyl and pyridyl, wherein said pyridyl is further optionally substituted with 1 to 3 substituents selected from F, Cl, Br, I, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy and said oxetanyl is further optionally substituted with 1 to 3 substituents selected from F and-OH. In certain aspects of this embodiment, R^D1、R^D3Each is H, R^D2Is F or Cl and R^D4Is vinyl, cyclopropyl, oxetanyl or pyridyl, wherein said pyridyl is further optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Alkoxy and said oxetanyl is further optionally substituted with 1 to 3 substituents selected from F and-OH.

In another embodiment, in the compounds of formula I, R^D2、R^D3And R^D4Each of one or more of (A) and (B) is independently selected from F, Cl, -CN, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_1-8Haloalkyl, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl and a 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from F, Cl, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent of alkoxy, and said C_2-7Heterocycloalkyl is further optionally substituted with 1 to 3 substituents selected from F and-OH; and the remaining R^D2、R^D3And R^D4Each is H.

In another embodiment, in the compounds of formula I, R^D2、R^D3And R^D4Two or more of (A) are each independently selected from F, Cl, -CN, C_2-8Alkenyl radical, C_1-8Alkyl radical, C_1-8Alkyl halidesBase, C_1-8Alkoxy radical, C_3-8Cycloalkyl radical, C_2-7Heterocycloalkyl, phenyl and a 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from F, Cl, -CN, C_1-4Alkyl radical, C_1-4Haloalkyl and C_1-4Substituent of alkoxy and said C_2-7Heterocycloalkyl is further optionally substituted with 1 to 3 substituents selected from F and-OH; and the remaining R^D2、R^D3And R^D4Is H.

In another embodiment, in the compounds of formula I, the a ring is phenyl, pyridyl, isoxazolyl, naphthyl, indolyl, isoquinolyl, indazolyl, benzothiazolyl, or quinolinyl.

In another embodiment, in the compounds of formula I, the a ring is phenyl or pyridyl.

In another embodiment, in the compounds of formula I, R¹Selected from: -NH₂、-NH(CH₃)、-N(CH₃)₂、

In another embodiment, in the compounds of formula I, R¹Selected from: -NH (CH)₃)、-N(CH₃)₂And

in another embodiment, in the compounds of formula I, X¹Is absent; x²is-O-; subscript m is 1; and- (L) -is-CH₂-or-CH₂-CH₂-。

In another embodiment, in the compounds of formula I, X¹is-O-; x²is-O-(ii) a Subscript m is 1; and- (L) -is selected from-C (H)₂-、–C(＝O)-、–C(H)(CH₃)-、–CH₂-CH₂-、-CH₂-C(H)(CH₃)-、–C(H)(CH₃)-C(H₂)-、–CH₂CH₂CH₂-、–CH₂-C(H)(CH₃)-CH₂-or-CH₂CH₂CH₂CH₂-。

In another embodiment, in the compounds of formula I, X¹is-O-; x²is-O-; subscript m is 1; and- (L) -is selected from-CH₂-CH₂-、–CH₂-C(H)(CH₃)-、–C(H)(CH₃)-C(H₂)-、–CH₂CH₂CH₂-、–CH₂-C(H)(CH₃)-CH₂-or-CH₂CH₂CH₂CH₂-。

In another embodiment, in the compounds of formula I, m is 0; x¹is-O-; and X²Is absent.

In another embodiment, in the compounds of formula I, R^ASelected from H, C_1-4Alkyl radical, C_1-4Haloalkyl, C_3-5Cycloalkyl, 3-to 6-membered heterocycloalkyl, 5-to 6-membered heteroaryl, phenyl, C_1-4Haloalkoxy, C_3-5Halocycloalkyl, F, Cl, Br, I, -OH, -NH₂、-CN、-NO₂、C_1-4Alkoxy, -S (O)_1-2R^A3、-C(＝O)-N(R^A1)(R^A2) and-N (R)^A1)(R^A2)。

In another embodiment, in the compounds of formula I, R^ASelected from H, C_1-4Alkyl radical, C_1-4Haloalkyl, 3-to 6-membered heterocycloalkyl, 5-6-membered heteroaryl, phenyl, C_1-4Haloalkoxy, Cl, -CN, C_1-4Alkoxy and-S (O)_1-2R^A3。

In another embodiment, in the compounds of formula I, R^AIs selected fromH. Trifluoromethyl, Cl, -OCH₂CH(CH₃)₂、-OCF₃、-OCH₂CF₂CHF₂Methyl, phenyl, -CN, thiazol-2-yl, methoxy, -SO₂CH₃Piperidin-1-yl, -OCH (CH)₃)₂And OCH₂CF₃。

In another embodiment, in the compounds of formula I, R^ASelected from H, trifluoromethyl, Cl, -OCF₃、-OCH₂CF₂CHF₂、-OCH(CH₃)₂And OCH₂CF₃。

In another embodiment, in the compounds of formula I, the group:

selected from:

in another embodiment, in the compounds of formula I, the group:

selected from:

it is to be understood that two or more embodiments of the compounds of formula I described above may be combined with each other.

In another embodiment, the compound of formula I is selected from the compounds listed in table 2 herein (below), or a pharmaceutically acceptable salt thereof.

Synthesis of Compounds

A compound of formula (I) (wherein X¹To O, S, NH) can be prepared by the method shown in scheme 1.

Scheme 1

The compound of formula (I) can be prepared from the compound of formula (IV) by replacing fluorine with the compound of formula (V) using a base such as potassium tert-butoxide, sodium hydride or potassium carbonate in a suitable solvent such as dimethylsulfoxide, N-dimethylformamide or tetrahydrofuran as described in reaction step (ii) in scheme 1. Formula (IV) can be prepared according to reaction step (i) as described in scheme 1 by activation of the benzoic acid group of formula (II) with a reagent such as thionyl chloride, oxalyl chloride, Carbonyldiimidazole (CDI), propylphosphonic anhydride, a urea-based amide coupling reagent, or a carbodiimide reagent followed by displacement with a sulfonamide of formula (III) in the presence of a nucleophilic base such as 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), N-diisopropylethylamine, or triethylamine.

Alternatively, compounds of formula (I) can be prepared according to scheme 1 by step (vi) of activating a benzoic acid group of formula (VIII) with a reagent such as oxalyl chloride, Carbonyldiimidazole (CDI), propylphosphonic anhydride, a urea-based amide coupling reagent, or a carbodiimide reagent, followed by displacement with a sulfonamide of formula (III) in the presence of a nucleophilic base such as DBU, N-diisopropylethylamine, or triethylamine. The compounds of formula (VIII) may be prepared by hydrolysis of the ester functional group in the compounds of formula (VII) by acidic or basic methods according to reaction step (v) using deprotecting group methodologies such as described in the references of ' Green's Protective Groups in Organic Synthesis '.

The compound of formula (VII) may be prepared from the compound of formula (VI) by replacing the fluoro substituent with the compound of formula (V) according to step (iv) using a suitable base such as potassium tert-butoxide, sodium hydride or potassium carbonate in a suitable solvent such as dimethylsulfoxide, N-dimethylformamide or tetrahydrofuran.

Alternatively, compounds of formula (VII) can be prepared from compounds of formula (XII) and compounds of formula (XI) according to reaction step (ix) in scheme 1 using a suitable base such as potassium tert-butoxide, sodium hydride or potassium carbonate in a suitable solvent such as dimethylsulfoxide, N-dimethylformamide or tetrahydrofuran. In addition, compounds of formula (XI) may be prepared from compounds of formula (X) by methods that remove functional group Z as described in reaction step (viii) using deprotection methodologies as described in references such as ' Greene's protective groups in Organic Synthesis '. The compound of formula (X) may be prepared from the compound of formula (VI) by replacing the fluoro substituent with the compound of formula (IX) according to reaction step (vii) using a suitable base such as potassium tert-butoxide, sodium hydride or potassium carbonate in a suitable solvent such as dimethylsulfoxide, N-dimethylformamide or tetrahydrofuran. Compounds of formula (VI) can be prepared from benzoic acid compounds of formula (II) using protection methodologies such as those described in the ' Green's Protective Groups in Organic Synthesis ' references.

A compound of formula (I) (wherein X¹Is absent and (L)_mIs CH₂) Can be prepared via reaction step (xiv) or (xx) as described in scheme 2.

Scheme 2

In reaction step (xiv), the compound of formula (I) may be prepared from the compound of formula (XVII) and the compound of formula (III) using palladium-catalyzed carbonylation reaction conditions. Suitable palladium-catalyzed carbonylation conditions are such as, but not limited to, in carbon monoxide gas or molybdenum hexacarbonyl (Mo (CO)₆) A carbon monoxide gas source as a solvent such as methanol or methanol-containing dioxane contains a ligand such as, but not limited to, XANTPHOS or dppf, and a base such as, but not limited to, palladium (II) acetate or dichlorobistriphenylphosphine palladium (II) of triethylamine, pyridine or diisopropylethylamine. Can be used in the reaction of tetrahydrofuran, dimethyl sulfoxideThe compound of formula (XVII) is prepared from the compound of formula (XVI) by replacing the leaving group (Lg) with the compound of formula (V) according to reaction step (xiii) using a suitable base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent for sulfone or N, N-dimethylformamide. Treatment of a compound of formula (XV) with methanesulfonyl chloride or toluenesulfonyl chloride in the presence of a base such as triethylamine, Hunig's base or pyridine in a suitable solvent such as dichloromethane or tetrahydrofuran gives a compound of formula (XVI) as depicted in scheme 2 as described in reaction step (xii). Further, the compound of formula (XV) can be prepared from the compound of formula (XIV) by treating with a reducing agent such as sodium borohydride, lithium borohydride or aluminum hydride in the presence of a solvent such as methanol, tetrahydrofuran or 1, 4-dioxane, as described in reaction step (xi).

The compounds of formula (XIV) can be prepared from benzoic acid compounds of formula (XIII) using protection methodologies such as those described in the ' Green's Protective Groups in Organic Synthesis ' references.

Alternatively, compounds of formula (l) can be prepared according to step (xx) in scheme 2 by activation of the benzoic acid group of formula (XXIV) with a reagent such as oxalyl chloride, Carbonyldiimidazole (CDI), propylphosphonic anhydride, urea-based amide coupling reagent, or carbodiimide reagent in the presence of a nucleophilic base such as DBU, N-diisopropylethylamine, or triethylamine followed by displacement with a sulfonamide of formula (III) (where X is¹Is absent and (L)_mIs CH₂). Compounds of formula (XXIV) may be synthesized by hydrolysis of the ester functionality in compounds of formula (XXIII) by acidic or basic methods according to reaction step (xix) using deprotecting group methodologies such as described in references such as ' Greene's Protective group in Organic Synthesis '. The compound of formula (XXIII) can be prepared from the compound of formula (XXI) by replacing leaving group (Lg) with the compound of formula (XXII) according to reaction step (xviii) using a suitable base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as tetrahydrofuran, dimethylsulfoxide or N, N-dimethylformamide. The compounds of formula (XXI) can be prepared from compounds of formula (XV) in four steps (reaction steps XV, xvi, xvii and xviii) as described in scheme 2A compound is provided. Protection of the hydroxy function in the compound of formula (XV) using a protection methodology as described in references such as ' Green's protective groups in Organic Synthesis ' gives the compound of formula (XVIII). In reaction step (xvi), the compound of formula (XIX) can be prepared from the compound of formula (XVIII) using palladium-catalyzed carbonylation conditions. Suitable palladium-catalyzed carbonylation conditions such as, but not limited to, palladium (II) acetate or dichlorobistriphenylphosphine palladium (II) with a ligand such as, but not limited to, XANTPHOS or dppf under pressure of carbon monoxide gas in a solvent such as methanol or a mixture of dioxane and methanol, and a base such as, but not limited to, triethylamine, pyridine or diisopropylethylamine. Compounds of formula (XX) may be prepared from compounds of formula (XIX) using deprotection methodologies as described in references such as ' Green's Protective Groups in organic Synthesis '. Treatment of compound of formula (XX) with methanesulfonyl chloride or toluenesulfonyl chloride in a suitable solvent such as dichloromethane or tetrahydrofuran in the presence of a base such as triethylamine, Hunig's base or pyridine affords compound of formula (XXI) as depicted in reaction step (xvii) shown in scheme 2.

Alternatively, a compound of formula (XXIII) can be prepared from a compound of formula (XXII) by replacing leaving group (Lg) with a compound of formula (XXII) according to reaction step (xvii) using a suitable base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as tetrahydrofuran, dimethylsulfoxide or N, N-dimethylformamide. Alternatively, compounds of formula (XXIII) can be prepared from compounds of formula (XXV) via steps (xxi) and (xxii) as shown in scheme 2. The compound of formula (XXV) can be converted to the compound of formula (XXVI) using N-bromosuccinimide in a solvent such as acetonitrile in the presence of a free radical initiator. Treating a compound of formula (XXVI) with a compound of formula (XXII) according to reaction step (XXII) using a suitable base such as sodium hydride, potassium carbonate or cesium carbonate in a suitable solvent such as tetrahydrofuran, dimethylsulfoxide or N, N-dimethylformamide affords a compound of formula (XXIII).

A compound of formula (I) (wherein R₅Is aryl or heteroaryl) can be prepared by the method shown in scheme 3.

Scheme 3

The compound of formula (I) can be prepared from the compound of formula (XXVII) by replacing the fluoro substituent with the compound of formula (V) according to step (xxxi) using a suitable base such as potassium tert-butoxide, sodium hydride or potassium carbonate in a suitable solvent such as dimethylsulfoxide, N-dimethylformamide or tetrahydrofuran. Compounds of formula (XXVII) may be prepared from compounds of formula (XXIX) and compounds of formula (XXVIII) by a palladium catalysed reaction in a solvent such as dioxane or dimethoxyethane using a suitable catalyst such as tetratriphenylphosphine palladium (0) and a base such as sodium carbonate. Compounds of formula (XXIX) can be prepared by activating a benzoic acid group of formula (XXX) with a reagent such as oxalyl chloride, Carbonyldiimidazole (CDI), propylphosphonic anhydride, a urea-based amide coupling reagent, or a carbodiimide reagent, followed by displacement with a sulfonamide of formula (III), according to step (XXIX) in scheme 3 in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide, in the presence of a nucleophilic base such as DBU, N-diisopropylethylamine, or triethylamine.

Alternatively, compounds of formula (I) wherein R is replaced with a sulfonamide of formula (III) can be prepared according to step (xxvi) as described in scheme 3 by activating a benzoic acid group of formula (XXXIV) with a reagent such as oxalyl chloride, carbonyldiimidazole (CDl), propylphosphonic anhydride, a urea-based amide coupling reagent, or a carbodiimide reagent in the presence of a nucleophilic base such as DBU, N-diisopropylethylamine, or triethylamine in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide (xxvi) followed by replacement with a sulfonamide of formula (III)₅Is aryl or heteroaryl). Compounds of formula (XXXIV) may be prepared by hydrolysis of the ester functionality in compounds of formula (XXXIII) by acidic or basic methods according to reaction step (xxv) using deprotecting group methodologies such as described in references such as ' Greene's Protective Groups in Organic Synthesis '. Compounds of formula (XXXIII) may be prepared by two separate routes as described in scheme 3. Can makeA compound of formula (XXXIII) is prepared from a compound of formula (XXXVI) by replacing the fluoro substituent with a compound of formula (V) according to step (xxiv) using a suitable base such as potassium tert-butoxide, sodium hydride or potassium carbonate in a suitable solvent such as dimethylsulfoxide, N-dimethylformamide or tetrahydrofuran. A compound of formula (XXVI) may be prepared from a compound of formula (XXXI) and a compound of formula (XXVIII) by a palladium catalysed reaction as described in reaction step (xxiii) using a suitable catalyst such as tetratriphenylphosphine palladium (0) and a base such as sodium carbonate in a solvent such as dioxane or dimethoxyethane. Compounds of formula (XXXI) may be prepared from benzoic acid compounds of formula (XXX) using protection methodologies as described in references such as ' Green's Protective Groups in Organic Synthesis '.

Alternatively, compounds of formula (XXXIII) may be prepared from compounds of formula (XXXII) and compounds of formula (XXVIII) by using palladium catalysed reaction conditions as described in reaction step (XXVIII) using a suitable catalyst such as tetratriphenylphosphine palladium (0) and a base such as sodium carbonate in a solvent such as dioxane or dimethoxyethane. Compounds of formula (XXXII) may be prepared from compounds of formula (XXXI) by replacing the fluoro substituent with compounds of formula (V) according to reaction step (xxvii) using a suitable base such as potassium tert-butoxide, sodium hydride or potassium carbonate in a suitable solvent such as dimethylsulfoxide, N-dimethylformamide or tetrahydrofuran.

Scheme 4

Compounds of formula (I) (wherein R is R) can be prepared by alkylation of compounds of formula (XXXVII) with compounds of formula (XXXVIII) according to the reaction procedure (xxxi) as described in scheme 4 using a suitable base such as sodium hydride, potassium carbonate or lithium bis (trimethylsilyl) amide (LHMDS) in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide¹is-NHR^1A). Can be dissolved in a suitable solvent such as dimethyl sulfoxide, N-dimethylformamide or tetrahydrofuranCompounds of formula (XXXVII) are prepared from compounds of formula (XXXVI) by replacing the fluoro substituent with a compound of formula (V) according to reaction step (xxx) with a suitable base such as potassium tert-butoxide, sodium hydride or potassium carbonate. Compounds of formula (XXXVI) can be prepared by activation of the benzoic acid group of formula (II) with a reagent such as oxalyl chloride, Carbonyldiimidazole (CDI), propylphosphonic anhydride, a urea-based amide coupling reagent, or a carbodiimide reagent followed by displacement with a sulfonamide of formula (XXXV) as described in reaction step (xxix) in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide in the presence of a nucleophilic base such as DBU, N-diisopropylethylamine, or triethylamine. Alternatively, compounds of formula (XXXVII) can be prepared by activating a benzoic acid group of formula (VIII) with a reagent such as oxalyl chloride, Carbonyldiimidazole (CDI), propylphosphonic anhydride, urea-based amide coupling reagent, or carbodiimide reagent followed by displacement with a sulfonamide of formula (XXXV) as described in step (xxxii) in a suitable solvent such as tetrahydrofuran or N, N-dimethylformamide diisopropylethylamine or triethylamine in the presence of a nucleophilic base such as DBU, N-diisopropylethylamine, or triethylamine.

B. Pharmaceutical compositions and administration

In addition to one or more compounds provided above (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs thereof), the present invention also provides compositions and medicaments comprising a compound of formula I and or embodiments thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. The compositions of the invention are useful for selectively inhibiting nav1.7 in a patient (e.g., a human).

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The phrase "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

In one embodiment, the present invention provides a pharmaceutical composition (or medicament) comprising a compound of formula I or embodiments thereof and stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs thereof) and a pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, the invention provides the preparation of a composition (or medicament) comprising a compound of the invention. In another embodiment, the present invention provides for administering a compound of formula I or embodiments thereof and a composition comprising a compound of formula I or embodiments thereof to a patient in need thereof (e.g., a human patient).

The compositions are formulated, administered and administered in a manner consistent with good medical practice. Factors considered in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the time course of administration, and other factors known to the practitioner. The effective amount of the compound to be administered will be determined by such considerations and is the minimum amount necessary to inhibit nav1.7 required to prevent or treat an undesirable disease or disorder, such as, for example, pain. For example, this amount may be lower than the amount that is toxic to normal cells or the mammal as a whole.

In one example, a therapeutically effective amount of a compound of the invention administered parenterally per dose will range from about 0.01-100mg/kg, or about, e.g., 0.1 to 20mg/kg of patient body weight per day, with a typical initial range of 0.3 to 15 mg/kg/day for the compound used. In certain embodiments, a given daily dose is a single daily dose or divided doses two to six times a day or in sustained release form. For a 70kg adult, the total daily dose will generally be from about 7mg to about 1,400 mg. The dosing regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered from 1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in any convenient form of use, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain ingredients conventional in pharmaceutical formulations, such as diluents, carriers, pH adjusting agents, sweeteners, fillers and additional active agents.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for topical treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal, intracerebral, intraocular, intralesional or subcutaneous administration.

Compositions comprising a compound of formula I or embodiments thereof are generally formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. Typical formulations are prepared by mixing a compound of the invention with a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail, for example, in Ansel, Howard C. et al, Ansel's Pharmaceutical Dosage Forms and Drug Delivery systems, Philad elphia, Lippincott, Williams & Wilkins, 2004; gennaro, Alfonso R. et al, Remington: The science and Practice of pharmacy Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond c.ha ndbook of Pharmaceutical excipients chicago, Pharmaceutical press, 2005. The formulations may also include one or more of buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, diluents, and other known additives to provide a refined appearance of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a medicament).

Suitable carriers, diluents and excipients are well known to those skilled in the art and include and are exemplified by the following: carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient employed will depend upon the mode and purpose for which the compounds of the present invention are to be employed. The solvent is generally selected based on the knowledge of one skilled in the art of safe (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), and the like, and mixtures thereof. The formulations may also include one or more buffering agents, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents and other known additives to provide an elegant appearance of the drug (i.e., a compound of the present invention or a pharmaceutical composition thereof) or to aid in the manufacture of the pharmaceutical product (i.e., a medicament).

Acceptable diluents, carriers, excipients, and stabilizers are non-toxic to recipients at the dosages and concentrations employed, and include: buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (e.g. octadecyl dimethyl benzyl ammonium chloride; hexa-hydrocarbyl quaternary ammonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or a system such as TWEEN^TM、PLURONICS^TMOr of polyethylene glycol (PEG)A nonionic surfactant. The active pharmaceutical ingredients of the present invention (e.g., compounds of formula I or embodiments thereof) may also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization (e.g., hydroxymethylcellulose or gelatin microcapsules and poly- (methylmethacylate) microcapsules, respectively), in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington, The Science and Practice of Pharmacy, Remington The Science and Practice of Pharmacy (2005), 21 st edition, Lippincott Williams&Wilkins,Philadelphia,PA。

Sustained release preparations of the compounds of the invention (e.g., a compound of formula I or an embodiment thereof) may be prepared. Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula I or an embodiment thereof, in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained release matrices include polyesters, hydrogels (e.g., poly (2-hydroxyethyl-methacrylate) or poly (vinyl alcohol), polylactides (U.S. Pat. No.3,773,919), copolymers of L-glutamic acid and γ -ethyl-L-glutamine (Sidman et al, Biopolymers22:547,1983), non-degradable ethylene-vinyl acetate (Langer et al, J.biomed.Mater.Res.15:167,1981), such as LUPRON DEPOT^TMDegradable lactic acid-glycolic acid copolymer (injectable microsphere composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D (-) -3-hydroxybutyric acid (EP 133,988A). Sustained release compositions also include liposome-embedded compounds, which can be prepared by methods known per se (Epstein et al, Proc. Natl. Acad. Sci. U.S. A.82:3688,1985; Hwang et al, Proc. Natl. Acad. Sci. U.S. A.77:4030,1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP102,324A). Typically, liposomes are of the small (about 200-800 angstroms) monolayer type, wherein the lipid content is greater than about 30 mole% cholesterol, with the selected ratio adjusted for optimal treatment.

The formulations include those suitable for the routes of administration detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations are generally found in Remington: The Science and Practice of Pharmacy: Remington The Science and Practice of Pharmacy (2005), 21 st edition, Lippincott Williams & Wilkins, Philadelphia, Pa. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.

Generally, the formulations are prepared by: the active ingredient is uniformly and finely associated with a liquid carrier, diluent or excipient or a finely divided solid carrier, diluent or excipient or both, and then, if desired, the product is shaped. Typical formulations are prepared by mixing a compound of the invention with a carrier, diluent or excipient. The formulations may be prepared using conventional dissolution and mixing procedures. For example, bulk drug substances (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent) are dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients.

In one example, a compound of formula I or an embodiment thereof may be formulated by mixing at ambient temperature at an appropriate pH and in the desired purity with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to recipients at the dosages and concentrations employed to galenical administration forms). The pH of the formulation depends primarily on the particular use and concentration of the compound, but is preferably in any range from about 3 to about 8. In one example, a compound of formula I (or embodiments thereof) is formulated as an acetate buffer at pH 5. In another embodiment, the compound of formula I or embodiments thereof is sterile. The compounds may be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

Formulations of a compound of the present invention (e.g., a compound of formula I or embodiments thereof) suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets, each containing a predetermined amount of a compound of the present invention.

Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained or controlled release of the active ingredient therein.

Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules (e.g., gelatin capsules), syrups or elixirs may be prepared for oral use. Formulations of the compounds of the present invention (e.g., compounds of formula I or embodiments thereof) intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of: sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be coated by known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Examples of suitable oral administration forms are tablets containing about 1mg, 5mg, 10mg, 25mg, 30mg, 50mg, 80mg, 100mg, 150mg, 250mg, 300mg and 500mg of a compound of the invention in admixture with about 90-30mg of anhydrous lactose, about 5-40mg of croscarmellose sodium, about 5-30mg of polyvinylpyrrolidone (PVP) K30 and about 1-10mg of magnesium stearate. The powdered components are first mixed together and then mixed with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared by: the compound of the invention, for example 5-400mg, is dissolved in a suitable buffer solution, such as phosphate buffer, if necessary with the addition of a tonicity modifier (tonicifier), such as a salt such as sodium chloride. The solution may be filtered, such as with a 0.2 micron filter, to remove impurities and contaminants.

For the treatment of the eye or other external tissues, such as the mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated as an ointment, the active ingredient may be used with a paraffinic base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, butane 1, 3-diol, mannitol, sorbitol, glycerol, and polyethylene glycols (including PEG 400), and mixtures thereof. Topical formulations may desirably include compounds that enhance absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin permeation enhancers include dimethyl sulfoxide and related analogs.

The oil phase of the emulsifier of the invention can be composed of known ingredients in a known manner. Although the phase may comprise only emulsifiers, it desirably comprises a mixture of at least one emulsifier with a fat or oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier may be included with a lipophilic emulsifier used as a stabilizer. It is also preferred to include both oil and fat. In summary, the emulsifier(s) with or without the stabilizer(s) constitute the so-called emulsifying wax, and the wax together with the oil and fat constitute the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulation. Emulsifying materials and emulsion stabilization suitable for use in the formulations of the present inventionThe agent comprises60、80. Cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

In one aspect of topical administration, it is desirable to administer an effective amount of the pharmaceutical composition according to the present invention to a target area, e.g., a skin surface, a mucosal membrane, etc., which is adjacent to the peripheral neurons to be treated. This amount will generally range from about 0.0001mg to about 1g of the compound of the invention per application, depending on the area to be treated, the use being diagnostic, prophylactic or therapeutic, the severity of the symptoms and the nature of the topical vehicle employed. Preferred topical preparations are ointments wherein about 0.001 to about 50mg of active ingredient is used per cc of ointment base. The pharmaceutical compositions can be formulated as transdermal compositions or transdermal delivery devices ("patches"). Such compositions include, for example, a backing, an active compound reservoir, a control film, a liner, and a contact adhesive. Such transdermal patches may be used to provide a continuous pulse or to deliver the compounds of the invention as needed.

Aqueous suspensions of the compounds of the invention (e.g., compounds of formula I or embodiments thereof) contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, as well as dispersing or wetting agents such as naturally-occurring phosphatides (e.g., lecithin), condensation products of an alkylene oxide with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

The formulations of the compounds of the present invention (e.g., compounds of formula I or embodiments thereof) may be in a sterile injectable preparation form, such as a sterile injectable aqueous or oleaginous suspension. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, such as a solution of 1, 3-butanediol or as a lyophilized powder. Acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will depend upon the subject being treated and the particular mode of administration. For example, a time release formulation intended for oral administration to humans may contain about 1 to 1000mg of the active substance in admixture with a suitable and convenient amount of carrier material which may vary from about 5 to about 95% by weight of the total composition. Pharmaceutical compositions can be prepared to provide an administration amount that can be readily measured. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μ g of active ingredient per ml of solution so that a suitable volume can be produced at a rate of about 30 ml/hour.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration to the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; candy lozenges comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration having a particle size, for example, in the range of 0.1 to 500 microns (including particles in the range between 0.1 and 500 microns, in increments of microns, such as 0.5 microns, 1 micron, 30 microns, 35 microns, etc.) are administered by rapid inhalation through the nasal passages or by oral inhalation to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds heretofore used in the treatment of conditions as described below.

The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile injectable liquid carrier, for example water, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as hereinbefore described, or a suitable fraction thereof, of the active ingredient.

Certain embodiments of the present invention provide compounds of formula I (or embodiments thereof) to cross the blood-brain barrier when the binding target is located in the brain. Certain neurodegenerative diseases are associated with increased permeability of the blood brain barrier, such that the compounds of formula I (or embodiments thereof) can be readily introduced into the brain. While the blood-brain barrier remains intact, there are several art-known methods for transporting molecules across the blood-brain barrier, including but not limited to physical methods, lipid-based methods, and receptor and channel-based methods.

Physical methods of transporting a compound of formula I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, completely circumventing the blood-brain barrier or by creating an opening in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injection into the brain (see, e.g., Papanastassiou et al, Gene therapy 9:398-406,2002), interstitial infusion/convection enhanced delivery (see, e.g., Bobo et al, Proc. Natl. Acad. Sci. U.S.A.91:2076-2080,1994), and implantation of delivery devices in the brain (see, e.g., Gill et al, Nature Med.9:589-595, 2003; and Gliadel Wafers^TM,Guildford。

Pharmaceutical). Methods of creating openings in a Barrier include, but are not limited to, sonication (see, e.g., U.S. patent publication No.2002/0038086), osmotic pressure (e.g., by application of hypertonic mannitol (Neuwelt, e.a., immunization of the Blood-Brain Barrier and its management, volumes 1 and 2, Plenum Press, n.y.,1989)), and by permeabilization of, e.g., bradykinin or a permeabilizer (permeiblizer) a-7 (see, e.g., U.S. patent nos. 5,112,596,5,268,164,5,506,206, and 5,686,416).

Lipid-based methods of transporting a compound of formula I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, encapsulating the compound of formula I (or embodiments thereof) in liposomes coupled to antibody-binding fragments that bind to receptors on the blood-brain barrier vascular endothelium (see, e.g., U.S. patent application publication No.2002/0025313) and coating the compound of formula I (or embodiments thereof) on low density lipoprotein particles (see, e.g., U.S. patent application publication No.2004/0204354) or apolipoprotein E (see, e.g., U.S. patent application publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formula I (or embodiments thereof) across the blood-brain barrier include, but are not limited to, the use of glucocorticoid blockers to increase the permeability of the blood-brain barrier (see, e.g., U.S. patent application publication nos. 2002/0065259, 2003/0162695, and 2005/0124533); activating potassium channels (see, e.g., U.S. patent application publication No.2005/0089473), inhibiting ABC drug transporters (see, e.g., U.S. patent application publication No. 2003/0073713); the compounds of formula I (or embodiments thereof) are coated with transferrin and modulate the activity of one or more transferrin receptors (see, e.g., U.S. patent application publication No.2003/0129186) and cationize the antibody (see, e.g., U.S. patent No.5,004,697).

For intracerebral use, in certain embodiments, the compounds may be administered continuously by infusion into the reservoir of the CNS, although a single injection is acceptable. The inhibitor may be administered to the ventricles of the brain or otherwise introduced into the CNS or cerebrospinal fluid. Administration can be by use of an indwelling catheter and a continuous administration device such as a pump or can be by implantation, e.g., intracerebral implantation of a slow release vehicle. More specifically, the inhibitor may be injected by a chronically implanted cannula or by a chronic infusion with the aid of an osmotic mini-pump. Subcutaneous pumps are available which deliver proteins to the ventricles of the brain through small tubes. Highly sophisticated pumps can be refilled through the skin and their delivery rate can be set in the case of surgery. Examples of suitable administration regimens and delivery systems involving continuous intraventricular infusion with subcutaneous pump devices or through fully implanted drug delivery systems are those used to administer dopamine, dopamine agonists and cholinergic agonists in alzheimer's patients as well as animal models of parkinson's disease, such as Harbaugh, j.neural trans. supplement 24:271,1987; and DeYebenes et al, Mov. Disord.2:143,1987.

The compounds of formula I (or embodiments thereof) for use in the present invention are formulated, administered and administered in a manner consistent with good medical practice. Factors considered in this context include the particular condition being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of delivery of the agent, the method of administration, the time course of administration, and other factors known to the practitioner. The compounds of formula I (or embodiments thereof) need not be, but are optionally formulated with one or more agents currently in use to prevent or treat the disorder in question. The effective amount of such other agents will depend on the amount of the compound of the invention present in the formulation, the type of disorder or treatment, and other factors discussed above.

These are generally used at the same dosages and routes of administration as described herein, or at dosages of about 1 to 99% as described herein or at any dosage or any route as appropriate empirically/clinically determined.

For the prevention or treatment of disease, the appropriate dosage of a compound of formula I (or embodiments thereof) (either alone or in combination with other agents) will depend upon the type of disease being treated, the nature of the compound, the severity and course of the disease, the compound being administered for prophylactic or therapeutic purposes, previous therapy, the patient's clinical history and response to the compound, and the judgment of the attending physician. The compound is suitably administered to the patient at once or over a series of treatment sessions. Depending on the type of disease and severity of the disease, for example, whether by one or more separate administrations or by continuous infusion, about 1 μ g/kg to 15mg/kg (e.g., 0.1mg/kg-10mg/kg) of the compound may be an initial candidate dose for administration to a patient. A typical daily dosage range may be from about 1. mu.g kg to 100mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer (depending on the patient), the treatment will usually be continued until the desired suppression of disease symptoms occurs. An exemplary dosage range for the compound of formula I (or embodiments thereof) will be from about 0.05mg/kg to about 10 mg/kg. Thus, one or more doses of about 0.5mg/kg, 2.0mg/kg, 4.0mg/kg, or 10mg/kg (or any combination thereof) may be administered to a patient. The dose can be administered intermittently, e.g., weekly or every three weeks (e.g., such that the patient receives from about two doses to about twenty doses, or, e.g., about six doses of the antibody). An initial higher loading dose may be administered followed by one or more lower doses. An exemplary dosing regimen comprises administration of an initial loading dose of about 4mg/kg followed by a weekly maintenance dose of about 2mgkg of compound. However, other dosing regimens may be useful. The course of the treatment is readily monitored by conventional techniques and assays.

Other typical daily dosage ranges may be, for example, from about 1g/kg up to 100mg/kg or more (e.g., from about 1 μ g kg to 1mg/kg, from about 1 μ g/kg to about 5mg/kg, from about 1mg kg to 10mg/kg, from about 5mg/kg to about 200mg/kg, from about 50mg/kg to about 150mg/mg, from about 100mg/kg to about 500mg/kg, from about 100mg/kg to about 400mg/kg and from about 200mg/kg to about 400mg/kg), depending on the factors mentioned above. Generally, the clinician will administer the compound until a dose is reached that ameliorates or, optimally, eliminates one or more symptoms of the disease or disorder being treated. The progress of the treatment is readily monitored by routine assays. One or more agents provided herein can be administered simultaneously or at different times (e.g., one agent is administered prior to administration of a second agent). One or more agents can be administered to a subject using different techniques (e.g., one agent can be administered orally while a second agent is administered intranasally via intramuscular injection). The one or more agents may be administered such that the one or more agents simultaneously have a pharmacological effect in the subject. Alternatively, one or more agents may be administered such that the pharmacological activity of the first administered agent expires prior to administration of one or more second administered agents (e.g., 1,2,3, or 4 second administered agents).

C. Therapeutic indications and methods

The compounds of the invention modulate, preferably inhibit, ion flux in mammals (e.g., humans) through voltage-dependent sodium channels. Any such modulation (whether it is partial or complete inhibition or prevention of ion flow) is sometimes referred to herein as "blocking" and the corresponding compound is referred to as a "blocker" or "inhibitor". In general, the compounds of the invention down-regulate sodium channel activity by inhibiting the voltage-dependent activity of sodium channels and/or reduce or prevent sodium ion flux across cell membranes by preventing sodium channel activity such as ion flux.

The compounds of the invention inhibit ion flow through voltage-dependent sodium channels. In one aspect, the compound is a state modulator or frequency-dependent modulator of sodium channels, having low affinity for the resting/closed state and high affinity for the inactivated state. Without being bound by any particular theory, it is believed that these compounds may interact with overlapping sites in the lumen of the sodium conduction pore of channels similar to the other state-dependent sodium channel blockers described (ceste, s. These compounds may also interact with sites outside the lumen and have an allosteric effect on sodium ion conduction through the channel pores.

Any of these effects may be the origin of the overall therapeutic benefit provided by these compounds.

Thus, the compounds of the present invention are sodium channel blockers and are therefore useful in the treatment of diseases and conditions in mammals (e.g., humans) and other organisms, including all those diseases and conditions that are the result of or can be ameliorated by the modulation of voltage-dependent sodium channel biological activity. In particular, the compounds of the present invention, i.e., the compounds of formula (I) as well as the embodiments and (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs thereof) are useful for treating diseases and conditions in mammals (e.g., humans) that are the result of abnormal voltage-dependent nav1.7 biological activity or that can be ameliorated by modulation, preferably inhibition, of nav1.7 biological activity. In certain aspects, the compounds of the invention selectively inhibit nav1.7 above nav 1.5.

As defined herein, a sodium channel-mediated disease or disorder refers to a disease or disorder in a mammal (preferably a human) that is ameliorated by modulation of sodium channels and includes, but is not limited to, pain, central nervous disorders such as epilepsy, anxiety, depression, and bipolar disease; cardiovascular disorders such as cardiac arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular disorders such as restless leg syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neurotrauma and multiple sclerosis; and channel pathologies such as erythromelalgia (erythromyyalgia) and familial proctalgia syndrome.

In one aspect, the invention relates to compounds, pharmaceutical compositions, and methods of using the compounds and pharmaceutical compositions for treating sodium channel-mediated diseases in a mammal (preferably a human) by administering to a mammal (e.g., a human) in need of such treatment an effective amount of a sodium channel blocker modulator (particularly an inhibitor), and preferably diseases and conditions associated with: pain, central nervous disorders such as epilepsy, anxiety, depression, and bipolar disease; cardiovascular disorders such as cardiac arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular disorders such as restless leg syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neurotrauma and multiple sclerosis; and channel pathologies such as erythromelalgia and familial proctalgia syndrome.

Sodium channel-mediated diseases or conditions also include pain associated with HIV, HIV treatment-induced neuropathy, trigeminal neuralgia, glossopharyngeal neuralgia, metastatic infiltration secondary to neuropathy, painful obesity, thalamic injury, hypertension, autoimmune disease, asthma, drug addiction (e.g., opiates, diazepam, amphetamine, cocaine, alcohol, butane inhalation), alzheimer, dementia, age-related memory impairment, Korsakoff syndrome, restenosis, urinary dysfunction, incontinence, parkinson's disease, cerebrovascular ischemia, neuropathy, gastrointestinal disorders, sickle cell anemia, transplant rejection, heart failure, myocardial infarction, reperfusion injury, intermittent claudication, angina, spasm, respiratory disorders, cerebral ischemia or myocardial ischemia, long QT syndrome, catecholamine polymorphous susceptibility ventricular tachycardia (e myocardial transplant rejection, chronic lymphocytic lymphotrophic disc), angina pectoris, hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate inhalation), or stroke, Ophthalmological diseases, spasticity, spastic paraplegia, myopathy, myasthenia gravis, myotonia congenita, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, alopecia, anxiety disorders, psychotic disorders, mania, paranoia, seasonal affective disorder, panic disorder, Obsessive Compulsive Disorder (OCD), phobias, autism, asperger Syndrome, Rett Syndrome, childhood disintegration, attention deficit disorder, aggression, impulse control disorders, thrombosis, preeclampsia, congestive heart failure, cardiac arrest, Freidrich ataxia, spinocerebellar ataxia (Spinocerebellar ataxia), myelopathy, radiculopathy, systemic lupus erythematosus, granulomatous disease, olive-bridge-cerebellar atrophy, spinocerebellar ataxia (spinocerebellar ataxia), paroxysmal ataxia, tic ataxia, myotonia congenita, hyperkalia, hyperkalemia, aponeurotic paralysis, anxiety, panic disorder, panic, Progressive pallidal atrophy (progressive pallidal atrophy), progressive supranuclear palsy and spasticity, traumatic brain injury, cerebral edema, hydrocephalus injury, spinal cord injury, anorexia nervosa, bulimia nervosa, Prader-Willi Syndrome (Prader-Willi Syndrome), obesity, optic neuritis, cataracts, retinal hemorrhage, ischemic retinopathy, retinitis pigmentosa, acute and chronic glaucoma, macular degeneration, retinal artery occlusion, chorea, huntington's chorea, cerebral edema, proctitis, postherpetic neuralgia, acute pain (eudynia), heat sensitivity, sarcoidosis, irritable bowel Syndrome, Tourette Syndrome (Tourette Syndrome), leich-Nyhan Syndrome (Lesch-Nyhan Syndrome), brugada Syndrome (Brugado Syndrome), linder Syndrome (Liddle Syndrome), crohn's disease, multiple sclerosis and pain associated with Multiple Sclerosis (MS) Amyotrophic Lateral Sclerosis (ALS), diffuse sclerosis, diabetic neuropathy, peripheral neuropathy, Charcot Marie Tooth Syndrome, arthritis, rheumatoid arthritis, osteoarthritis, chondrocaliosis, atherosclerosis, dystonia burst, myasthenia Syndrome, myotonia, dystrophic myotonia, muscular dystrophy, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, psychological deficiency, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia, primary erythromelalgia, rectal pain, cancer, epilepsy, local and systemic tonic seizures, febrile convulsions, absence seizures (mild epilepsy), myoclonic seizures, dystonic seizures, clonic seizures, Lennox Gastaut, West Syndrome (West Synme) (contracture seizures), Various refractory seizures (multiresistant seires), seizure prophylaxis (anti-epileptogenesis), familial mediterranean fever syndrome, gout, restless leg syndrome, arrhythmia, fibromyalgia, neuroprotection under ischemic conditions caused by stroke or nerve trauma, tachy-arrhythmia, atrial and ventricular fibrillation and as a general or local anesthetic.

As used herein, the term "pain" refers to all classes of pain and is considered to include, but is not limited to, neuropathic pain, inflammatory pain, nociceptive pain, primary pain, neuropathic pain, orofacial pain, burning pain, mouth burn syndrome, somatic pain, visceral pain, facial muscle pain, dental pain, cancer pain, chemotherapy pain, wound pain, surgical pain, post-operative pain, labor pain, Chronic Regional Pain Syndrome (CRPS), reflex sympathetic dystrophy, brachial plexus avulsion, neurogenic bladder disorder, acute pain (e.g., musculoskeletal and post-operative pain), chronic pain, persistent pain, peripheral mediated pain, central mediated pain, chronic headache, migraine, hereditary hemiplegic migraine, headache-related illness, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, post-stroke pain, Thalamic injury, radiculopathy, HIV pain, post-herpetic pain, non-cardiogenic chest pain, irritable bowel syndrome and pain associated with bowel disease and dyspepsia and combinations thereof.

In addition, sodium channel blockers have clinical uses other than pain. The invention therefore also relates to compounds, pharmaceutical compositions and methods of using the compounds and pharmaceutical compositions for treating diseases or conditions such as cancer and pruritus (itch).

Pruritus, commonly referred to as itch, is a common dermatological condition. Although the exact cause of pruritus is complex and not fully understood, there has long been evidence that itch involves sensory neurons, particularly C-fibers, similar to those that mediate pain (Schmelz, m. et al, j. neurosci, (1997),17: 8003-8). In particular, it is believed that sodium influx through the voltage gated sodium channel is essential for transmitting itch sensations from the skin. The delivery of the itch pulse creates an unpleasant sensation that causes the desire to scratch or the reflex.

Various causes and electrical pathways for itch are known. In humans, itch may be caused by histamine or PAR-2 agonists such as mucunain (mucunain), which activate a unique population of C fibers (Namer, b. et al, j. neurophysiol (2008),100: 2062-9). Various neurotrophic peptides are known to mediate itch in animal models (Wang, H. and Yospiovitch, G., International Journal of Dermatology (2010),49: 1-11). Itching can also be caused by opiates (opioids), which is a unique pharmacological evidence from pain responses.

There is a complex interaction between the itch and pain responses, which is caused in part by overlapping sensory inputs from the skin (Ikoma, a. et al, arch. dermaltol. (2003),139:1475-8) and also from different etiologies of both pain and itch. The pain response may exacerbate itch by enhancing central sensitization or produce pain-suppressing scratching. Particularly severe forms of chronic itching occur when a painful response is absent, such as post-herpetic itching (Oaklander, A.L. et al, Pain (2002),96: 9-12).

The compounds of the invention are also useful in the treatment of pruritus. The rationale for treatment of itch with inhibitors of the sodium channels of the voltage gate, particularly nav1.7, is as follows:

1) the propagation of electrical activity in the C-fibers of the sensory purine stimulant (pruritinergic stimulant) requires sodium to enter through the voltage gated sodium channel.

2) NaV1.7 is expressed in C fibers and keratinocytes in human skin (Zhao, P. et al, Pain (2008),139: 90-105).

3) Functional mutations that result in NaV1.7(L858F) causing erythromelalgia also cause chronic itching (Li, Y., et al, Clinical and Experimental department (2009),34: e313-e 4).

4) Chronic itch can be alleviated by treatment with sodium channel blockers, such as the local anesthetic lidocaine (Oaklander, a.l., et al, Pain (2002),96: 9-12; villamil, A.G., et al, The American Journal of medicine (2005),118: 1160-3). In these reports, lidocaine is effective when administered intravenously or topically (Lidoderm patch). Lidocaine can have multiple activities where plasma concentrations are reached when administered systemically, but when administered locally, plasma concentrations are only about 1 μ M (drug evaluation and research center NDA 20-612). At these concentrations, lidocaine is selective for sodium channel blockade and inhibits spontaneous electrical activity in C fibers and Pain response in animal models (Xiao, w.h., and Bennett, g.j.. Pain (2008),137: 218-28). Types of itch or skin irritation include, but are not limited to:

a) psoriasis pruritus, pruritus due to hemodialysis (hemodyalisis), pruritus due to aqueous (aguagenicpruritus), and pruritus caused by skin conditions (e.g., contact dermatitis), systemic conditions, neuropathy, psychogenic factors, or mixtures thereof;

b) itch caused by allergic reactions, insect bites, allergies (e.g., dry skin, acne, eczema, psoriasis), inflammatory conditions or injuries;

c) itch associated with vulvar vestibulitis; and

d) skin irritation or inflammatory effects from the administration of another therapeutic agent such as, for example, antibiotics, antivirals, and antihistamines.

The compounds of the present invention are also useful for the treatment of certain cancers, such as hormone sensitive cancers, such as prostate cancer (adenocarcinoma), breast cancer, ovarian cancer, testicular cancer, and thyroid neoplasia, in mammals, preferably humans. It has been demonstrated that voltage gated sodium channels are to be expressed in prostate and breast cancer cells. An integral part of the metastatic process in human breast cancer is the upregulation of nascent nav1.5 and can be used as a novel marker for both metastatic phenotype and therapeutic targets (clin. cancer res. (2005), august 1 day; 11(15): 5381-9). Functional expression of the voltage gated sodium channel α -subunit, particularly nav1.7, correlates with strong metastatic potential of prostate cancer (CaP) in vitro. Using antibodies specific for the sodium channel alpha subunit, voltage gated sodium channel alpha subunit immunostaining was evident in prostate tissue and significantly stronger in CaP versus non-CaP patients (Prostatcancer Prostatic Dis., 2005; 8(3): 266-73). See also Diss, J.K.J., et al, mol.cell.Neurosci. (2008),37: 537-.

In view of the above, in one embodiment, the present invention provides a method for treating or protecting a mammal from a sodium channel-mediated disease, particularly pain, comprising administering to a mammal, particularly a human, in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, wherein the compound modulates the activity of one or more voltage-dependent sodium channels.

Another embodiment of the present invention is a method of treating a disease or disorder in a mammal, preferably a human, wherein the disease or disorder is selected from the group consisting of pain, depression, cardiovascular disease, respiratory disease and psychiatric disease and combinations thereof, and wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof or a pharmaceutically acceptable salt, solvate or prodrug thereof, or an embodiment of a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or a mixture thereof or a pharmaceutically acceptable salt, solvate or prodrug thereof and a pharmaceutically acceptable excipient.

An embodiment of this embodiment is where the disease or disorder is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain, labor pain, birth pain, neurogenic bladder disorder, ulcerative colitis, chronic pain, persistent pain, peripheral mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, and combinations thereof.

Another embodiment of this embodiment is where the disease or disorder is selected from the group consisting of HIV-associated pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, thermal sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, pain associated with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-associated disease, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, or a combination thereof, Local and systemic tonic attacks, restless legs syndrome, cardiac arrhythmias, fibromyalgia, neuroprotection under ischemic conditions caused by stroke or nerve trauma, tachyarrhythmia, atrial fibrillation and ventricular fibrillation.

Another embodiment of the present invention is a method of treating, but not preventing, pain in a mammal, wherein the method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

An embodiment of this embodiment is a method, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, wound pain, surgical pain, post-surgical pain, labor pain, birth pain, dental pain, chronic pain, persistent pain, peripheral mediated pain, centrally mediated pain, chronic headache, migraine, sinus headache, tension headache, phantom limb pain, peripheral nerve injury, trigeminal neuralgia, post-herpetic neuralgia, acute pain, familial erythromelalgia, primary erythromelalgia, familial rectal pain or fibromyalgia, and combinations thereof.

Another embodiment of this embodiment is a method, wherein said pain is associated with a disease or condition selected from the group consisting of: HIV, HIV treatment-induced neuropathy, heat sensitivity, sarcoidosis, irritable bowel syndrome, crohn's disease, multiple sclerosis, amyotrophic lateral sclerosis, diabetic neuropathy, peripheral neuropathy, rheumatoid arthritis, osteoarthritis, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-associated diseases, neurogenic bladder disorders, ulcerative colitis, cancer, epilepsy, local and systemic tonic attacks, restless leg syndrome, cardiac arrhythmias, ischemic conditions resulting from stroke or nerve trauma, tachyarrhythmia, atrial fibrillation, and ventricular fibrillation.

Another embodiment of the present invention is a method of treating pain in a mammal, preferably a human, by inhibiting the flow of ions through voltage-dependent sodium channels in the mammal, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof or pharmaceutically acceptable salts, solvates or prodrugs thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof or pharmaceutically acceptable salts, solvates or prodrugs thereof, and a pharmaceutically acceptable excipient.

Another embodiment of the present invention is a method of treating pruritus in a mammal, preferably a human, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or an embodiment of a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

Another embodiment of the present invention is a method of treating cancer in a mammal, preferably a human, wherein said method comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or an embodiment of a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, as listed above, as a stereoisomer, enantiomer or tautomer thereof or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable excipient.

Another embodiment of the invention is a method of reducing ion flow through a voltage-dependent sodium channel in a mammalian cell, wherein the method comprises contacting the cell with an embodiment of a compound of the invention, as set forth above, as a stereoisomer, enantiomer or tautomer thereof, or mixtures thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Another embodiment of the present invention is a method of selectively inhibiting a first voltage gated sodium channel on a second voltage gated sodium channel in a mammal, wherein the method comprises administering to the mammal an inhibitory amount of a compound of formula (I) or an embodiment of a compound of formula (I).

Another embodiment of the invention is a method of selectively inhibiting nav1.7 (as compared to nav 1.5) in a mammal or mammalian cells, wherein the method comprises administering to a mammal in need thereof an inhibitory amount of a compound of formula (I) or an embodiment thereof.

For each of the above embodiments relating to the treatment of diseases and conditions in mammals, the present invention also contemplates in relation thereto a compound of formula I or an embodiment thereof for use as a medicament for the treatment of such diseases and conditions.

For each of the above embodiments relating to the treatment of diseases and conditions in mammals, the invention also relatedly encompasses the use of a compound of formula I or an embodiment thereof for the manufacture of a medicament for the treatment of such diseases and conditions.

Another embodiment of the invention is a method of using a compound of formula (I) as a standard or control for in vitro or in vivo assays to determine the efficacy of test compounds in modulating the efficacy of voltage-dependent sodium channels.

In another embodiment of the invention, the compounds of formula (I) are isotopically labeled having one or more atoms therein, replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present invention. Examples of isotopes that can be incorporated into compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as, but not limited to²H、³H、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and¹²⁵I. these isotopically labeled compounds will be useful to help determine or measure the effectiveness of the compounds by characterizing, for example, the site or mode of action on the sodium channel or the binding affinity to a pharmaceutically important site of action on the sodium channel, particularly nav 1.7. Certain isotopically labelledCompounds of formula (I) (e.g., those incorporating radioisotopes) are useful for drug and/or matrix tissue distribution studies. Radioisotope tritium, i.e.³H and carbon-14, i.e.,¹⁴c, are particularly useful for this purpose, based on their ease of incorporation and rapid detection methods.

Via heavier isotopes such as deuterium (i.e. deuterium)²H) Substitution may provide certain therapeutic advantages resulting from greater metabolic stability, for example, prolonged in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances.

Such as¹¹C、¹⁸F、¹⁵O and¹³positron emitting isotope substitution of N can be used in Positron Emission Tomography (PET) studies for examination of stromal receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those set out below in the examples, using appropriate isotopically-labelled reagents in place of the unlabelled reagents previously used.

Test compounds

The assessment of the compounds of the invention in mediating, in particular inhibiting, sodium channel ion flow may be determined using the assays described below. Alternatively, the assessment of compounds in the treatment of human conditions and diseases can be established in industry standard animal models for demonstrating the efficacy of compounds in the treatment of pain. Animal models of human neuropathic pain patients have been developed that produce reproducible sensory shortages (allodynia, hyperesthesia, and spontaneous pain) over a sustained period of time that can be assessed by sensory testing. By establishing the extent of mechanical, chemical and temperature induced by the presence of allodynia and hyperesthesia, several physiological conditions observed in humans can be mimicked, allowing the evaluation of drug therapy.

In a rat model of peripheral nerve injury, ectopic activity in the injured nerve corresponds to behavioral signs of pain. In these models, sodium channel blockers and local anestheticsIntravenous administration of cocaine inhibits ectopic activity and reverses tactile allodynia at concentrations that do not affect general behavioral and motor functions (Mao, J. and Chen, L.L, Pain (2000),87: 7-17). Dose allometric scaling (allometric scaling) effective in these rat models was converted to doses similar to those shown to be effective in humans (Tanelian, d.l. and Brose, w.g., Anesthesiology (1991),74(5): 949-. In addition, applied in the form of a skin patchLidocaine is currently FDA approved for the treatment of post-herpetic neuralgia (Devers, a. and Glaler, b.s., clin.j.pain (2000),16(3): 205-8).

The present invention readily provides a number of different ways to identify sodium channel modulators useful as therapeutic agents. Identification of sodium channel modulators can be assessed using a variety of in vitro and in vivo assays, e.g., measuring current, measuring membrane potential, measuring ion current (e.g., sodium or guanidinium salts), measuring sodium concentration, measuring second messenger and transcript levels, and using, e.g., voltage sensitive dyes, radiotracers, and patch clamp electrophysiology.

One such protocol involves screening for chemical agents capable of modulating the activity of sodium channels, thereby identifying them as modulators.

Typical assays described in Bean et al, J.general Physiology (1983),83: 613-. Such techniques are known to those skilled in the art and can be developed using current techniques into either low-throughput assays or medium-throughput assays for evaluating compounds' ability to modulate sodium channel behavior.

The throughput of the test compound is an important consideration in selecting the screening assay to be used. In some strategies, where hundreds of thousands of compounds are to be tested, it is not desirable to use a low-throughput approach. However, in other cases, it is desirable to identify low throughput important differences between a limited number of compounds. It will often be necessary to combine assay types to identify a particular sodium channel modulating compound.

Electrophysiological assays using the patch clamp technique are recognized as the gold standard for detailed characterization of sodium channel compound interactions and are described in Bean et al, op.cit, and Leuwer, m. There are manual Low Throughput Screening (LTS) methods that can compare 2-10 compounds per day; recently developed systems for daily automated Medium Throughput Screening (MTS)20-50 patches (i.e. compounds); and from Molecular Devices Corporation (Sunnyvale, CA), which allows automated High Throughput Screening (HTS)1000-3000 patches (i.e., compounds) per day.

An automated patch clamp system employs planar electrode technology to accelerate the rate of drug discovery. The planar electrodes enable high impedance, cell-adhesive sealing followed by stable, low noise whole-cell recordings, which are comparable to conventional recordings. A suitable instrument is PatchXpress7000A (Axon Instruments Inc., Union City, Calif.). The success rate and stability of sealing was graded for various cell lines and culture techniques, including adherent cells and cells that grow spontaneously in suspension. Immortalized cells (e.g., HEK and CHO) that stably express high levels of the associated sodium ion channel can be adapted to high density suspension culture.

Other assays may be selected that allow the researcher to identify compounds that block a particular state of a channel, such as an open state, a closed state, or a resting state, or that block a transition from an open state to a closed state, a closed state to a resting state, or a resting state to an open state. Those skilled in the art are generally familiar with such assays.

Binding assays may also be used. The design included either a traditional radioactive filter-based binding assay or a confocal-based fluorescence system, both HTS, obtained from company of the Evotec OAI group (Hamburg, Germany).

Radioactive flow measurements may also be used. In this assay, the channel opening is stimulated with veratridine or aconitine and maintained in a stable on state with the toxin, and the channel blocker is identified by its ability to prevent ion influx. The assay may use radioactive 22[ Na ] and 14[ C ] guanidine ions as tracers. FlashPlate & Cytostar-T plates in live cells avoid the isolation step and are amenable to HTS. The scintillator plate technology has also advanced the process to HTS suitability. The amount of information is quite good due to the functional aspects of the assay.

Yet another format measures redistributed membrane potentials using the FLIPR system membrane potential kit (HTS) obtained from Molecular Dynamics (a department of Amersham Biosciences, Piscataway, NJ). This approach is limited to slow membrane potential changes. Some problems may arise from the fluorescent background of the compound. Test compounds may also directly affect the fluidity of the cell membrane and lead to an increase in intracellular dye concentration. In addition, the amount of information is quite good due to the functional aspects of the assay.

Sodium dyes can be used to measure the rate or amount of sodium ion influx through a channel. This type of assay provides a very high amount of information about possible channel blockers. The assay is functional and will measure Na + influx directly. CoroNa Red, SBFI, and/OR sodium green (Molecular Probes, inc. eugene OR) can be used to measure Na influx; all Na-responsive dyes. They can be used in combination with the FLIPR instrument. The use of these dyes in screening has not previously been described in the literature. In this form, it is also possible to use calcium dyes.

In another assay, a FRET-based voltage sensor is used to measure the ability of a test compound to directly block Na influx. Commercially available HTS systems include VIPR^TMThe II FRET system (Life Technologies, or department of Aurora Biosciences Corporation, San Diego, CA, Vertex Pharmaceuticals, Inc.), which can be used in conjunction with FRET dyes, was also obtained from Aurora Biosciences. The assay measures the sub-second response to voltage changes. There is no need for a modifier of channel function. The assay measures depolarization and hyperpolarization and provides a reference output for quantification. Slightly less expensive MTS version of the assayThis utilizes FLEXstation bound to FRET dyes from Aurora Biosciences^TM(Molecular Devices Corporation). Other methods of testing the compounds disclosed herein are also readily known and available to those skilled in the art.

The modulators so identified are then tested in a variety of in vivo models to determine if they have minimal adverse events to alleviate pain, particularly chronic pain or other afflictions such as cancer and pruritus (itch). The assays described in the bioassay section below can be used to assess the biological activity of the compounds of the invention.

Generally, the efficacy of a compound of the invention is expressed in terms of its IC50 value ("inhibitory concentration-50%"), which is a measure of the amount of compound required to achieve 50% inhibition of the target sodium channel activity over a specified period of time. For example, representative compounds of the invention have shown a range of IC50 in patch voltage clamp nav1.7 electrophysiological assays described herein of less than 100 nanomolar to less than 10 micromolar.

In another aspect of the invention, for comparative purposes, the compounds of the invention may be used as exemplary agents in vitro or in vivo studies to find other compounds that may also be useful in treating or protecting against the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 activity, preferably nav1.7 activity, in a biological sample or a mammal, preferably a human, comprising administering to the mammal, preferably a human, a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) or contacting the biological sample with a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I). The term "biological sample", as used herein, includes, but is not limited to, cell cultures or extracts thereof; obtaining a biopsy material from a mammal or an extract thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of nav1.1, nav1.2, nav1.3, nav1.4, nav1.5, nav1.6, nav1.7, nav1.8 or nav1.9 activity in a biological sample can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and comparative evaluation of novel sodium channel inhibitors.

The compounds of the present invention (or stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts or prodrugs thereof) and/or the pharmaceutical compositions described herein comprising a pharmaceutically acceptable excipient and one or more compounds of the present invention are useful for the preparation of a medicament for the treatment of a sodium channel-mediated disease or condition in a mammal.

D. Combination therapy

In the treatment of sodium channel-mediated diseases and conditions, the compounds of the present invention may be effectively combined with one or more other compounds of the present invention or one or more other therapeutic agents, or any combination thereof. For example, the compounds of the present invention may be administered simultaneously, sequentially or separately in combination with other therapeutic agents, including but not limited to:

opiate analgesics, such as morphine, heroin, cocaine, oxymorphone, levorphanol, oxycodone, codeine, dihydrocodeine, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, melimidine (meripidine), methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine;

non-opiate analgesics, e.g., acemenifen (acementoniphen), salicylates (e.g., aspirin);

non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, fenoprofen, ketoprofen, celecoxib, diclofenac, flubensal (diflusinal), etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen (nitroflurbiprofen), olsalazine, oxaprozin, phenylbutazone, piroxicam, azasulfapyridine, sulindac, tolmetin, and zomepirac;

anticonvulsants, e.g., carbamazepine, oxcarbazepine, lamotrigine, valproate, topiramate, gabapentin and pregabalin;

antidepressants such as tricyclic antidepressants, e.g., amitriptyline, clomipramine, desipramine (despramine), imipramine and nortriptyline;

COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib and lumiracoxib;

α -adrenergic agents, such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil and 4-amino-6, 7-dimethoxy-2- (5-methanesulfonamido-1, 2,3, 4-tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline;

barbiturate sedatives, such as amobarbital, alprental, butarbital (butarbital), butabarbital (butarbital), mebendal, methamphetal, methohexital, pentobarbital, phenobarbital (phenobarbital), secobarbital, talbarbital, thiopentobarbital (theomylal), and thiobarbital;

tachykinin (NK) antagonists, in particular NK-3, NK-2 or NK-1 antagonists, such as (aR,9R) -7- [3, 5-bis (trifluoromethyl) benzyl) ] -8,9,10, 11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazocino (diazocino) [2,1-g ] [1,7] -naphthyridine-6-13-dione (TAK-637), 5- [ [2R,3S) -2- [ (1R) -1- [3, 5-bis (trifluoromethylphenyl ] ethoxy-3- (4-fluorophenyl) -4-morpholinyl ] -methyl ] -1, 2-dihydro-3H-1, 2, 4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3- [ [ 2-methoxy 5- (trifluoromethoxy) phenyl ] -methylamino ] -2-phenylpiperidine (2S, 3S);

coal tar analgesics, especially acetaminophen;

serotonin reuptake inhibitors, such as paroxetine, sertraline, norfluoxetine (norfluoxetine demethylated metabolite), the metabolite desmethylsertraline, ` 3 fluvoxamine, paroxetine, citalopram, the citalopram metabolite desmethylcitalopram, escitalopram, d, l-fenfluramine, femoxetine, efoxetine, cyanoduloxetine (cyanodithiepin), ritoxetine, dapoxetine, nefazodone, cilazalone, trazodone and fluoxetine;

norepinephrine (noradrenaline) reuptake inhibitors, e.g. maprotiline, lofepramine, mirtazapine (mirtazepine), oxaprotiline, fezolamine, tomoxetine, mianserin, bupropion (buproprion), the bupropion metabolite hydroxyamphetane, nomifensine and viloxazineIn particular selective norepinephrine reuptake inhibitors such as reboxetine, in particular (S, S) -reboxetine and venlafaxine duloxetine neuroleptic sedatives/anxiolytics;

dual serotonin-norepinephrine reuptake inhibitors such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, and imipramine;

acetylcholinesterase inhibitors such as donepezil;

5-HT3 antagonists such as ondansetron;

metabotropic glutamate receptor (mGluR) antagonists;

local anesthetics such as mexiletine and lidocaine;

corticosteroids such as dexamethasone;

antiarrhythmic agents, such as mexiletine and phenytoin;

muscarinic antagonists, such as tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, tilmicoline and ipratropium;

cannabinol;

capsaicin receptor agonists (e.g., cactus toxin (resiniferatoxin)) or antagonists (e.g., capsaicin receptor blockers (capsazepine));

sedatives, such as glutethimide, meprobamate, methaqualone, and dichlofenoxaprop;

anxiolytics such as diazepam,

an antidepressant such as mirtazapine,

topical agents (e.g., lidocaine, capsaicin, and resiniferatoxin);

muscle relaxants such as diazepam, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and oxyphenamine (orphradine);

an antihistamine or H1 antagonist;

an NMDA receptor antagonist;

5-HT receptor agonists/antagonists;

PDEV inhibitors;

·

cholinergic (nicotinic) analgesics;

alpha-2-ligand;

prostaglandin E2 subtype antagonists;

leukotriene B4 antagonist;

5-lipoxygenase inhibitors; and

5-HT3 antagonists.

Sodium channel-mediated diseases and conditions that may be treated and/or prevented using such combinations include, but are not limited to, pain, central and peripheral nerve-mediated acute, chronic, neurological and other diseases associated with: pain and other central nervous disorders such as epilepsy, anxiety, depression, and bipolar disease; or cardiovascular disorders such as cardiac arrhythmia, atrial fibrillation, and ventricular fibrillation; neuromuscular disorders such as restless leg syndrome and muscle paralysis or tetanus; neuroprotection against stroke, neurotrauma and multiple sclerosis; and channel pathologies such as erythromelalgia and familial proctalgia syndrome.

As used herein, "combination" refers to any mixture or permutation of one or more compounds of the present invention with one or more other compounds of the present invention or one or more additional therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include simultaneous or sequential delivery of a compound of the invention and one or more therapeutic agents. Unless the context clearly indicates otherwise, "combination" may include dosage forms of a compound of the invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include the route of administration of a compound of the invention with another therapeutic agent. Unless the context clearly indicates otherwise, "combination" may include formulation of a compound of the invention with another therapeutic agent. Dosage forms, routes of administration, and pharmaceutical compositions include, but are not limited to, those described herein.

The invention will be more fully understood by reference to the following examples. However, the examples should not be construed as limiting the scope of the invention.

D. Examples of the embodiments

These examples are intended to provide guidance to the skilled artisan in preparing and using the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention have been described, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.

The chemical reactions described in the examples (preparations) can be readily modified to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully carried out by modifications apparent to those skilled in the art, e.g., by appropriate protection of interfering groups, by using other suitable reagents known in the art other than those described, and/or by making routine modifications to the reaction conditions.

In the following examples, all temperatures are listed in degrees celsius unless otherwise indicated. Commercially viable reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge and used without further purification unless otherwise indicated. The reactions listed below are typically carried out under a positive pressure of nitrogen or argon or in anhydrous solvents with dry tubes (unless otherwise specified), and the reaction flask is typically equipped with a rubber septum for introducing substrates and reagents via syringe. The glassware is dried and/or heat dried. Deuterated CDCl using Trimethylsilyl (TMS) or residual non-deuterated solvent peaks as reference standard₃、d₆-DMSO、CH₃OD or d₆Acetone solvent solution (reported in ppm)¹H NMR spectrum. When peak diversity is reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet, br (broadening), dd (doublet of doublet), dt (doublet of triplet).

All abbreviations used for describing reagents, reaction conditions or equipment are intended to be consistent with the definitions listed in the "standard abbreviations and acronym lists". The chemical name of the discrete (discrete) compound of the present invention was obtained using the structural naming features of the ChemDraw naming program.

HPLC method a: XBridge C18, 30X 50mm, 5 um; mobile phase: water A (0.1% TFA), B CH₃CN (0.1% TFA); gradient: 15% -95% of B in 8.25min, and then keeping 95% of B for 1 min; flow rate: 60 mL/min.

HPLC method B: XBridge C18, 30X 50mm, 5 um; mobile phase: water A (0.1% TFA), B CH₃CN (0.1% TFA); gradient: 10% -95% of B in 7.25min, and then keeping 95% of B for 1 min; flow rate: 60 mL/min.

HPLC method C: XBridge C18, 30X 50mm, 5 um; mobile phase: water A (0.1% TFA), B CH₃CN (0.1% TFA); gradient: 15% -75% of B in 8.25min, and then keeping 95% of B for 1 min; flow rate: 60 mL/min.

Abbreviations used herein are as follows:

synthesis of preparation of ethyl 14- ((3, 4-dichlorophenoxy) methyl) benzoate

A mixture of 3, 4-dichlorophenol (3.08g, 18.9mmol), ethyl 4- (bromomethyl) benzoate (4.59g, 18.9mmol) and potassium carbonate (5.22g, 37.8mmol) in dry dimethylformamide (50mL) was heated to 60 ℃ under nitrogen. After 1.5h, the reaction mixture was diluted with ethyl acetate (150mL), washed with water (50mL), saturated ammonium chloride (2 × 50mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. Concentrating the filtrate in vacuoTo give the title compound (4.04g, 66%):¹H NMR(300MHz,CDCl₃)8.05(d,J＝7.9Hz,2H),7.44(d,J＝7.9Hz,2H),7.30(d,J＝9.1Hz,1H),7.04(d,J＝2.9Hz,1H),6.79(dd,J＝8.8,2.8Hz,1H),5.06(s,2H),4.36(q,J＝7.0Hz,2H),1.38(t,J＝7.1Hz,3H)；MS(ES+)m/z:324.8,326.7(M+1)。

synthesis of 24- ((3, 4-dichlorophenoxy) methyl) benzoic acid

A mixture of ethyl 4- ((3, 4-dichlorophenoxy) methyl) benzoate (preparation 1,1.26g, 3.87mmol) and sodium hydroxide (0.62g, 15.5mmol) in tetrahydrofuran (50mL) and water (20mL) was heated to reflux for 18 h. The organic solvent was removed in vacuo and the aqueous solution was cooled to 0 ℃. The aqueous solution was slowly acidified to pH-2 with concentrated hydrochloric acid. The solid was filtered and washed with water to give the title compound as a white solid (1.15g, quantitative yield);¹H NMR(300MHz,DMSO-d₆)13.00(br s,1H),7.93(d,J＝8.0Hz,2H),7.54-7.46(m,3H),7.32-7.28(m,1H),7.03-6.97(m,1H),5.19(s,2H)；MS(ES-)m/z:294.8,296.8(M-1)。

synthesis of 35-chloro-N- (N, N-dimethylsulfamoyl) -2, 4-difluorobenzamide

To a mixture of 5-chloro-2, 4-difluorobenzoic acid (9.69g, 50.3mmol) in anhydrous tetrahydrofuran was added 1, 1' -carbonyldiimidazole (16.1g, 99.3 mmol). The resulting mixture was heated at reflux for 0.5h and then cooled to ambient temperature. N, N-dimethylsulfonamide (12.3g, 99.1mmol) was added followed by 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (22.4mL, 145 mmol.) the reaction mixture was stirred at ambient temperature for 4 d.the reaction mixture was diluted with ethyl acetate (500mL), washed with 1N hydrochloric acid (2 × 400mL), brine (2 × 400mL)Washed, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a mixture of the title compound and 5-chloro-2, 4-difluorobenzoic acid. Anhydrous tetrahydrofuran (100mL) and 1, 1' -carbonyldiimidazole (6.49g, 40.0mmol) were added to the mixture, followed by heating at reflux for 45 minutes, and then cooling to ambient temperature. N, N-dimethylsulfonamide (5.02g, 40.4mmol) was added followed by 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (7.9mL, 52mmol) and the reaction mixture was stirred at ambient temperature for 22h the reaction mixture was diluted with ethyl acetate (500mL), washed with 1N hydrochloric acid (2 × 400mL), brine (2 × 400mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo to give the title compound as a white solid (10.4g, 69%):¹H NMR(300MHz,CDCl₃)8.69(d,J＝12.9Hz,1H),8.13(t,J＝8.0Hz,1H),7.04(dd,J＝8.2,11.1Hz,1H),3.01(s,6H)；MS(ES-)m/z 297.1,299.1(M-1)。

synthesis for preparation of 45-chloro-4- (3-chloro-4- (trifluoromethoxy) -phenoxy) -2-fluorobenzoic acid

To a mixture of tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) -phenoxy) -2-fluorobenzoate (preparation 5,1.98g,4.49mmol) in dichloromethane (30mL) was added trifluoroacetic acid (4 mL). The reaction mixture was stirred at ambient temperature for 3h, then the solvent was concentrated in vacuo to give the title compound as a white powder (1.64g, 95%):¹H NMR(300MHz,CDCl₃)9.72(br,1H),8.15(d,J＝7.3Hz,1H),7.39-7.36(m,1H),7.20(d,J＝2.8Hz,1H),7.00(dd,J＝2.8,9.0Hz,1H),6.68(d,J＝10.9Hz,1H)；MS(ES-)m/z 383.0,385.0(M-1)。

synthesis for preparation of tert-butyl 55-chloro-4- (3-chloro-4- (trifluoromethoxy) -phenoxy) -2-fluorobenzoate

To a mixture of tert-butyl 5-chloro-2, 4-difluorobenzoate (WO2012007883a1,1.17g,4.72mmol) and 3-chloro-4- (trifluoromethoxy) phenol (1.02g,4.80mmol) in anhydrous N, N-dimethylformamide (10mL) was added potassium carbonate (1.31g,9.45mmol), the mixture was stirred at ambient temperature for 19h, the reaction mixture was then diluted with ether (200mL), washed with saturated aqueous sodium bicarbonate solution (2 × 200mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo to give the title compound as a white solid (2.02g, 97%):¹H NMR(300MHz,CDCl₃)7.98(d,J＝7.3Hz,1H),7.34-7.31(m,1H),7.12(d,J＝2.9Hz,1H),6.93(dd,J＝2.9,9.0Hz,1H),6.68(d,J＝10.8Hz,1H),1.57(s,9H)；MS(ES+)m/z 440.9,441.9(M+1)。

synthesis for preparation of 65-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) -pyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid

To a mixture of methyl 5-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) -pyridin-3-yl) oxy) methyl) -2-fluorobenzoate (preparation 7,0.97g,2.11mmol) in tetrahydrofuran (30mL) and water (15mL) was added lithium hydroxide (0.300g,12.5mmol), the reaction mixture was heated to reflux for 1h after cooling to ambient temperature, the mixture was diluted with ethyl acetate (200mL), washed with 1N hydrochloric acid (2 × 150mL), brine (200mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated in vacuo to give the title compound as a white solid (0.91g, 97%):¹H NMR(300MHz,DMSO-d₆)13.63(s,1H),7.99-7.86(m,3H),7.59(d,J＝11.0Hz,1H),6.59(tt,J＝4.5,51.9Hz,1H),5.22(s,2H),4.85(t,J＝14.0Hz,2H)；MS(ES-)m/z 444.0,446.0(M-1)。

synthesis for preparation of methyl 75-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) -pyridin-3-yl) oxy) methyl) -2-fluorobenzoate

To a cold (0 ℃) mixture of methyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate (preparation 8, 0.800g, 3.66mmol) in anhydrous tetrahydrofuran (50mL) were added methanesulfonyl chloride (0.37mL,4.8mmol) and N, N-diisopropylethylamine (0.96mL,5.5mmol), the reaction mixture was warmed to ambient temperature and stirred for 17h, the reaction mixture was diluted with ethyl acetate (200mL), washed with 1N hydrochloric acid (200mL), brine (200mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated in vacuo and dimethylsulfoxide (25mL) was added to the mixture, 5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-ol (WO2012007869a2, 1.47g, 5.66mmol) and potassium carbonate (1.01g,7.30mmol) were added to the reaction mixture, stirred for 3h at ambient temperature, then diluted with ethyl acetate (200mL), washed with saturated aqueous solution of sodium bicarbonate (0.58% and filtered to obtain the title compound as a white solid, purified over silica gel column, purified over anhydrous sodium sulfate, filtered over silica gel column, filtered over anhydrous silica gel, filtered over anhydrous sodium sulfate, filtered, yield 0.58 mL, and purified over anhydrous sodium bicarbonate, filtered over silica gel column, filtered:¹H NMR(300MHz,CDCl₃)7.97(d,J＝6.3Hz,1H),7.77(d,J＝2.7Hz,1H),7.43(d,J＝2.7Hz,1H),7.37(d,J＝10.8Hz,1H),6.06(tt,J＝5.0Hz,53.1Hz,1H),5.12(s,2H),4.70(t,J＝12.2Hz,2H),3.93(s,3H)；MS(ES+)459.9,461.9(M+1)。

synthesis for preparing methyl 85-chloro-2-fluoro-4- (hydroxymethyl) benzoate

To a mixture of methyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -5-chloro-2-fluorobenzoate (preparation 9,2.18g,6.55mmol) in 1, 4-dioxane (75mL) was added 3N hydrochloric acid (4 mL.) the reaction mixture was stirred at ambient temperature for 3.5h, then diluted with ethyl acetate (200mL), washed with 1N hydrochloric acid (2 × 200mL), brine (200mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo and the residue was washed with 0-30% ethyl acetate in hexane as eluentPurification via silica gel column chromatography to give the title compound as a white solid (0.80g, 56% yield):¹H NMR(300MHz,CDCl₃)7.89(d,J＝6.4Hz,1H),7.37(d,J＝11.1Hz,1H),4.78(s,2H),3.91(s,3H),2.04(brs,1H)；MS(ES+)219.1,221.1(M+1)。

synthesis of methyl 94- ((tert-butyldimethylsilyloxy) methyl) -5-chloro-2-fluorobenzoate

To a mixture of (4-bromo-2-chloro-5-fluorobenzyloxy) (tert-butyl) dimethylsilane (preparation 10, 4.56g, 12.9mmol), palladium (II) acetate (0.88g,1.29mmol), XANTPHOS (0.75g,1.29mmol), triethylamine (2.62g,25.9mmol) and methanol (8.30g,25.9mmol) in dioxane (100mL) was washed with carbon monoxide for 10 min. The reaction mixture was then refluxed for 16h under carbon monoxide (1 atm). The solid was filtered through a pad of celite and the filtrate was diluted with ethyl acetate (100mL), washed with saturated ammonium chloride (3x20mL), brine (3x20mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography using a 0-10% gradient elution with ethyl acetate-containing hexane to give the title compound (0.71g, 34% yield based on 2.27g of recovered 4-bromo-2-chloro-5-fluorobenzyloxy) (tert-butyl) dimethylsilane) as a viscous liquid:¹H NMR(300MHz,CDCl₃)7.85(d,J＝6.4Hz,1H),7.35(d,J＝11.4Hz,1H),4.75(s,2H),3.90(s,3H),0.94(s,9H),0.12(s,6H)。

synthesis for preparation of 10 (4-bromo-2-chloro-5-fluorobenzyloxy) (tert-butyl) dimethylsilane

(4-bromo-2-chloro-5-fluorophenyl) methanol (preparation 17, 10.0g, 44.7mmol), tert-butyldimethylchlorosilane (10.1g,67.1mmol) and imidazole (9.10g,134mmol) were reacted in N, N-dimethyl etherThe mixture in dimethylformamide (50mL) was stirred at ambient temperature for 6 h. The reaction mixture was diluted with ethyl acetate (600mL), washed with brine (3 × 250mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography eluting with ethyl acetate-containing hexanes using a 0-10% gradient to give the title compound as a viscous liquid (14.1g, 89% yield):¹H NMR(300MHz,CDCl₃)7.90(d,J＝6.4Hz,1H),7.42(d,J＝11.4Hz,1H),4.75(s,2H),0.91(s,9H),0.12(s,6H)。

synthesis for preparing 115-bromo-3-chloro-2-isobutoxypyridine

A solution of 2-methylpropan-1-ol (7.92g,107mmol) was added to a slurry of sodium hydride (3.21g,134mmol, 60% dispersion in oil) in N, N-dimethylformamide (50mL) at 0 ℃. The reaction mixture was stirred for 0.5h, then a solution of 5-bromo-2, 3-dichloropyridine (20.2g,89.0mmol) in N, N-dimethylformamide (80mL) was added at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1h, then quenched with brine (100 mL). The organic layer was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography eluting with ethyl acetate-containing hexanes using a 10-30% gradient to give the title compound as a colorless liquid (22.9g, 81% yield):¹H NMR(300MHz,CDCl₃)8.04(s,1H),7.72(s,1H),4.08(d,J＝3.0Hz,2H),2.17-1.97(m 1H),1.00(d,J＝9.0Hz,6H)。

synthesis for preparation of 123-chloro-2-isobutoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

A mixture of 5-bromo-3-chloro-2-isobutoxypyridine (preparation 11, 10.6g, 40.0mmol), borane pinacol ester (12.7g, 50.0mmol), dichlorobis triphenylphosphine palladium (II) (2.80g,4.00mmol) and potassium acetate (11.8g,120mmol) in dioxane was refluxed for 4 h. The reaction mixture was cooled to ambient temperature and then diluted with ethyl acetate (300mL), washed with brine (3 × 100mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography eluting with ethyl acetate in hexanes using a 10-30% gradient to give the title compound as a colorless liquid (11.9g, 95% yield) which was used in the next step without further characterization: MS (ES +)312.2,314.2(M + 1).

Synthesis for preparing 135-chloro-6-isobutoxy pyridin-3-ol

A mixture of 3-chloro-2-isobutoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (preparation 12,11.9g,38.3mmol) and 35% hydrogen peroxide (4.90g,4.3mL.153mmol) in tetrahydrofuran (100mL) was stirred at ambient temperature for 4 h. The reaction was diluted with acetate (200mL), washed with saturated ammonium chloride (3x100mL), brine (3x 50mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colorless liquid (7.69g, quantitative yield) which was used in the next step (preparation 18) without any further purification: MS (ES-)200.2,202.2 (M-1).

Synthesis for preparation of 142, 3-dichloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

Following the procedure as described in preparation 12 and varying as needed to replace 5-bromo-3-chloro-2-isobutoxypyridine with 5-bromo-2, 3-dichloropyridine the title compound was obtained as a yellow gum (5.46g, quantitative yield) and used in the next step (preparation 15) without any further characterization: MS (ES +)274.0,276.0, (M +1),190.1,192.1 (M-80).

Synthesis for preparing 155, 6-dichloropyridin-3-ol

Following the procedure as described in preparation 13 and varying as required to replace 3-chloro-2-isobutoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine with 2, 3-dichloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (preparation 14) the title compound was obtained as a yellow gum (3.28g, quantitative yield) and used in the next step without any further characterization: MS (ES +)164.03,166.03(M + 1).

Synthesis of preparation 165-chloro-4- ((5, 6-dichloropyridin-3-yl) oxy) -2-fluorobenzoic acid

Following the procedure as described in preparation 4, the procedure was followed as appropriate to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 5-chloro-4- ((5, 6-dichloropyridin-3-yl) oxy) -2-fluorobenzoate (preparation 21) to obtain the title compound as a white solid (quantitative):¹H NMR(300MHz,CDCl₃)8.18-8.14(m,2H),7.50(d,J＝2.6Hz,1H),6.75(d,J＝10.5Hz,1H)；MS(ES-)333.9,335.9(M-1)。

synthesis of 17 (4-bromo-2-chloro-5-fluorophenyl) methanol

To a mixture of methyl 4-bromo-2-chloro-5-fluorobenzoate (15.4g,57.6mmol) and methanol (3.70g,5.1mL,115.0mmol) in tetrahydrofuran at ambient temperatureA solution of lithium borohydride in tetrahydrofuran (28.8mL,115.0mmol,1.0M solution in tetrahydrofuran) was added to the solution. The reaction solution was refluxed for 6h and then cooled to ambient temperature. Methanol (50mL) was added to the reaction mixture, followed by dilution with ethyl acetate (500 mL). The reaction mixture was washed with 10% aqueous HCl (3x100mL), brine (3x100mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue triturated with ether to give the title compound as a colourless solid (12.9g, quantitative yield):¹H NMR(300MHz,CDCl₃)7.51(d,J＝6.1Hz,1H),7.30(d,J＝8.9Hz,1H),4.69(s,2H),2.14(br,1H)；MS(ES-)239.0,237.1(M-1)。

synthesis of preparation 185-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid

To a mixture of 5-chloro-6-isobutoxypyridin-3-ol (preparation 13, 0.32g, 1.56mmol) and tert-butyl 5-chloro-2, 4-difluorobenzoate (preparation WO2012007883A,10.39g,1.56mmol) in anhydrous dimethyl sulfoxide (5mL) was added potassium carbonate (0.431g, 3.12 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with ethyl acetate (100mL) and water (10mL) was added. The organic phase was washed with water (10mL), brine (10mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a pale yellow solid (0.51g, 76%). The compound was used in the next step without further purification. To a mixture of tert-butyl 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoate (0.51g,1.19mmol) in dichloromethane (20mL) was added trifluoroacetic acid (4mL) and the reaction mixture was stirred at room temperature for 16 h. After concentration in vacuo, the residue was triturated in ether/hexanes (1:1,5mL) to give the title compound as an off-white solid (0.38g, 84% yield):¹H NMR(300MHz,CDCl₃)10.04(br s,1H),8.10(d,J＝7.3Hz,1H),7.94(d,J＝2.4Hz,1H),7.51(d,J＝2.4Hz,1H),6.54(d,J＝11.2Hz,1H),4.12(d,J＝6.5Hz,2H),2.19–2.07(m,1H),1.04(d,J＝6.7Hz,6H)；MS(ES-)m/z 372.1,374.1(M-1)。

synthesis for preparation of 195-chloro-4- (5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) -pyridin-3-yloxy) -2-fluorobenzoic acid

To a mixture of tert-butyl 5-chloro-4- (5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) -pyridin-3-yloxy) -2-fluorobenzoate (preparation 20,3.30g,6.79mmol) in dichloromethane (100mL) was added trifluoroacetic acid (20 mL). The reaction mixture was stirred at ambient temperature for 3 h. The reaction was washed with saturated ammonium chloride solution (3 × 25mL), brine (3 × 25mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colourless solid (1.93g, 66% yield): MS (ES +) M/z 431.9,433.9(M + 1).

Synthesis for preparation of 205-chloro-4- (5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) -pyridin-3-yloxy) -2-fluorobenzoic acid tert-butyl ester

A mixture of 5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-ol (preparation WO2012007869A2, 2.59g, 10.0mmol), tert-butyl 5-chloro-2, 4-difluorobenzoate (preparation WO2012007883A1, 2.48g, 10.0mmol) and potassium carbonate (2.07g,15.0mmol) in dry N, N-dimethylformamide (20mL) was stirred at ambient temperature for 16h and then filtered. The residue was washed with ethyl acetate (100 mL). The filtrate was washed with saturated ammonium chloride solution (3 × 20mL), brine (3 × 20mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography eluting with ethyl acetate-containing hexanes using a 10-30% gradient to give the title compound as a pale yellow gum (3.30g, 70% yield): MS (ES +) M/z 487.9,489.9(M + 1).

Synthesis for preparation of 215-chloro-4- (5, 6-dichloropyridin-3-yloxy) -2-fluorobenzoic acid tert-butyl ester

A mixture of 5, 6-dichloropyridin-3-ol (preparation 15, 3.28g, 20.0mmol), tert-butyl 5-chloro-2, 4-difluorobenzoate (preparation WO2012007883, 4.96g, 20.0mmol) and potassium carbonate (4.15g, 30.0mmol) in dry N, N-dimethylformamide (30mL) was stirred at ambient temperature for 6h and then filtered. The residue was washed with ethyl acetate (100 mL). The filtrate was washed with saturated ammonium chloride solution (3 × 20mL), brine (3 × 20mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified via silica gel column chromatography eluting with ethyl acetate-containing hexanes using a 10-30% gradient to give the title compound as a colorless solid (0.51g, 7% yield):¹H NMR(300MHz,CDCl₃)8.09(d,J＝2.7Hz,1H),8.00(d,J＝7.3Hz,1H),7.41(d,J＝2.7Hz,1H),6.74(d,J＝10.4Hz,1H),1.58(s,9H)。

synthesis of preparation 221-bromo-5-chloro-4- ((3, 4-dichlorophenoxy) -methyl) -2-fluorobenzene

A mixture of 4-bromo-2-chloro-5-fluorobenzylmethanesulfinate (preparation 23, 3.17g, 10.0mmol), 3, 4-dichlorophenol (1.79g, 11.0mmol) and potassium carbonate (2.03g, 15.0mmol) in dry N, N-dimethylformamide (20mL) was stirred at ambient temperature for 3h and then filtered. The residue was washed with ethyl acetate (100 mL). The filtrate was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colourless solid (2.50g, 65% yield): MS (ES +) M/z 384.8,386.7(M + 1).

Synthesis for preparing 234-bromo-2-chloro-5-fluorobenzyl methanesulfinate

To a solution of (4-bromo-2-chloro-5-fluorophenyl) methanol (preparation 17, 6.50g, 29.1mmol) in tetrahydrofuran at ambient temperature was added triethylamine (4.41g, 6.1mL, 43.7mmol) followed by methanesulfonyl chloride (4.14g, 36.1 mmol). The reaction was stirred at ambient temperature for 16h, then diluted with ethyl acetate (200mL), washed with 1N aqueous HCL (3x 50mL), brine (3x100mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a viscous liquid (7.1g, 77% yield) that turned into a solid on standing:¹H NMR(300MHz,CDCl₃)7.94(dd,J＝6.3,0.9Hz,1H),7.64(d,J＝9.0Hz,1H),5.25(s,2H),3.28(s,3H)。

synthesis for preparation of 245-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

To a mixture of 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid (WO2012007883a1, 0.74g, 2.00mmol) in anhydrous tetrahydrofuran (4mL) was added 1, 1' -carbonyldiimidazole (0.65g, 4.00 mmol). The reaction mixture was stirred at 70 ℃ for 0.5h and then cooled to ambient temperature. N, N-dimethylsulfonamide (0.50g, 4.00mmol) was added followed by 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (0.9mL,6.0mmol) and the reaction mixture was stirred at 70 ℃ for 2h after cooling to ambient temperature, the mixture was diluted with dichloromethane (80mL), washed with hydrochloric acid (1N, 3 × 10mL), brine (10mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo to provide a residue which was triturated in ether (15mL) to give the title compound as a white solid (0.70g, 74% yield):¹H NMR(300MHz,DMSO-d₆)12.00(s,1H),7.96(d,J＝7.0Hz,1H),7.79(d,J＝8.8Hz,1H),7.62(d,J＝2.7Hz,1H),7.41(dd,J＝8.8,2.8Hz,1H),7.33(d,J＝10.8Hz,1H),2.89(s,6H)；MS(ES-)m/z 473.0,475.0(M-1)。

synthesis for preparation of 254- ((3, 4-dichlorophenoxy) methyl) -N- (N, N-dimethylsulfamoyl) benzamide

Following the procedure as described in preparation 24 and varying as needed to replace 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid with 4- ((3, 4-dichlorophenoxy) methyl) benzoic acid (preparation 2) gave the title compound as a white solid (0.20g, 50%):¹H NMR(300MHz,DMSO-d₆)11.84(s,1H),7.94(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),7.54(d,J＝8.4Hz,1H),7.35(d,J＝2.6Hz,1H),7.05(dd,J＝8.9,2.6Hz,1H),5.25(s,2H),2.89(s,6H)；MS(ES-)m/z 401.1,403.1(M-1)。

synthesis for preparation of 265-chloro-4- ((3, 4-dichlorophenoxy) methyl) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

To a mixture of 1-bromo-5-chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzene (preparation 22, 0.23g, 0.60mmol) in anhydrous dioxane (2mL) was added palladium (II) acetate (13mg, 0.06mmol), xantphos (69mg,0.12mmol), N-dimethylsulfonamide (0.22g,1.80mmol) and triethylamine (0.33mL, 2.4 mmol). The reaction mixture was heated to reflux under carbon monoxide atmosphere for 24 h. After cooling to ambient temperature, the reaction mixture was quenched with hydrochloric acid (1N,10mL) and diluted with ethyl acetate (150 mL). The organic phase was washed with hydrochloric acid (1N,10mL), water (10mL), brine (10mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give a residue, which was purified by silica gel column chromatography using 0-40% ethyl acetate in hexane as eluent to give the title compound (0.068 g) as a white solid25% yield):¹H NMR(300MHz,DMSO-d₆)12.08(br s,1H),7.81(d,J＝5.5Hz,1H),7.66–7.54(m,2H),7.44(s,1H),7.11(d,J＝8.4Hz,1H),5.24(s,2H),2.89(s,6H)；MS(ES-)m/z 453.0,455.0(M-1)。

preparation of 275-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

To a mixture of 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid (preparation 18, 0.19g, 0.50mmol) in anhydrous tetrahydrofuran (2mL) was added 1, 1' -carbonyldiimidazole (0.162g, 1.0 mmol). The resulting mixture was stirred at 70 ℃ for 0.5h and then cooled to ambient temperature. N, N-dimethylsulfonamide (124mg, 1.0mmol) was added followed by 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (0.21mL, 1.5mmol) and the reaction mixture stirred at ambient temperature for 16h the mixture was diluted with ethyl acetate (100mL), washed with 1N hydrochloric acid (2 × 10mL), water (10mL), brine (10mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo to provide a residue which was triturated in ether/hexane (1:1,10mL) to give the title compound as an off-white solid (0.18g, 73% yield):¹H NMR(300MHz,DMSO-d₆)11.93(s,1H),8.09–8.07(m,1H),7.98(d,J＝2.3Hz,1H),7.90(d,J＝7.1Hz,1H),7.09(d,J＝11.2Hz,1H),4.12(d,J＝6.4Hz,2H),2.88(s,6H),2.13-2.00(m,1H),1.00(d,J＝6.5Hz,6H)；MS(ES-)m/z 478.1,480.1(M-1)。

preparation of 285-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N-sulfamoylbenzamide

Following the procedure as described in preparation 27 and substituting sulfonamide for N, N-dimethyl as requiredThe sulfamide was varied and triturated in methanol to give the title compound as an off white solid (0.15g, 65%):¹H NMR(300MHz,DMSO-d₆)11.90(s,1H),8.09-8.07(m,1H),7.99(d,J＝2.2Hz,1H),7.82(d,J＝7.1Hz,1H),7.65(s,2H),7.06(d,J＝11.1Hz,1H),4.12(d,J＝6.5Hz,2H),2.14–2.00(m,1H),1.00(d,J＝6.7Hz,6H)；MS(ES-)m/z 450.0,452.0(M-1)。

synthesis for preparation of 295-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 27 and varying as needed to replace N, N-dimethylsulfonamide with (methylsulfamoyl) amine and purification by silica gel column chromatography using 0-30% ethyl acetate in hexane as eluent, the title compound was obtained as a white solid (0.172g, 23%):¹H NMR(300MHz,DMSO-d₆)11.84(s,1H),7.99(d,J＝2.9Hz,1H)8.08(d,＝2.6Hz,1H),7.88(d,J＝7.1Hz,1H),7.79-7.72(m,1H),7.08(d,J＝11.1Hz,1H),4.12(d,J＝6.6Hz,2H),2.56(d,J＝4.1Hz,3H),2.14-2.01(m,1H),1.00(d,J＝6.7Hz,6H)；MS(ES-)m/z 464.1,466.1(M-1)。

synthesis for preparation of 30N- (N-benzylsulfamoyl) -5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzamide

Following the procedure as described in preparation 27 and substituting N, N-dimethyl sulfonamide with N-benzyl sulfonamide as required and purification by silica gel column chromatography using 0-30% ethyl acetate in hexane as eluent, the changes were carried out to obtain the title compound as a white solid (0.14g, 66%):¹H NMR(300MHz,DMSO-d₆)11.91(br s,1H),8.69-8.54(m,1H),8.10-8.05(m,1H),8.01-7.96(m,1H),7.53–7.45(m,1H),7.38-7.19(m,5H),7.04(d,J＝11.1Hz,1H),4.20(d,J＝5.0Hz,2H),4.12(d,J＝6.5Hz,2H),2.13-1.99(m,1H),1.00(d,J＝6.6Hz,6H)；MS(ES+)m/z 542.1,544.1(M+1)。

preparation of 31N- (N-benzyl-N-methylsulfamoyl) -5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzamide

Following the procedure as described in preparation 27 and varying as necessary to replace N, N-dimethyl sulfonamide with amino-N-benzyl-N-methyl sulfonamide and purification by silica gel column chromatography using 0-30% ethyl acetate in hexanes as eluent, the title compound was obtained as a white solid (0.14g, 62%):¹H NMR(300MHz,DMSO-d₆)12.17(brs,1H),8.09(d,J＝2.5Hz,1H),8.02-7.97(m,1H),7.90(d,J＝7.0Hz,1H),7.44-7.28(m,5H),7.10(d,J＝11.1Hz,1H),4.45(s,2H),4.13(d,J＝6.5Hz,2H),2.80(s,3H),2.14–2.01(m,1H),1.00(d,J＝6.7Hz,6H)；MS(ES+)m/z 556.1,558.1(M+1)。

preparation of 325-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (N- (pyridin-2-ylmethyl) sulfamoyl) benzamide Synthesis of 2,2, 2-trifluoroacetate

Following the procedure as described in preparation 27 and substituting N- (pyridin-2-ylmethyl) sulfonamide for N, N-dimethylsulfonamide as required and purification by HPLC using method a, the title compound was obtained as a white solid (0.10g, 37%):¹H NMR(300MHz,DMSO-d₆)8.72(s,1H),8.54(d,J＝4.7Hz,1H),8.09(d,J＝2.3Hz,1H),8.00(d,J＝2.3Hz,1H),7.96-7.89(m,1H),7.73(d,J＝7.1Hz,1H),7.56(d,J＝7.7Hz,1H),7.43-7.36(m,1H),7.07(d,J＝11.1Hz,1H),4.38(s,2H),4.13(d,J＝6.5Hz,2H),2.13–2.01(m,1H),1.00(d,J＝6.6Hz,6H)；MS(ES+)m/z 543.1,545.1(M+1)。

preparation of 335-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -N- (N- (4-cyanophenyl) sulfamoyl) -2-fluorobenzamide

Following the procedure as described in preparation 27 and substituting N- (4-cyanophenyl) sulfonamide for N, N-dimethyl sulfonamide as required and purification by silica gel column chromatography using 0-30% ethyl acetate in hexane as eluent, the title compound was obtained as a white solid (0.12g, 56%):¹H NMR(300MHz,DMSO-d₆)12.61(br s,1H),11.40(br s,1H),8.07-8.05(m,1H),7.98-7.95(m,1H),7.80(d,J＝7.9Hz,2H),7.75(d,J＝7.2Hz,1H),7.34(d,J＝8.0Hz,2H),7.03(d,J＝11.2Hz,1H),4.11(d,J＝6.3Hz,2H),2.12–2.01(m,1H),0.99(d,J＝6.7Hz,6H)；MS(ES-)m/z 551.1,553.1(M-1)。

preparation of 345-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (N- (pyridin-3-ylmethyl) sulfamoyl) benzamide Synthesis of 2,2, 2-trifluoroacetate

Following the procedure as described in preparation 27 and varying as necessary to replace N, N-dimethylsulfonamide with N- (pyridin-3-ylmethyl) sulfonamide and purification by HPLC method a, the title compound was obtained as a white solid (0.07g, 27%):¹H NMR(300MHz,DMSO-d₆)8.82-8.74(m,1H),8.69(s,1H),8.64(d,J＝4.7Hz,1H),8.12(d,J＝7.8Hz,1H),8.10-8.07(m,1H),8.01–7.98(m,1H),7.72-7.64(m,2H),7.06(d,J＝11.2Hz,1H),4.34(d,J＝4.8Hz,2H),4.13(d,J＝6.6Hz,2H),2.14-2.01(m,1H),1.00(d,J＝6.7Hz,6H)；MS(ES+)m/z543.1,545.1(M+1)。

synthesis for preparation of 355-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluoro-N-sulfamoylbenzamide

Following the procedure as described in preparation 27 and substituting 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid for 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid and sulfonamide for N, N-dimethylsulfonamide as required, the title compound was obtained as a white solid (2.31g, 95%) by trituration in hexane:¹H NMR(300MHz,DMSO-d₆)11.95(br s,1H),7.87(dd,J＝7.1,0.8Hz,1H),7.79(d,J＝8.8Hz,1H),7.68(s,2H),7.62(d,J＝2.8Hz,1H),7.42(dd,J＝8.8,2.7Hz,1H),7.29(dd,J＝10.8,0.7Hz,1H)；MS(ES-)m/z 445.0,447.0(M-1)。

preparation of 365-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -N- (N, N-dibutylsulfamoyl) -2-fluorobenzamide Synthesis

Following the procedure as described in preparation 27 and varying as necessary to replace N, N-dimethylsulfonamide with N, N-dibutylsulfonamide and purification by HPLC method a, the title compound was obtained as a colorless solid (0.086g, 38%):¹HNMR(300MHz,DMSO-d₆)11.92(br s,1H),8.06-8.03(m,1H),7.97-7.94(m,1H),7.79(d,J＝7.0Hz,1H),7.03(d,J＝11.2Hz,1H),4.08(d,J＝6.6Hz,1H),3.32-3.20(m,5H),2.11-1.96(m,1H),1.54-1.39(m,4H),1.30-1.15(m,4H),0.99-0.92(m,6H),0.84(t,J＝7.3Hz,6H)；MS(ES-)m/z:562.1,564.2(M-1)。

preparation of 375-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (pyrrolidin-1-ylsulfonyl) benzamide Synthesis

Following the procedure as described in preparation 27 and varying as necessary to replace N, N-dimethylsulfonamide with pyrrolidine-1-sulfonamide and purification by HPLC method a afforded the title compound as a colorless solid (0.026g, 13%);¹H NMR(300MHz,DMSO-d₆)11.87(br s,1H),8.05-8.02(m,1H),7.95-7.93(m,1H),7.88-7.84(m,1H),7.04(d,J＝10.2Hz,1H),4.04(d,J＝5.8Hz,2H),3.42-3.33(m,4H),2.11-1.95(m,1H),1.85-1.74(m,4H),0.96(d,J＝6.6Hz,6H)；MS(ES-)m/z:504.0,506.0(M-1)。

synthesis of preparation 385-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (piperidin-1-ylsulfonyl) benzamide

Following the procedure as described in preparation 27 and varying as required to replace N, N-dimethylsulfonamide with 1-piperidine sulfonamide and purification by HPLC method a, the title compound was obtained as a colorless solid (0.020g, 10%);¹H NMR(300MHz,DMSO-d₆)11.89(br s,1H),8.05-8.03(m,1H),7.94(d,J＝2.6Hz,1H),7.84(d,J＝7.0Hz,1H),7.04(d,J＝11.1Hz,1H),4.08(d,J＝6.4Hz,2H),3.33-3.26(m,4H),2.09-1.96(m,1H),1.57-1.38(m,6H),0.96(d,J＝7.0Hz,6H)；MS(ES-)m/z:518.1,520.1(M-1)。

preparation of 39N- (azepan-1-ylsulfonyl) -5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzamide

Following the procedure as described in preparation 27 and substituting azepane-1-sulfonamide for N, N-dimethyl as requiredThe sulfamide was varied and purified by HPLC method a to afford the title compound as a colorless solid (0.005g, 2%):¹HNMR(300MHz,DMSO-d₆)11.89(br s,1H),8.05-8.02(m,1H),7.96-7.92(m,1H),7.83(d,J＝7.0Hz,1H),7.03(d,J＝11.1Hz,1H),4.08(d,J＝6.4Hz,2H),3.40-3.33(m,4H),2.11-1.94(m,1H),1.69-1.56(m,4H),1.55-1.42(m,4H),0.96(d,J＝6.7Hz,6H)；MS(ES-)m/z:532.0,534.1(M-1)。

preparation of 405-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (N-isopropyl-N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 27 and using [ methyl (prop-2-yl) sulfamoyl ] as required]Variation of the amine in place of N, N-dimethylsulfonamide and purification by HPLC method a afforded the title compound as a colorless solid (0.063g, 33%):¹H NMR(300MHz,DMSO-d₆)11.92(br s,1H),8.07-8.02(m,1H),7.97-7.93(m,1H),7.84-7.77(m,1H),7.04(d,J＝11.1Hz,1H),4.12-3.98(m,3H),2.78(s,3H),2.11-1.96(m,1H),1.06(d,J＝6.4Hz,6H),0.96(d,J＝6.7Hz,6H)；MS(ES-)m/z:506.1,508.0(M-1)。

synthesis for preparation of 415-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluoro-N- (N-methylsulfamoyl) benzamide

To a cold (0 ℃) mixture of 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluoro-N-sulfamoylbenzamide (preparation 36) (9.45g, 1.00mmol) in DMF (10mL) was added a solution of lithium bis (trimethylsilyl) amide in THF (1M,3.0 mL). The resulting mixture was stirred at 0 ℃ for 1h, followed by the addition of methyl iodide (62. mu.L, 1.00 mmol). The reaction mixture was allowed to warm to ambient temperature over 16 h. The reaction mixture was washed with hydrochloric acid (1N)5mL) and the mixture was diluted with ethyl acetate (100 mL). The organic phase was washed with brine (10mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to provide a residue which was purified using HPLC method B to afford the title compound as a white solid (0.10g, 21%):¹H NMR(300MHz,DMSO-d₆)11.91(br s,1H),7.94(d,J＝7.0Hz,1H),7.83–7.75(m,2H),7.62(d,J＝2.0Hz,1H),7.42(dd,J＝8.9,2.0Hz,1H),7.32(d,J＝10.8Hz,1H),2.58(d,J＝2.9Hz,3H)；MS(ES-)m/z 459.0,461.0(M-1)。

synthesis for preparation of 42N- (azetidin-1-ylsulfonyl) -5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzamide

Following the procedure as described in preparation 41 and varying as required to replace methyl iodide with 1, 3-dibromopropane, the title compound was obtained as a white solid (0.14g, 28%):¹H NMR(300MHz,DMSO-d₆)12.03(br s,1H),8.02(dd,J＝7.1,1.0Hz,1H),7.80(d,J＝8.8Hz,1H),7.62(d,J＝1.8Hz,1H),7.42(dd,J＝8.6,2.2Hz,1H),7.34(dd,J＝10.9,1.0Hz,1H),4.07(t,J＝7.6Hz,4H),2.19(dt,J＝7.5,7.5Hz,2H)；MS(ES-)m/z 485.0,487.0(M-1)。

synthesis for preparation of 435-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- ((1-methyl-1H-imidazol-4-yl) sulfonyl) benzamide

To a mixture of 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid (preparation 18) (0.15g,0.40mmol) in anhydrous tetrahydrofuran (10mL) was added 1, 1' -carbonyldiimidazole (0.13g,0.80 mmol). The resulting mixture was heated at reflux for 0.75h and then cooled to ambient temperature. 1-methyl-1H-imidazole-4-sulfonamide (0.13g, 0) was added82mmol) followed by the addition of 1, 8-diazabicyclo [5.4.0]Undec-7-ene (0.2mL,1.20mmol) and the reaction mixture was stirred at ambient temperature for 16h the mixture was diluted with ethyl acetate (150mL), washed with 1N hydrochloric acid (2 × 200mL), brine (2 × 200mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo to provide a residue which was purified via HPLC method a to give the title compound as a white solid (0.02g, 11% yield):¹H NMR(300MHz,DMSO-d₆)12.40(br s,1H),8.03-7.74(m,5H),6.99(d,J＝11.1Hz,1H),4.08(d,J＝6.4Hz,2H),3.70(s,3H),2.07-1.99(m,1H),0.96(d,J＝6.5Hz,6H)；MS(ES-)m/z 515.0,517.0(M-1)。

preparation of 445-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (indolin-1-ylsulfonyl) benzamide Synthesis

To a mixture of 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid (preparation 18, 0.15g,0.40mmol) in anhydrous tetrahydrofuran (10mL) was added 1, 1' -carbonyldiimidazole (0.13g,0.80 mmol). The resulting mixture was heated at reflux for 0.75h and then cooled to ambient temperature. Indoline-1-sulfonamide (0.16g, 0.81mmol) was added followed by 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (0.2mL,1.20mmol) and the reaction mixture stirred at ambient temperature for 16h the reaction mixture was diluted with ethyl acetate (150mL), washed with 1N hydrochloric acid (2 × 200mL), brine (2 × 200mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo to provide a residue which was purified via silica gel column chromatography using 0-30% ethyl acetate in hexane as eluent to give the title compound as a white solid (0.03g, 13%):¹H NMR(300MHz,DMSO-d₆)12.53(br s,1H),8.02-8.01(m,1H),7.93-7.92(m,1H),7.66(d,J＝7.0Hz,1H),7.22-7.12(m,3H),7.00-6.94(m,2H),4.23(t,J＝8.3Hz,2H),4.07(d,J＝6.5Hz,2H),3.09(t,J＝8.2Hz,2H),2.09-1.96(m,1H),0.95(d,J＝6.6Hz,6H)；MS(ES-)m/z 552.0,554.0(M-1)。

synthesis of 45N- ((1H-imidazol-4-yl) sulfonyl) -5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzamide

Following the procedure as described in preparation 43, with changes as required to replace 1-methyl-1H-imidazole-4-sulfonamide with 1H-imidazole-4-sulfonamide and purification by HPLC method a, the title compound was obtained as a white solid (0.02g, 11%):¹H NMR(300MHz,DMSO-d₆)12.90(br s,1H),8.03-7.91(m,4H),7.75(d,J＝7.1Hz,1H),6.99(d,J＝11.2Hz,1H),4.08(d,J＝6.5Hz,2H),2.08-1.99(m,1H),0.96(d,J＝6.6Hz,6H)；MS(ES-)m/z 501.0,503.0(M-1)。

preparation of 461- (N- (5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoyl) sulfamoyl) piperidine-4-carboxylic acid methyl ester

Following the procedure as described in preparation 43, changing as needed to replace 1-methyl-1H-imidazole-4-sulfonamide with methyl 1-sulfamoylpiperidine-4-carboxylate and purification by HPLC method a afforded the title compound (0.02g, 11%) as a white solid:¹H NMR(300MHz,DMSO-d₆)11.97(s,1H),8.04-8.03(m,1H),7.94-7.93(m,1H),7.83(d,J＝7.0Hz,1H),7.05(d,J＝11.1Hz,1H),4.08(d,J＝6.5Hz,2H),3.65-3.53(m,5H),3.04-2.94(m,2H),2.53-2.42(m,1H),2.08-1.97(m,1H),1.90-1.86(m,2H),1.58-1.47(m,2H),0.96(d,J＝6.6Hz,6H)；MS(ES-)m/z 576.0,578.0(M-1)。

preparation of 475-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluoro-N- (pyridin-3-ylsulfonyl) benzamide A Synthesis

Following the procedure as described in preparation 43, varying as needed to replace 1-methyl-1H-imidazole-4-sulfonamide with pyridine-3-sulfonamide and purifying by trituration in methanol (20mL) the title compound was obtained as a white solid (0.03g, 13%):¹H NMR(300MHz,DMSO-d₆)9.08(s,1H),8.86(d,J＝4.3Hz,1H),8.34(d,J＝8.0Hz,1H),8.03-8.02(m,1H),7.94-7.93(m,1H),7.86(d,J＝7.2Hz,1H),7.67(dd,J＝4.9,7.9Hz,1H),7.01(d,J＝11.3Hz,1H),4.07(d,J＝6.5Hz,2H),2.07-1.98(m,1H),0.95(d,J＝6.6Hz,6H)；MS(ES-)m/z 512.0,514.0(M-1)。

synthesis of 48N- (5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoyl) sulfamoylcarbamic acid tert-butyl ester

Following the procedure as described in preparation 43, varying as necessary to replace 1-methyl-1H-imidazole-4-sulfonamide with tert-butyl sulfamoylcarbamate and purification by HPLC method a afforded the title compound (0.02g, 10%) as a white solid:¹H NMR(300MHz,DMSO-d₆)12.66(br s,1H),11.96(br s,1H),8.05-8.04(m,1H),7.97-7.96(m,1H),7.77(d,J＝7.1Hz,1H),7.03(d,J＝11.0Hz,1H),4.08(d,J＝6.5Hz,2H),2.08-1.99(m,1H),1.37(s,9H),0.96(d,J＝6.6Hz,6H)；MS(ES-)m/z 550.0,552.0(M-1)。

synthesis of 495-chloro-4- ((3, 4-dichlorobenzyl) oxy) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

To a mixture of 3, 4-dichlorobenzyl alcohol (0.21g,1.20mmol) in DMSO (5mL) was added tert-butanolPotassium (0.29g,2.58 mmol.) the mixture is stirred at ambient temperature for 5 minutes and 5-chloro-N- (N, N-dimethylsulfamoyl) -2, 4-difluorobenzamide (preparation 3) (0.30g,1.01mmol) is added after 0.5h, the reaction mixture is diluted with ethyl acetate (150mL), washed with 1N hydrochloric acid (2 × 150mL), brine (150mL), dried over anhydrous sodium sulfate and filtered.¹H NMR(300MHz,DMSO-d₆)11.78(s,1H),7.75-7.66(m,3H),7.43(d,J＝8.2Hz,1H),7.31(d,J＝12.1Hz,1H),5.28(s,2H),2.83(s,6H)；MS(ES-)m/z453.0,455.0(M-1)。

Synthesis for preparation of 505-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluoro-N-sulfamoylbenzamide

To a mixture of 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoic acid (preparation 4) (1.04g,2.69mmol) in anhydrous tetrahydrofuran (70mL) was added 1, 1' -carbonyldiimidazole (1.09g,6.72 mmol). The resulting reaction mixture was heated to reflux for 40 minutes and then cooled to ambient temperature. Sulfonamide (0.65g,6.77mmol) was added followed by 1, 8-diazabicyclo [ 5.4.0%]Undec-7-ene (1.2mL,8.0mmol) and the reaction mixture stirred at ambient temperature for 3d the reaction mixture was diluted with ethyl acetate (200mL), washed with 1N hydrochloric acid (2 × 200mL), brine (2 × 200mL), dried over anhydrous sodium sulfate and filtered the filtrate was concentrated in vacuo to provide a residue which was triturated in ether (20mL) to give the title compound as a white solid (0.43g, 34% yield):¹H NMR(300MHz,DMSO-d₆)11.90(s,1H),7.83(d,J＝7.0Hz,1H),7.65-7.58(m,3H),7.49(d,J＝1.6Hz,1H),7.28(d,J＝10.6Hz,1H),7.17-7.13(m,1H)；MS(ES-)m/z 460.9,462.9(M-1)。

preparation of 51 and 525-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluoro-N- (N-methylsulfamoyl) benzamide and Synthesis of 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

To a cold (0 ℃) mixture of 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluoro-N-sulfamoylbenzamide (preparation 51) (0.37g,0.81mmol) in anhydrous N, N-dimethylformamide (10mL) was added a 1.0M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (2.4mL,2.4mmol), after 1h and 4h (0.02mL,0.32mmol) was added iodomethane (0.06mL,0.99mmol), after stirring for 6h, the reaction mixture was diluted with ethyl acetate (200mL), washed with 1N hydrochloric acid (2 × 200mL), brine (2 × 200mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated in vacuo to provide a residue which was purified by HPLC using method a to provide pure isolated 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluoro-N- (methylsulfonyl) benzamide (preparation 51) (0.37g,0.81mmol) to provide the first isolated 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluoro-N-sulfamoyl) benzamide (5-chloro-4- (3-4- (trifluoromethoxy) phenoxy) -2-methanesulfonyl benzamide and the second, eluting compound:¹H NMR(300MHz,DMSO-d₆)11.90(s,1H),7.90(d, J ═ 7.0Hz,1H),7.76 to 7.75(m,1H),7.60(d, J ═ 9.0Hz,1H),7.48(d, J ═ 2.4Hz,1H),7.31(d, J ═ 10.6Hz,1H),7.14(dd, J ═ 2.4,9.0Hz,1H),2.54(d, J ═ 2.8Hz, 3H); MS (ES-) M/z 474.9,476.9 (M-1). Data for the second eluting compound: white solid (0.03g, 7% yield), (preparation 52):¹H NMR(300MHz,DMSO-d₆)12.00(s,1H),7.92(d,J＝7.0Hz,1H),7.60(d,J＝9.0Hz,1H),7.48(d,J＝2.8Hz,1H),7.32(d,J＝10.6Hz,1H),7.14(dd,J＝2.4,9.1Hz,1H),2.85(s,6H)；MS(ES-)m/z 488.9,490.9(M-1)。

synthesis for preparation of 535-chloro-4- ((5, 6-dichloropyridin-3-yl) oxy) -2-fluoro-N-sulfamoylbenzamide

Following the procedure as described in preparation 50, the title compound was obtained as a white solid (0.508g, 94%) by substituting 5-chloro-4- ((5, 6-dichloropyridin-3-yl) oxy) -2-fluorobenzoic acid (preparation 16) for 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoic acid as required:¹H NMR(300MHz,DMSO-d₆)11.91(s,1H),8.33(d,J＝2.7Hz,1H),8.13(d,J＝2.7Hz,1H),7.83(d,J＝7.1Hz,1H),7.65(s,2H),7.34(d,J＝10.9Hz,1H),；MS(ES-)m/z 411.9,413.9(M-1)。

synthesis of 545-chloro-4- ((5, 6-dichloropyridin-3-yl) oxy) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

Following the procedure as described in preparation 52, varying as necessary to replace 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluoro-N-sulfamoylbenzamide with 5-chloro-4- ((5, 6-dichloropyridin-3-yl) oxy) -2-fluoro-N-sulfamoylbenzamide (preparation 53) and purification by HPLC using method a, the title compound was obtained as a white solid (0.03g, 7% yield):¹H NMR(300MHz,DMSO-d₆)11.96(br s,1H),8.32(d,J＝2.6Hz,1H),8.11(d,J＝2.6Hz,1H),7.91(d,J＝7.1Hz,1H),7.36(d,J＝10.9Hz,1H),2.84(s,6H)；MS(ES-)m/z 440.0,442.0(M-1)。

synthesis for preparation of 555-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) methyl) -2-fluoro-N-sulfamoylbenzamide

Following the procedure as described in preparation 51, 5-chloro-4- (3-chloro-4- (trifluoromethoxy-methoxy) -pyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid (preparation 6) was replaced with 5-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid as required) Variation of phenoxy) -2-fluorobenzoic acid and trituration in ether (20mL) gave the title compound as a white solid (0.508g, 94%):¹HNMR(300MHz,DMSO-d₆)12.00(s,1H),7.99(d,J＝2.7Hz,1H),7.92(d,J＝2.7Hz,1H),7.70-7.68(m,3H),7.61(d,J＝10.4Hz,1H),6.59(tt,J＝5.2,51.9Hz,1H),5.22(s,2H),4.86(t,J＝14.1Hz,2H)；MS(ES-)m/z 522.0,524.0(M-1)。

preparation of 564- (3-chloro-4- (trifluoromethoxy) phenoxy) -N- (N, N-dimethylsulfamoyl) -2, 5-difluorobenzamide

Following the procedure as described in preparation 27 and varying as required to replace 5-chloro-4- (5-chloro-6-isobutoxypyridin-3-yloxy) -2-fluorobenzoic acid with 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2, 5-difluorobenzoic acid (preparation WO2012007883a1) and purification by HPLC using method a gave the title compound as a white solid (0.14g, 14%):¹H NMR(300MHz,DMSO-d₆)11.95(s,1H),7.77(dd,J＝10.6,6.4Hz,1H),7.61(dd,J＝9.1,1.2Hz,1H),7.51(d,J＝2.9Hz,1H),7.37(dd,J＝10.4,6.6Hz,1H),7.18(dd,J＝9.1,3.0Hz,1H),2.85(s,6H)；MS(ES+)m/z474.98,476.97(M+1)。

synthesis for preparation of 575-chloro-4- (5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yloxy) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

Following the procedure as described in preparation 27 and substituting 5-chloro-4- (5-chloro-6-isobutoxypyridin-3-yloxy) -2-fluorobenzoic acid (preparation 19) with 5-chloro-4- (5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yloxy) -2-fluorobenzoic acid as required, and purification by HPLC using method a gave the title compound as a white solid (0.06g, 11%):¹H NMR(300MHz,DMSO-d₆)11.91(s,1H),8.10(d,J＝2.6Hz,1H),8.06(d,J＝2.6Hz,1H),7.88(d,J＝7.3Hz,1H),7.11(d,J＝11.1Hz,1H),7.01-6.43(m,1H),4.91(t,J＝14.1Hz,2H),2.85(s,6H)；MS(ES+)m/z 536.2,535.2(M+1)。

synthesis for preparation of 585-chloro-4- ((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 27 and substituting 5-chloro-4- (5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yloxy) -2-fluorobenzoic acid (preparation 19) for 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid as required, the change was made with (methylsulfamoyl) amine for N, N-dimethylsulfonamide and purification by HPLC method C gave the title compound as a white solid (0.057g, 29%):¹H NMR(300MHz,DMSO-d₆)12.00(brs,1H),8.15(d,J＝2.6Hz,1H),8.09(d,J＝2.6Hz,1H),7.90(d,J＝7.1Hz,1H),7.79–7.73(m,1H),7.14(d,J＝11.1Hz,1H),6.66(tt,1H,J＝51.9,5.2Hz,1H),4.94(t,J＝14.1Hz,2H),2.56(d,J＝4.1Hz,3H)；MS(ES-)m/z 522.0,524.0(M-1)。

preparation of 595-chloro-4- ((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) -2-fluoro-N-sulfamoylbenzamide synthesis

Following the procedure as described in preparation 27 and substituting 5-chloro-4- (5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yloxy) -2-fluorobenzoic acid (preparation 19) for 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid as required, the change was made by substituting sulfonamide for N, N-dimethylsulfonamide, and purification by HPLC method C afforded the title compound as a white solid (0.412g, 40%):¹H NMR(300MHz,DMSO-d₆)12.15(s,1H),8.15(d,J＝2.6Hz,1H),8.10(d,J＝2.6Hz,1H),7.83(d,J＝7.2Hz,1H),7.65(s,2H),7.11(d,J＝11.1Hz,1H),6.66(tt,J＝51.9,5.2Hz,1H),4.94(t,J＝14.1Hz,2H)；¹⁹F NMR(282MHz,DMSO-d₆)-110.2(s,1F),-124.6(t,J＝5.3Hz,2F),-138.5(t,J＝5.3Hz,2F)；MS(ES-)m/z508.0,510.0(M-1)。

preparation of 60N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxy-pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzamide Synthesis

Step 1.2 preparation of tert-butyl 2, 4-difluoro-5-iodobenzoate

To a solution of 2, 4-difluoro-5-iodobenzoic acid (preparation WO 2005113508A1, 20.0g, 70.4mmol) in THF (200mL) was added di-tert-butyl dicarbonate (30.7g,141mmol) and N, N-dimethyl-4-aminopyridine (1.72g, 14.1 mmol). The reaction mixture was stirred for 24h, then diluted with ethyl acetate (200mL) and washed with saturated sodium bicarbonate (3x100mL), 1N hydrochloric acid (3x100mL), brine (3x100mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a colourless solid (20.1g, 84% yield):¹H NMR(300MHz,CDCl₃)8.34(dd,J＝7.5,7.5Hz,1H),6.88(dd,J＝10.3,7.7Hz,1H),1.59(s,9H)。

step 2.4 preparation of tert-butyl- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-iodobenzoate

Following the procedure as described in preparation 5 and substituting tert-butyl 2, 4-difluorobenzoate with tert-butyl 2, 4-difluoro-5-iodobenzoate as required (preparation WO2012007883a1) and 3-chloro-4- (trifluoromethoxy) phenol with 5-chloro-6-isopropoxypyridin-3-ol gave the title compound as a colorless solid (8.88g, 92%): MS (ES +) M/z 507.0,509.1(M + 1).

Step 3.4 preparation of tert-butyl- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoate

To a mixture of tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-iodobenzoate (0.75g, 1.48mmol) in dioxane (10mL) was added cyclopropylboronic acid (0.38g, 4.44mmol), tripotassium phosphate (1.26g, 5.92mmol) and tetrakis (triphenylphosphine) palladium (0.17g,0.15 mmol). The reaction mixture was degassed thoroughly by passing through argon and then heated to 150 ℃ in a microwave for 0.5 h. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (50mL) and filtered through sodium phosphate. Removal of all volatiles under reduced pressure gave a residue which was purified by column chromatography using a gradient of 0-15% ethyl acetate in hexanes as eluent to give the title compound as a colorless oil (0.70g, quantitative yield): MS (ES-) M/z 422.1,424.1 (M-1).

Step 4.4 preparation of- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in preparation 4 and varying as required to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoate and purification by column chromatography using a gradient of 0-100% ethyl acetate in hexanes as eluent, the title compound was obtained as a colorless solid (0.49g, 91% yield): MS (ES-) M/z 346.2,366.2 (M-1).

Step 5 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxy-pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in preparation 24 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide as required, the title compound was obtained as a colorless solid (0.05g, 10% yield) by reverse phase HPLC:¹H NMR(300MHz,DMSO-d₆)11.79(br s,1H),8.03(d,1H,J＝2.6Hz,1H),7.85(d,J＝2.6Hz,1H),7.28(d,J＝7.9Hz,1H),6.83(d,J＝11.5Hz,1H),5.33-5.22(m,1H),4.04(t,J＝7.7Hz,4H),2.22-2.06(m,3H),1.34(d,J＝6.2Hz,6H),0.98-0.90(m,2H),0.83-0.77(m,2H)；MS(ES-)m/z 482.3,484.3(M-1)。

synthesis of 614- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -5-cyclopropyl-2-fluoro-N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 27 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoic acid for 5-chloro-4- ((5-chloro-6-isobutoxypyridin-3-yl) oxy) -2-fluorobenzoic acid and (methylsulfamoyl) amine for N, N-dimethylsulfonamide as required, the title compound was obtained as a colorless solid (0.27g, 44% yield):¹H NMR(300MHz,DMSO-d₆)11.68(s,1H),8.02(d,J＝2.7Hz,1H),7.86(d,J＝2.7Hz,1H),7.70-7.63(m,1H),7.23(d,J＝7.9Hz,1H),6.81(d,J＝11.5Hz,1H),5.34-5.20(m,1H),2.55(d,J＝4.9Hz,3H),2.16-2.04(m,1H),1.34(d,J＝6.2Hz,6H),0.98-0.90(m,2H),0.83-0.76(m,2H)；MS(ES-)m/z 456.2,458.2(M-1)。

synthesis for preparation of 62N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3-cyclopropylbenzamide

Step 1.4 preparation of- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3-cyclopropylbenzoic acid

Following the procedure as described in preparation 4 and varying as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3-cyclopropylbenzoate to give the title compound as a light yellow oil (0.35g, 86% yield) which was used in the next step without further purification: MS (ES +) M/z 346.3,348.3 (M-1).

Step 2 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3-cyclopropylbenzamide

Following the procedure as described in preparation 24 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3-cyclopropylbenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide as required, the title compound was obtained as a colorless solid (0.05g, 10% yield) by purification by reverse phase HPLC:¹H NMR(300MHz,DMSO-d₆)11.80(br s,1H),8.00(d,J＝2.7Hz,1H),7.81(d,J＝2.7Hz,1H),7.75(dd,J＝8.6,2.2Hz,1H),7.60(d,J＝2.1Hz,1H),6.88(d,J＝8.6Hz,1H),5.31-5.22(m,1H),4.02(t,J＝7.7Hz,4H),2.22-2.07(m,3H),1.33(d,J＝6.2Hz,6H),1.02-0.94(m,2H),0.87-0.80(m,2H)；MS(ES+)m/z 466.2,468.1(M+1)。

preparation of 63N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-hydroxyoxetan-3-yl) benzamide

Step 1.4 preparation of tert-butyl- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-hydroxyoxetan-3-yl) benzoate

To a cold (-40 ℃) mixture of 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-iodobenzoic acid tert-butyl ester (2.03g,4.0mmol) in anhydrous tetrahydrofuran (20mL) was added isopropylmagnesium chloride lithium chloride complex (3.53mL of a 1.7M solution in tetrahydrofuran, 6.0 mmol.) the reaction mixture was stirred at-40 ℃ for 1h, then oxetan-3-one (0.86g, 12.0mmol) was added, the reaction mixture was warmed to ambient temperature and stirred for 16h, after quenching the reaction mixture with saturated ammonium chloride solution (5mL), the mixture was extracted with ethyl acetate (3 × 20 mL.) the combined organic phases were washed with brine (5mL), dried over sodium sulfate and filtered the filtrate concentrated in vacuo:. the residue was purified by column chromatography using ethyl acetate containing a gradient of 0-50% in hexane as eluent to give the title compound as an amorphous solid (1.05% yield):¹H NMR(300MHz,CDCl₃)7.87-7.83(m,2H),7.40(d,J＝2.6Hz,1H),6.43(d,J＝11.4Hz,1H),5.36-5.26(m,1H),5.15(d,J＝7.3Hz,2H),4.86(d,J＝7.7Hz,2H),3.09-2.97(m,1H),1.56(s,9H),1.39(d,J＝6.2Hz,6H)。

step 2.4 preparation of- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-hydroxyoxetan-3-yl) benzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-hydroxyoxetan-3-yl) benzoate the title compound was obtained as a colorless oil (0.27g, quantitative yield) which was used without further purification: MS (ES-) M/z 398.1,400.1 (M-1).

Step 3 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-hydroxyoxetan-3-yl) benzamide

Following the procedure as described in preparation 24 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-hydroxyoxetan-3-yl) benzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide as required, the changes were made and purification by reverse phase HPLC gave the title compound as a colorless solid (0.03g, 10% yield):¹H NMR(300MHz,DMSO-d₆)11.91(brs,1H),8.06(d,J＝2.6Hz,1H),7.89(d,J＝2.6Hz,1H),7.70(d,J＝8.0Hz,1H),6.82(d,J＝11.6Hz,1H),6.30(s,1H),5.35-5.23(m,1H),5.13(d,J＝7.0Hz,2H),4.68(d,J＝7.0Hz,2H),4.01(t,J＝7.6,7.6Hz,4H),2.21-2.08(m,2H),1.34(d,J＝6.2Hz,6H)；¹⁹F NMR(282MHz,DMSO-d₆)-110.0(s,1F)；MS(ES-)m/z 514.2,516.2(M-1)。

preparation of 64N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-fluorooxetan-3-yl) benzamide Synthesis

Step 1.4 preparation of tert-butyl- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-fluorooxetan-3-yl) benzoate

To a solution of tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-hydroxyoxetan-3-yl) benzoate (0.45g, 1.0mmol) in anhydrous dichloromethane (10mL) was added diethylaminosulfur trifluoride (0.17mL,1.30mmol) at-78 ℃. The reaction mixture was stirred at-78 ℃ for 2h, warmed to-20 ℃ and then quenched by the addition of 1N sodium hydroxide solution (5 mL). The mixture was warmed to ambient temperature and diluted with dichloromethane (50 mL). The organic phase was washed with brine (5mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-35% ethyl acetate in hexanes as eluent to give the title compound as a colorless oil (0.25g, 55% yield):¹H NMR(300MHz,CDCl₃)7.91-7.84(m,2H),7.40(d,J＝2.7Hz,1H),6.45(d,J＝11.4Hz,1H),5.36-5.26(m,1H),5.24(d,J＝8.4Hz,1H),5.15(d,J＝8.4Hz,1H),5.11(d,J＝8.4Hz,1H),5.04(d,J＝8.3Hz,1H),1.56(s,9H),1.39(d,J＝6.2Hz,6H)；¹⁹F NMR(282MHz,CDCl₃)-101.83(d,J＝5.4Hz,1F),-135.03(d,J＝5.4Hz,1F)；MS(ES-)m/z456.2,458.2(M+1)。

step 2.4 preparation of- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-fluorooxetan-3-yl) benzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-fluorooxetan-3-yl) benzoate the title compound was obtained as a colorless solid (0.22g, quantitative yield) using without further purification:¹H NMR(300MHz,CDCl₃)9.48(br s,1H),8.04(dd,J＝7.8,1.9Hz,1H),7.90(d,J＝2.7Hz,1H),7.45(d,J＝2.7Hz,1H),6.52(d,J＝11.5Hz,1H),5.36-5.27(m,2H),5.23(d,J＝8.6Hz,1H),5.18(d,J＝8.5Hz,1H),5.11(d,J＝8.5Hz,1H),1.40(d,J＝6.2Hz,6H)；¹⁹F NMR(282MHz,CDCl₃)-99.5(d,J＝5.0Hz,1F),-136.05(d,J＝5.0Hz,1F)；MS(ES-)m/z 398.2,400.2(M-1)。

step 3 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-fluorooxetan-3-yl) benzamide

Following the procedure as described in preparation 24 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5- (3-fluorooxetan-3-yl) benzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide as required, the changes were made and purification by reverse phase HPLC gave the title compound as a colorless solid (0.09g, 33% yield):¹H NMR(300MHz,DMSO-d₆)11.95(brs,1H),8.11(d,J＝2.6Hz,1H),8.00(d,J＝2.6Hz,1H),7.87(dd,J＝7.6,1.8Hz,1H),6.94(d,J＝11.7Hz,1H),5.30(dd,J＝26.1,9.1Hz,2H),5.30-5.22(m,1H),4.96(dd,J＝22.1,9.0Hz,2H),4.06(t,J＝7.6Hz,4H),2.23-2.11(m,2H),1.35(d,6H,J＝6.2Hz,6H)；¹⁹F NMR(282MHz,DMSO-d₆)-106.0(d,J＝5.7Hz,1F),-132.5(d,J＝5.5Hz,1F)；MS(ES-)m/z516.1,518.1(M-1)。

preparation of 65N- (azetidin-1-ylsulfonyl) -4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (3-hydroxyoxetan-3-yl) benzamide Synthesis

Step 1.3 preparation of tert-butyl 3-bromo-4- (3-chloro-4- (trifluoromethoxy) phenoxy) benzoate

Following the procedure as described in preparation 5 and using as requiredTert-butyl 3-bromo-4-fluorobenzoate (WO2012007883a1) was changed instead of tert-butyl 5-chloro-2, 4-difluorobenzoate to obtain the title compound as a colorless solid (28.8g, 95%):¹H NMR(300MHz,CDCl₃)8.25(d,J＝2.0Hz,1H),7.91(dd,J＝2.0,8.5,1H),7.31-7.26(m,1H),7.06(d,J＝2.9Hz,1H),6.97(d,J＝8.5Hz,1H),6.88(dd,J＝9.1,2.9Hz,1H),1.57(s,9H)；MS(ES+)m/z 467.0,469.1(M+1)。

step 2.4 preparation of tert-butyl 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (3-hydroxyoxetan-3-yl) benzoate

Following the procedure as described in preparation 63, step 1 and a non-critical change substituting tert-butyl 3-bromo-4- (3-chloro-4- (trifluoromethoxy) phenoxy) benzoate for tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-iodobenzoate, the title compound was obtained as a solid (1.00g, 63% yield):¹H NMR(300MHz,CDCl₃)7.96(d,J＝1.9Hz,1H),7.93-7.87(m,1H),7.33-7.27(m,1H),7.14(d,J＝2.8Hz,1H),6.98-6.92(m,1H),6.83(d,J＝8.6Hz,1H),5.15(d,J＝7.5Hz,2H),4.83(d,J＝7.5Hz,2H),3.38(br s,1H),1.55(s,9H)；MS(ES+)m/z 461.1,463.1(M+1)。

step 3.4 preparation of 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (3-hydroxyoxetan-3-yl) benzoic acid

Following the procedure as described in preparation 4 and varying as required to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (3-hydroxyoxetan-3-yl) benzoate the title compound was obtained as a solid (0.60g, quantitative yield): MS (ES-) M/z403.2,405.2 (M-1).

Step 4. preparation of N- (azetidin-1-ylsulfonyl) -4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (3-hydroxyoxetan-3-yl) benzamide

Following the procedure as described in preparation 24 and substituting 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (3-hydroxyoxetan-3-yl) benzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide as required, the title compound was obtained as a colorless solid (0.06g, 16%) by reverse phase HPLC purification (preparation D):¹H NMR(300MHz,DMSO-d₆)11.86(brs,1H),8.01(d,J＝2.3Hz,1H),7.92(dd,J＝8.8,2.3Hz,1H),7.63-7.57(m,1H),7.43(d,J＝2.9Hz,1H),7.15(dd,J＝9.1,2.9Hz,1H),7.00(d,J＝8.6Hz,1H),6.24(s,1H),5.09(d,J＝7.2Hz,2H),4.65(d,J＝7.2Hz,2H),4.02(t,J＝7.7Hz,4H),2.18-2.05(m,2H)；MS(ES+)m/z523.2,525.2(M+1)。

preparation of 66N- (azetidin-1-ylsulfonyl) -4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (2-methoxypyridin-3-yl) benzamide Synthesis

Step 1.3 preparation of methyl 3-bromo-4- (3-chloro-4- (trifluoromethoxy) phenoxy) benzoate

Following the procedure as described in preparation 5 and substituting methyl 3-bromo-4-fluorobenzoate (WO2012007883a1) for tert-butyl 5-chloro-2, 4-difluorobenzoate as required, the title compound was obtained as a colorless solid (5.60g, 63%):¹H NMR(300MHz,CDCl₃)8.31(d,J＝2.0Hz,1H),7.95(dd,J＝8.5,2.0Hz,1H),7.32-7.27(m,1H),7.09(d,J＝2.9Hz,1H),6.96(d,J＝8.6Hz,1H),6.90(dd,J＝9.1,2.9Hz,1H),3.91(s,3H)。

step 2.4 preparation of methyl 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (2-methoxypyridin-3-yl) benzoate

A degassed mixture of methyl 3-bromo-4- (3-chloro-4- (trifluoromethoxy) phenoxy) benzoate (1.5g, 3.52mmol), (2-methoxypyridin-3-yl) boronic acid (0.81g, 5.28mmol) and 2.0M sodium carbonate (7.0mL, 14.1mmol) in dimethoxyethane (40mL) was treated with tetrakis (triphenylphosphine) palladium (0.20g, 0.18 mmol). The resulting mixture was refluxed for 7h under nitrogen. The mixture was diluted with ethyl acetate (150mL), washed with water (100mL), saturated ammonium chloride (100mL), brine (100mL), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo. The residue was purified by flash chromatography (R in 4:1 hexane in ethyl acetate)_fPurification to afford the title compound (1.26g, 79% yield):¹H NMR(300MHz,CDCl₃)8.16-8.12(m,1H),8.07-8.00(m,2H),7.54-7.49(m,1H),7.25-7.18(m,1H),7.06-6.99(m,2H),6.94-6.89(m,1H),6.88-6.82(m,1H),3.90(s,3H),3.77(s,3H)；MS(ES+)m/z 454.0,456.0(M+1)。

step 3.4 preparation of 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (2-methoxypyridin-3-yl) benzoic acid

A mixture of methyl 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (2-methoxypyridin-3-yl) benzoate (1.26g, 2.78mmol) and lithium hydroxide monohydrate (0.35g, 8.34mmol) in tetrahydrofuran (35mL) and water (15mL) was refluxed for 3 h. The mixture was acidified with 3.0M hydrochloric acid and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (2 × 100mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (1.22g, quantitative yield):¹H NMR(300MHz,DMSO-d₆)12.97(br s,1H),8.13(dd,J＝5.0,1.9Hz,1H),7.96(dd,J＝8.6,2.3Hz,1H),7.88(d,J＝2.2Hz,1H),7.67(dd,J＝7.3,2.0Hz,1H),7.52-7.47(m,1H),7.25(d,J＝2.9Hz,1H),7.15(d,J＝8.5Hz,1H),7.05-6.98(m,2H),3.67(s,3H)；MS(ES+)m/z440.0,442.0(M+1)。

step 4. preparation of N- (azetidin-1-ylsulfonyl) -4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (2-methoxypyridin-3-yl) benzamide

A solution of 4- (3-chloro-4- (trifluoromethoxy) phenoxy) -3- (2-methoxypyridin-3-yl) benzoic acid (0.35g, 0.68mmol) and 1, 1' carbonyldiimidazole (0.22g, 1.36mmol) in dry tetrahydrofuran (20mL) was refluxed under nitrogen for 2 h. The reaction mixture was cooled to ambient temperature, treated with sulfonamide (0.13, 1.36mmol) and 1, 8-diazabicycloundec-7-ene (0.31mL, 2.05mmol) and stirred for 16 h. The reaction mixture was diluted with ethyl acetate (50mL), washed with 1.0M hydrochloric acid (2 × 40mL), brine (60mL), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo. The residue was dissolved in anhydrous dimethylformamide (12mL), cooled to 0 deg.C, and treated with 1.0M lithium bis (trimethylsilyl) amide in tetrahydrofuran (2.4mL, 2.4 mmol). The resulting mixture was stirred for 3h, then treated with 1, 3-dibromopropane (0.080mL, 0.80 mmol). The resulting mixture was stirred for 18h, then quenched with water (0.5 mL). The mixture was diluted with ethyl acetate (80mL), washed with 1.0M hydrochloric acid (40mL), brine (2 × 60mL), dried over anhydrous sodium sulfate, filtered through celite and concentrated in vacuo. The residue was purified by reverse phase HPLC (preparation E) to provide the title compound (0.070g, 16%):¹H NMR(300MHz,DMSO-d₆)11.89(br s,1H),8.16(dd,J＝5.0,1.9Hz,1H),8.04-7.97(m,2H),7.78-7.72(m,1H),7.59-7.54(m,1H),7.28(d,J＝2.8Hz,1H),7.25-7.18(m,1H),7.12-7.05(m,2H),4.12-4.01(m,4H),3.71(s,3H),2.22-2.10(m,2H)；MS(ES+)m/z:558.09,560.08(M+H)。

synthesis for preparation of 67N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzamide

Step 1.1 preparation of tert-butyl 4-methyl 5-chloro-2-fluorophthalate

To a-40 ℃ solution of methyl 4-bromo-2-chloro-5-fluorobenzoate (8.00g, 30mmol) in anhydrous tetrahydrofuran (150mL) was added a solution of isopropyl magnesium chloride in tetrahydrofuran (2.0M, 30mL, 60mmol) the mixture was stirred at-40 ℃ for 2h, di-tert-butyl dicarbonate (13.1g, 60mmol) was added, the reaction solution was allowed to warm to ambient temperature and stirred for 20h, the reaction was diluted with ethyl acetate (300mL), washed with 1M hydrochloric acid (2 × 300mL), brine (300mL), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated in vacuo to give the title compound as a colorless slurry (8.89g, quantitative yield):¹H NMR(300MHz,CDCl₃)7.87(d,J＝6.3Hz,1H),7.54(d,J＝10.3Hz,1H),3.91(s,3H),1.56(s,9H)；MS(ES+)m/z 233.0,235.0(M-55)。

step 2.1 preparation of tert-butyl 4-methyl 5-cyclopropyl-2-fluorophthalate

To a solution of tert-butyl 4-methyl 5-chloro-2-fluoroterephthalate (9.00g, 31.2mmol) in toluene (150mL) and water (15mL) was added tripotassium phosphate (19.9g, 93.6mmol), cyclopropylboronic acid (13.4g, 156mmol), tricyclohexylphosphine tetrafluoroborate (6.92g, 18.8mmol) and palladium (II) acetate trimer (2.11g,9.4 mmol). The reaction vessel was evacuated and released to an argon atmosphere twice, and then heated to reflux under an argon atmosphere for 2 h. The reaction mixture was cooled to ambient temperature, filtered through a pad of celite and rinsed with ethyl acetate (400 mL). The filtrate was washed with saturated aqueous ammonium chloride (2X 400mL) and over anhydrous magnesium sulfateDried, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0-10% ethyl acetate in hexanes to give the title compound as a beige solid (7.02g, 77% yield):¹H NMR(300MHz,CDCl₃)7.50-7.46(m,2H),3.90(s,3H),2.56-2.46(m,1H),1.56(s,9H),0.98-0.93(m,2H),0.68-0.63(m,2H)；MS(ES+)m/z 239.1(M-55)。

step 3.5 preparation of cyclopropyl-2-fluoro-4- (hydroxymethyl) benzoic acid tert-butyl ester

To a solution of 1-tert-butyl 4-methyl 5-cyclopropyl-2-fluorophthalate (1.50g, 5.08mmol) in anhydrous tetrahydrofuran (30mL) were added anhydrous methanol (0.61mL, 15mmol) and sodium borohydride (0.583g, 15.4 mmol). The mixture was refluxed for 9h and cooled to ambient temperature. The reaction was quenched by slow addition of saturated aqueous ammonium chloride (10mL) and diluted with ethyl acetate (200 mL). The mixture was washed with 1M hydrochloric acid (200mL) and brine (200mL), then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate in hexanes to give the title compound as a colorless solid (0.90g, 67% yield):¹H NMR(300MHz,CDCl₃)7.45(d,J＝7.2Hz,1H),7.18(d,J＝11.6Hz,1H),4.86(s,2H),2.39(brs,1H),1.78-1.68(m,1H),1.55(s,9H),0.92-0.86(m,2H),0.63-0.58(m,2H)；MS(ES+)m/z 289.1(M+23)。

step 4.5 preparation of tert-butyl cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoate

Following the procedure as described in preparation 7 and substituting tert-butyl 5-cyclopropyl-2-fluoro-4- (hydroxymethyl) benzoate as required for methyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate andnoncritical changes were made by replacing 5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-ol with 3, 5-dichlorophenol to obtain the title compound as a pale yellow syrup (0.62g, 83% yield):¹H NMR(300MHz,CDCl₃)7.56(d,J＝7.1Hz,1H),7.17(d,J＝11.3Hz,1H),6.98-6.97(m,1H),6.86-6.85(m,2H),5.19(s,2H),1.85-1.76(m,1H),1.57(s,9H),1.00-0.93(m,2H),0.72-0.66(m,2H)；MS(ES+)m/z 411.1,413.1(M+1)。

step 5.5 preparation of cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 5-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoate, the title compound was obtained as a colorless solid (0.52g, 97% yield):¹H NMR(300MHz,DMSO-d₆)13.2(br s,1H),7.43(d,J＝7.3Hz,1H),7.36(d,J＝11.6Hz,1H),7.22-7.21(m,2H),7.18-7.17(m,1H),5.32(s,2H),2.03-1.94(m,1H),0.95-0.89(m,2H),0.65-0.60(m,2H)；MS(ES-)m/z 353.2,355.2(M-1)。

step 6 Synthesis of N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzamide

To a solution of 5-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoic acid (0.16g, 0.45mmol) in anhydrous dichloromethane (10mL) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.26g, 1.33mmol) and 4- (dimethylamino) pyridine (0.17g, 1.38 mmol). The mixture was stirred at ambient temperature for 5 minutes, followed by the addition of azetidine-1-sulfonamide (0.16g, 1.15 mmol). The mixture was stirred for 16h and then washed withEthyl acetate (100mL) was diluted, washed with 1M hydrochloric acid (2 × 100mL), brine (2 × 100mL), dried over anhydrous magnesium sulfate, filtered and dried in vacuo the residue was triturated in ether (10mL) to give the title compound as a colourless solid (0.130g, 61% yield):¹H NMR(300MHz,DMSO-d₆)11.89(br s,1H),7.40(d,J＝11.1Hz,1H),7.25-7.18(m,4H),5.33(s,2H),4.03(t,J＝7.6Hz,4H),2.20-2.10(m,2H),2.04-1.95(m,1H),0.95-0.89(m,2H),0.74-0.69(m,2H)；¹⁹F NMR(282MHz,DMSO-d₆)-117.2(s,1F)；MS(ES-)m/z 471.1,473.1(M-1)。

preparation of 68N- (azetidin-1-ylsulfonyl) -4- ((3-chloro-5- (trifluoromethoxy) phenoxy) methyl) -5-cyclopropyl-2-fluorobenzamide Synthesis

Step 1.4 preparation of tert-butyl- ((3-chloro-5- (trifluoromethoxy) phenoxy) methyl) -5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in preparation 7 and substituting 5-cyclopropyl-2-fluoro-4- (hydroxymethyl) benzoic acid tert-butyl ester for methyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate and 3-chloro-5- (trifluoromethoxy) phenol for 5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-ol as required, noncritical changes were made to obtain the title compound as a colorless slurry (1.29g, 83% yield):¹H NMR(300MHz,CDCl₃)7.57(d,J＝7.1Hz,1H),7.17(d,J＝11.2Hz,1H),6.89-6.86(m,2H),6.73(s,1H),5.20(s,2H),1.86-1.76(m,1H),1.57(s,9H),0.99-0.93(m,2H),0.72-0.66(m,2H)；¹⁹F NMR(282MHz,CDCl₃)-57.8(s,3F),-112.8(s,1F)；MS(ES+)m/z461.1,463.1(M+1)。

step 2.4 Synthesis of- ((3-chloro-5- (trifluoromethoxy) phenoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid

Following the procedure as described in preparation 4 and substituting tert-butyl 4- ((3-chloro-5- (trifluoromethoxy) phenoxy) methyl) -5-cyclopropyl-2-fluorobenzoate for tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate as required, the title compound was obtained as a colorless solid (1.13g, quantitative yield):¹H NMR(300MHz,DMSO-d₆)13.20(br s,1H),7.43(d,J＝7.3Hz,1H),7.39(d,J＝11.6Hz,1H),7.31-7.29(m,1H),7.14-7.12(m,2H),5.34(s,2H),2.03-1.94(m,1H),0.96-0.89(m,2H),0.66-0.60(m,2H)；MS(ES-)m/z 403.1,405.1(M-1)。

step 3 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((3-chloro-5- (trifluoromethoxy) phenoxy) methyl) -5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in preparation 67, step 6 and varying as needed to replace 5-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoic acid with 4- ((3-chloro-5- (trifluoromethoxy) phenoxy) methyl) -5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained as a colorless solid after trituration in a 1:1 mixture of diethyl ether and hexane (0.08g, 47% yield):¹H NMR(300MHz,DMSO-d₆)11.89(br s,1H),7.42(d,J＝11.1Hz,1H),7.30(s,1H),7.24(d,J＝6.9Hz,1H),7.15-7.12(m,2H),5.35(s,2H),4.03(t,J＝7.7Hz,4H),2.20-2.10(m,2H),2.04-1.96(m,1H),0.95-0.89(m,2H),0.74-0.69(m,2H)；¹⁹F NMR(282MHz,DMSO-d₆)-56.8(s,3F),-117.2(s,1F)；MS(ES-)m/z 521.1,523.1(M-1)。

preparation of 69N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-vinylbenzamide

Step 1.5 Synthesis of bromo-3-chloro-2- (2,2, 2-trifluoroethoxy) pyridine

Following the procedure as described in preparation 11 and making noncritical changes as necessary to replace 2-methylpropan-1-ol with 2,2, 2-trifluoroethanol, the title compound was obtained as a colorless liquid (32.8g, 95% yield): MS (ES +) M/z 316.9,314.9(M + 1).

Step 2.3-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (2,2, 2-trifluoroethoxy) pyridine Synthesis

Following the procedure as described in preparation 12 and making non-critical changes as required to replace 5-bromo-3-chloro-2-isobutoxypyridine with 5-bromo-3-chloro-2- (2,2, 2-trifluoroethoxy) pyridine, the title compound was obtained as a colorless gum (20.1g, 99% yield): MS (ES +) M/z 338.1,340.1(M + 1).

Step 3.5 Synthesis of chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-ol

Following the procedure as described in preparation 13 and substituting 3-chloro-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (2,2, 2-trifluoroethoxy) pyridine for 3-chloro-2-isobutoxy-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine as required, a noncritical change was made to obtain the title compound as a colorless solid (11.3g, 84% yield): MS (ES +) M/z 228.1,230.1(M + 1).

Step 4.4 Synthesis of tert-butyl 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-iodobenzoate

Following the procedure as described in preparation 5 and substituting tert-butyl 2, 4-difluoro-5-iodobenzoate (preparation 60, step 1) for tert-butyl 5-chloro-2, 4-difluorobenzoate and 5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-ol for 3-chloro-4- (trifluoromethoxy) phenol as required, the title compound was obtained as a colorless solid (5.10g, 93%): MS (ES +) M/z 547.9,549.9(M + 1).

Step 5.4 Synthesis of tert-butyl 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-vinylbenzoate

Following the procedure as described in preparation 66, step 2 and substituting tert-butyl 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-iodobenzoate for 3-bromo-4- (3-chloro-4- (trifluoromethoxy) phenoxy) benzoate and 4,4,5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolan for (2-methoxypyridin-3-yl) boronic acid, noncritical changes were made to obtain the title compound as a pale yellow gum (1.54g, 54% yield):¹H NMR(300MHz,CDCl₃)8.61(d,J＝14.9Hz,1H),8.34(d,J＝8.8Hz,1H),7.88(d,J＝2.6Hz,1H),7.50(d,J＝2.6Hz,1H),6.48(d,J＝13.0Hz,1H),5.90(d,J＝17.7Hz,1H),5.45(d,J＝11.2Hz,1H),4.85-4.77(m,2H),1.62(3,9H)。

step 6.4 Synthesis of- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-ethenylbenzoic acid

Following the procedure as described in preparation 4 and substituting tert-butyl 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-vinylbenzoate for tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate as required for the noncritical change the title compound was obtained as a colorless solid (0.71g, 53% yield): MS (ES +) M/z 391.9,393.9(M + 1).

Step 7 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-vinylbenzamide

Following the procedure as described in preparation 67, step 6 and substituting 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-vinylbenzoic acid for 5-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoic acid, a non-critical change was made to obtain the title compound as a colorless solid (0.05g, 45% yield):¹H NMR(300MHz,CDCl₃)8.61(d,J＝14.9Hz,1H),8.34(d,J＝8.8Hz,1H),7.88(d,J＝2.6Hz,1H),7.50(d,J＝2.6Hz,1H),7.00-6.91(m,1H),6.48(d,J＝13.0Hz,1H),5.90(d,J＝17.7Hz,1H),5.45(d,J＝11.2Hz,1H),4.85-4.77(m,2H),4.25(t,J＝7.7Hz,4H),2.33-2.23(m,2H)；¹⁹F NMR(282MHz,CDCl₃)-73.7(s,3F),-108.6(s,1F)；MS(ES-)m/z 508.1,510.1(M-1)。

preparation of 70N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzamide Synthesis

Step 1.4 preparation of tert-butyl- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in preparation 60, step 1 and replacing 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-iodobenzoic acid with tert-butyl 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluoro-5-iodobenzoic acidNon-critical changes of tert-butyl ester and replacement of microwave heating to 150 ℃ with reflux in dioxane for 16h and 0.5h to obtain the title compound as gum (1.20g, 71% yield):¹H NMR(300MHz,CDCl₃)8.38(dd,J＝7.8,1.1Hz,1H),7.89(dd,J＝2.6,1.2Hz,1H),7.51(d,J＝2.5,1.2Hz,1H),6.48(d,J＝11.2,1.0Hz,1H),4.85-4.77(m,2H),2.16-2.07(m,1H),1.60(s,9H),1.04-0.91(m,2H),0.83-0.73(m,2H)；MS(ES+)m/z 462.0,464.0(M+1)。

step 2.4 preparation of- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoic acid

The title compound was obtained as gum (1.10g, 83% yield) following the procedure as described in preparation 4 and varying as required to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoate to give the title compound as gum (1.10g, 83% yield) which was used directly without any further purification: MS (ES +) M/z 405.1,407.1(M + 1).

Step 3 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzamide

Following the procedure as described in preparation 67, step 6 and substituting 4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -5-cyclopropyl-2-fluorobenzoic acid for-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoic acid, a non-critical change was made to obtain the title compound as a colorless solid (0.04g, 12% yield):¹H NMR(300MHz,CDCl₃)8.62(br s,1H),7.87(d,J＝2.5Hz,1H),7.70(d,J＝8.7Hz,1H),7.50(d,J＝2.5Hz,1H),6.48(d,J＝12.9Hz,1H),4.85-4.77(m,2H),4.24(t,J＝7.7Hz,4H),2.32-2.21(m,2H),2.16-2.07(m,1H),1.04-0.73(m,4H)；¹⁹F NMR(282MHz,CDCl₃)-73.7(s,3F),-111.2(s,1F)；MS(ES-)m/z 522.1,524.0(M-1)。

preparation of 71N- (azetidin-1-ylsulfonyl) -5-chloro-4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluorobenzamide

Step 1.preparation of tert-butyl 5-chloro-4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridine-3-ol) oxy) -2-fluorobenzoate

Following the procedure as described in preparation 5 and changing as needed to replace 3-chloro-4- (trifluoromethoxy) phenol with 5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-ol gave the title compound as a colorless solid (3.86g, 85% yield):¹H NMR(300MHz,CDCl₃)7.98(d,J＝7.6Hz,1H),7.88(d,J＝2.6Hz,1H),7.50(d,J＝2.6Hz,1H),6.59(d,J＝10.9Hz,1H),4.87-4.78(m,2H),1.61(s,9H)。

step 2.5 preparation of chloro-4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluorobenzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 5-chloro-4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluorobenzoate to obtain the title compound as a colorless solid (0.44g, 59% yield): MS (ES +) M/z399.9,401.9(M + 1).

Step 3 Synthesis of N- (azetidin-1-ylsulfonyl) -5-chloro-4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluorobenzamide

Following the procedure as described in preparation 67, step 6 and changing as needed to replace 5-cyclopropyl-4- ((3, 5-dichlorophenoxy) methyl) -2-fluorobenzoic acid with 5-chloro-4- ((5-chloro-6- (2,2, 2-trifluoroethoxy) pyridin-3-yl) oxy) -2-fluorobenzoic acid gave the title compound as a colorless solid (0.05g, 34% yield):¹H NMR(300MHz,CDCl₃)8.58(d,J＝14.2Hz,1H),8.25(d,J＝7.8Hz,1H),7.91(d,J＝2.6Hz,1H),7.53(d,J＝7.5,1H),6.59(d,J＝12.4Hz,1H),4.86-4.78(m,2H),4.24(t,J＝15.5Hz,4H),2.33-2.22(m,2H)；¹⁹F NMR(282MHz,CDCl₃)-73.7(s,3F),-108.8(s,1F)；MS(ES-)m/z 516.0,518.0(M-1)。

preparation of 72N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-vinylbenzamide Synthesis

Step 1.4 preparation of methyl- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-vinylbenzoate

Following the procedure as described in preparation 66, step 2 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-iodobenzoic acid methyl ester for 3-bromo-4- (3-chloro-4- (trifluoromethoxy) phenoxy) benzoate and 4,4,5, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolan for (2-methoxypyridin-3-yl) boronic acid, noncritical changes were made to obtain the title compound as a colorless solid (0.17g, 16% yield):¹H NMR(300MHz,CDCl₃)8.15(d,J＝8.1Hz,1H),7.85(d,J＝2.7Hz,1H),7.40(d,J＝2.7Hz,1H),6.96(dd,J＝11.2,17.7Hz,1H),6.42(d,J＝11.7Hz,1H),5.83(d,J＝17.6Hz,1H),5.38(d,J＝11.2Hz,1H),5.35-5.26(m,1H),3.91(s,3H),1.39(d,J＝6.2Hz,6H)；MS(ES+)m/z 366.0,368.0(M+1)。

step 2.4 preparation of- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-vinylbenzoic acid

To a solution of methyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-vinylbenzoate (0.17g, 0.47mmol) in tetrahydrofuran (10mL) and water (5mL) was added lithium hydroxide (0.09g,3.8mmol), the mixture was heated at reflux for 1.5h and cooled to ambient temperature, the mixture was diluted with 1M hydrochloric acid (100mL) and extracted with ethyl acetate (2 × 100mL), the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a colourless solid (0.16g, 96% yield):¹H NMR(300MHz,CDCl₃)10.54(br s,1H),8.22(d,J＝8.1Hz,1H),7.88(d,J＝2.7Hz,1H),7.43(d,J＝2.7Hz,1H),6.97(dd,J＝11.2,17.7Hz,1H),6.44(d,J＝11.7Hz,1H),5.84(d,J＝17.6Hz,1H),5.40(d,J＝11.4Hz,1H),5.35-5.27(m,1H),1.40(d,J＝6.2Hz,6H)；MS(ES-)m/z 550.2,552.2(M-1)。

step 3 Synthesis of N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-vinylbenzamide

Following the procedure as described in preparation 24 and varying as needed to replace 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid with 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -2-fluoro-5-vinylbenzoic acid and N, N-dimethylsulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid (0.19g, 49% yield):¹H NMR(300MHz,DMSO-d₆)12.19(br s,1H),8.31(d,J＝2.7Hz,1H),8.26(d,J＝8.0Hz,1H),8.16(d,J＝2.7Hz,1H),7.25(dd,J＝11.3,17.8Hz,1H),7.17(d,J＝11.5Hz,1H),6.29(d,J＝17.2Hz,1H),5.72(d,J＝11.6Hz,1H),5.60-5.52(m,1H),4.35(t,J＝7.7Hz,4H),2.52-2.41(m,2H),1.62(d,J＝6.2Hz,6H)；¹⁹F NMR(282MHz,DMSO-d₆)-106.0(s,1F)；MS(ES-)m/z 468.1,470.1(M-1)。

preparation of 734- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) -N- (N-methylsulfamoyl) benzamide

Step 1.3 preparation of tert-butyl 3-bromo-4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) benzoate

Following the procedure as described in preparation 5 and substituting tert-butyl 3-bromo-4-fluorobenzoate for tert-butyl 5-chloro-2, 4-difluorobenzoate and 5-chloro-6-isopropoxypyridin-3-ol for 3-chloro-4- (trifluoromethoxy) phenol as required, the title compound was obtained as a colorless syrup (1.47g, 76% yield):¹H NMR(300MHz,CDCl₃)8.21(d,J＝1.9Hz,1H),7.86-7.82(m,2H),7.37(d,J＝2.6Hz,1H),6.79(d,J＝8.6Hz,1H),5.35-5.22(m,1H),1.56(s,9H),1.37(d,J＝6.2Hz,6H)；MS(ES+)m/z442.0,444.0(M+1)。

step 2.4 preparation of tert-butyl- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) benzoate

Following the procedure as described in preparation 66, step 2 and substituting 3-bromo-4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) benzoate for methyl 3-bromo-4-fluorobenzoate for the noncritical change the title compound was obtained as a colorless foam (0.56g, 67% yield):¹H NMR(300MHz,CDCl₃)8.18-8.16(m,1H),7.94-7.92(m,2H),7.78-7.77(m,1H),7.57-7.55(m,1H),7.34-7.33(m,1H),6.95(dd,J＝5.4,6.9Hz,1H),6.87-6.84(m,1H),5.32-5.19(m,1H),3.84(s,3H),1.56(s,9H),1.36(d,J＝6.2Hz,6H)；MS(ES+)m/z471.1,473.1(M+1)。

step 3.4 preparation of- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) benzoic acid

Following the procedure as described in preparation 4 and varying as required to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) benzoate the title compound was obtained as a colourless slurry (0.92g, quantitative yield):¹H NMR(300MHz,CDCl₃)12.43(br s,1H),8.38(d,J＝5.3Hz,1H),8.23-8.10(m,3H),7.90(d,J＝2.7Hz,1H),7.50-7.45(m,2H),6.93(d,J＝8.7Hz,1H),5.28-5.16(m,1H),4.30(s,3H),1.40(d,J＝6.1Hz,6H)；MS(ES+)m/z 415.0,417.0(M+1)。

step 4.4 Synthesis of- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) -N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 24 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) benzyl for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and methylsulfonamide for N, N-dimethylsulfonamide as required for noncritical changes, the title compound was obtained as a colorless solid (0.23g, 76% yield):¹H NMR(300MHz,DMSO-d₆)11.71(br s,1H),8.18(dd,J＝1.9,5.0Hz,1H),7.98-7.90(m,3H),7.76(dd,J＝1.9,7.3Hz,1H),7.69(d,J＝2.6Hz,1H),7.60-7.55(m,1H),7.07(dd,J＝5.0,7.3Hz,1H),7.00(d,J＝8.6Hz,1H),5.27-5.15(m,1H),3.76(s,3H),2.51-2.50(m,3H),1.28(d,J＝6.2Hz,6H)；MS(ES-)m/z 505.2,507.2(M-1)。

preparation of 74N- (azetidin-1-ylsulfonyl) -4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) benzamide Synthesis

Following the procedure as described in preparation 24 and substituting 4- ((5-chloro-6-isopropoxypyridin-3-yl) oxy) -3- (2-methoxypyridin-3-yl) benzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide as required, noncritical changes were made to obtain the title compound as a colorless solid (0.05g, 14% yield):¹H NMR(300MHz,DMSO-d₆)11.78(br s,1H),8.18(dd,J＝1.8,5.0Hz,1H),7.99-7.90(m,3H),7.77(dd,J＝1.8,7.2Hz,1H),7.69(d,J＝2.6Hz,1H),7.08(dd,J＝5.0,7.2Hz,1H),7.01(d,J＝8.6Hz,1H),5.28-5.15(m,1H),4.03(t,J＝7.7Hz,4H),3.76(s,3H),2.17-2.06(m,2H),1.29(d,J＝6.2Hz,6H)；MS(ES-)m/z 531.2,533.2(M-1)。

preparation of 75N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzamide

Step 1.5 preparation of tert-butyl cyclopropyl-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoate

Following the procedure as described in preparation 7 and substituting 5-cyclopropyl-2-fluoro-4- (hydroxymethyl) benzoic acid tert-butyl ester for methyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate and 3, 4-dichlorophenol for 5-chloro-6- (2,2,3, 3-trifluoropropoxy) pyridin-3-ol as required, noncritical changes were made to obtain the title compound as a colorless slurry (0.46g, 53% yield):¹H NMR(300MHz,DMSO-d₆)7.53(d,J＝8.9,1H),7.41-7.32(m,3H),7.10-7.06(m,1H),5.31(s,1H),2.02-1.93(m,1H),1.49(s,9H),0.95-0.88(m,2H),0.65-0.60(m,2H)；MS(ES+)m/z354.9,356.9(M+1)。

step 2.5 preparation of cyclopropyl-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoic acid

Following the procedure as described in preparation 4 and substituting tert-butyl 5-cyclopropyl-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoate for tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate for noncritical change the title compound was obtained as a colorless solid (0.32g, 75% yield), which was carried on without further characterization.

Step 3 Synthesis of N- (azetidin-1-ylsulfonyl) -5-cyclopropyl-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzamide

Following the procedure as described in preparation 24 and varying as needed to replace 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid with 5-cyclopropyl-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoic acid and N, N-dimethylsulfonamide with azetidine-1-sulfonamide gave the title compound as a colorless solid (0.12g, 51% yield):¹H NMR(300MHz,CDCl₃)8.72(d,J＝15.1Hz,1H),7.81(d,J＝7.7Hz,1H),7.37-7.29(m,2H),7.08(d,J＝2.9,1H),6.86-6.82(m,1H),5.23(s,2H),4.25(t,J＝7.8,4H),2.32-2.22(m,2H),1.87-1.78(m,1H),1.05-0.99(m,2H),0.77-0.71(m,2H)；MS(ES-)m/z 471.0,473.0(M-1)。

synthesis of 765-chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Step 1.Synthesis of tert-butyl 4- (((tert-butyldimethylsilyl) oxy) methyl) -5-chloro-2-fluorobenzoate

Following the procedure as described in preparation 67, step 1 and substituting ((4-bromo-2-chloro-5-fluorobenzyl) oxy) (tert-butyl) dimethylsilane (preparation 10) for methyl 4-bromo-2-chloro-5-fluorobenzoate for non-critical changes, the title compound was obtained as a pale yellow oil (16.0g, quantitative yield):¹H NMR(300MHz,CDCl₃)7.75(d,J＝6.4Hz,1H),7.30(d,J＝11.4Hz,1H),4.70(s,2H),1.55(s,9H),0.93(s,9H),0.10(s,6H)。

step 2.5 Synthesis of chloro-2-fluoro-4- (hydroxymethyl) benzoic acid tert-butyl ester

To a 0 ℃ solution of 4- (((tert-butyldimethylsilyl) oxy) methyl) -5-chloro-2-fluorobenzoic acid tert-butyl ester (4.90g,13.1mmol) in anhydrous tetrahydrofuran (100mL) was added a solution of tetra-n-butylammonium fluoride (1.0M in tetrahydrofuran, 14.5mL, 14.5 mmol). the mixture was stirred at 0 ℃ under a nitrogen atmosphere for 1.5h, then diluted with ethyl acetate (300mL), washed with brine (2 × 300mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo.the residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate in hexane to give the title compound as a colorless syrup (3.08g, 91% yield):¹H NMR(300MHz,CDCl₃)7.73(d,J＝6.4Hz,1H),7.28(d,J＝11.2Hz,1H),4.72(s,2H),2.68(br s,1H),1.55(s,9H)。

step 3.5 Synthesis of tert-butyl chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoate

Following the procedure as described in preparation 7 and substituting 5-chloro-2-fluoro-4- (hydroxymethyl) benzoic acid tert-butyl ester for methyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate and 3, 4-dichlorophenol for 5-chloro-6- (2,2,3, 3-trifluoropropoxy) pyridin-3-ol as required, noncritical changes were made to obtain the title compound as a colorless solid (0.73g, 63% yield):¹HNMR(300MHz,CDCl₃)7.87(d,J＝6.4Hz,1H),7.36-7.29(m,2H),7.07(d,J＝2.9Hz,1H),6.82(dd,J＝2.9,8.9Hz,1H),5.09(s,2H),1.58(s,9H)。

step 4.5 Synthesis of chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 5-chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoate, the title compound was obtained as a colorless solid (0.61g, 98% yield):¹H NMR(300MHz,DMSO-d₆)13.62(br s,1H),7.88(d,J＝6.5Hz,1H),7.59-7.52(m,2H),7.40(d,J＝2.9Hz,1H),7.08(dd,J＝2.9,9.0Hz,1H),5.19(s,2H)；MS(ES-)m/z 347.1,349.1(M-1)。

step 5.5 Synthesis of chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 24 and substituting 5-chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and methylsulfonamide for N, N-dimethylsulfonamide as required, the changes were made byThe title compound was obtained as a colorless solid after phase HPLC purification (0.03g, 8% yield):¹H NMR(300MHz,DMSO-d₆)11.95(br s,1H),7.76(d,J＝6.2Hz,2H),7.59(d,J＝10.4Hz,1H),7.54(d,J＝8.9Hz,1H),7.40(d,J＝2.9Hz,1H),7.08(dd,J＝2.9,9.0Hz,1H),5.20(s,2H),2.54(d,J＝4.0Hz,3H)；MS(ES-)m/z 439.0,441.0(M-1)。

synthesis for preparation of 77N- (azetidin-1-ylsulfonyl) -5-chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzamide

Following the procedure as described in preparation 24 and varying as needed to replace 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid with 5-chloro-4- ((3, 4-dichlorophenoxy) methyl) -2-fluorobenzoic acid and N, N-dimethylsulfonamide with azetidine-1-sulfonamide, the title compound was obtained as a colorless solid after purification by reverse phase HPLC (0.04g, 10% yield):¹H NMR(300MHz,DMSO-d₆)12.09(br s,1H),7.83(d,J＝6.2Hz,1H),7.60(d,J＝10.4Hz,1H),7.55(d,J＝8.9Hz,1H),7.40(d,J＝2.9Hz,1H),7.08(dd,J＝2.9,9.0Hz,1H),5.21(s,2H),4.02(t,J＝7.7Hz,4H),2.20-2.10(m,2H)；MS(ES-)m/z465.0,467.0(M-1)。

preparation of 785-chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide Synthesis

Step 1.5 Synthesis of tert-butyl chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluorobenzoate

Following the procedure as described in preparation 7 and substituting tert-butyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate for methyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate and 4-chloro-3- (trifluoromethyl) benzene as appropriateNon-critical changes were made to phenol instead of 5-chloro-6- (2,2,3, 3-trifluoropropoxy) pyridin-3-ol to obtain the title compound as a colorless solid (0.33g, 31% yield):¹H NMR(300MHz,CDCl₃)7.88(d,J＝6.4Hz,1H),7.41(d,J＝8.8Hz,1H),7.34-7.29(m,2H),7.04(dd,J＝2.9,8.8Hz,1H),5.13(s,2H),1.58(s,9H)。

step 2.5 Synthesis of chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluorobenzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 5-chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluorobenzoate, the title compound was obtained as a colorless solid (0.55g, quantitative yield):¹H NMR(300MHz,DMSO-d₆)13.62(br s,1H),7.88(d,J＝6.5Hz,1H),7.65-7.60(m,2H),7.52(d,J＝2.9Hz,1H),7.39(dd,J＝2.9,8.9Hz,1H),5.26(s,2H)；MS(ES-)m/z 381.1,383.1(M-1)。

step 3.5 Synthesis of chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 24 and substituting 5-chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and methylsulfonamide for N, N-dimethylsulfonamide, the title compound was obtained as a colorless solid (0.15g, 44% yield):¹HNMR(300MHz,DMSO-d₆)11.96(br s,1H),7.79-7.75(m,2H),7.66-7.62(m,2H),7.52(d,J＝2.9Hz,1H),7.39(dd,J＝2.9,8.9Hz,1H),5.26(s,2H),2.55(d,J＝4.1Hz,3H)；MS(ES-)m/z473.1,475.1(M-1)。

preparation of 79N- (azetidin-1-ylsulfonyl) -5-chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluorobenzamide

Following the procedure as described in preparation 24 and substituting 5-chloro-4- ((4-chloro-3- (trifluoromethyl) phenoxy) methyl) -2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide, the title compound was obtained as a colorless solid after reverse phase HPLC (0.01g, 3% yield):¹H NMR(300MHz,DMSO-d₆)12.11(br s,1H),7.83(d,J＝6.2Hz,1H),7.66-7.62(m,2H),7.52(d,J＝2.8Hz,1H),7.39(dd,J＝8.9,2.8Hz,1H),5.27(s,2H),4.02(t,J＝7.7Hz,4H),2.20-2.10(m,2H)；MS(ES-)m/z 499.0,501.0(M-1)。

synthesis for preparation of 805-chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Step 1.5 Synthesis of tert-butyl chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) methyl) -2-fluorobenzoate

Following the procedure as described in preparation 7 and substituting tert-butyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate for methyl 5-chloro-2-fluoro-4- (hydroxymethyl) benzoate and 3-chloro-4- (trifluoromethoxy) phenol for 5-chloro-6- (2,2,3, 3-trifluoropropoxy) pyridin-3-ol as required, noncritical changes were made to obtain the title compound as a colorless solid (1.04g, 80% yield):¹H NMR(300MHz,CDCl₃)7.87(d,J＝6.4Hz,1H),7.32(d,J＝10.8Hz,1H),7.26-7.23(m,2H),7.07(d,J＝3.0Hz,1H),6.86(dd,J＝3.0,9.1Hz,1H),5.10(s,2H),1.58(s,9H)。

step 2.5 Synthesis of chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) methyl) -2-fluorobenzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 5-chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate, the title compound was obtained as a colorless solid (0.88g, 99% yield):¹H NMR(300MHz,DMSO-d₆)13.62(br s,1H),7.88(d,J＝6.5Hz,1H),7.59(d,J＝11.0Hz,1H),7.52-7.48(m,1H),7.44(d,J＝3.0Hz,1H),7.14(dd,J＝3.0,9.1Hz,1H),5.22(s,2H)；MS(ES-)m/z 397.0,399.0(M-1)。

step 3.5 Synthesis of chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 24 and substituting 5-chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) methyl) -2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and methylsulfonamide for N, N-dimethylsulfonamide, the title compound was obtained as a colorless solid (0.18g, 55% yield):¹HNMR(300MHz,DMSO-d₆)11.96(br s,1H),7.79-7.75(m,2H),7.60(d,J＝10.4Hz,1H),7.52-7.49(m,1H),7.44(d,J＝3.0Hz,1H),7.14(dd,J＝3.0,9.1Hz,1H),5.22(s,2H),2.55(d,J＝4.0Hz,3H)；MS(ES-)m/z 489.1,491.1(M-1)。

preparation of 81N- (azetidin-1-ylsulfonyl) -5-chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) methyl) -2-fluorobenzamide

Following the procedure as described in preparation 24 and substituting 5-chloro-4- ((3-chloro-4- (trifluoromethoxy) phenoxy) methyl) -2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide for N, N-dimethylsulfonamide, the title compound was obtained as a colorless solid after purification by reverse phase HPLC (0.021g, 6% yield):¹H NMR(300MHz,DMSO-d₆)12.09(br s,1H),7.84(d,J＝6.2Hz,1H),7.61(d,J＝10.4Hz,1H),7.52-7.48(m,1H),7.43(d,J＝3.0Hz,1H),7.14(dd,J＝9.1,3.0Hz,1H),5.23(s,2H),4.03(t,J＝7.7Hz,4H),2.21-2.10(m,2H)；MS(ES-)m/z515.1,517.1(M-1)。

synthesis for preparation of 825-chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Step 1.5 Synthesis of chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid tert-butyl ester

Following the procedure as described in preparation 7 and making noncritical changes as necessary to replace 5-chloro-6- (2,2,3, 3-trifluoropropoxy) pyridin-3-ol with 5-chloro-6-isopropoxypyridin-3-ol gave the title compound as a colorless slurry (0.72g, 85% yield):¹H NMR(300MHz,CDCl₃)7.84(d,J＝6.4Hz,1H),7.73(d,J＝2.8Hz,1H),7.34(d,J＝2.8Hz,1H),7.30(d,J＝10.9Hz,1H),5.27-5.15(m,1H),5.06(s,2H),1.56(s,9H),1.33(d,J＝6.2Hz,6H)；MS(ES+)m/z430.1,432.0(M+1)。

step 2.5 Synthesis of chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid

Following the procedure as described in preparation 4 and changing as needed to replace tert-butyl 5-chloro-4- (3-chloro-4- (trifluoromethoxy) phenoxy) -2-fluorobenzoate with tert-butyl 5-chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluorobenzoate, the title compound was obtained as a colorless solid (0.64g, quantitative yield):¹H NMR(300MHz,CDCl₃)8.04(d,J＝6.3Hz,1H),7.81(d,J＝2.7Hz,1H),7.45-7.42(m,2H),6.75(br s,1H),5.24-5.16(m,1H),5.12(s,2H),1.36(d,J＝6.2Hz,6H)；MS(ES-)m/z372.1,374.1(M-1)。

step 3.5 Synthesis of chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluoro-N- (N-methylsulfamoyl) benzamide

Following the procedure as described in preparation 24 and substituting 5-chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and methylsulphonamide for N, N-dimethylsulphonamide, the non-critical change was carried out to obtain the title compound as a colorless solid (0.19g, 47% yield):¹H NMR(300MHz,DMSO-d₆)11.93(br s,1H),7.94(d,J＝2.8Hz,1H),7.80-7.74(m,3H),7.59(d,J＝10.4Hz,1H),5.21-5.12(m,3H),2.55(d,J＝3.8Hz,3H),1.26(d,J＝6.2Hz,6H)；MS(ES-)m/z 464.2,466.2(M-1)。

synthesis for preparation of 83N- (azetidin-1-ylsulfonyl) -5-chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluorobenzamide

Following the procedure as described in preparation 24Non-critical changes were made sequentially with 5-chloro-4- (((5-chloro-6-isopropoxypyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid instead of 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide instead of N, N-dimethylsulfonamide to give the title compound as a colorless solid after purification by reverse phase HPLC (0.06g, 15% yield):¹H NMR(300MHz,DMSO-d₆)12.08(br s,1H),7.94(d,J＝2.7Hz,1H),7.83(d,J＝6.2Hz,1H),7.80(d,J＝2.7Hz,1H),7.61(d,J＝10.4Hz,1H),5.20-5.12(m,3H),4.03(t,J＝7.7Hz,4H),2.21-2.11(m,2H),1.26(d,J＝6.2Hz,6H)；MS(ES-)m/z 490.2,492.1(M-1)。

synthesis for preparation of 845-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) methyl) -N- (N, N-dimethylsulfamoyl) -2-fluorobenzamide

Following the procedure as described in preparation 24 and substituting 5-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid for 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid, a noncritical change was made to obtain the title compound as a colorless solid (0.02g, 4% yield):¹H NMR(300MHz,DMSO-d₆)12.02(s,1H),7.99(d,J＝2.7Hz,1H),7.92(d,J＝2.7Hz,1H),7.77(d,J＝6.2Hz,1H),7.61(d,J＝10.4Hz,1H),6.59(tt,J＝52.1,5.3Hz,1H),5.23(s,2H),4.85(t,J＝14.1Hz,2H),2.85(s,6H)；MS(ES-)m/z 550.0,552.0(M-1)。

synthesis for preparation of 85N- (azetidin-1-ylsulfonyl) -5-chloro-4- (((5-chloro-6- (2,2,3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) methyl) -2-fluorobenzamide

The procedure as described in preparation 24 was followed and the residue was purified from 5-chloro-4- (((5-chloro-6- (2,non-critical changes were made to 3, 3-tetrafluoropropoxy) pyridin-3-yl) oxy) methyl) -2-fluorobenzoic acid instead of 5-chloro-4- (4-chloro-3- (trifluoromethyl) phenoxy) -2-fluorobenzoic acid and azetidine-1-sulfonamide instead of N, N-dimethylsulfonamide to obtain the title compound as a colorless solid after purification by reverse phase HPLC (0.04g, 10% yield):¹H NMR(300MHz,DMSO-d₆)12.07(br s,1H),7.99(d,J＝2.7Hz,1H),7.92(d,J＝2.7Hz,1H),7.84(d,J＝6.2Hz,1H),7.63(d,J＝10.4Hz,1H),6.59(tt,J＝51.9,5.2Hz,1H),5.24(s,2H),4.86(t,J＝14.1Hz,2H),4.04(t,J＝7.7Hz,4H),2.21-2.11(m,2H)；MS(ES-)m/z 562.1,564.1(M-1)。

electrophysiological assay (in vitro assay)

Patch voltage clamp electrophysiology allows direct measurement and quantification of the blockade of the sodium channel of the voltage gate (NaV), as well as determination of the time and voltage dependence of the blockade, which has been explained in conjunction with the differences in the resting, open and inactivated states of the sodium channel (hill, b., Journal of General Physiology (1977),69: 497-.

The following patch voltage clamp electrophysiology studies were performed on representative compounds of the invention with human embryonic kidney cells (HEK) grown in medium containing 10% FBS, 1% PSG, and 0.5mg/mL G418 at 37 ℃ in 5% CO2, persistently transfected with an expression vector containing the full-length cDNA encoding the desired human sodium channel α -subunit. For all studies, HEK cells used for Electrophysiology (EP) recordings had passage numbers less than 40 and were used within three days from plating time. NaV1.7 and NaV1.5 cDNAs (NM-002977 and AC 137587; SCN5A, respectively) were stably expressed in HEK-293 cells. The β 1 subunit is co-expressed in nav1.7 and nav1.5 cell lines.

Sodium current was measured in whole cell mode using patch xpress automated voltage clamp or manually using an Axopatch 200b (axon instruments) or Model 2400(a-M system) amplifier using patch clamp technique. The manual voltage clamp scheme is as follows: the borosilicate glass micropipette was fire polished to the tip diameter, producing a resistance of 2-4 mega ohms in the working solution. Fill the pipettor with a solution consisting of: 5mM NaCl, 10mM CsCl, 120mM CsF, 0.1mM CaCl2, 2mM MgCl2, 10mM HEPES, 10mM EGTA; and adjusted to pH 7.2 with CsOH. The topical solution had the following composition: 140mM NaCl, 5mM KCl, 2mM CaCl2, 1mM MgCl2, 10mM HEPES; and adjusted to pH7.4 with NaOH. In some studies, the external sodium was reduced by equimolar replacement with choline. The permeability of the CsF internal solution and NaCl external solution was adjusted to 300mOsm/kg and 310mOsm/kg with glucose, respectively. All recordings were performed at ambient temperature in a water bath chamber with a volume of 150. mu.L. Control sodium current was measured in 0.5% DMSO. Control and representative compounds of the invention were administered to the recording room via a 4-pinch valve or 8-pinch valve perfusion system manufactured by ALA Scientific Instruments.

The current was filtered and stored at 5Hz using the Digidata-1322A analog/digital interface at 40kHz sampling frequency with pClamp software (Axon Instruments). Series resistance compensation (60-80%) was applied. If the current shows insufficient voltage control (as judged by the IV relationship during stepwise activation), the cell is rejected. All statistics in this study are given as mean ± SD.

The membrane potential was maintained at a voltage where the channel was completely inactive (-60 mV for both nav1.7 and nav 1.5). The voltage was then pulled back to a very negative (Vhold 150mV) voltage for 20ms, and then test pulses were applied to quantify compound blockade. A brief repolarization of 20ms is long enough for the compound-free channel to recover completely from rapid inactivation, but the slower recovery of the compound-bound channel is such that negligible recovery can occur during this interval. The percentage of reduction in sodium current after washing off (wash-on) the compound was considered as the percentage of blockade of sodium channels.

When tested in this model, the compounds of the invention show affinity for the inactivated state of nav1.7 and nav1.5, as listed in tables 1 and 2 below.

Binding assays

The tritium-containing compound bound to the membrane is isolated from cells heterologously expressing hNav1.7 and β 1 subunits.

Preparation of membranes containing recombinantly expressed sodium channels: frozen recombinant cell pellets were thawed on ice and diluted to 4 cell pellet weights with ice cold 50mM Tris HCl, pH7.4 buffer. The cell suspension was homogenized on ice using a motorized glass dounce homogenizer (glass dounce homogenizer). The homogenate was re-diluted 8.4 fold with ice-cold 50mM TrisHCl, pH7.4 buffer and then centrifuged at 200x g for 15min at 4 ℃. The supernatant was collected and centrifuged at 10000x g for 50min at 4 ℃. The pellet was then resuspended in 100mM NaCl, 20mM Tris HCl, pH7.4 buffer (Calbiochem) containing 1% v/v protease inhibitor and re-homogenized on ice. The homogenized membrane was then processed through a syringe fitted with a 26 gauge needle. Protein concentration was determined by Bradford assay and membranes were stored at-80 ℃.

Radioligand binding studies: and (4) performing saturation experiments. Tritiating a representative compound of formula (I). Incorporation of three tritium atoms in place of methyl hydrogen to give [ 2 ]³H]A compound is provided. The binding of the radioligand was performed at room temperature in a 5mL borosilicate glass test tube. By adding the membrane to increasing concentrations of [ 2 ] in a buffer solution of 100mM NaCl, 20mM Tris HCl, pH7.4 containing 0.01% w/v Bovine Serum Albumin (BSA)³H]The compound was held for 18h to begin binding. Non-specific binding was determined in the presence of 1 μ M unlabeled compound. After 18h, the reaction was filtered through a GF/C glass fiber filter pre-soaked in 0.5% w/v polyethyleneimine. The filters were washed with 15mL of ice-cold 100mM NaCl, 20mM Tris HCl, pH7.4 buffer containing 0.25% BSA to separate bound ligand from free ligand. 2 to the filter³H]Compounds were quantified by liquid scintillation counting.

Competitive binding assays. The conjugation reaction was performed at room temperature in 96-well polypropylene plates for 18 h. In 360. mu.L, the membrane is used with 100pM 2³H]Compounds were incubated with increasing concentrations of test compounds. Nonspecific binding was defined in the presence of 1 μ M unlabeled compound. The reaction was transferred and passed through a 96-well fiberglass/C filter plate pre-impregnated with 0.5% polyethyleneimineAnd (5) filtering. The filtered reaction was washed 5 times with 200 μ L of ice cold buffer containing 0.25% BSA. Bound radioactivity was determined by liquid scintillation counting.

And (3) data analysis: for saturation experiments, non-specific binding was subtracted from the total binding to provide specific binding and these values were recalculated in pmol ligand binding/mg protein. A saturation curve was constructed and dissociation constants were calculated using a single site ligand binding model: beq ═ X (Bmax X)/(X + Kd), where Beq is the amount of bound ligand at equilibrium, Bmax is the maximum receptor density, Kd is the dissociation constant of the ligand, and X is the free ligand concentration. For competitive studies, percent inhibition was determined using XL fitting using a 4-parameter logistic model (percent inhibition ═ a + ((B-a)/(1+ ((x/C) ^ D)))) and IC was calculated using XL fitting₅₀Values where A and B are maximum and minimum inhibition, respectively, and C is IC₅₀Concentration and D is the (Hill) slope.

When tested in this model, the compounds of the invention showed affinity for the inactivated state of nav1.7 membrane binding (as listed in tables 1 and 2).

TABLE 1

TABLE 2

Sodium channel blocker induced analgesia

Thermally induced tailgating latency test

In this test, the analgesic effect produced by administration of the compounds of the invention was observed by heat-induced tail flicking in mice. The test includes a heat source consisting of a projector lamp containing a beam of light focused and directed to a point on the tail of the mouse being tested. Tail flick latencies assessed prior to drug treatment and in response to noxious thermal stimuli, i.e., response times from application of radiant heat on the dorsal surface of the tail to the onset of tail flick, were measured and recorded at 40, 80, 120 and 160 minutes.

For the first part of the study, 65 animals were subjected to an assessment of baseline tail flick latency once daily over two consecutive days. The animals were then randomly assigned to one of 11 different treatment groups, including vehicle control, morphine control and 9 compounds administered intramuscularly at 30 mg/Kg. Following dose administration, the animals were closely monitored for toxic symptoms including tremor or epilepsy, hyperactivity, shallow, rapid or depressed breathing and unhairing. The optimal incubation time for each compound was determined via regression analysis. The analgesic activity of the test compound was expressed as a percentage of the maximum possible effect (% MPE) and was calculated using the formula:

post-dose latency-the latency time spent by each individual animal before the tail is removed (flicked) from the heat source after receiving the drug.

Pre-dose latency-the latency time spent by each individual animal before tail-flicking off the heat source before receiving the drug.

The cutoff time (10s) is the maximum value of exposure to the heat source.

Acute pain (formalin test)

The formalin test is used as an animal model for acute pain. In the formalin test, the animals were briefly habituated to the plexiglas test chamber for 20 minutes on the day before the experimental day. On the day of testing, animals were injected randomly with test articles. 30 minutes after drug administration, 50 μ L of 10% formalin was injected subcutaneously into the plantar surface of the rat's left hind paw. Video data acquisition was started immediately after formalin administration for 90 minutes.

Images were acquired using the Actimetrix Limelight software, which stored the files under the Cilli extension, which were then converted to MPEG-4 encoding. The video was then analyzed using The behavioral analysis software "The Observer 5.1" (version 5.0, Noldus Information Technology, Wageningen, The Netherlands). Video analysis was performed by observing animal behavior and scoring each type of record and defining the length of the behavior (Dubuisson and dennis, 1977). The behavior of scoring includes: (1) normal behavior, (2) no weight gain on the paw, (3) paw lifting, (4) licking/biting or scratching of the paw. Elevation, support (racing), or over licking, biting, and scratching injection paws indicate a painful response. An analgesic response or protection from the compound is indicated if the paw is resting on the floor without significant support, excessive licking, biting or scratching of the injected paw.

Analysis of formalin test data was performed according to two factors: (1) percent of maximum possible inhibitory effect (% MPIE) and (2) pain score. The% MPIE was calculated by a series of steps where the length of the abnormal behavior (behaviors 1,2, 3) of each animal was first summed. Individual values for the vehicle group were obtained by averaging all fractions within the vehicle treated group. MPIE values were calculated for each animal as follows:

MPIE (%) ═ 100- [ (sum of treatments/mean vehicle value) X100% ]

The pain score is calculated from the weighted scale as described above. The duration of the behavior was multiplied by the body weight (the grade of response severity) and divided by the total length observed to determine the pain grade for each animal. The calculation is represented by the following formula:

pain rating ═ 0(To) +1(T1) +2(T2) +3(T3) ]/(To + T1+ T2+ T3)

CFA-induced chronic inflammatory pain

In this test, tactile allodynia was assessed using calibrated Frey (von Frey) filaments. One full week after acclimation to the animal facility, 150 μ L of a "freund's complete adjuvant" (CFA) emulsion (CFA suspended in an oil/saline (1:1) emulsion at a concentration of 0.5 mg/mL) was injected subcutaneously onto the plantar surface of the left hind paw of rats under mild isoflurane anesthesia. Animals were allowed to recover from anesthesia and all animals were evaluated for baseline thermal and mechanical nociceptive thresholds one week after administration of CFA. All animals were habituated to the experimental set-up for 20 minutes on the day before the start of the experiment. The test article and control article are administered to the animal and the nociceptive threshold is measured at defined time points after drug administration to determine the analgesic response of each of the six available treatments. The time points of use were previously determined to show the highest analgesic effect of each test compound.

Animals were assessed for thermal injury thresholds using the Hargreaves test. Animals were placed in Plexiglas housing units on top of a high glass platform with heating means. For all test experiments, the glass platform was thermostatically controlled at a temperature of about 30 ℃. Animals were allowed to acclimate for 20 minutes after being placed in the housing until all exploratory activity ceased. A Model226 Plantar/caudal Stimulator analgesic Meter (IITC, Woodland Hills, Calif.) was used to apply radiant heat from under the glass plate to the Plantar surface of the hind paw. During all test experiments, the idle and active densities of the heat source were set to 1 and 45, respectively, and a 20 second cut-off time was employed to prevent tissue damage.

Following the Hargreaves test, the animal's response threshold to tactile stimuli was measured using a Model 2290Electrovonfrey anesthesiologimeter (IITC life science, Woodland Hills, CA). Animals were placed in a high resin glass housing device on the wire mesh surface. After 10 minutes of acclimation, pre-calibrated flea hairs were applied perpendicularly to the plantar surfaces of both paws of the animal in ascending order starting from 0.1g of hairs with sufficient force to cause slight flexing of the hairs to the paws. The test continues until a hair with a minimum force is determined that induces rapid retraction of the jaws or when a severing force of about 20g is reached. This cutting force was used because it represents approximately 10% of the animal's body weight and serves to prevent the limbs from lifting due to the use of harder hair, which would alter the nature of the stimulus.

Post-operative nociceptive model

In this model, the hyperesthesia caused by the planar incision in the paw was measured by: increasing tactile stimuli were applied to the paw until the animal retracted its paw from the applied stimulus. When animals were anesthetized with 3.5% isoflurane (isoflurane) delivered via the nasal vertebrae, a 1cm longitudinal incision was made using a No. 10 scalpel blade in the plantar aspect of the left hind paw through the skin and fascia, starting 0.5cm from the proximal heel and extending toward the toes. After the incision, the skin is closed using 2,3-0 sterilized silk sutures (aposed). The site of injury was covered with polyacidin (polysporarin) and povidone iodine (β dine). The animals returned to their original cages for overnight recovery.

Animals receiving surgery (ipsilateral) and non-surgery (contralateral) paws can be measured for withdrawal thresholds for tactile stimuli using a Model 2290electrovon frey anaesthesia meter (IITC Life Science, woodland hills, CA). Animals were placed in a high resin glass housing device on the wire mesh surface. After at least 10 minutes of acclimation, pre-calibrated flea hairs were applied perpendicularly to the plantar surfaces of both paws of the animal in ascending order starting from 10g hairs with sufficient force to cause slight hair-to-paw flexion. The test continues until a hair with a minimum force is determined that induces rapid retraction of the jaws or when a severing force of about 20g is reached. This cutting force was used because it represents approximately 10% of the animal's body weight and serves to prevent the limbs from lifting due to the use of harder hair, which would alter the nature of the stimulus.

A neuropathic pain model; chronic compressive injury

Briefly, an approximately 3cm incision was made through the skin and fascia at the level of the middle thigh of the left hind limb of the animal using a No. 10 scalpel blade. The left sciatic nerve was exposed by careful passage through blunt dissection of the biceps femoris muscle to minimize bleeding. Four loose ligatures along the sciatic nerve system at 1 to 2mm intervals were sutured using 4-0 non-degradable sterilized silk. The loose ligature is sufficiently tight in tension to induce a slight contraction of the sciatic nerve when viewed under a 4-fold magnification dissecting microscope. In sham operated animals, the left sciatic nerve was exposed without further treatment. The antibacterial ointment was applied directly to the wound and the muscles were closed using sterilized sutures. Povidone was applied to the muscle and its surroundings, followed by skin suturing with surgical clips.

The threshold response of the animals to tactile stimuli was measured using a Model 2290Electrovonfrey anaesthesia meter (IITC Life Science, woodland hills, CA). Animals were placed in a high resin glass housing device on the wire mesh surface. After 10 minutes of acclimation, pre-calibrated flea hairs were applied perpendicularly to the plantar surfaces of both paws of the animal in ascending order starting from 0.1g of hairs with sufficient force to cause slight flexing of the hairs to the paws. The test continues until a hair with a minimum force is determined that induces rapid retraction of the jaws or when a severing force of about 20g is reached. This cutting force was used because it represents approximately 10% of the animal's body weight and serves to prevent the limbs from lifting due to the use of harder hair, which would alter the nature of the stimulus.

Animals were assessed for thermal injury thresholds using the Hargreaves test. After measuring the tactile threshold, the animal was placed in a plexiglas housing device on top of a high glass platform with a heating device. For all test experiments, the glass platform was thermostatically controlled at a temperature of about 24 ℃ to 26 ℃. Animals were allowed to acclimate for 10 minutes after being placed in the housing until all exploratory activity ceased. A Model226 Plantar/caudal stimulator analgesic Meter (Tail Stimulus Analgesia Meter) (IITC, Woodland Hills, Calif.) was used to apply radiant heat from under the glass plate to the Plantar surface of the hind paw. During all test experiments, the idle and active densities of the heat source were set to 1 and 55, respectively, and a 20 second cut-off time was used to prevent tissue damage.

Neuropathic pain model: spinal nerve ligation

A Spinal Nerve Ligation (SNL) neuropathic pain model was used as an animal (i.e., rat) model of neuropathic pain. In the SNL test, the lumbar roots of spinal nerves L5 and L6 were tightly ligated to cause nerve damage, which resulted in the formation of mechanosensitivity, mechanical allodynia, and heat allergy. Surgery was performed two weeks prior to the test day to fully develop a painful state in the animals. Several spinal nerve ligation changes were used to characterize the analgesic properties of the compounds of the present invention.

(1) Ligation of the spinal nerve of L5;

(2) ligation of spinal nerves L5 and L6;

(3) ligation and transection of the spinal nerve L5;

(4) ligation and transection of the spinal nerves L5 and L6; or

(5) Mild stimulation of the L4 spinal nerve in combination with any of (1) - (4) above.

When animals were anesthetized under 3.5% isoflurane delivered via the nasal vertebrae, using the level of the posterior iliac crest as the midpoint of the incision, a longitudinal incision of approximately 2.5cm was made in the skin just lateral to the dorsal midline using a No. 10 scalpel blade. After the incision, isoflurane was readjusted to maintain the level (1.5% -2.5%). In the mid-sacral region, an incision is made with a dissecting blade, which is slid along the lateral (in the sagittal plane) side of the spine until the blade encounters the sacrum. The tip is introduced through the incision and the muscles and ligaments are removed from the spine to expose 2-3cm of the spine. Muscles and fascia are removed from the spine to locate the point where the nerve exits the spine. A small glass hook was placed in the middle of the spinal nerve and the spinal nerve was gently lifted from the surrounding tissue. Once the spinal nerve had been isolated, a small section of non-degradable 6-0 sterilized silk was wrapped twice around the ball at the tip of the glass hook and passed back under the nerve. The spinal nerves are then tied firmly by tying to ensure that the nerves are raised on both sides of the ligature. This procedure can be repeated as necessary. In some animals, the L4 spinal nerves can be gently rubbed with a small glass hook (up to 20 times) to maximize the neuropathic pain that develops. The antibacterial ointment was applied directly to the incision and the muscles were closed using sterilized sutures. Povidone was applied to the muscle and its surroundings, followed by skin suturing with surgical staples or sterile, non-absorbent monofilament 5-0 nylon suture.

The analgesic effect produced by topical administration of the compounds of the present invention to an animal can then be observed by measuring the paw withdrawal threshold of the animal to a mechano-tactile stimulus. These can be measured using a mechanical allodynia procedure or a mechanical hyperesthesia procedure as described below. After establishing an appropriate baseline measurement by either method, topical formulations of the compounds of the present invention are applied to the ipsilateral ankle and foot. The animals were then placed in a plastic booth for 15 minutes to prevent them from licking the treated area and removing the compounds. Animals were placed in an acrylic housing for 15 minutes, then the ipsilateral paw was tested by either method described below and responses were recorded at 0.5, 1.0, and 2.0 hours post treatment.

A. Mechanical allodynia method

Pain thresholds for mechanical analgesia in animals for surgical and control animals can be measured approximately 14 days post-surgery using manually calibrated fleley filaments as follows. Animals were placed in a high resin glass housing device on the wire mesh surface. Animals were acclimated to the new environment for 20-30 minutes. Pre-calibrated fleabane was applied perpendicularly to the plantar surface of the ipsilateral paw of the animal starting with 2.0g of hair with sufficient force to cause slight paw-to-paw flexion of the hair to establish a baseline measurement. Stimuli were presented in a sequential manner (in ascending or descending order) until the first change in response was noted, after which four additional responses were recorded for a total of six responses. Six response measurements measured in grams are input as Chaplan, s.r. et al, j.neurosci.methods,1994 Jul; 53(1) 55-63, and calculating a 50% retraction threshold. This constitutes a mechanical allodynia value.

B. Method for mechanical hyperesthesia

The threshold response of animals to tactile stimuli was measured using a Model 2290Electrovonfrey anaesthesia meter (IITCLife Science, Woodland Hills, CA). Animals were placed in a high resin glass housing device on the wire mesh surface. After 15 minutes of accommodation in the housing, flea (measured in grams) was applied perpendicularly to the plantar surface of the ipsilateral hindpaw of the animal with sufficient force to induce a paw curl response. The response indicates withdrawal from the painful stimulus and constitutes an efficacy endpoint. The data is expressed as a percentage of change from the baseline threshold measured in grams.

In vivo assay for treating pruritus

The activity of the compounds of the present invention as antipruritic agents can be evaluated by in vivo assays using rodent models. One established model for peripherally induced pruritus is by injecting serotonin into the mouth-side back region (neck) of hairless rats. Prior to serotonin injection (e.g., 2mg/mL, 50 μ L), one dose of a compound of the invention may be administered systemically or locally to a circular area of fixed diameter (e.g., 18mm) by oral, intravenous or intraperitoneal routes. Following administration, a serotonin injection is given in the area of local administration. Following serotonin injection, animal behavior and number of scratches over time compared to vehicle treated animals were monitored by recording videos from 20min to 1.5 h. Thus, administration of the compounds of the invention can inhibit serotonin-induced scratching in rats.

All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification are incorporated herein by reference, in their entirety.

Although the foregoing invention has been described in some detail for purposes of clarity of understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims. Accordingly, the described embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

Claims (24)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein in formula I:

R¹is selected from-NR^1AR^1BAnd a 5-10 membered heteroaryl ring comprising 1 to 4 nitrogen atoms;

R^1Aand R^1BEach independently selected from hydrogen and C_1-8Alkyl radical、-C(＝Y¹)OR^R1CAnd- (X)^1R)_0-1R^x(ii) a Or

R^1AAnd R^1BOptionally combine to form a 4-10 membered heterocyclic ring optionally containing 1 additional heteroatom selected from N and O as the ring vertex;

R^R1Cis selected from C_1-8An alkyl group;

X^1Rindependently selected from C_1-4An alkylene group;

Y¹independently is O;

R^xindependently selected from 6-membered aryl, 5-10 membered heteroaryl containing 1 to 5 heteroatoms selected from N and C_3-8A cycloalkyl group; and is

Wherein R is¹Optionally further substituted by 1 to 5 substituents independently selected from C_1-8Alkyl, -CN and- (X)^1R)₀C(＝O)OR^R1aSubstituted with the substituent(s);

R^R1aindependently selected from C_1-8An alkyl group;

R^Nis hydrogen;

D¹is C (R)^D1)；

D³Is C (R)^D3)；

R^D1Selected from H, Cl, Br and I;

R^D2selected from H, F, Cl, Br and I;

R^D3selected from H, F, Cl, Br and I;

R^D4selected from H, F, Cl, Br, I, -CN, C_3-8Cycloalkyl, C containing 1 heteroatom selected from O_2-7Heterocycloalkyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, wherein said 5-6 membered heteroaryl is further optionally substituted with 1 to 3 heteroatoms selected from C_1-4Substituent substitution of alkoxy;

l is selected from C_1-4A linker to an alkylene group;

the subscript m represents an integer of 0 or 1;

X¹and X²Each independently selected from absent and-O-, and wherein if said subscript m is 0, then X is¹Or X²One of which is absent; and is

Selected from:

2. the compound of claim 1, wherein the compound of formula Ia is a compound of formula Ib

3. The compound of claim 1, wherein R¹Selected from: -NH₂、-NH(CH₃)、-N(CH₃)₂、

4. The compound of claim 1, wherein R¹Selected from:

5. the compound of claim 1, wherein X¹is-O-; x²Is absent; the subscript m is 1; and- (L) -is selected from C_1-4An alkylene group.

6. The compound of claim 1, wherein X¹is-O-; x²Is absent; the subscript m is 1; and- (L) -is selected from-CH₂-、-C(H)(CH₃)-、-CH₂-CH₂-、-CH₂-C(H)(CH₃)-、-C(H)(CH₃)-C(H₂)-、-CH₂CH₂CH₂-、-CH₂-C(H)(CH₃)-CH₂-or-CH₂CH₂CH₂CH₂-。

7. The compound of claim 1 wherein X¹is-O-; the subscript m is 1 and- (L) -is-CH₂-or-CH₂-CH₂-。

8. The compound of claim 1, wherein X¹Is absent; x²is-O-; the subscript m is 1; and- (L) -is selected from-C (H)₂-、-C(H)(CH₃)-、-CH₂-CH₂-、-CH₂-C(H)(CH₃)-、-C(H)(CH₃)-C(H₂)-、-CH₂CH₂CH₂-、-CH₂-C(H)(CH₃)-CH₂-or-CH₂CH₂CH₂CH₂-。

9. The compound of claim 1, wherein m is 0; x¹Is selected from-O-; and X²Is absent.

10. A compound selected from

Or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pain.

13. The use of claim 12, wherein the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-surgical pain, neurogenic bladder disorder pain, ulcerative colitis pain, chronic pain, persistent pain, peripheral mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury pain, or a combination thereof.

14. The use of claim 12, wherein the pain is labor pain.

15. The use of claim 12, wherein the pain is associated with a disease or condition selected from: HIV-associated pain, HIV therapy-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, heat sensitivity, sarcoidosis, irritable bowel syndrome, Crohn's disease, pain associated with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-associated disease, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, local and systemic myotonia, restless leg syndrome, arrhythmia, fibromyalgia, neuroprotective pain under ischemic conditions caused by stroke or neurotrauma, Tachy-arrhythmia, atrial fibrillation, and ventricular fibrillation.

16. The use of claim 12, wherein the pain is associated with a disease or condition selected from: rheumatoid arthritis and osteoarthritis.

17. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting ion flow through a voltage-dependent sodium channel in a mammal for treating pain in the mammal.

18. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for reducing the ion flow through voltage-dependent sodium channels in mammalian cells.

19. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating pruritus in a mammal.

20. Use of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating, but not preventing, pain in a mammal.

21. The use of claim 20, wherein the pain is selected from neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-surgical pain, neurogenic bladder disorder pain, ulcerative colitis pain, chronic pain, persistent pain, peripheral mediated pain, centrally mediated pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury pain, or a combination thereof.

22. The use of claim 20, wherein the pain is labor pain.

23. The use of claim 20, wherein the pain is associated with a disease or condition selected from: HIV, HIV therapy-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, acute pain, thermal sensitivity, sarcoidosis, irritable bowel syndrome, crohn's disease, pain associated with Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis, atherosclerosis, sudden dystonia, myasthenia syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related diseases, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, local and systemic myotonia, restless leg syndrome, arrhythmia, fibromyalgia, neuroprotection in ischemic conditions caused by stroke or nerve trauma, neuropathic pain, Tachy-arrhythmia, atrial fibrillation, and ventricular fibrillation.

24. The use of claim 20, wherein the pain is associated with a disease or condition selected from: rheumatoid arthritis and osteoarthritis.