Pyridazine compounds that inhibit NaV1.8

Abstract

Na V Pyridazine compounds for inhibiting 1.8, and Na V Methods for treating conditions, diseases, or disorders associated with increased activity or expression of 1.8 are disclosed.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 62 / 695,510, filed July 9, 2018, which is incorporated by reference in its entirety. [Background technology]

[0002] Modern pharmacopoeias offer a variety of treatments for acute and chronic pain, including steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), amine reuptake inhibitors, and opioids (analgesics). All have disadvantages, and extensive efforts have been made to develop novel approaches to pain management (Yekkirala et al., 2017), especially in light of the recent opioid abuse epidemic (Skolnick, 2018). Voltage-gated sodium channels (Na v s) (Catterall 2012) are rational targets for pain management given their important role in nerve conduction in sensory neurons (Ruiz et al., 2015).

[0003] There are a total of nine known subtypes of the major pore-forming α subunits. v 1.1, Na v 1.2 and Na v The 1.3 subtype is expressed primarily in the central nervous system (CNS) and v 1.4 and Na v 1.5 is abundant in skeletal and cardiac muscles. v 1.6 has been shown to be expressed in both the peripheral nervous system (PNS) and CNS, but Na v 1.7, Na v 1.8 and Na v1.9 is generally thought to be restricted to the PNS (Yu and Catterall, 2003). Nonselective sodium channel blockers are available as antiarrhythmics, anticonvulsants, and local anesthetics, but none are suitable for the general treatment of chronic pain (Eijkelkamp, ​​et al., 2012). v The family is highly homologous, and obtaining selective drug-like ligands is a significant challenge (Bagal, et al., 2014). However, the identification of selective inhibitors (Jukic, et al., 2014) or activators (Deuis, et al., 2017) of specific isoforms holds promise in many disorders.

[0004] Na v 1.7 and Na v Both isoforms, Na+, 1.8, and 1.9, are present in nociceptors in the PNS and have attracted considerable attention as targets for pain treatment (Jukic, et al., 2014). Following extensive human genetic validation of this channel (Bennett and Woods, 2014) and the discovery of a class of selective inhibitors (McCormack et al., 2013), Na+ v There is active work being done to achieve a target of 1.7 (Vetter, et al., 2017). However, some selective Na v Human clinical trials of 1.7 inhibitors have been disappointing (Donnell et al., 2018; Zakrzewska et al., 2017), and Na v It has been suggested that 1.8 is an alternative target ( Han et al., 2016 ).

[0005] Na vThe pore-forming α subunit of the 1.8 sodium channel is encoded by the SCN10A gene and is expressed primarily (but not exclusively) in dorsal root ganglion (DRG) neurons as well as trigeminal and nodose ganglion neurons (Akopian et al., 1996; Shields et al., 2012). These neurons mediate most of the inward sodium current during the depolarization phase of the neuronal action potential, which is important for action potential transmission and repetitive firing (Akopian et al., 1999). Knockout and knockdown studies of the scn10a gene in rodents have demonstrated that Na+ is involved in inflammatory and neuropathic pain. v 1.8 has been implicated (Dong et al., 2007). Heterozygous gain-of-function mutations in SCN10A cause abnormal firing of DRG neurons and are associated with painful small fiber neuropathy in humans, which is associated with Na v further linking 1.8 with the function of nociceptive neurons ( Faber et al., 2012 ).

[0006] Na v 1.8 inhibitors have potential beyond pain treatment. v 1.8 is expressed in the brain (Lu et al., 2015), and increasing evidence suggests that it is involved in the pathogenesis of multiple sclerosis (MS). v It has been shown that 1.8 is ectopically expressed in experimental autoimmune encephalomyelitis (EAE) mice (Black et al., 2000) and in cerebellar Purkinje neurons of MS patients (Damarjian et al., 2004). v Ectopically expressed 1.8 produces abnormal firing patterns in cerebellar Purkinje cells, resulting in impaired motor coordination despite the absence of overt signs of ataxia in mouse models ( Shields et al., 2012 ).

[0007] Importantly, Na vTreatment with 1.8 blocker 1 (Figure 1, prior art) reverses cerebellar damage in a mouse model of MS, thereby establishing a potential novel approach towards the treatment of MS (Shields et al., 2015). Data on the physiology of cortical neurons in an ex vivo cortical development model with disrupted transcription factor 4 (TCF4) demonstrate in vivo evidence that TCF4 normally represses expression of the SCN10A gene in the CNS. In an ex vivo cellular model and two independent rodent models of a genetic form of autism called Pitt Hopkins syndrome (PTHS) defined by TCF4 haploinsufficiency (Sweatt, 2013), TCF4 deficiency gives rise to abnormal electrophysiological phenotypes characterized by a marked reduction in action potential output, and these phenotypes are related to the downregulation of SCN10A (Na v 1.8) (Rannals et al., 2016). Furthermore, in these PTHS models, increased expression of Na+, such as 2 and 5 (Figure 1, prior art) v These results suggest that 1.8 inhibitors can rapidly reverse some of the excitatory phenotype. v Ectopic expression of 1.8 in the brain may be responsible for some of the symptoms of PTHS. v These results suggest that inhibitors of 1.8 may be of therapeutic value for patients with PTHS.

[0008] Na v Na 1.8 channels are also expressed in dorsal structures (Bucknill et al., 2002) and dental pulp (Renton et al., 2005) and have been implicated in causal pain (Shembalkar et al., 2001) and inflammatory bowel disease (Beyak and Vanner 2005). v There is evidence that the 1.8 channel is involved.

[0009] Na v1.8 is significantly different from most other members of the voltage-gated ion channel family in that it is "resistant" to inhibition by tetrodotoxin, a classical sodium channel inhibitor that inhibits most other members of the family (Cestele and Catterall, 2000). v 1.8 inhibitors, such as 1 (Bagal et al., 2015), 5, (Kort et al., 2008) and 6 (Zhang et al., 2010) (Figure 1, prior art), are known in the literature. Their efficacy in various pain models has been investigated, and they have been shown to be effective in rodent models of both inflammatory and neuropathic pain (Jarvis et al., 2007; Payne et al., 2015). These compounds and others similar to them suffer from various drawbacks, including selectivity over other ion channels and poor pharmacokinetics. Summary of the Invention

[0010] In some embodiments, the subject matter of the present disclosure is a compound of formula (I): [ka] (I) [In the formula, R1 is selected from the group consisting of aryl or heteroaryl, wherein the aryl or heteroaryl is halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, C3-C 10 Cycloalkyl, cyano, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl, -S(O)R' and -S(O2)R' (wherein each R' is independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, -NR7R8 (wherein R7 and R8 are independently selected from C1-C8 alkyl and C1-C8 haloalkyl) and -O-CHR 12-R 13 (In the formula, R 12 is H or C1-C8 alkyl; R 13 is C-C cycloalkyl); R3 and R4 are each independently selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, C1-C8 haloalkoxyl, cyano, -S(O)R', and -S(O2)R'; [ka] and; R5 is selected from the group consisting of aryl or heteroaryl, wherein the aryl or heteroaryl is halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, cyano, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl), -S(O)R', -S(O2)R', -NR7R8 (wherein R7 and R8 are independently selected from C1-C8 alkyl and C1-C8 haloalkyl), -NR9R 10 (Wherein, R9 and R 10 are taken together to form a saturated heterocycle selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and 2-oxa-6-azaspiro[3.3]heptan-6-yl, each of which is optionally substituted with one or more substituents selected from the group consisting of deuterium, C1-C8 alkyl, or halogen; R6 is hydrogen or C1-C8 alkyl; or Pharmaceutically acceptable salts thereof are provided.

[0011] In another aspect, the subject matter of the present disclosure is Na v 1.8 Provided is a method of modulating a sodium ion channel, comprising administering to a subject in need thereof a modulating effective amount for said subject of a compound of formula (I).

[0012] In another aspect, the subject matter of the present disclosure is Na v 1.8, comprising administering to a subject in need thereof an inhibitory effective amount for said subject of a compound of formula (I).

[0013] In yet another aspect, the subject matter of the present disclosure is a method for the preparation of a medicament for treating a pulmonary artery disease comprising administering to a patient a therapeutically effective amount of Na v The present invention provides a method for treating a condition, disease or disorder associated with increased activity or expression of 1.8, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula (I) for the subject.

[0014] In certain embodiments, Na v The condition, disease or disorder associated with increased activity or expression of 1.8 is selected from the group consisting of pain, respiratory disorders, neurological disorders and psychiatric disorders, and combinations thereof.

[0015] While certain aspects of the presently disclosed subject matter described above have been set forth in whole or in part by the presently disclosed subject matter, other aspects will become apparent as the description proceeds in connection with the accompanying examples best described herein below. [Brief description of the drawings]

[0016] Having thus described the subject matter of the present disclosure in general terms, reference is now made to the accompanying figures, which are not necessarily drawn to scale. [Figure 1] FIG. 1 depicts representative preclinical and clinical NaV1.8 inhibitors known in the art (prior art). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The subject matter of the present disclosure will be described in more detail below. The subject matter of the present disclosure can be embodied in many different forms and should not be construed as being limited to the embodiments set forth herein, which are provided so that the disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the subject matter of the present disclosure described herein will come to mind to one skilled in the art to which the subject matter of the present disclosure pertains having the benefit of the teachings set forth in the foregoing description. Therefore, it is to be understood that the subject matter of the present disclosure is not limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims.

[0018] (Na V 1. Pyridazine compounds for inhibiting 8) The subject matter of the present disclosure is sodium channel inhibitors and Na v The present invention also provides uses thereof for treating conditions, diseases or disorders associated with increased activity or expression of 1.8.

[0019] A. Representative Compounds of Formula (I) In some embodiments, the subject matter of the present disclosure is a compound of formula (I): [ka] [In the formula, R1 is selected from the group consisting of aryl or heteroaryl, wherein the aryl or heteroaryl is halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, C3-C 10 Cycloalkyl, cyano, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10cycloalkyl and C1-C8 haloalkyl, -S(O)R' and -S(O2)R' (wherein each R' is independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, -NR7R8 (wherein R7 and R8 are independently selected from C1-C8 alkyl and C1-C8 haloalkyl) and -O-CHR 12 -R 13 (In the formula, R 12 is H or C1-C8 alkyl; R 13 is C-C cycloalkyl); R3 and R4 are each independently selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, C1-C8 haloalkoxyl, cyano, -S(O)R', and -S(O2)R'; [ka] and; R5 is selected from the group consisting of aryl or heteroaryl, wherein the aryl or heteroaryl is halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, cyano, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl), -S(O)R', -S(O2)R', -NR7R8 (wherein R7 and R8 are independently selected from C1-C8 alkyl and C1-C8 haloalkyl), -NR9R 10 (Wherein, R9 and R 10are taken together to form a saturated heterocycle selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and 2-oxa-6-azaspiro[3.3]heptan-6-yl, each of which is optionally substituted with one or more substituents selected from the group consisting of deuterium, C1-C8 alkyl, or halogen; R6 is hydrogen or C1-C8 alkyl; or Pharmaceutically acceptable salts thereof are provided.

[0020] In certain embodiments, the compound of formula (I) has the following structure: [ka] [In the formula, X1, X2, X3 and X4 each independently represent -CR x - or nitrogen; Any of X1, X2, X3 or X4 is -CR x - If, then each R x is independently selected from the group consisting of halogen, C1-C8 alkyl, and C1-C8 haloalkyl; R6 is hydrogen or C1-C8 alkyl; Y is selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, azaspiro[3.3]heptanyl, 1,4-oxazepanyl, and azabicyclo[2.2.1]heptanyl, each of which may be substituted with one or more C1-C8 alkyl. has.

[0021] In a more particular embodiment, the compound of formula (I) has the following structure: [ka] (In the formula, n is an integer selected from 0, 1, 2, 3, 4 and 5; m is an integer selected from 0, 1, 2, 3, and 4; Each R 11 are independently H, C1-C8 alkyl, halogen, cyano, C1-C8 alkoxyl, C1-C8 haloalkyl, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl) and -O-CHR 12 -R 13 (In the formula, R 12 is H or C1-C8 alkyl, R 13 is C3-C8 cycloalkyl) selected from the group consisting of; R2 is [ka] (In the formula, n is an integer selected from 0, 1, 2, 3, 4 and 5; m is an integer selected from 0, 1, 2, 3, and 4; p is an integer selected from 0, 1, 2 and 3; Each R6 is independently hydrogen or C1-C8 alkyl; Each R 14 are independently halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, cyano, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl), -S(O)R', -S(O2)R', -NR7R8 (wherein R7 and R8 are independently selected from C1-C8 alkyl and C1-C8 haloalkyl), -NR9R 10 (Wherein, R9 and R 10are taken together to form a saturated heterocycle selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, and 2-oxa-6-azaspiro[3.3]heptan-6-yl, each of which is optionally substituted with deuterium, C1-C8 alkyl, or halogen. selected from the group consisting of: as well as pharma- ceutically acceptable salts thereof.

[0022] In some embodiments, the compound of formula (I) has the following structure: [ka] [In the formula, q is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; t is an integer selected from 0, 1, 2, and 3; Each R 15 is independently selected from deuterium, hydrogen, C1-C4 alkyl, and -CF3; Each R 16 is independently selected from hydrogen and halogen; R1 is, [ka] (In the formula, n is an integer selected from 0, 1, 2, 3, 4 and 5; m is an integer selected from 0, 1, 2, 3, and 4; Each R 11 are independently H, C1-C8 alkyl, halogen, cyano, C1-C8 alkoxyl, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl) and -O-CHR 12 -R 13 (In the formula, R12 is H or C1-C8 alkyl, R 13 is C3-C8 cycloalkyl) Select from has.

[0023] In certain embodiments, the compound of formula (I) has the following structure: [ka] (In the formula, n is an integer selected from 0, 1, 2, 3, 4 and 5; m is an integer selected from 0, 1, 2, 3, and 4; Each R 11 are independently C1-C8 alkyl, halogen, cyano, C1-C8 alkoxyl, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl) and -O-CHR 12 -R 13 (In the formula, R 12 is H or C1-C8 alkyl, R 13 is C3-C8 cycloalkyl) Select from has.

[0024] In certain embodiments, the compound of formula (I) has the following structure: [ka] (In the formula, R 11a is halogen or C1-C8 haloalkyl; R 11b is -O-CHR 12 -R 13 (In the formula, R 12 is hydrogen or C1-C8 alkyl; R 13is C3-C8 cycloalkyl is] has.

[0025] In certain embodiments, the compound of formula (I) has the following structure: [ka] (In the formula, R 11a is H; R 11b is halogen or cyano; R 16 is a halogen] has.

[0026] In certain embodiments, the compound of formula (I) has the following structure: [ka] [In the formula, R 11 is halogen, cyano and -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C1-C8 haloalkyl. has.

[0027] In certain embodiments, the compound of formula (I) has the following structure: [ka] (In the formula, R 11a is H; R 11b is halogen or -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C1-C8 haloalkyl); R 16 is C1-C4 alkyl] has.

[0028] In certain embodiments, the compound of formula (I) has the following structure: [ka] (In the formula, R 11a is H; R 11b is halogen or -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C1-C8 haloalkyl); R 15 is C1-C4 alkyl] has.

[0029] In certain embodiments, the compound of formula (I) has the following structure: [ka] (In the formula, m is an integer selected from 0, 1, 2, 3, and 4; n is an integer selected from 0, 1, 2, 3, 4 and 5; p is an integer selected from 0, 1, 2 and 3. selected from the group consisting of; R3 is hydrogen or halogen; R6 is hydrogen or halogen; Each R 14 are independently halogen, C1-C8 alkyl, C1-C8 alkoxyl, C1-C8 haloalkyl, cyano, -O-(CH2) p -R y where p is an integer selected from 0, 1, 2, 3, and 4; R y is C3-C 10 cycloalkyl and C1-C8 haloalkyl), -S(O)R', -S(O2)R', -NR7R8 (wherein R7 and R8 are independently selected from C1-C8 alkyl and C1-C8 haloalkyl), -NR9R10 (Wherein, R9 and R 10 are taken together to form a saturated heterocycle selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 1,4-oxazepan-4-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and 2-oxa-6-azaspiro[3.3]heptan-6-yl, each of which is optionally substituted with deuterium, C1-C8 alkyl, or halogen. has.

[0030] In certain embodiments, the compound of formula (I) has the following structure: [ka] [In the formula, z is an integer selected from 0, 1, 2 and 3; R3 is hydrogen or halogen; R6 is hydrogen or C1-C4 alkyl; Y is selected from the group consisting of C1-C4 alkyl, C1-C8 alkoxyl, and -S(=O)2-R', where R' is C1-C4 alkyl; R 17 is a halogen] has.

[0031] In certain embodiments, the compound of formula (I) is 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide; 6-(4-butoxy-3-chloro-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(6-chloro-3-pyridyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chlorophenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-chloro-2-methyl-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-isobutoxyphenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; N-[(2-morpholino-3-pyridyl)methyl]-6-[4-(trifluoromethoxy)phenyl]pyridazine-4-carboxamide; N-[(2-morpholino-3-pyridyl)methyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-ethoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-propoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-isopropoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-ethoxy-3-fluoro-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-fluoro-4-propoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-fluoro-4-isopropoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[6-(cyclopropylmethoxy)-3-pyridyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1-methylimino-1-oxo-1,4-thiazinen-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2,2,2-trifluoroethoxy)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1,4-oxazepan-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(6-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(5-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(dimethylamino)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-pyrrolidin-1-yl-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1-piperidyl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(4-morpholinopyrimidin-5-yl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(3-morpholinopyrazin-2-yl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)-N-(1-(2-methoxypyridin-3-yl)ethyl)pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclobutylmethoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(1-cyclopropylethoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)-3-fluoro-phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-methoxy-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)phenyl]-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)phenyl]-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-methylsulfonylphenyl)methyl]pyridazine-4-carboxamide (LI-1693); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-methoxyphenyl)methyl]pyridazine-4-carboxamide (LI-1694); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-(o-tolylmethyl)pyridazine-4-carboxamide (LI-1699); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1701); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-[2-(trifluoromethyl)morpholin-4-yl]-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1702); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(5-fluoro-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1722); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-ethylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1723); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-isopropoxy-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1724); 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-methoxy-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1646); 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1685); 6-[4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-2126); 6-(4-cyanophenyl)-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1668); 6-(4-chlorophenyl)-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1669); 6-(4-chlorophenyl)-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1673); 6-[4-(difluoromethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1675); 6-[4-(trifluoromethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1682); 6-(4-cyanophenyl)-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1683); 6-[4-(trifluoromethoxy)phenyl]-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1678); 6-(4-chlorophenyl)-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1681); 6-[4-(trifluoromethoxy)phenyl]-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1679); and 6-(4-Chlorophenyl)-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1680) is selected from the group consisting of:

[0032] B. Methods of Treating Conditions, Diseases, or Disorders Associated with Increased Activity or Expression of NaV1.8 In some embodiments, the subject matter of the present disclosure is Na v 1.8 Provided is a method of modulating a sodium ion channel, comprising administering to a subject in need thereof a modulating effective amount for said subject of a compound of formula (I).

[0033] In other embodiments, the subject matter of the present disclosure is Na v 1.8, comprising administering to a subject in need thereof an inhibitory effective amount for said subject of a compound of formula (I).

[0034] As used herein, the term "inhibit" and grammatical derivatives thereof refer to the ability of a compound of the present disclosure, e.g., a compound of the present disclosure of Formula (I), to inhibit Na v"Inhibit" refers to the ability to block, partially block, impede, reduce or decrease the activity or expression of 1.8. Thus, one of skill in the art will understand that the term "inhibit" encompasses complete and / or partial reduction in the function of the channel, for example, at least a 10% reduction, and in some embodiments, at least a 20%, 30%, 50%, 75%, 95%, 98% and less, including 100%.

[0035] In certain embodiments, the subject matter of the present disclosure is Na v In a further embodiment, the present invention provides a method for treating a condition, disease, or disorder associated with increased activity or expression of Na. v The condition, disease or disorder associated with increased activity or expression of 1.8 is selected from the group consisting of pain, particularly inflammatory pain, visceral pain and neuropathic pain, neurological disorders, particularly multiple sclerosis, autism, particularly Pitt Hopkins syndrome and psychiatric disorders and combinations thereof, and the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of formula I or a pharma- ceutical acceptable salt thereof.

[0036] In certain embodiments, the disease or condition is selected from the group consisting of neuropathic pain, inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumatic pain, surgical pain, post-operative pain, labor pain, labour pain, neuropathic bladder, ulcerative colitis, chronic pain, persistent pain, peripheral pain, central pain, chronic headache, migraine headache, sinus headache, tension headache, phantom limb pain, dental pain, peripheral nerve injury, or a combination thereof.

[0037] In other embodiments, the disease or condition is HIV-associated pain, HIV treatment-induced neuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heat hypersensitivity, tosarcoidosis, 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, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant hyperthermia. The therapeutic agent is selected from the group consisting of cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia, sodium channel toxin-related disease, familial erythromelalgia, primary erythromelalgia, familial rectal pain, cancer, epilepsy, partial and generalized tonic seizures, restless legs syndrome, arrhythmia, fibromyalgia, neuroprotection under ischemic conditions caused by stroke or neurotrauma, tachyarrhythmia, atrial fibrillation and ventricular fibrillation.

[0038] In some embodiments, the disease or condition is Pitt-Hopkins Syndrome (PTHS).

[0039] The subject matter of the present disclosure includes Na v Also included is the use of a compound of formula (I) in the manufacture of a medicament for treating a condition, disease or disorder associated with increased activity or expression of 1.8 in a subject suffering from such a disorder.

[0040] The "subject" treated by the disclosed method in many embodiments thereof is desirably a human subject, although it is understood that the methods described herein are effective for all vertebrate species intended to be included in the term "subject". Thus, a "subject" may include a human subject for medical purposes, such as treatment of an existing condition or disease or prophylactic treatment to prevent the onset of a condition or disease, or an animal subject for medical, veterinary, or development purposes. Suitable animal subjects include, but are not limited to, primates, such as humans, monkeys, apes, etc.; bovines, such as cattle, bulls, etc.; ovines, such as sheep, etc.; goats, such as goats, etc.; swine, such as pigs, adult pigs, etc.; equines, such as horses, donkeys, zebras, etc.; cats, including wild and domestic cats; canines, including dogs; rabbits, including rabbits, hares, etc.; and mammals, including rodents, including mice, rats, etc. The animal may be a transgenic animal. In some embodiments, the subject is a human, including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Additionally, a "subject" may include a patient suffering from or suspected of suffering from a condition or disease. Thus, the terms "subject" and "patient" are used interchangeably herein. The term "subject" also refers to an organism, tissue, cell, or collection of cells derived from a subject.

[0041] In general, an "effective amount" of an active agent or drug delivery device refers to the amount necessary to elicit a desired biological response. As one skilled in the art can appreciate, the effective amount of an agent or device can vary depending on factors such as the desired biological endpoint, the agent being delivered, the composition of the pharmaceutical composition, the target tissue, and the like.

[0042] The term "combination" is used in its broadest sense and means administering to a subject at least two agents, more specifically a compound of formula (I) and at least one analgesic; and, optionally, one or more analgesics. More specifically, the term "in combination" refers to administering two (or more) active agents simultaneously, for example, for the treatment of a single medical condition. As used herein, the active agents may be combined and administered in a single dosage form, or may be administered contemporaneously as separate dosage forms, or may be administered in separate dosage forms that are administered alternately or sequentially on the same or different days. In one embodiment of the subject matter of the present disclosure, the active agents are combined and administered in a single dosage form. In another embodiment, the active agents are administered in separate dosage forms (e.g., it is desirable to change the amount of one without changing the amount of the other). The single dosage form may include an additional active agent for the treatment of a medical condition.

[0043] Additionally, the compounds of formula (I) described herein may be administered alone or in combination with adjuvants that enhance the stability of the compounds of formula (I), alone or in combination with one or more analgesic agents, in certain embodiments to facilitate administration of pharmaceutical compositions containing them, increase dissolution or dispersion, enhance inhibitory activity, provide adjunctive therapy with other active ingredients, etc. Advantageously, such combination therapies require lower doses of conventional therapeutic agents, thereby avoiding toxic and adverse side effects that may occur when those agents are used as monotherapy.

[0044] The timing of administration of the compound of formula (I) and at least one additional therapeutic agent can be varied, so long as the beneficial effects of the combination of these agents are obtained. Thus, the term "in combination with" refers to administration of the compound of formula (I) and at least one additional therapeutic agent simultaneously, sequentially, or any combination thereof. Thus, a subject receiving a combination of the compound of formula (I) and at least one additional therapeutic agent can receive the compound of formula (I) and at least one additional therapeutic agent at the same time (i.e., simultaneously) or at different times (i.e., sequentially, in any order, on the same day or on different days), so long as the beneficial effects of the combination of both agents are obtained in the subject.

[0045] When administered sequentially, the agents can be administered within 1, 5, 10, 30, 60, 120, 180, 240 minutes or more of each other. In other embodiments, sequentially administered agents can be administered within 1, 5, 10, 15, 20 or more days of each other. When a compound of formula (I) and at least one additional therapeutic agent are administered simultaneously, they can be administered to the subject as separate pharmaceutical compositions each containing either the compound of formula (I) or the at least one additional therapeutic agent, or they can be administered to the subject as a single pharmaceutical composition containing both agents.

[0046] When administered in combination, the effective concentration of each agent to elicit a particular biological response may be lower than the effective concentration of each agent when administered alone, thereby allowing the dosage of one or more agents to be reduced from that required when that agent is administered as a single agent. The effects of the multiple agents may be, but need not be, additive or synergistic. The agents may be administered multiple times.

[0047] In some embodiments, two or more agents can exert a synergistic effect when administered in combination. As used herein, the terms "synergistic effect," "synergistic," "synergistically," and their derivatives, such as "synergistic effect" or "synergistic combination" or "synergistic composition," refer to a situation in which the biological activity of the combination of a compound of formula (I) and at least one additional therapeutic agent is greater than the sum of the biological activities of each agent when administered individually.

[0048] Synergy can be expressed as a "synergy index (SI)", which can usually be determined by the method described in F. C. Kull et al., Applied Microbiology 9, 538 (1961), from the ratio calculated as follows: Q a / Q A + Q b / Q B = Synergy Index (SI) [In the formula, Q A is the concentration of component A acting alone that produced the endpoint for component A; Q a is the concentration of component A in the mixture that gave rise to the endpoint; Q B is the concentration of component B acting alone that produced the endpoint for component B; Q b is the concentration of component B in the mixture that gave rise to the endpoint.

[0049] In general, Q a / Q A and Q b / Q BWhen the sum of SI and SI is greater than 1, it indicates antagonism. When the sum is equal to 1, it indicates additive effect. When the sum is less than 1, it indicates synergy. The lower the SI, the greater the synergistic effect of that particular mixture. Thus, a "synergistic combination" has greater activity than would be expected based on the activity observed when the individual components are used alone. Furthermore, a "synergistically effective amount" of a component refers to the amount of that component required to elicit a synergistic effect, for example, in another therapeutic agent present in the composition.

[0050] More specifically, in some embodiments, the methods of the present disclosure include co-administering to a subject a compound of formula (I) and / or a pharma- ceutically acceptable salt thereof with one or more compounds selected from the group consisting of one or more of the following compounds: Nonsteroidal anti-inflammatory drugs (NSAIDs), such as, but not limited to, aspirin, diclofenac, diflucinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin, and zomepirac; Opioid analgesics, including, but not limited to, morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine and pentazocine; Barbiturates, including but not limited to amobarbital, aprobarbital, butabarbital, mephobarbital, metharbital, methohexital, pentobarbital, phenobarbital, secobarbital, talbutal, thiamylal and thiopental; Benzodiazapines, including but not limited to, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam and triazolam; Histamine H1 antagonists, including but not limited to diphenhydramine, pyrilamine, promethazine, chlorpheniramine and chlorcyclizine; Sedatives, such as, but not limited to, glutethimide, meprobamate, methaqualone and dichloralphenazone; Skeletal muscle relaxants, such as, but not limited to, baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenazine; NMDA receptor antagonists, such as, but not limited to, dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including NR2B antagonists, such as ifenprodil, traxoprodil and (−)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone; Transient receptor potential ion channel antagonists; α-adrenergic agonists, such as, but not limited to, doxazosin, tamsulosin, clonidine, guanfacine, dexmetatomidine, modafinil and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline; Tricyclic antidepressants, including but not limited to desipramine, imipramine, amitriptyline and nortriptyline; Anticonvulsants, including but not limited to, carbamazepine (Tegretol®), lamotrigine, topiramate, lacosamide (Vimpat®), and valproate; Tachykinin antagonists, particularly NK-3, NK-2 or NK-1 antagonists, such as, but not limited to, (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-637), 5-[[(2R,3S)-2-[(1 R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant and 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S); Muscarinic antagonists, such as, but not limited to, oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine and ipratropium; Cyclooxygenase-2 selective (COX-2) inhibitors, such as, but not limited to, celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib and lumiracoxib; Coal tar analgesics, such as, but not limited to, paracetamol; Neuroleptics, such as, but not limited to, droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindole, eplivanserin, osanetant, rimonabant, meclineltant, Miraxion® and sarizotan; Vanilloid receptor agonists, such as, but not limited to, resiniferatoxin or civamide; Vanilloid receptor antagonists, including but not limited to capsazepine, GRC-15300; β-adrenergic agonists, including but not limited to, propranolol; Local anesthetics, such as, but not limited to, mexiletine; Corticosteroids, including but not limited to dexamethasone and prednisone; 5-HT receptor agonists or antagonists, in particular 5-HT1B / 1D agonists, such as, but not limited to, eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan; 5-HT2A receptor antagonists, including but not limited to, R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907), eplivanserin, ketanserin, and pimavanserin; Cholinergic (nicotinic) analgesics, such as, but not limited to, ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) and nicotine; α2δ ligands, such as, but not limited to, gabapentin (Neurontin®), gabapentin GR (Gralise®), gabapentin enacarbil (Horizant®), pregabalin (Lyrica®), 3-methylgabapentin, (1[α],3[α],5[α])(3-amino-methyl-bicyclo[3. 2.0]hept-3-yl)acetic acid, (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)proline, [(1R,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid, 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadiazine Azol-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl]-methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; Cannabinoid receptor ligands, such as, but not limited to, KHK-6188; Metabotropic glutamate subtype 1 receptor antagonists; Serotonin reuptake inhibitors, such as, but not limited to, sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, cericlamine, and trazodone; noradrenaline (norepinephrine) reuptake inhibitors, such as, but not limited to, maprotiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin, buproprion, the buproprion metabolite hydroxybuproprion, nomifensine and viloxazine (Vivalan®), particularly selective noradrenaline reuptake inhibitors, such as reboxetine, particularly (S,S)-reboxetine; Dual serotonin-noradrenaline reuptake inhibitors, such as, but not limited to, venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta®), milnacipran, and imipramine; Rho kinase inhibitors; Inducible nitric oxide synthase (iNOS) inhibitors, such as, but not limited to, S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-S-chloro-S-pyridinecarbonitrile; 2-[[(1R,3S)-3-amino-4-hydroxy-1-( 5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolybutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN-462 and guanidinoethyl disulfide; Acetylcholinesterase inhibitors, including but not limited to donepezil; Prostaglandin E2 subtype 4 antagonists, such as, but not limited to, N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide and 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid; Leukotriene B4 antagonists, such as, but not limited to, 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]-valeric acid (ONO-4057) and DPC-11870; 5-lipoxygenase inhibitors, such as, but not limited to, zileuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138) and 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504); Sodium channel blockers, including but not limited to, lidocaine, lidocaine + tetracaine cream (ZRS-201) and eslicarbazepine acetate; 5-HT3 antagonists, including but not limited to, ondansetron; N-methyl-D-aspartate receptor antagonists; Voltage-dependent calcium channel blockers (e.g., N-type and T-type), such as, but not limited to, diconctide, Z-160, (R)-2-(4-cyclopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetamide; KCNQ openers (e.g., KCNQ2 / 3(K v 7.2 / 3)); TPRV 1 receptor agonists, including but not limited to capsaicin (Neuroges®, Qutenza®); and pharma- ceutically acceptable salts and solvates thereof; Nicotinic receptor antagonists, including but not limited to, varenicline; Nerve growth factor antagonists, including but not limited to, tanezumab; Endopeptidase stimulators, such as, but not limited to, senrebotase; Angiotensin II antagonists, such as, but not limited to, EMA-401; Tramadol®, tramadol ER (Ultram ER®), tapentadol ER (Nucynta®); PDE5 inhibitors, such as, but not limited to, 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2',1':6,1]-pyrido[3, 4-b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazo 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridinyl)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine -7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; Na V1.7 Blockers, such as, but not limited to, XEN-402, XEN403, TV-45070, PF-0509771, CNV1014802, GDC-0276, RG7893 and those disclosed in WO 2011 / 140425; WO 2012 / 106499; WO 2012 / 112743; WO 2012 / 125613, WO 2012 / 116440, WO 2011026240, U.S. Patent Nos. 8,883,840 or 8,466,188 or PCT / US2013 / 21535, the entire contents of each of which are incorporated by reference; and Na V1.7 Blockers, such as, but not limited to, 2-benzylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl)-(4-isopropoxy-3-methyl-phenyl)methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3, 4-Dihydropyrrolo[1-,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(4-isobutoxy-3-methoxy-phenyl)methanone, 1-(4-benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy)ethoxy]propan-2-ol, 4-butoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, [8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, Pyrro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-(5-isopropoxy-6-methyl-2-pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 5-[2-methyl-4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1 ,4'-piperidine]-1'-carbonyl]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-Trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-3,-3-dimethyl-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2-methyl-L-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, (4-isopropoxy-3-methoxy-phenyl)-[2-methyl-6-(trifluoro Methyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[(3S)-2,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl]spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]- 6-yl]-2,2,2-trifluoro-ethanone, 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropoxy]phenyl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopropoxy-6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]ethanone, 1-[1'- [4-Methoxy-3-(trifluoromethyl)benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl-phenyl)-[2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone, 2-methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-Piperidin]-1'-yl]-[4-(3,3,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl]benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6-(1,1,2,2,2-pentafluoroethyl)spiro[34-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine]-1'-yl]methanone.

[0051] In some embodiments, the methods comprise administering to the subject a therapeutically effective amount of a compound described herein or a pharma- ceutically acceptable salt, with or without a pharma- ceutically acceptable carrier, in combination with a second therapeutic agent selected from the group consisting of acetaminophen, an NSAID, an opioid analgesic, and combinations thereof.

[0052] In some embodiments, the method includes administering to the subject a therapeutically effective amount of a compound described herein or a pharma- ceutically acceptable salt, with or without a pharma- ceutically acceptable carrier, in combination with one or more additional therapeutic agents for treating pain. In one embodiment, the additional therapeutic agent is selected from the group consisting of acetaminophen, an NSAID (such as aspirin, ibuprofen, and naproxen), and an opioid analgesic. In another embodiment, the additional therapeutic agent is acetaminophen. In another embodiment, the additional therapeutic agent is an NSAID. In another embodiment, the additional therapeutic agent is an opioid analgesic.

[0053] C. Pharmaceutical Compositions and Administration In another aspect, the present disclosure provides pharmaceutical compositions comprising one compound of formula (I), alone or in combination with one or more additional therapeutic agents, in admixture with a pharma- ceutically acceptable excipient. Those skilled in the art will recognize that the pharmaceutical compositions include pharma- ceutically acceptable salts of the above-mentioned compounds. Pharmaceutically acceptable salts are generally well known to those skilled in the art and include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituent moieties found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent, or by replacing one basic counterion (base) of the ionic complex with another by ion exchange. Examples of pharma- ceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts.

[0054] When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent, or by replacing one acidic counterion (acid) of the ionic complex with another by ion exchange. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid or phosphoric acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids, such as arginine salts, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19).Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0055] Thus, pharma- ceutically acceptable salts suitable for use with the subject matter of the present disclosure include, by way of non-limiting example, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydroxypropyl amine ... These include labamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, acetate, succinate, sulfate, tannate, tartrate or teoclate. Other pharma- ceutically acceptable salts can be found, for example, in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[0056] For therapeutic and / or diagnostic applications, the compounds of the present disclosure can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations can generally be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000).

[0057] Depending on the particular condition being treated, such agents can be formulated into liquid or solid dosage forms and administered systemically or locally. Agents can be delivered, for example, in timed or sustained sustained release forms, as known to those skilled in the art. Techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injection, and intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, intralesional, intracranial, intraperitoneal, intranasal or intraocular injection or other delivery modes.

[0058] For injection, the agents of the present disclosure can be formulated and diluted in aqueous solutions, such as physiologically compatible buffers, such as Hanks' solution, Ringer's solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0059] It is within the scope of the present disclosure to use a pharma- ceutically acceptable inert carrier to formulate the compounds disclosed herein into dosages suitable for systemic administration for the implementation of the present disclosure. With the appropriate selection of carriers and appropriate manufacturing practices, the compositions of the present disclosure, particularly those formulated as solutions, can be administered parenterally, such as by intravenous injection. The compounds can be easily formulated into dosages suitable for oral administration using pharma- ceutically acceptable carriers well known in the art. With such carriers, the compounds of the present disclosure can be formulated into tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, etc., to be orally ingested by the subject (e.g., patient) to be treated.

[0060] For nasal or inhalation delivery, the agents of the present disclosure can be formulated by methods known to those skilled in the art and can include, for example, but are not limited to, solubilizing, diluent or dispersing agents such as saline; preservatives such as benzyl alcohol; absorption enhancers; and fluorocarbons.

[0061] Pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active ingredient is contained in an amount effective to achieve its intended purpose. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein. In general, the compounds according to the present disclosure are effective over a wide dosage range. For example, in the treatment of an adult, dosages of 0.01-1000 mg per day, 0.5-100 mg, 1-50 mg per day, and 5-40 mg per day are examples of dosages that may be used. A non-limiting dosage is 10-30 mg per day. The exact dosage will depend on the route of administration, the form in which the compound is administered, the subject being treated, the body weight of the subject being treated, the bioavailability of the compound(s), the absorption, distribution, metabolism, and excretion (ADME) and toxicity of the compound(s), and the preference and experience of the attending physician.

[0062] In addition to the active ingredient, these pharmaceutical compositions can contain suitable pharma- ceutically acceptable carriers, including excipients and auxiliaries that facilitate the processing of the active compounds into pharma- ceutically usable preparations. Preparations formulated for oral administration can be in the form of tablets, dragees, capsules or solutions.

[0063] Pharmaceutical preparations for oral use can be obtained by combining active compounds with solid excipients, optionally grinding the resulting mixture, adding suitable auxiliaries as necessary, and then processing the mixture of granules to obtain tablets or dragee cores.Suitable excipients include, in particular, sugars such as lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or fillers such as polyvinylpyrrolidone (PVP: povidone).If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts such as sodium alginate can be added.

[0064] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer liquids and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0065] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain the active ingredient mixed with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). Additionally, stabilizers can be added.

[0066] (II. Definition) Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the subject matter described herein belongs.

[0067] While the following terms relating to compounds of formula (I) are believed to be well understood by those of skill in the art, the following definitions are provided to facilitate explanation of the subject matter of this disclosure. These definitions are intended to supplement and explain, but not preclude, those definitions that would be apparent to those of skill in the art upon review of this disclosure.

[0068] As used herein, the terms substituted (whether preceded by the term "optionally" or not) and substituents refer to the ability to change one functional group on a molecule to another, provided that the valences of all atoms are maintained, as understood by those skilled in the art. When multiple positions in any given structure can be substituted with multiple substituents selected from a particular group, the substituents can be the same or different at all positions. Substituents can also be further substituted (e.g., an aryl substituent can have another substituent, such as another aryl group, which is further substituted at one or more positions).

[0069] When substituents or linking groups are designated by conventional chemical formulas written from left to right, they are intended to equally encompass the chemically identical substituents that would result if the structure were written from right to left; for example, -CHO- is equivalent to -OCH-; -C(=O)O- is equivalent to -OC(=O)-; -OC(=O)NR- is equivalent to -NRC(=O)O-, etc.

[0070] When using the term "independently selected," the substituents being referenced (e.g., R groups such as groups R1, R2, or variables such as "m" and "n") can be the same or different. For example, both R1 and R2 can be substituted alkyls, R1 can be hydrogen and R2 can be substituted alkyl, etc.

[0071] The terms "a", "an" or "a(n)" as used herein with respect to a group of substituents means at least one. For example, if a compound is substituted with "an" alkyl or aryl, the compound is optionally substituted with at least one alkyl and / or at least one aryl. Additionally, if a moiety is substituted with R substituents, the group may be referred to as "R-substituted." If a moiety is R-substituted, the moiety is substituted with at least one R substituent, and each R substituent is optionally different.

[0072] A named "R" or group will generally have the art-recognized structure corresponding to the group bearing that name, unless otherwise specified herein. For purposes of illustration, certain representative "R" groups as described above are defined below.

[0073] The description of the compounds of the present disclosure is limited by the principles of chemical bonding known to those skilled in the art.Therefore, when a group can be substituted with one or more of several substituents, such substituents are selected to give a compound that is not inherently unstable and / or that would be known to those skilled in the art to be likely to be unstable under ambient conditions, such as aqueous, neutral and some known physiological conditions.For example, heterocycloalkyl or heteroaryl is bonded to the rest of the molecule through the heteroatom of the ring according to the principles of chemical bonding known to those skilled in the art, thereby avoiding inherently unstable compounds.

[0074] As used herein, unless expressly defined otherwise, a "substituent" includes a functional group selected from one or more of the following moieties, as defined herein:

[0075] As used herein, the term "hydrocarbon" refers to any chemical group containing hydrogen and carbon. Hydrocarbons may be substituted or unsubstituted. As known to those skilled in the art, when substitutions are made, all valences must be satisfied. Hydrocarbons may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Exemplary hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, and the like.

[0076] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, straight-chain (i.e., unbranched) or branched-chain, acyclic or cyclic hydrocarbon radicals, or combinations thereof, which may be fully saturated, mono- or polyunsaturated, and which can include divalent and polyvalent radicals, having the specified number of carbon atoms (i.e., C 1-10 means 1 to 10 carbons, including 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 carbons. 1-20 A hydrocarbon radical derived by removing one hydrogen atom from a hydrocarbon moiety containing 1 to 20 carbon atoms, which may be linear (i.e., "straight chain"), branched or cyclic, saturated or at least partially unsaturated, and in some cases fully unsaturated (i.e., alkenyl and alkynyl), within the range of 1 to 20 carbon atoms.

[0077] Representative saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof.

[0078] "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl, or propyl, is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having 1 to about 8 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C 1-8 "Higher alkyl" refers to an alkyl group having from about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain embodiments, "alkyl" refers to, inter alia, C 1-8 In another embodiment, "alkyl" refers to, inter alia, C 1-8 Refers to branched chain alkyl.

[0079] An alkyl group can be optionally substituted (referred to as a "substituted alkyl") with one or more alkyl group substituents, which can be the same or different. The term "alkyl group substituent" includes, but is not limited to, alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. Optionally inserted along the alkyl chain can be one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms, where the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl"), or aryl.

[0080] Thus, as used herein, the term "substituted alkyl" includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including, for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, cyano, and mercapto.

[0081] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable linear or branched chain or cyclic hydrocarbon radical having 1 to 20 carbon atoms or heteroatoms, or a combination thereof, consisting of at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P, and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2CH2N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2CH2S(O)2CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CHN(CH3)-CH3, O-CH3, -OCH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3.

[0082] As noted above, heteroalkyl groups as used herein include groups that are attached to the remainder of the molecule via a heteroatom, such as -C(O)NR', ​​-NR'R'', -OR', -SR, -S(O)R and / or -S(O2)R'. When describing "heteroalkyl" followed by a specific heteroalkyl group, such as -NR'R, it will be understood that the terms heteroalkyl and NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl group is described to add clarity. Thus, the term "heteroalkyl" should not be construed herein to exclude specific heteroalkyl groups, such as -NR'R''.

[0083] "Cyclic" and "cycloalkyl" refer to a non-aromatic monocyclic or polycyclic ring system having about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Cycloalkyl groups may be optionally partially unsaturated. Cycloalkyl groups may also be optionally substituted with alkyl group substituents, oxo and / or alkylene, as defined herein. Optionally, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (wherein the nitrogen substituents are hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl) may be inserted along the cyclic alkyl chain, thereby resulting in a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Polycyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, as well as fused ring systems such as dihydronaphthalene and tetrahydronaphthalene.

[0084] As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group as defined herein, including an alkylene moiety also defined above, such as C 1-20 It refers to a cycloalkyl group that is attached to the parent molecular moiety through an alkylene moiety. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0085] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a 3- to 10-membered substituted or unsubstituted cycloalkyl ring system, containing one or more heteroatoms, which may be the same or different and are selected from the group consisting of nitrogen (N), oxygen (O), sulfur (S), phosphorus (P) and silicon (Si), and which may optionally contain one or more double bonds.

[0086] Cycloheteroalkyl rings can be optionally fused or otherwise attached to other cycloheteroalkyl rings and / or non-aromatic hydrocarbon rings. Heterocycles include those having 1 to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, where the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatom can be optionally quaternized. In certain embodiments, the term heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group in which at least one ring atom is a heteroatom selected from O, S, and N (the nitrogen and sulfur heteroatoms may optionally be oxidized), including, but not limited to, bi- or tricyclic groups containing fused 6-membered rings having 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, where (i) each 5-membered ring has 0-2 double bonds, each 6-membered ring has 0-2 double bonds, and each 7-membered ring has 0-3 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocycles may be fused to an aryl or heteroaryl ring. Representative cycloheteroalkyl ring systems include, but are not limited to, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.

[0087] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The terms "cycloalkylene" and "heterocycloalkylene" refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0088] Unsaturated hydrocarbons have one or more double or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 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. Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl".

[0089] More specifically, as used herein, the term "alkenyl" refers to an alkyl group having at least one carbon-carbon double bond. 2-20 Alkenyl refers to a monovalent group obtained by removing one hydrogen molecule from a straight-chain or branched hydrocarbon moiety within the alkyl group of the formula (I) or (II). Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-buten-1-yl, pentenyl, hexenyl, octenyl, allenyl, and butadienyl.

[0090] As used herein, the term "cycloalkenyl" refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond. Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.

[0091] As used herein, the term "alkynyl" refers to a straight or branched C alkyl group containing at least one carbon-carbon triple bond and having the specified number of carbon atoms. 2-20 It refers to a monovalent group derived from a hydrocarbon. Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl), 1-propynyl, pentynyl, hexynyl, and heptynyl groups, and the like.

[0092] The term "alkylene," by itself or as part of another substituent, refers to a straight or branched chain divalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group may be straight chain, branched, or cyclic. The alkylene group may also be optionally unsaturated and / or substituted with one or more "alkyl group substituents." Optionally, one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl") may be inserted along the alkylene group, with the nitrogen substituent being alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-CH6-, ... 10 -);-CH=CH-CH=CH-;-CH=CH-CH2-;-CH2CH2CH2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2CH(CH2CH2CH3)CH2-, -(CH2) q N(R)(CH2) r- (wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or a lower alkyl); methylenedioxyl (-O-CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). Alkylene groups can have from about 2 to about 3 carbon atoms, and can further have from 6 to 20 carbons. Generally, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with groups having 10 or fewer carbon atoms being some embodiments of the present disclosure. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having 8 or fewer carbon atoms.

[0093] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from a heteroalkyl, exemplified by, but not limited to, -CH-CH-S-CH-CH- and -CH-S-CH-CH-NH-CH-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0094] The term "aryl", unless otherwise specified, means an aromatic hydrocarbon substituent which may be a single ring or multiple rings (e.g., 1 to 3 rings) that are fused or covalently linked together. The term "heteroaryl" refers to an aryl group (or ring) containing from 1 to 4 heteroatoms (in the case of multiple rings, each in a separate ring) selected from N, O, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom(s) are optionally quaternized. Heteroaryl groups can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl. , 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. The terms "arylene" and "heteroarylene" refer to the divalent forms of aryl and heteroaryl, respectively.

[0095] For the sake of brevity, the term "aryl", when used in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl), includes both aryl and heteroaryl rings as defined above. Thus, the terms "arylalkyl" and "heteroarylalkyl" are meant to include groups in which an aryl or heteroaryl group is bonded to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, etc.), and include groups in which a carbon atom (e.g., a methylene group) is bonded to an alkyl group that is, for example, substituted with an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, etc.). However, as used herein, the term "haloaryl" is meant to include only aryl substituted with one or more halogens.

[0096] When a heteroalkyl, heterocycloalkyl, or heteroaryl contains a specific number of members (eg, "3 to 7 members"), the term "member" refers to a carbon or a heteroatom.

[0097] Additionally, as used herein, the formula [ka] The structure generally represented by refers to a ring structure, for example, but not limited to, aliphatic and / or aromatic ring compounds including saturated, partially saturated and unsaturated ring structures, such as those having 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, etc., and containing a substituent R group, where the R group may or may not be present, and when present, one or more R groups may each be substituted on one or more available carbon atoms of the ring structure. The presence or absence of an R group and the number of R groups is determined by the value of the variable "n", which is generally an integer having a value from 0 to the number of carbon atoms on the ring that can be substituted. Each R group, when present, is substituted on an available carbon of the ring structure, rather than on another R group. For example, the above structure, where n is 0-2, can be represented by [ka] and the like, but are not limited to such compounds.

[0098] A dashed line representing a bond in a cyclic structure indicates that the bond may or may not be present in the ring, i.e., the dashed line representing a bond in a cyclic structure indicates that the ring structure is selected from the group consisting of saturated ring structures, partially saturated ring structures, and unsaturated ring structures.

[0099] JPEG0007623275000020.jpg1136 shows the point of attachment of a site to the rest of the molecule.

[0100] When a named atom of an aromatic or heteroaromatic ring is defined as "absent," the named atom is replaced with a direct bond.

[0101] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl" and "heterocycloalkyl," "aryl," "heteroaryl," "phosphonate" and "sulfonate" and their divalent derivatives) are meant to include both substituted and unsubstituted forms of the indicated radical. Optional substituents for each type of radical are provided below.

[0102] Substituents for monovalent and divalent derivatives of alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups (including groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) include, but are not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', -halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R'''', -NR''C(O)OR', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -CN, CF3, fluorinated C(O)1-4 R′, R″, R′″ and R″″ may each independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. As used herein, an “alkoxy” group is an alkyl linked to the remainder of the molecule through a divalent oxygen. For example, when a compound of the present disclosure includes multiple R groups, each R group is independently selected, as are each R′, R″, R′″ and R″″ groups when multiples of these groups are present. When R′ and R″ are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NR'R'' is meant to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups that contain carbon atoms bonded to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyls (e.g., -C(O)CH3, -C(O)CF3, -C(O)CHOCH3, etc.).

[0103] Similar to the substituents described above for the alkyl groups, exemplary substituents for the aryl and heteroaryl groups (and their divalent derivatives) are varied and include, for example, halogen, -OR', -NR'R'', -SR', -SiR'R''R''', -OC(O)R', -C(O)R', -COR', -C(O)NR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'-C(O)NR''R''', -NR''C(O)OR', -NR-C(NR'R''R'')=NR'''', NR-C(NR'R'')=NR''', -S(O)R', -S(O)R', -S(O)NR'R'', -NRSO2R', -CN and -NO2, -R', -N3, -CH(Ph)2, fluoro(C 1-4 ) Alkoxo and Fluoro (C 1-4 ) alkyl, in a number selected from 0 to the total number of open valences in the aromatic ring system, where R', R'', R''', and R'''' can be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. For example, when a compound of the present disclosure includes multiple R groups, each R group is independently selected, as are each R', R'', R''', and R'''' groups when multiples of these groups are present.

[0104] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring are optionally represented by the formula -TC(O)-(CRR') q -U-, where T and U are each independently -NR-, -O-, -CRR'- or a single bond, and q is an integer from 0 to 3. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -A-(CH2) r In the formula, A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer of 1 to 4.

[0105] One of the single bonds of the new ring thus formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be a group of the formula -(CRR') s -X'-(C''R'') d where s and d are independently integers from 0 to 3 and X' is -O-, -NR'-, -S-, -S(O)-, -S(O)2- or -S(O)2NR'-. The substituents R, R', R'' and R''' may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0106] As used herein, the term "acyl" refers to an organic acid group in which the -OH of the carboxyl group is replaced with another substituent and has the general formula RC(=O)-, where R is an alkyl, alkenyl, alkynyl, aryl, carboxyl, heterocyclic or aromatic heterocyclic group as defined herein. Thus, the term "acyl" specifically includes aryl acyl groups such as 2-(furan-2-yl)acetyl)- and 2-phenylacetyl groups. Specific examples of acyl groups include acetyl and benzoyl. Acyl groups are also intended to include amides, -RC(=O)NR', ​​esters, -RC(=O)OR', ketones, -RC(=O)R', and aldehydes, -RC(=O)H.

[0107] The terms "alkoxyl" or "alkoxy" are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, where the terms "alkyl", "alkenyl" and "alkynyl" are as defined above and include, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, tert-butoxyl, and n-pentoxyl, neopentoxyl, n-hexoxyl, and the like. 1-20The oxo-hydrocarbon chain may be linear, branched or cyclic, saturated or unsaturated, and may include any of the following:

[0108] As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.

[0109] "Aryloxyl" refers to an aryl-O group, where the aryl group is as previously described, including substituted aryl. As used herein, the term "aryloxyl" can refer to phenyloxyl or hexyloxyl, as well as phenyloxyl or hexyloxyl substituted with alkyl, substituted alkyl, halo, or alkoxyl.

[0110] "Aralkyl" refers to the group aryl-alkyl-, where the aryl and alkyl are as previously described, including substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.

[0111] "Aralkyloxyl" refers to an aralkyl-O- group, where the aralkyl group is as previously described. An exemplary aralkyloxyl group is benzyloxyl, i.e., C6H5-CH2-O-. The aralkyloxyl group can be optionally substituted.

[0112] "Alkoxycarbonyl" refers to the alkyl-OC(=O)- group. Exemplary alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and tert-butyloxycarbonyl.

[0113] "Aryloxycarbonyl" refers to the group aryl-OC(=O)-. Exemplary aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.

[0114] "Aralkoxycarbonyl" refers to the group aralkyl-OC(=O)-. An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.

[0115] "Carbamoyl" refers to an amide group of the formula -C(=O)NH2. "Alkylcarbamoyl" refers to the group R'RN-C(=O)- where one of R and R' is hydrogen and the other of R and R' is alkyl and / or substituted alkyl as defined above. The term "dialkylcarbamoyl" refers to the group R'RN-C(=O)- where each of R and R' is independently alkyl and / or substituted alkyl as defined above.

[0116] As used herein, the term "carbonyldioxyl" refers to a carbonate group of formula -OC(=O)-OR.

[0117] The term "acyloxyl" refers to an acyl-O- group, where acyl is as previously described.

[0118] The term "amino" refers to the -NH group, and also to nitrogen-containing groups, as known in the art, derived from ammonia by replacing one or more hydrogen radicals with an organic group. For example, the terms "acylamino" and "alkylamino" refer to certain N-substituted organic groups having acyl and alkyl substituents, respectively.

[0119] As used herein, "aminoalkyl" refers to an amino group covalently bonded to an alkylene linker. More specifically, as used herein, the terms alkylamino, dialkylamino, and trialkylamino refer to one, two, or three alkyl groups, as defined above, respectively, attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to a group having the structure -NHR', where R' is an alkyl group, as defined above; whereas, the term dialkylamino refers to a group having the structure -NR'R'', where R' and R'' are each independently selected from the group consisting of alkyl groups. The term trialkylamino refers to a group having the structure -NR'R''R''', where R', R'', and R''' are each independently selected from the group consisting of alkyl groups. Additionally, R', R'', and / or R''', taken together, can optionally be -(CH2) k -(k is an integer from 2 to 6). Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, isopropylamino, piperidino, trimethylamino, and propylamino.

[0120] An amino group is -NR'R'', where R' and R'' are generally selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0121] The terms alkylthioether and thioalkoxyl refer to saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) groups attached to the parent molecular moiety through a sulfur atom. Examples of thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.

[0122] "Acylamino" refers to an acyl-NH- group in which acyl is as previously described. "Aroylamino" refers to an aroyl-NH- group in which aroyl is as previously described.

[0123] The term "carbonyl" refers to the group -C(=O)- and can include aldehyde groups of the general formula RC(=O)H.

[0124] The term "carboxyl" refers to a -COOH group. Such a group is also referred to herein as a "carboxylic acid" moiety.

[0125] The term "cyano" refers to the group -C≡N.

[0126] As used herein, the terms "halo", "halide" or "halogen" refer to fluoro, chloro, bromo and iodo groups. Additionally, terms such as "haloalkyl" are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(C 1-4 )Alkyl" is meant to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0127] The term "hydroxyl" refers to the group --OH.

[0128] The term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0129] The term "mercapto" refers to the group --SH.

[0130] As used herein, the term "oxo" means an oxygen atom that is double bonded to a carbon atom or another element.

[0131] The term "nitro" refers to the group --NO.sub.2.

[0132] The term "thio" refers to a compound as described hereinbefore, wherein a carbon or oxygen atom has been replaced with a sulfur atom.

[0133] The term "sulfate" refers to the -SO4 group.

[0134] As used herein, the term thiohydroxyl or thiol refers to a group of formula -SH.

[0135] More specifically, the term "sulfide" refers to a compound having a group of formula -SR.

[0136] The term "sulfone" refers to a compound that has a sulfonyl group, -S(O2)R'.

[0137] The term "sulfoxide" refers to a compound with a sulfinyl group -S(O)R.

[0138] The term "ureido" refers to a urea group of formula -NH-CO-NH2.

[0139] Throughout this specification and the claims, a given chemical formula or name is intended to encompass all tautomers, homologs, and optical and stereoisomers, as well as racemic mixtures where such isomers and mixtures exist.

[0140] Certain compounds of the present disclosure may have asymmetric carbon atoms (optical or chiral centers) or double bonds (enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisomers that may be defined in terms of absolute stereochemistry as (R)- or (S)-, or in the case of amino acids as D- or L-), and each and every isomer is encompassed within the scope of the present disclosure. Compounds of the present disclosure do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is meant to include compounds in racemic, scalemic and optically pure form. Optically active (R)- and (S)- or D- and L-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound described herein contains an olefin bond or other center of geometric asymmetry, unless otherwise specified, it is intended that the compound include both E and Z geometric isomers.

[0141] Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0142] It will be apparent to one of ordinary skill in the art that certain compounds of the present disclosure may exist in tautomeric forms, and all tautomers of such compounds are within the scope of the present disclosure. As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another.

[0143] Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures in which hydrogen is replaced by deuterium or tritium or compounds having carbon replaced by isotopically enriched atoms are also intended to include compounds having the present structures. 13 C or 14 Compounds having this structure substituted with C-enriched carbons are within the scope of this disclosure.

[0144] The compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0145] The compounds of the present disclosure may exist as salts. The present disclosure includes such salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts of amino acids such as glutamic acid. These salts can be prepared by methods known to those skilled in the art. Also included are base addition salts or similar salts, such as sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts, or magnesium salts. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent, or by ion exchange. Examples of acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid or phosphoric acid, as well as salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as arginate and salts of organic acids such as glucuronic acid or galacturonic acid. Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0146] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0147] Certain compounds of the present disclosure can exist in solvated forms, including hydrated forms, as well as nonsolvated forms.In general, solvated forms are equivalent to nonsolvated forms and are included within the scope of the present disclosure.Certain compounds of the present disclosure can exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the use contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0148] In addition to salt forms, the present disclosure provides compounds that are in prodrug form. Prodrugs of the compounds described herein are compounds that undergo easy chemical changes under physiological conditions to provide the compounds of the present disclosure. In addition, prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0149] The term "protecting group" refers to chemical moieties that protect some or all reactive sites in a compound and prevent such sites from participating in chemical reactions until the protecting group is removed, such as those listed and described in TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). When different protecting groups are used, it may be advantageous for each (different) protecting group to be removable by different means. Such protecting groups can be differentially removed by protecting groups that are cleaved under completely different reaction conditions. For example, protecting groups can be removed by acid, base and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid-labile and their use to protect carboxy- and hydroxy-reactive sites can be carried out in the presence of amino groups protected with hydrogenolysis-removable Cbz and base-labile Fmoc groups. Protection of carboxylic acid and hydroxy reactive sites with base-reactive groups, including but not limited to methyl, ethyl and acetyl, can be accomplished in the presence of acid-reactive groups such as tert-butyl carbamate or carbamate-protected amines that are both acid- and base-stable but hydrolytically removable.

[0150] Carboxylic acid and hydroxy reactive sites can also be protected with hydrolytically removable protecting groups such as benzyl groups, and amine groups capable of hydrogen bonding with acids can be protected with base reactive groups such as Fmoc. Carboxylic acid reactive sites can be protected with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, and coexisting amino groups can be protected with fluoride reactive silyl carbamates.

[0151] Allyl blocking groups are useful when acid and base protecting groups are present because the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, allyl-protected carboxylic acids can be deprotected by palladium(O) catalysis in the presence of acid-labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is protected and cannot react. Once released from the resin, the functional group becomes available to react.

[0152] Representative blocking / protecting groups include the following moieties: [ka] These include, but are not limited to:

[0153] Following long-standing patent law convention, the terms "a" and "an" and "the" mean "one or more" when used in this application, including the claims. Thus, for example, reference to a "subject" includes a plurality of subjects unless the context is clear to the contrary (e.g., a plurality of subjects).

[0154] Throughout this specification and the claims, the terms "comprises" and "comprising" are used in a non-exclusive sense unless the context indicates otherwise. Similarly, the term "include" and its grammatical variations are intended to be open-ended, and the recitation of items in a list does not exclude other similar items that may be substituted for or added to the items in the list.

[0155] For purposes of this specification and the appended claims, unless otherwise indicated, all numbers expressing quantities, sizes, dimensions, ratios, shapes, formulations, parameters, percentages, portions, properties, and other numerical values ​​used in the specification and claims are to be understood as being modified in all instances by the term "about," even if the term "about" does not explicitly appear in conjunction with a value, amount, or range. Thus, unless expressly stated to the contrary, the numerical parameters set forth in the following specification and the appended claims are not, and need not be, precise, but may be approximate and / or larger or smaller as necessary, reflecting tolerances, conversion factors, rounding, measurement errors, and the like, as well as other factors known to those of ordinary skill in the art, depending upon the desired properties sought to be obtained by the subject matter of the present disclosure. For example, the term "about," when referring to a value, can be meant to encompass variations in some embodiments of ±100%, in some embodiments of ±50%, in some embodiments of ±20%, in some embodiments of ±10%, in some embodiments of ±5%, in some embodiments of ±1%, in some embodiments of ±0.5%, and in some embodiments of ±0.1% from the specified amount, as such variations are reasonable in practicing the disclosed methods or utilizing the disclosed compositions.

[0156] Furthermore, the term "about," when used in connection with one or more numerical values ​​or numerical ranges, should be understood to refer to all such numerical values, including every numerical value within that range, and modify that range by extending the upper and lower numerical limits set forth. The recitation of numerical ranges by endpoints includes all numerical values ​​subsumed within that range, for example, whole integers including fractions thereof (e.g., the recitation of 1 to 5 includes 1, 2, 3, 4, and 5 as well as fractions thereof, e.g., 1.5, 2.25, 3.75, 4.1, etc.), and any range within that range. EXAMPLES

[0157] The following examples are included to provide those skilled in the art with guidance for practicing representative embodiments of the subject matter of the present disclosure. In light of this disclosure and the general level of skill of those skilled in the art, those skilled in the art will understand that the following examples are intended to be merely illustrative, and many changes, modifications and alterations can be made without departing from the scope of the subject matter of the present disclosure. The following synthetic descriptions and specific examples are for illustrative purposes only, and should not be construed as limiting the making of the compounds of the present disclosure in any other way.

[0158] (Synthetic Procedure) Exemplary compounds were prepared via several general synthetic routes described in the Examples below. Any of the compounds of the present disclosure can be prepared by following one or more of these synthetic routes or specific examples, or via modifications thereof available to one of skill in the art.

[0159] (Example 1; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide) [Method A] [ka]

[0160] Step 1: Synthesis of 2-morpholinonicotinonitrile [ka] To a 20 mL scintillation vial was added 2-fluoronicotinonitrile (1 g, 8.2 mmol) and DCM (15 mL). Morpholine (1.4 mL, 16.4 mmol) was added and the mixture was stirred at room temperature for approximately 18 h. The crude mixture was filtered through a plug of silica gel and the filtrate was concentrated to give a colorless crystalline solid that was used without further purification (Yield: 1.1 g, 71%).

[0161] Step 2: Synthesis of (2-morpholinopyridin-3-yl)methanamine [ka] A round-bottom flask was charged with 2-morpholinonicotinonitrile (500 mg, 4.1 mmol) and a suspension of Raney nickel (large excess). The mixture was stirred under a hydrogen atmosphere (balloon) for approximately 18 hours, after which the solids were removed by filtration. The clear filtrate was concentrated under reduced pressure to give an oil containing the title product, which was used without further purification.

[0162] Step 3: Synthesis of 6-chloro-N-((2-morpholinopyridin-3-yl)methyl)pyridazine-4-carboxamide [ka] A round bottom flask was charged with 6-chloropyridazine-4-carboxylic acid (1.48 g, 9.31 mmol). This was suspended in DCM (45 mL) and then trimethylamine (2.6 mL, 18.6 mmol) was added. HBTU (3.53 g, 9.31 mmol) was added and the mixture was stirred for 15 min. (2-morpholinopyridin-3-yl)methanamine (1.8 g, 9.31 mmol) was added in one portion and the mixture was stirred at room temperature for 5 h. The mixture was filtered through a basic alumina plug and the filtrate was concentrated. This was purified by preparative reverse phase MPLC (0-100% ACN in water) to give the product as an off-white solid. (Yield: 1.8 g, 57.9%).

[0163] Step 4: Synthesis of 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)-N-((2-morpholinopyridin-3-yl)methyl)pyridazine-4-carboxamide [ka] Intermediate A (155 mg, 0.46 mmol) was added to a microwave vial followed by (3-chloro-4-(cyclopropylmethoxy)phenyl)boronic acid (210 mg, 0.93 mmol), palladium acetate (5.2 mg, 0.02 mmol), SPhos (19 mg, 0.05 mmol) and potassium phosphate tribasic (100 mg, 0.46 mmol). The microwave vial was sealed and evacuated and refilled with nitrogen three times before THF (2.5 mL) and water (0.25 mL) were introduced via syringe. The mixture was heated on a hot plate at 80° C. for approximately 18 hours, then diluted with dichloromethane (approximately 5 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and purified by preparative HPLC eluting with a 10-100% acetonitrile / water gradient adjusted with 0.003M NH4OH ("High pH Method") to give the desired product as a beige foam (Yield: 112 mg, 50%).

[0164] The following compounds were synthesized according to Method A: [ka] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0165] (Example 18: 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1-methylimino-1-oxo-1,4-thiazin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide) [Method B]

[0166] Step 1: Synthesis of methyl 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)pyridazine-4-carboxylate [ka] A microwave vial was charged with methyl 6-chloropyridazine-4-carboxylate (1 g, 5.8 mmol), [3-chloro-4-(cyclopropylmethoxy)phenyl]boronic acid (1.44 g, 6.37 mmol), palladium XPhos G1 precatalyst (214 mg, 0.29 mmol) and potassium phosphate tribasic (2.46 g, 11.59 mmol). The vial was sealed and evacuated and backfilled with nitrogen three times. THF (10 mL) and water (1 mL) were introduced via syringe and the mixture was heated at 80° C. for about t h. The crude solution was filtered through Celite, concentrated and purified by silica gel chromatography (0-5% MeOH in DCM) to give the desired product as a beige solid (yield: 800 mg, 43%).

[0167] Step 2: Synthesis of 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)pyridazine-4-carboxylic acid [ka] To a vial equipped with a stir bar was added methyl 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]pyridazine-4-carboxylate (1.25 g, 3.92 mmol). Methanol (15 mL) and water (2 mL) were added followed by excess solid sodium hydroxide. After stirring at room temperature for 3 hours, the solution was diluted with water (ca. 100 mL) and acidified by the addition of 6N HCl. The resulting precipitate was collected by filtration, rinsed with water, and dried under vacuum to give the desired product as a solid which was used without further purification. (Yield: 1 g, 84%).

[0168] Step 3: Synthesis of 2-thiomorpholinopyridine-3-carbonitrile [ka] A round bottom flask equipped with a magnetic stir bar was charged with 2-fluoropyridine-3-carbonitrile (2.43 g, 19.9 mmol) and DMSO (10 mL) was added. Triethylamine (2.0 g, 19.9 mmol) and thiomorpholine (2.05 g, 19.9 mmol) were added and the resulting mixture was heated at 70° C. for 18 h. The crude mixture was directly purified by preparative MPLC (0-75% ACN / water gradient, 0.1% TFA modifier) ​​to give the desired product as a pale yellow solid. (Yield: 3.65 g, 89%).

[0169] Step 4: Synthesis of (2-thiomorpholino-3-pyridyl)methanamine [ka] To a round bottom flask equipped with a magnetic stir bar was added 2-thiomorpholinopyridine-3-carbonitrile (1.0 g, 4.87 mmol) and dissolved in methanol (15 mL). Excess Raney Nickel was added and the mixture was stirred under a hydrogen atmosphere (balloon) for 3 h. The resulting solution was filtered through Celite and the clear filtrate was concentrated to give a yellow oil containing the desired product, which was used without further purification.

[0170] Step 5: Synthesis of 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1-methylimino-1-oxo-1,4-thiazinen-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide [ka] A solution of intermediate B (80 mg, 0.26 mmol) in DCM (2.5 mL) was treated with HATU (74.1 mg, 0.32 mmol) and trimethylamine (0.073 mL, 0.53 mmol). The resulting mixture was stirred at room temperature for approximately 2 h, after which (2-thiomorpholino-3-pyridyl)methanamine (83.1 mg, 0.33 mmol) was added. Stirring was continued for an additional 30 min, and the crude mixture was concentrated and purified by preparative HPLC (10-100% ACN / water gradient, 0.1% TFA modifier) ​​to give the desired product as a foam. MS, ES+ m / z 497 (M+H). + .1H-NMR (400 MHz, DMSO-d6) δ ppm 9.45-9.57 (m, 2H), 8.57 (d, J = 2.0 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.15-8.26 (m, 2H), 7.71 (dd, J = 7.6, 2.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.07 (dd, J = 7.6, 4.8 Hz, 1H), 4.57 (d, J = 5.6 Hz, 2H), 4.04 (d, J = 7.1 Hz, 2H), 3.24-3.34 (m, 4H), 2.74-2.83 (m, 4H), 1.24-1.35 (m, 1H), 0.55-0.66 (m, 2H), 0.30-0.43 (m, 2H).

[0171] The following compounds were synthesized according to Method B: [ka] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11]

[0172] (Example 43, 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)-N-(1-(2-methoxypyridin-3-yl)ethyl)pyridazine-4-carboxamide) [Method C] [ka]

[0173] Step 1: Synthesis of (E)-N-((2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide [ka] 2-Methoxypyridine-3-carbaldehyde (2.35 g, 17.1 mmol) was added to a round bottom flask and dissolved in DCM (25 mL). 2-Methyl-2-propanesulfinamide (3.1 g, 25.7 mmol) was added followed by titanium tetraisopropoxide (10.1 mL, 34.3 mmol). The resulting mixture was stirred at room temperature for approximately 18 hours and then poured into brine (approximately 250 mL) with vigorous stirring. The biphasic mixture was filtered through Celite and the organic layer was collected, dried and concentrated to give the product as a yellow oil (Yield: 3.1 g, 75%).

[0174] Step 2: Synthesis of N-(1-(2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide [ka] (E)-N-((2-methoxypyridin-3-yl)methylene)-2-methylpropane-2-sulfinamide (531 mg, 2.2 mmol) was added to a round bottom flask and dissolved in THF (10 mL). The mixture was cooled to -78°C and methylmagnesium chloride (3M in THF, 1.1 mL, 3.3 mmol) was added dropwise. After stirring at -78°C for 10 min, the mixture was allowed to warm to room temperature and the reaction was quenched by careful addition of water (~2 mL). The mixture was diluted with dichloromethane, filtered through Celite, and the filtrate was concentrated to give a colorless oil containing the desired product, which was used without further purification.

[0175] Step 3: Synthesis of 1-(2-methoxy-3-pyridyl)ethanamine [ka] A solution of N-(1-(2-methoxypyridin-3-yl)ethyl)-2-methylpropane-2-sulfinamide (566 mg, 2.2 mmol) in DCM (10 mL) was treated with 4 M HCl in dioxane (1.66 mL, 6.63 mmol) and stirred at room temperature for 1.5 h. Methanol (5 mL) was added to dissolve the solid and the volatiles were evaporated under reduced pressure to give a yellow solid. This was redissolved in saturated sodium bicarbonate solution (25 mL) and extracted with dichloromethane. The organic layer was collected, dried and concentrated under reduced pressure to give a pale yellow oil which was used without further characterization.

[0176] Step 4: Synthesis of 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)-N-(1-(2-methoxypyridin-3-yl)ethyl)pyridazine-4-carboxamide (Example 43) [ka] To a suspension of intermediate B (50 mg, 0.16 mmol) in DCM (2.5 mL) was added trimethylamine (0.046 mL, 0.73 mmol) and HBTU (68.5 mg, 0.18 mmol) and the resulting mixture was stirred at room temperature for 2 h. 1-(2-Methoxy-3-pyridyl)ethanamine (30 mg, 0.2 mmol) was added as a solution in DCM (1 mL) and stirring was continued for an additional 1 h. The mixture was filtered through a basic alumina plug, concentrated, and purified by preparative HPLC (10-100% ACN / water gradient, 0.1% TFA modifier) ​​to give the desired product as a solid (43 mg, 60%). ES+ m / z 439.0 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ ppm 9.45 (d, J=2.02 Hz, 1 H), 8.57 (d, J=2.02 Hz, 1 H), 8.33 (d, J=2.27 Hz, 1 H), 8.21 (dd, J=8.84, 2.27 Hz, 1 H), 8.09 (dd, J=5.05, 1.77 Hz, 1 H), 7.36 (d, J=8.59 Hz, 1 H), 7.00 (dd, J=7.33, 4.80 Hz, 1 H), 4.05 (d, J=6.82 Hz, 2 H), 3.94 (s, 3 H), 1.48 (d, J=7.07 Hz, 3H), 0.63 (dd, J=8.08, 1.77 Hz, 2 H), 0.41 (dd, J=4.67, 1.64 Hz, 2 H)

[0177] (Example 44; 6-[3-chloro-4-(cyclobutylmethoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide) [Method D] [ka]

[0178] Step 1: Synthesis of 2-chloro-1-(cyclobutylmethoxy)-4-nitrobenzene [ka] To a solution of 2-chloro-4-nitrophenol (2.0 g, 11.5 mmol) in DMSO (10 mL) was added cesium carbonate (5.63 g, 17.3 mmol) and bromomethylcyclobutane (1.94 mL, 17.3 mmol). The mixture was heated at 100° C. for about 18 hours and then poured into about 100 mL of water. The pH was adjusted to about 2 by the addition of 6N HCl solution and the aqueous emulsion was extracted with diethyl ether. The organic layer was collected, dried and concentrated to give a dark oil which was used without further purification.

[0179] Step 2: Synthesis of 3-chloro-4-(cyclobutylmethoxy)aniline [ka] A round bottom flask was charged with 2-chloro-1-(cyclobutylmethoxy)-4-nitrobenzene (2.79 g, 11.5 mmol) and dissolved in 25 mL of methanol. 6N HCl solution (5 mL) was added followed by excess tin metal. The mixture was heated to reflux for approximately 30 minutes and then filtered to remove unreacted tin. Concentrated ammonium hydroxide solution was added to make the filtrate strongly basic and filtered through Celite. The clear filtrate was then extracted with dichloromethane and the organic layer was collected, dried and concentrated to give an oil containing the desired product. This oil was used without further purification.

[0180] Step 3: Synthesis of 2-(3-chloro-4-(cyclobutylmethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] A round bottom flask was charged with 3-chloro-4-(cyclobutylmethoxy)aniline (2.44 g, 11.5 mmol) and acetonitrile (25 mL). To this solution was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.22 g, 12.7 mmol) and tert-butyl nitrite (2.1 mL, 17.3 mmol). The mixture was heated at 75° C. until gas evolution ceased (approximately 35 min) and then concentrated. The resulting residue was purified by silica gel chromatography (0-10% ethyl acetate in heptane gradient) to give the desired product as a pale yellow oil (yield: 2.3 g, 62%).

[0181] Step 4: Synthesis of 6-(3-chloro-4-(cyclobutylmethoxy)phenyl)-N-((2-morpholinopyridin-3-yl)methyl)pyridazine-4-carboxamide [ka] A microwave vial was charged with Intermediate A (100 mg, 0.3 mmol), 2-(3-chloro-4-(cyclobutylmethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (145 mg, 0.5 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (24 mg, 0.03 mmol) and cesium carbonate (195 mg, 0.6 mmol). The vial was sealed and evacuated and backfilled with nitrogen three times, after which THF (2.5 mL) and water (0.25 mL) were introduced via syringe and the mixture was heated at 160° C. for 10 min under microwave irradiation. The crude mixture was diluted with ethyl acetate and filtered through Celite followed by a plug of basic alumina. The filtrate was concentrated and purified by preparative HPLC (10-100% ACN / water gradient, 0.1% TFA modifier) ​​to give the desired product as a foam (73 mg, 49%). ES+ m / z 494.2 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 9.54 (t, J = 5.8 Hz, 1H), 9.50 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 2 Hz, 1H), 8.30 (d, J = 2.3 Hz, 1H), 8.17-8.27 (m, 2H), 7.72 (dd, J = 7.6, 1.8 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.08 (dd, J = 7.6, 4.8 Hz, 1H), 4.61 (d, J = 5.8 Hz, 2H), 4.16 (d, J = 6.3 Hz, 2H), 3.71-3.81 (m, 4H), 3.01-3.12 (m, 4H), 2.73-2.84 (m, 1H), 2.05-2.15 (m, 2H), 1.86-1.97 (m, 4H).

[0182] The following compounds were synthesized according to Method D: [ka] [Table 3-1] [Table 3-2]

[0183] Example 48: 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-methoxy-3-pyridyl)methyl]pyridazine-4-carboxamide [Method E] [ka]

[0184] Step 1: Synthesis of methyl 6-[4-(cyclopropylmethoxy)phenyl]pyridazine-4-carboxylate [ka] Methyl 6-chloropyridazine-4-carboxylate (1.50 g, 8.70 mmol), [4-(cyclopropylmethoxy)phenyl]boronic acid (1.84 g, 9.56 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium(II)·dichloromethane complex (709 mg, 0.869 mmol) and cesium carbonate (5.66 g, 17.4 mmol) were added to a microwave vial containing a magnetic stir bar, the vial was sealed, and evacuated and backfilled with nitrogen three times. THF (6 mL) and water (0.6 mL) were introduced via syringe and the mixture was heated at 145 °C for 35 min. The crude mixture was diluted with ethyl acetate (20 mL), filtered through Celite, and the filtrate was concentrated and purified by silica gel chromatography (0-100% EtOAc in heptane gradient) to give the desired product as a solid (1.6 g, 65%).

[0185] Step 2: Synthesis of 6-[4-(cyclopropylmethoxy)phenyl]pyridazine-4-carboxylic acid [ka] Methyl 6-[4-(cyclopropylmethoxy)phenyl]pyridazine-4-carboxylate (1.6 g, 5.63 mmol) was added to a round bottom flask equipped with a stir bar and dissolved in methanol (10 mL). Water (1 mL) was added followed by excess solid sodium hydroxide and the resulting mixture was stirred at room temperature for approximately 2 hours. The mixture was diluted with water (50 mL) and the pH was adjusted to approximately 3 by the addition of 6N HCl solution. The resulting precipitate was collected by filtration, rinsed with water and dried under vacuum to give the title compound as a white powder which was used without further purification. (1.43 g, 94%)

[0186] Step 3: Synthesis of 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-methoxy-3-pyridyl)methyl]pyridazine-4-carboxamide [ka] 6-[4-(Cyclopropylmethoxy)phenyl]pyridazine-4-carboxylic acid (100 mg, 0.37 mmol) was placed in a screw-top vial and suspended in dichloromethane (2.5 mL). Oxalyl chloride (0.04 mL, 0.41 mmol) was added followed by one drop of DMF. After stirring at room temperature for 1 h, the volatiles were evaporated under reduced pressure, the residue was redissolved in DCM (2.5 mL) and the mixture was cooled in an ice bath. (2-Methoxy-3-pyridyl)methanamine (56 mg, 0.41 mmol) and trimethylamine (0.1 mL, 0.74 mmol) were added dropwise as a solution in DCM and the mixture was allowed to reach room temperature. The crude mixture was filtered through a plug of basic alumina and concentrated to give an oil. This was purified by preparative HPLC (10-100% ACN / water gradient, 0.1% TFA modifier) ​​to give the title product as a glass (56 mg, 38%). MS, ES+ m / z 391 (M+H). +.1H-NMR (400 MHz, DMSO-d6) δ 9.43-9.54 (m, 2H), 8.51 (d, J = 2.0 Hz, 1H), 8.15-8.23 (m, 2H), 8.10 (dd, J = 4.9, 1.9 Hz, 1H), 7.65-7.72 (m, 1H), 7.11-7.17 (m, 2H), 6.99 (dd, J = 7.2, 4.9 Hz, 1H), 4.48 (d, J = 5.3 Hz, 2H), 3.87-3.97 (m, 5H), 1.21-1.32 (m, 1H), 0.55-0.64 (m, 2H), 0.32-0.40 (m, 2H).

[0187] The following compounds were synthesized according to Method E: [ka] [Table 4-1] [Table 4-2]

[0188] Example 53: 6-(4-cyanophenyl)-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide [Method F] [ka]

[0189] Step 1: Synthesis of 6-chloro-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide [ka] 6-Chloropyridazine-4-carboxylic acid (250 mg, 1.58 mmol) was added to a round bottom flask and dissolved in dichloromethane (10 mL). Oxalyl chloride (152 μL, 1.73 mmol) was added followed by one drop of DMF and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane (5 mL). Triethylamine (242 μL, 0.73 mmol) and (5-fluoro-2-morpholino-3-pyridyl)methanamine were added dropwise as a solution in dichloromethane (5 mL). The crude mixture was concentrated under reduced pressure and purified by preparative reverse phase HPLC (high pH method) to give the title compound (403 mg, 1.3 mmol) as a foam. MS, ES+ m / z 352 (M+H) +

[0190] Step 2: Synthesis of 6-(4-cyanophenyl)-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide [ka] To a microwave vial equipped with a magnetic stir bar was added 6-chloro-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (82 mg, 0.23 mmol), 4-cyanophenylboronic acid (51 mg, 0.35 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 0.02 mmol) and cesium carbonate (152 mg, 0.47 mmol). THF (2.5 mL) and water (0.25 mL) were added, the vial was sealed and the mixture was heated at 160° C. under microwave irradiation for 10 min. The crude mixture was filtered through Celite, concentrated and purified by preparative reverse phase HPLC (high pH method) to give the desired product as a solid. (40 mg, 0.1 mmol). MS, ES+ m / z 419 (M+H) +.1H NMR (400 MHz, DMSO-d6) δ ppm 2.95 - 3.10 (m, 4 H) 3.67 - 3.82 (m, 4 H) 4.62 (d, J=5.81 Hz, 2 H) 7.70 (dd, J=9.09, 3.03 Hz, 1 H) 8.07 -8.15 (m, 2 H) 8.24 (d, J=2.78 Hz, 1 H) 8.36 - 8.47 (m, 2 H) 8.70 (d, J=2.02 Hz, 1 H) 9.54 - 9.68 (m, 2 H).

[0191] The following compounds were synthesized according to Method F: [ka] [Table 5]

[0192] Example 55: 6-(4-chlorophenyl)-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide [Method G] [ka]

[0193] Step 1: Synthesis of 6-chloro-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide [ka] A round bottom flask was charged with 6-chloropyridazine-4-carboxylic acid (165 mg, 1.04 mmol) and dichloromethane (5 mL) was added. Oxalyl chloride (91 μL, 1.04 mmol) was added followed by one drop of DMF and the mixture was stirred at room temperature for 1.5 h. The volatiles were removed under reduced pressure and the residue was dissolved in 5 mL of dichloromethane. Triethylamine (145 μL, 1.04 mmol) and (2-morpholinophenyl)methanamine (200 mg, 1.04 mmol) were added dropwise as a solution in 3 mL of dichloromethane. After stirring for an additional 5 min, the mixture was concentrated and purified by silica gel chromatography eluting with a 0-5% methanol in dichloromethane gradient to give the desired product (200 mg, 0.6 mmol, 58% yield) as a colorless solid. MS, ES+ m / z 333 (M+H) +

[0194] Step 2: Synthesis of 6-(4-chlorophenyl)-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide [ka] To a microwave vial equipped with a magnetic stir bar was added 6-chloro-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (100 mg, 0.3 mmol), 4-chlorophenylboronic acid (70 mg, 0.45 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (25 mg, 0.03 mmol) and cesium carbonate (152 mg, 0.47 mmol). THF (2.5 mL) and water (0.25 mL) were added, the vial was sealed and the mixture was heated under microwave irradiation at 160° C. for 10 min. The crude mixture was filtered through Celite, concentrated and purified by preparative reverse phase HPLC (high pH method) to give the desired product as a solid. MS, ES+ m / z 409 (M+H) + 1H NMR (400 MHz, DMSO-d 6) δ ppm 2.84 - 3.02 (m, 4 H) 3.69 - 3.88 (m, 4 H) 4.68 (d, J=5.81 Hz, 2 H) 7.06 - 7.23 (m, 2 H) 7.23 - 7.46 (m, 2 H)7.65 - 7.84 (m, 2 H) 8.22 - 8.39 (m, 2 H) 8.61 (d, J=2.02 Hz, 1 H) 9.45 - 9.54 (m, 1 H) 9.57 (d, J=1.77 Hz, 1 H).

[0195] The following compounds were synthesized according to Method G: [Table 6]

[0196] (Example 59: N-[(4-methyl-2-morpholino-3-pyridyl)methyl]-6-[4-(trifluoromethoxy)phenyl]pyridazine-4-carboxamide) [Method H] [ka]

[0197] Step 1: Synthesis of 4-methyl-2-morpholino-pyridine-3-carbonitrile [ka] A 20 L scintillation vial equipped with a magnetic stir bar was charged with 2-chloro-4-methyl-pyridine-3-carbonitrile (1.0 g, 6.6 mmol) and DMSO (5 mL). Morpholine (1.1 g, 13.1 mmol) was added and the resulting mixture was stirred at 50° C. for 18 h. After cooling to room temperature, the crude mixture was directly purified by preparative MPLC (high pH method) to give the desired product (1.3 g, 6.6 mmol, 100% yield) as a pale yellow oil. MS, ES+ m / z 204 (M+H). + .

[0198] Step 2: Synthesis of (4-methyl-2-morpholino-3-pyridyl)methanamine [ka] A round bottom flask was charged with 4-methyl-2-morpholino-pyridine-3-carbonitrile (1.3 g, 6.6 mmol) and methanol (25 mL) was added. Excess Raney Nickel was added as an aqueous slurry and the resulting mixture was stirred under a hydrogen atmosphere (balloon) for approximately 18 hours. Solids were removed by filtration through Celite and the clear filtrate was concentrated to give an oil containing the desired product. The product was used without further purification. MS, ES+ m / z 208 (M+H) +

[0199] Step 3: Synthesis of 6-chloro-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide [ka] A round bottom flask was charged with 6-chloropyridazine-4-carboxylic acid (325 mg, 2.05 mmol) and dichloromethane (5 mL). Oxalyl chloride (270 μL, 3.08 mmol) and DMF (1 drop) were added and the mixture was stirred at room temperature for 1.5 h. Triethylamine (572 μL, 4.1 mmol) and (4-methyl-2-morpholino-3-pyridyl)methanamine (425 mg, 2.05 mmol) were added dropwise as a solution in dichloromethane (5 mL). The crude mixture was concentrated and purified by silica gel chromatography (eluting with a 0-5% methanol in DCM gradient) to give the desired product (539 mg, 1.55 mmol, 76% yield) as a colorless solid. MS, ES+ m / z 348 (M+H) + .

[0200] Step 4: N-[(4-methyl-2-morpholino-3-pyridyl)methyl]-6-[4-(trifluoromethoxy)phenyl]pyridazine-4-carboxamide [ka] To a microwave vial equipped with a magnetic stir bar was added 6-chloro-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (100 mg, 0.29 mmol), 4-trifluoromethoxyphenylboronic acid (89 mg, 0.43 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 0.03 mmol) and cesium carbonate (187 mg, 0.58 mmol). THF (2.5 mL) and water (0.25 mL) were added, the vial was sealed and the mixture was heated at 160° C. under microwave irradiation for 10 min. The crude mixture was filtered through Celite, concentrated and purified by preparative reverse phase HPLC (high pH method) to give the desired product (41 mg, 0.09 mmol, 30% yield) as a solid. MS, ES+ m / z 474 (M+H) + .1H NMR (500 MHz, DMSO-d6) δ ppm 2.39 (s, 3 H) 2.98 - 3.12 (m, 4 H) 3.69 - 3.81 (m, 4 H) 4.57 (d, J=5.34 Hz, 2 H) 6.92 (d, J=7.70 Hz, 1 H) 7.55-7.66 (m, 3 H) 8.35 (d, J=8.80 Hz, 2 H) 8.60 (d, J=1.89 Hz, 1 H) 9.50 (t, J=5.42 Hz, 1 H) 9.57 (d, J=1.73 Hz, 1 H).

[0201] The following examples were synthesized according to Method H. [ka] [Table 7]

[0202] (Example 61: N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]-6-[4-(trifluoromethoxy)phenyl]pyridazine-4-carboxamide) [Method I] [ka]

[0203] Step 1: Synthesis of 2-(3-methylmorpholin-4-yl)pyridine-3-carbonitrile [ka] To a round bottom flask equipped with a magnetic stir bar was added 2-fluoropyridine-3-carbonitrile (1.2 g, 9.9 mmol) and DMSO (5 mL). Triethylamine (1.4 mL, 9.9 mmol) and 3-methylmorpholine were added and the resulting mixture was heated to 50° C. with stirring for 18 h. After cooling to room temperature, the crude mixture was directly purified by preparative MPLC (high pH method) to give the desired product (1.7 g, 8.4 mmol, 85% yield) as an oil that solidified on standing. MS, ES+ m / z 204 (M+H). + .

[0204] Step 2: Synthesis of [2-(3-methylmorpholin-4-yl)-3-pyridyl]methanamine [ka] A round bottom flask was charged with 2-(3-methylmorpholin-4-yl)pyridine-3-carbonitrile (1.7 g, 8.4 mmol) and methanol (25 mL) was added. Excess Raney Nickel was added as an aqueous slurry and the resulting mixture was stirred under a hydrogen atmosphere (balloon) for approximately 18 hours. Solids were removed by filtration through Celite and the clear filtrate was concentrated to give an oil containing the desired product. The product was used without further purification. MS, ES+ m / z 208 (M+H) + .

[0205] Step 3: Synthesis of 6-chloro-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide [ka] To a round bottom flask equipped with a magnetic stir bar was added 6-chloropyridazine-4-carboxylic acid (250 mg, 1.58 mmol) and dichloromethane (10 mL). Oxalyl chloride (152 μL, 1.73 mmol) and DMF (1 drop) were added and the mixture was stirred at room temperature for 1 h before being concentrated to dryness. The residue was dissolved in DCM (5 mL) and trimethylamine (242 μL, 1.73 mmol) and [2-(3-methylmorpholin-4-yl)-3-pyridyl]methanamine (360 mg, 1.73 mmol) were added dropwise as a solution in DCM (5 mL). The crude mixture was concentrated under reduced pressure and purified by preparative MPLC (high pH method) to give the desired product as a foam (241 mg, 0.7 mmol, 44% yield). MS, ES+ m / z 348 (M+H). + .

[0206] Step 4: Synthesis of N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]-6-[4-(trifluoromethoxy)phenyl]pyridazine-4-carboxamide [ka] To a microwave vial equipped with a magnetic stir bar was added 6-chloro-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (100 mg, 0.29 mmol), 4-trifluoromethoxyphenylboronic acid (89 mg, 0.43 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (23 mg, 0.03 mmol) and cesium carbonate (187 mg, 0.58 mmol). THF (2.5 mL) and water (0.25 mL) were added, the vial was sealed and the mixture was heated at 160° C. under microwave irradiation for 10 min. The crude mixture was filtered through Celite, concentrated and purified by preparative reverse phase HPLC (high pH method) to give the desired product as a solid (61 mg, 0.13 mmol, 45% yield). MS, ES+ m / z 348 (M+H) +.1H NMR (500 MHz, DMSO-d6) δ ppm 0.83 (d, J=6.13 Hz, 3 H) 2.76 - 2.86 (m, 1 H) 3.11 (d, J=12.26 Hz, 1 H) 3.34 - 3.41 (m, 1 H) 3.45 - 3.54 (m,1 H) 3.68 - 3.87 (m, 3 H) 4.65 (d, J=5.50 Hz, 2 H) 7.15 (dd, J=7.55, 4.72 Hz, 1 H) 7.62 (d, J=8.17 Hz, 2 H) 7.77 (d, J=7.55 Hz, 1 H) 8.27 - 8.41 (m, 3H) 8.61 (d, J=1.89 Hz, 1 H) 9.48 - 9.61 (m, 2 H).

[0207] The following compounds were synthesized according to Method I: [ka] [Table 8]

[0208] Assay Method The ability of the above exemplified pyridine carboxamide derivatives to inhibit the Nav1.8 channel was measured using one or more of the methods described below.

[0209] (HEK Nav1.8 β1 / β2 stable expressing cell line) We constructed a HEK293 cell line stably expressing the human Nav1.8 (hNav1.8) ion channel with β1 / β2 subunits. This cell line demonstrated high IC in fluorescence- and electrophysiology-based assays. 50It is also suitable for performing mechanistic pharmacological studies in electrophysiological assays. HEK293 Nav1.8 cells are grown as adherent monolayers in DMEM / high glucose medium, 10% fetal bovine serum, Na pyruvate (2 mM), Hepes (10 mM) containing the selection agents G418 (400 mg / L) and puromycin (0.5 mg / L) at 37°C and 10% CO2.

[0210] (Nav1.8 fluorescence inhibition assay) Compounds were either prepared as 10-mM stock solutions or delivered as 10-mM stock solutions using DMSO as the vehicle. Concentration-response curves were generated using a Matrix multichannel pipettor. Compound source plates were prepared by diluting 10 mM compound stocks to make 500 μM (100x) solutions in DMSO in 96-well V-bottom plates. Compounds were then serially diluted in 100% DMSO to generate dose-response curves with a 5-point, 4-fold dilution scheme. 2 μL of the 100x dose-response curve was then added to the preincubation and stimulation assay plates. 100 μL of preincubation buffer and 200 μL of stimulation buffer were then added to the plate, resulting in a final assay test concentration range of 5 μM to 0.02 μM with a final DMSO concentration of 1%.

[0211] On the day of the assay, the plate was washed with 2K EBSS buffer (135 mM NaCl, 2 mM KCl, 5 mM glucose, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4) to remove the cell culture medium. The Na-sensitive fluorescent dye Asante Natrium Green-2 (ANG-2) was incubated for 60 minutes for equilibration, and then washed with 2K EBSS. The plate was then read on a fluorescent plate reader (FLIPR TMThe wells were transferred to a 30-well plate (Molecular Devices) and fluorescence measurements were performed using an excitation wavelength of 490 nm and an emission wavelength of 565 nm. Compounds were pre-incubated for 5 min at the final test concentration in the presence of ouabain (30 μM) to inhibit Na+ efflux through the Na+ / K+ exchanger. Following the pre-incubation step, hNav1.8 channels were stimulated with 10 μM of the pyrethroid deltamethrin to prevent channel inactivation. Vehicle and 30 μM tetracaine were used as negative and positive controls, respectively, and the assay was performed for 15 min. Peak changes in fluorescence for negative and positive control wells were calculated and fitted to a logistic equation to determine the IC 50 It was decided.

[0212] (Nav1.8 inhibition assay by PatchXpress) HEK-Nav1.8 β1 / β2 cells were recorded by whole-cell patch clamp using the PatchXpress automated patch clamp platform (Molecular Devices). Cell suspensions were obtained by trypsinizing attached monolayers followed by gentle rocking for a minimum of 30 min. Compounds were prepared from 10 mM DMSO stocks. [ka]

[0213] Mutant forms of Nav1.8 channels were assessed using protocol 1, in which cells were first voltage-clamped at a holding potential of -100 mV to maintain Nav1.8 in a closed, resting state. After the current amplitude stabilized, a series of 5-s adjustment steps to gradually depolarizing voltages (-100 to 0 mV) were used to determine the midpoint voltage of steady-state inactivation for each cell. The holding potential was then adjusted to the voltage at which Nav1.8 is approximately 50% inactivated (V 半分-automatically set by PatchXpress script) to allow for the assessment of inhibition of closed and inactivated channels. Protocol 1 was run at a frequency of 0.1 Hz until current amplitudes stabilized (automatically determined by PatchXpress script). The effect of test reagents on Nav current amplitudes was monitored using a custom PatchXpress stability script that determined the timing of compound addition and washout.

[0214] Data was processed and analyzed using DataXpress 2.0 (Molecular Devices). Percent inhibition was calculated using Microsoft Excel, such that compound inhibition was normalized to the mean of control and washout currents according to the formula: % inhibition = (((control + washout) / 2) - drug) / ((control + washout) / 2) * 100 (see schematic above). Normalized concentration-response relationships were fitted using a four-parameter logistic or sigmoidal dose-response model in XLfit software (IDBS).

[0215] (hNa V 1.8 Automated patch clamp - IonFlux HT Assay) Inward sodium currents were recorded using an IonFlux HT automated whole-cell patch clamp apparatus (Fluxion Biosciences, Alameda, Calif., USA).

[0216] HEK-293 cells were stably transfected with human NaV1.8 cDNA (X-type voltage-gated sodium channel α subunit, accession number NM_006514) and human β subunit 1 (accession number NM_001037). Cells were harvested with trypsin and kept at room temperature in serum-free medium before recording. Cells were washed and resuspended in extracellular solution before loading into the device.

[0217] Test concentrations: Stock solutions were prepared in DMSO at 300x the final assay concentration and stored at -80°C until the day of assay. On the day of assay, aliquots of the stock solutions were thawed and diluted into external solution to give the final test concentrations. A final concentration of 0.33% DMSO was maintained for each concentration of assay compound and control.

[0218] Recording conditions: Intracellular solution (mM): 100 CsF, 45 CsCl, 5 NaCl, 10 HEPES, 5 EGTA (pH 7.3, titrated with 1M CsOH).

[0219] Extracellular solution (mM): 150 NaCl, 4 BaCl, 1 MgCl2, 1.8 CaCl2, 10 HEPES, 5 glucose, (pH 7.4, titrated with 10M NaOH).

[0220] When sodium channels are held at a depolarized membrane potential, the channels open and become inactivated, remaining inactivated until the membrane potential is returned to a hyperpolarized membrane potential, restoring the inactivated channels to the closed state. Compounds that show greater inhibition with pulse 2 compared to pulse 1 are state-dependent inhibitors. One example is tetracaine, which is a more potent inhibitor in the inactivated state than in the tonic or open state.

[0221] Cells were held at -120 mV for 50 ms, then stepped to -10 mV for 2 s to fully inactivate sodium channels (pulse 1), returned to -120 mV for 10 ms (to fully recover from inactivation, but inhibitor-bound channels may not recover from inactivation), and stepped back to -10 mV for 50 ms (pulse 2). The sweep interval was 20 s (0.05 Hz). Each compound concentration was applied for 2 min. The assay was performed at room temperature.

[0222] Reference compound: Tetracaine was used as a positive control and was tested simultaneously with the test compounds.

[0223] Data analysis: Only current amplitudes above 3 nA during the reference phase were analyzed. Sodium current amplitudes were calculated by measuring the difference between the peak inward current (i.e., the peak of the current) when stepping to -10 mV and the remaining current at the end of the step. Sodium currents were assessed in vehicle control conditions and then at the end of each 2 min compound application. Individual cell trap results were normalized to the vehicle control amplitude and the mean ± SEM was calculated for each compound concentration. These values ​​were then plotted and an estimated IC 50 Curve fits were calculated.

[0224] Estimated IC of the pyridine carboxamide compounds exemplified above 50 The values ​​are shown in Table 1. [Table 9]

[0225] (References) All publications, patent applications, patents, and other references mentioned in this specification are indicative of the level of ordinary skill in the art to which the subject matter of this disclosure pertains. All publications, patent applications, patents, and other references are incorporated herein by reference to the same extent as if each individual publication, patent application, patent, and other reference was specifically and individually indicated to be incorporated by reference. Although a number of patent applications, patents, and other references are referenced herein, it will be understood that such reference is not an admission that any of these documents form part of the general knowledge in the art. Pain Medicine: An Essential Review, Young, RJ, Nguyen, M, Nelson, E, Urman, Eds. Springer, Cham, Switzerland. 2017, ISBN 978-3-319-43131-4. Yekkirala, A. S.; Roberson, D. P.; Bean, B. P.; Woolf, C. J., Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov 2017, 16 (8), 544-563. Skolnick, P., The Opioid Epidemic: Crisis and Solutions. Annual Review of Pharmacology and Toxicology, Vol 58 2018, 58, 143-159. Catterall, W. A., Voltage-gated sodium channels at 60: structure, function and pathophysiology. J Physiol-London 2012, 590 (11), 2577-2589. Ruiz, M. D.; Kraus, R. L., Voltage-Gated Sodium Channels: Structure, Function, Pharmacology, and Clinical Indications. J Med Chem 2015, 58 (18), 7093-7118. Yu, F. H.; Catterall, W. A., Overview of the voltage-gated sodium channel family. Genome Biol 2003, 4 (3). Eijkelkamp, N.; Linley, J. E.; Baker, M. D.; Minett, M. S.; Cregg, R.; Werdehausen, R.; Rugiero, F.; Wood, J. N., Neurological perspectives on voltage-gated sodium channels. Brain 2012, 135, 2585-2612. Bagal, S. K.; Chapman, M. L.; Marron, B. E.; Prime, R.; Storer, R. I.; Swain, N. A., Recent progress in sodium channel modulators for pain. Bioorganic & medicinal chemistry letters 2014, 24 (16), 3690-3699. Jukic, M.; Kikelj, D.; Anderluh, M., Isoform Selective Voltage-Gated Sodium Channel Modulators and the Therapy of Pain. Curr Med Chem 2014, 21 (2), 164-186. Deuis, J. R.; Mueller, A.; Israel, M. R.; Vetter, I., The pharmacology of voltage-gated sodium channel activators. Neuropharmacology 2017, 127, 87-108. Vetter, I.; Deuis, J. R.; Mueller, A.; Israel, M. R.; Starobova, H.; Zhang, A.; Rash, L. D.; Mobli, M., Na(V)1.7 as a pain target - From gene to pharmacology. Pharmacology & Therapeutics 2017, 172, 73-100. Bennett, D. L. H.; Woods, C. G., Painful and painless channelopathies. Lancet Neurol 2014, 13 (6), 587-599. McCormack, K.; Santos, S.; Chapman, M. L.; Krafte, D. S.; Marron, B. E.; West, C. W.; Krambis, M. J.; Antonio, B. M.; Zellmer, S. G.; Printzenhoff, D.; Padilla, K. M.; Lin, Z. X.; Wagoner, P. K.; Swain, N. A.; Stupple, P. A.; de Groot, M.; Butt, R. P.; Castle, N. A., Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels. P Natl Acad Sci USA 2013, 110 (29), E2724-E2732. Donnell, A.; Collins, S.; Ali, Z.; Iavarone, L.; Surujbally, R.; Kirby, S.; Butt, R. P., Efficacy of the Nav1. 7 Blocker Pf-05089771 in A Randomised, Placebo-Controlled, Double-Blind Clinical Study in Subjects with Painful Diabetic Peripheral Neuropathy. Pain 2018. Zakrzewska, J. M.; Palmer, J.; Morisset, V.; Giblin, G. M. P.; Obermann, M.; Ettlin, D. A.; Cruccu, G.; Bendtsen, L.; Estacion, M.; Derjean, D.; Waxman, S. G.; Layton, G.; Gunn, K.; Tate, S., Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. The Lancet Neurology 2017, 16 (4), 291-300. Han, C. Y.; Huang, J. Y.; Waxman, S. G., Sodium channel Na(v)1.8 Emerging links to human disease. Neurology 2016, 86 (5), 473-483. Akopian, A. N.; Sivilotti, L.; Wood, J. N., A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 1996, 379 (6562), 257. Shields, S. D.; Ahn, H.-S.; Yang, Y.; Han, C.; Seal, R. P.; Wood, J. N.; Waxman, S. G.; Dib-Hajj, S. D., Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. PAIN(registered trademark) 2012, 153 (10), 2017-2030. Akopian, A. N.; Souslova, V.; England, S.; Okuse, K.; Ogata, N.; Ure, J.; Smith, A.; Kerr, B. J.; McMahon, S. B.; Boyce, S.; Hill, R.; Stanfa, L. C.; Dickenson, A. H.; Wood, J. N., The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci 1999, 2, 541. Dong, X.-W.; Goregoaker, S.; Engler, H.; Zhou, X.; Mark, L.; Crona, J.; Terry, R.; Hunter, J.; Priestley, T., Small interfering RNA-mediated selective knockdown of NaV1. 8 tetrodotoxin-resistant sodium channel reverses mechanical allodynia in neuropathic rats. Neuroscience 2007, 146 (2), 812-821. Faber, C. G.; Lauria, G.; Merkies, I. S. J.; Cheng, X.; Han, C.; Ahn, H.-S.; Persson, A.-K.; Hoeijmakers, J. G. J.; Gerrits, M. M.; Pierro, T.; Lombardi, R.; Kapetis, D.; Dib-Hajj, S. D.; Waxman, S. G., Gain-of-function Na v 1.8 mutations in painful neuropathy. Proceedings of the National Academy of Sciences 2012, 109 (47), 19444-19449. Lu, V. B.; Ikeda, S. R.; Puhl, H. L., A 3.7 kb Fragment of the Mouse Scn10a Gene Promoter Directs Neural Crest But Not Placodal Lineage EGFP Expression in a Transgenic Animal. J Neurosci 2015, 35 (20), 8021-8034. Black, J. A.; Dib-Hajj, S.; Baker, D.; Newcombe, J.; Cuzner, M. L.; Waxman, S. G., Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis. P Natl Acad Sci USA 2000, 97 (21), 11598-11602. Damarjian, T. G.; Craner, M. J.; Black, J. A.; Waxman, S. G., Upregulation and colocalization of p75 and Na(v)1.8 in Purkinje neurons in experimental autoimmune encephalomyelitis. Neurosci Lett 2004, 369 (3), 186-190. Shields, S. D.; Cheng, X. Y.; Gasser, A.; Saab, C. Y.; Tyrrell, L.; Eastman, E. M.; Iwata, M.; Zwinger, P. J.; Black, J. A.; Dib-Hajj, S. D.; Waxman, S. G., A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis. Ann Neurol 2012, 71 (2), 186-194. Shields, S. D.; Butt, R. P.; Dib-Hajj, S. D.; Waxman, S. G., Oral Administration of PF-01247324, a Subtype-Selective Nav1.8 Blocker, Reverses Cerebellar Deficits in a Mouse Model of Multiple Sclerosis. Plos One 2015, 10 (3). Sweatt, J. D., Pitt-Hopkins Syndrome: intellectual disability due to loss of TCF4-regulated gene transcription. Exp Mol Med 2013, 45. Rannals, M. D.; Hamersky, G. R.; Page, S. C.; Campbell, M. N.; Briley, A.; Gallo, R. A.; Phan, B. N.; Hyde, T. M.; Kleinman, J. E.; Shin, J. H.; Jaffe, A. E.; Weinberger, D. R.; Maher, B. J., Psychiatric Risk Gene Transcription Factor 4 Regulates Intrinsic Excitability of Prefrontal Neurons via Repression of SCN10a and KCNQ1. Neuron 2016, 90 (1), 43-55. Bucknill, A. T.; Coward, K.; Plumpton, C.; Tate, S.; Bountra, C.; Birch, R.; Sandison, A.; Hughes, S. P.; Anand, P., Nerve fibers in lumbar spine structures and injured spinal roots express the sensory neuron-specific sodium channels SNS / PN3 and NaN / SNS2. Spine 2002, 27 (2), 135-140. Renton, T.; Yiangou, Y.; Plumpton, C.; Tate, S.; Bountra, C.; Anand, P., Sodium channel Na v 1.8 immunoreactivity in painful human dental pulp. BMC oral health 2005, 5 (1), 5. Shembalkar, P. K.; Till, S.; Boettger, M. K.; Terenghi, G.; Tate, S.; Bountra, C.; Anand, P., Increased sodium channel SNS / PN3 immunoreactivity in a causalgic finger. Eur J Pain 2001, 5 (3), 319-323. Beyak, M.; Vanner, S., Inflammation‐induced hyperexcitability of nociceptive gastrointestinal DRG neurones: the role of voltage‐gated ion channels. Neurogastroenterology & Motility 2005, 17 (2), 175-186. Cestele, S.; Catterall, W. A., Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 2000, 82 (9-10), 883-892. Bagal, S. K.; Bungay, P. J.; Denton, S. M.; Gibson, K. R.; Glossop, M. S.; Hay, T. L.; Kemp, M. I.; Lane, C. A. L.; Lewis, M. L.; Maw, G. N.; Million, W. A.; Payne, C. E.; Poinsard, C.; Rawson, D. J.; Stammen, B. L.; Stevens, E. B.; Thompson, L. R., Discovery and Optimization of Selective Na(v)1.8 Modulator Series That Demonstrate Efficacy in Preclinical Models of Pain. Acs Med Chem Lett 2015, 6 (6), 650-654. Kort, M. E.; Drizin, I.; Gregg, R. J.; Scanio, M. J. C.; Shi, L.; Gross, M. F.; Atkinson, R. N.; Johnson, M. S.; Pacofsky, G. J.; Thomas, J. B.; Carroll, W. A.; Krambis, M. J.; Liu, D.; Shieh, C. C.; Zhang, X. F.; Hernandez, G.; Mikusa, J. P.; Zhong, C. M.; Joshi, S.; Honore, P.; Roeloffs, R.; Marsh, K. C.; Murray, B. P.; Liu, J. R.; Werness, S.; Faltynek, C. R.; Krafte, D. S.; Jarvis, M. F.; Chapman, M. L.; Marron, B. E., Discovery and biological evaluation of 5-aryl-2-furfuramides, potent and selective blockers of the Na(v)1.8 sodium channel with efficacy in models of neuropathic and inflammatory pain. J Med Chem 2008, 51 (3), 407-416. Zhang, X. F.; Shieh, C. C.; Chapman, M. L.; Matulenko, M. A.; Hakeem, A. H.; Atkinson, R. N.; Kort, M. E.; Marron, B. E.; Joshi, S.; Honore, P.; Faltynek, C. R.; Krafte, D. S.; Jarvis, M. F., A-887826 is a structurally novel, potent and voltage-dependent Na(v)1.8 sodium channel blocker that attenuates neuropathic tactile allodynia in rats. Neuropharmacology 2010, 59 (3), 201-207. Jarvis, M. F.; Honore, P.; Shieh, C. C.; Chapman, M.; Joshi, S.; Zhang, X. F.; Kort, M.; Carroll, W.; Marron, B.; Atkinson, R.; Thomas, J.; Liu, D.; Krambis, M.; Liu, Y.; McGaraughty, S.; Chu, K.; Roeloffs, R.; Zhong, C. M.; Mikusa, J. P.; Hernandez, G.; Gauvin, D.; Wade, C.; Zhu, C.; Pai, M.; Scanio, M.; Shi, L.; Drizin, I.; Gregg, R.; Matulenko, M.; Hakeem, A.; Grosst, M.; Johnson, M.; Marsh, K.; Wagoner, P. K.; Sullivan, J. P.; Faltynek, C. R.; Krafte, D. S., A-803467, a potent and selective Na(v)1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. P Natl Acad Sci USA 2007, 104 (20), 8520-8525. Payne, CE; Brown, AR; Theile, JW; Loucif, AJC; Alexandrou, AJ; Fuller, MD; Mahoney, JH; Antonio, BM; Gerlach, AC; Printzenhoff, DM; Prime, RL; Stockbridge, G.; Kirkup, AJ; Anand, P.; Bungay, P.J.; Kemp, M.; U.S. Patent No. 10,005,768 issued June 26, 2018 to Yao et al. for Carboxamide Derivatives and Use Thereof; U.S. Patent No. 10,005,724 issued June 26, 2018 to Andrez et al. for Therapeutic Compounds and Methods of Use Thereof; U.S. Patent No. 10,000,475 issued June 19, 2018 to Tadesse et al. for Triazine Carboxamides as Sodium Channel Blockers; U.S. Patent No. 9,969,693 issued May 15, 2018 to Bogdan et al. for 6-heteroaryloxy- or 6-aryloxy-quinoline-2-Carboxamides and Method of Use; U.S. Patent No. 9,828,397 issued November 28, 2017 to Anderson et al. for Prodrugs of Pyridone Amides Useful as Modulators of Sodium Channels; U.S. Patent No. 9,783,501 issued on October 10, 2017 to Hadida-Ruah et al. for Substituted Quinolines as Modulators of Sodium Channels; U.S. Patent No. 8,536,195 issued September 17, 2013 to Termin et al. for Bicylic Derivatives as Modulators of Voltage Gated Ion Channels; U.S. Patent No. 8,492,403 issued July 23, 2013 to Kawatkar et al. for Bicylic Derivatives as Modulators of Voltage Gated Ion Channels; U.S. Patent No. 8,314,125 issued November 20, 2012 to Termin et al. for Bicyclic Derivatives as Modulators of Ion Channels; U.S. Patent No. 8,309,543 to Gonzalez et al., issued November 13, 2012, for Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels; U.S. Patent No. 8,236,833 issued August 7, 2012 to Martinborough et al. for Biphenyl Derivatives as Modulators of Voltage Gated Ion Channels; U.S. Patent No. 8,236,829 to Neubert et al., issued August 7, 2012, for Bicyclic Derivatives as Modulators of Voltage Gated ION Channels; U.S. Patent No. 7,989,481 issued August 2, 2011 to Neubert et al. for Indane Derivatives as Modulators of Sodium Channels; U.S. Patent No. 7,705,031 issued April 28, 2010 to Wilson et al. for Benzimidazoles Useful as Modulators of Ion Channels. U.S. Patent Application Publication No. 2019 / 0016671 A1 to Ahmad et al., published January 17, 2019, for Carboxamides as Modulators of Sodium Channels.

[0226] Although the foregoing subject matter has been described in some detail by way of illustration and example, for purposes of clarity of understanding, those skilled in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

1. Compound of formula (ID): 【Chemistry 1】 (In the formula, R １１ａ is halogen or C １ -C ８ haloalkyl; R １１ｂ is -O-CHR １２ -R １３ (In the formula, R １２ is hydrogen or C １ -C ８ alkyl, R １３ is C ３ -C ８ cycloalkyl) is.]

2. Compound of formula (I-F): 【Chemistry 2】 R １１ｂ is halogen or cyano; R １６ is a halogen.

3. Compound of formula (I-H): 【Chemistry 3】 (In the formula, R １１ａ is H; R １１ｂ is halogen or -O-(CH ２ ) ｐ -R ｙ where p is an integer selected from 0, 1, 2, 3, and 4; R ｙ is C １ -C ８ haloalkyl); R １６ is C １ -C ４ is alkyl.

4. Compound of formula (II): 【Chemistry 4】 (In the formula, R １１ａ is H; R １１ｂ is halogen or -O-(CH ２ ) ｐ -R ｙ where p is an integer selected from 0, 1, 2, 3, and 4; R ｙ is C １ -C ８ haloalkyl) ； R １５ is C １ -C ４ is alkyl.

5. Compound of formula (IB / E): 【Chemistry 5】 (In the formula, m is an integer selected from 0, 1, 2, 3 and 4; n is an integer selected from 0, 1, 2, 3, 4 and 5; p is an integer selected from 0, 1, 2 and 3. selected from the group consisting of: R ３ is hydrogen or halogen; R ６ is hydrogen or C １ -C ８ is alkyl; Each R １４ are independently halogen, C １ -C ８ Alkyl, C １ -C ８ Alkoxyl, C １ -C ８ Haloalkyl, cyano, -O-(CH ２ ) ｐ -R ｙ where p is an integer selected from 0, 1, 2, 3, and 4; R ｙ is C ３ -C １０ Cycloalkyl and C １ -C ８ haloalkyl), —S(O)R′, —S(O ２ )R', where each R' is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, and C 1 -C 8 haloalkyl; -NR ７ R ８ (In the formula, R ７ and R ８ is independently １ -C ８ Alkyl and C １ -C ８ haloalkyl), and -NR ９ R １０ (In the formula, R ９ and R １０ are taken together to form a saturated heterocycle selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, thiomorpholinyl, 1,4-oxazepan-4-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, and 2-oxa-6-azaspiro[3.3]heptan-6-yl, each of which optionally contains deuterium, C １ -C ８ and n is an integer from 1 to 3. The substituents are selected from the group consisting of aryl, aryloxy ...

6. Compound of formula (IC): 【Chemistry 6】 [In the formula, z is an integer selected from 0, 1, 2 and 3; R ３ is hydrogen or halogen; R ６ is hydrogen or C １ -C ４ is alkyl; Y is C １ -C ４ Alkyl, C １ -C ８ Alkoxyl and -S(=O) ２ -R', where R' is C １ -C ４ alkyl; R １７ is a halogen.

7. 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide; 6-(4-butoxy-3-chloro-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(6-chloro-3-pyridyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chlorophenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-chloro-2-methyl-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-isobutoxyphenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; N-[(2-morpholino-3-pyridyl)methyl]-6-[4-(trifluoromethoxy)phenyl]pyridazine-4-carboxamide; N-[(2-morpholino-3-pyridyl)methyl]-6-[4-(2,2,2-trifluoroethoxy)phenyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-ethoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-propoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-isopropoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-ethoxy-3-fluoro-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-fluoro-4-propoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(3-fluoro-4-isopropoxy-phenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropoxy)phenyl]-N-[(2-morpholino-3-pyridyl) methyl]pyridazine-4-carboxamide; 6-[6-(cyclopropylmethoxy)-3-pyridyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1-methylimino-1-oxo-1,4-thiazin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2,2,2-trifluoroethoxy)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1,4-oxazepan-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(6-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(5-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(dimethylamino)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-pyrrolidin-1-yl-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(1-piperidyl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(4-morpholinopyrimidin-5-yl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(3-morpholinopyrazin-2-yl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)-N-(1-(2-methoxypyridin-3-yl)ethyl)pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclobutylmethoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(1-cyclopropylethoxy)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)-3-fluoro-phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)-3-(trifluoromethyl)phenyl]-N-[(2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)phenyl]-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide; 6-[4-(cyclopropylmethoxy)phenyl]-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide; 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-methylsulfonylphenyl)methyl]pyridazine-4-carboxamide (LI-1693); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-methoxyphenyl)methyl]pyridazine-4-carboxamide (LI-1694); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-(o-tolylmethyl)pyridazine-4-carboxamide (LI-1699); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2,2,3,3,5,5,6,6-octadeuteriomorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1701); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-[2-(trifluoromethyl)morpholin-4-yl]-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1702); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(5-fluoro-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1722); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-ethylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1723); 6-[3-chloro-4-(cyclopropylmethoxy)phenyl]-N-[(2-isopropoxy-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1724); 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-methoxy-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1646); 6-[4-(cyclopropylmethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1685); 6-[4-(cyclopropylmethoxy)phenyl]-N-[[2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-2126); 6-(4-cyanophenyl)-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1668); 6-(4-chlorophenyl)-N-[(5-fluoro-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1669); 6-(4-chlorophenyl)-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1673); 6-[4-(difluoromethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1675); 6-[4-(trifluoromethoxy)phenyl]-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1682); 6-(4-cyanophenyl)-N-[(2-morpholinophenyl)methyl]pyridazine-4-carboxamide (LI-1683); 6-[4-(trifluoromethoxy)phenyl]-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1678); 6-(4-chlorophenyl)-N-[(4-methyl-2-morpholino-3-pyridyl)methyl]pyridazine-4-carboxamide (LI-1681); 6-[4-(trifluoromethoxy)phenyl]-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1679); 6-(4-chlorophenyl)-N-[[2-(3-methylmorpholin-4-yl)-3-pyridyl]methyl]pyridazine-4-carboxamide (LI-1680); and 6-(3-chloro-4-(cyclopropylmethoxy)phenyl)-N-((2-morpholinopyridin-3-yl)methyl)pyridazine-4-carboxamide A compound selected from the group consisting of:

Images