TETRAHYDROPYRIDAZINES, COMPOSITIONS COMPRISING THEM AND USES THEREOF
RELATED APPLICATION
The present application claims priority under applicable law to United States provisional application No. 63/265,583 filed on December 17, 2021, the content of which is incorporated herein by reference in its entirety for all purposes.
TECHNICAL FIELD
This disclosure generally relates to compounds, especially tetrahydropyridazine compounds, pharmaceutical compositions comprising them and their use and methods of use in the treatment and prevention of diseases and disorders.
BACKGROUND
It is generally known that activation of the cannabinoid CBi receptor increases appetite, increases the biosynthesis and storage of lipids, inhibits the actions of insulin and leptin, and promotes inflammation and fibrosis. Research was thus focused on developing CBi receptor inhibitors for the potential treatment of obesity and the metabolic disorder associated therewith, referred to as metabolic syndrome. Rimonabant was shown effective in treating metabolic syndrome but caused neuropsychiatric (i.e. CNS-related) side effects, which resulted in its withdrawal from the market.
There remains a need for the development of alternative compounds targeting the CBi receptor for the treatment or prevention of disorders associated thereto.
SUMMARY
According to one aspect, the present technology relates to compounds and their tautomeric forms and/or pharmaceutically acceptable salt thereof, their pharmaceutical compositions, uses thereof and methods of treatment comprising their administration. More specifically, the following embodiments are provided:
Embodiment 1. A compound of Formula I:
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wherein,
R1 is independently in each occurrence selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted boronate, optionally substituted silyl, and imino;
R2 and R3 are each independently selected from optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups; R4 is selected from -C(O)R5, -S(O)2R5, -C(=NR6)R5, and -C(=NR6)NHC(O)R5; R5 is selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted
heteroaryl;
R6 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R6 is taken together with R5 and their adjacent atoms to form an optionally substituted heterocycloalkyl or heteroaryl; X1 is selected from SO2 and C=O; and a is 0, 1,2, 3, 4 or 5;
or an isomer and/or tautomer thereof, or a pharmaceutically acceptable salt thereof.
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Embodiment 2. 1(a):
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The compound of embodiment 1, wherein said compound is of Formula
Formula l(a)
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wherein R1 to R4, X1, and a are as defined in embodiment 1.
Embodiment 3. The compound of embodiment 1, wherein said compound is of Formula
l(b):
Formula l(b)
wherein R1 to R4, X1, and a are as defined in embodiment 1.
Embodiment 4. The compound of any one of embodiments 1 to 3, wherein R4 is -C(O)R5, - C(=NR6)R5, or-C(=NR6)NHC(O)R5.
Embodiment 5. The compound of embodiment 4, wherein R4 is -C(=NR6)NHC(O)R5.
Embodiment 6. The compound of any one of embodiments 1 to 5, wherein R5 is an optionally substituted C-i-ealkyl, optionally substituted Ci-6alkoxy, optionally substituted Ci. 6alkylamino or di C-i-6alkylamino.
Embodiment 7. The compound of embodiment 6, wherein R5 is Ci_6alkyl, e.g. methyl.
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Embodiment 8. The compound of any one of embodiments 1 to 5, wherein R5 is an optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.
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Embodiment 9. The compound of any one of embodiments 1 to 8, wherein R6 is H.
Embodiment 10. The compound of any one of embodiments 1 to 5, wherein R6 is taken together with R5 and their adjacent atoms to form an optionally substituted heterocycloalkyl or
heteroaryl.
optionally substituted C2-6alkyl group.
Embodiment 11. The compound of any one of embodiments 1 to 10, wherein X1 is SO2.
Embodiment 12. is halogen.
The compound of any one of embodiments 1 to 11, wherein a is 1 and R1
Embodiment 13. The compound of embodiment 12, wherein R1 is Cl.
Embodiment 14. The compound of any one of embodiments 1 to 13, wherein R3 is an
optionally substituted Cearyl, C5-6heteroaryl or C5-7heterocycloalkyl group.
Embodiment 15. The compound of any one of embodiments 1 to 13, wherein R3 is an
Embodiment 16. The compound of embodiment 15, wherein R3 is of the formula:
l ^ i )
(R7)c
wherein,
R7 is independently in each occurrence selected from halogen, OH, CN, NO2, C(O)R9, C(O)N(R8)2, C(R10)=NR10, SO2R9, SO2N(R8)2, N(R10)C(O)R9, N(R10)SO2R9,
N(R10)C(O)N(R8)2, N(R10)SO2N(R8)2, N(R8)2i P(O)(R8)2i P(O)(OR8)2i B(OR8)2i Ci.6alkyl, C2. 6alkenyl, C2-6alkynyl, OCi-6alkyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4- -loheterocycloalkyl;
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R8 is independently in each occurrence selected from H, C-i-ealkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C4-ioheterocycloalkyl, Cearyl, and C5-ioheteroaryl, or two R8 are taken together with their adjacent atom(s) to form a C4-ioheterocycloalkyl group; R9 is independently in each occurrence selected from C-i-ealkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyl, Cearyl, and C5-6heteroaryl; and R10 is independently in each occurrence selected from H, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, Cearyl, and C5-6heteroaryl; and c is 0, 1,2, 3, 4 or 5;
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.
Embodiment 17. The compound of embodiment 15, wherein R3 is of the formula:
^ X 3
X2 ^ ^ X 4
wherein,
X2, X3, X4, X5, and X6 are each independently selected from N and CR11, wherein at most three of X2, X3, X4, X5, and X6 are N.
R11 is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R9, C(O)N(R8)2, C(R10)=NR10, SO2R9, SO2N(R8)2, N(R10)C(O)R9, N(R10)SO2R9,
N(R10)C(O)N(R8)2i N(R10)SO2N(R8)2, N(R8)2i P(O)(R8)2i P(O)(OR8)2i B(OR8)2i Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, OCi-6alkyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4- -loheterocycloalkyl; and c is 0, 1,2, 3, 4 or 5;
wherein R8, R9, and R10 are as defined in embodiment 16; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.
Embodiment 18. The compound of embodiment 15, wherein R3 is of the formula:
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X8 ^ x 10 I I
b . x 7 x x 11 ^ x 12
wherein,
X7 is selected from N and CR11;
X8, X9, X10, X11, and X12 are each independently selected from O, NRX and C(Ry)2, wherein at most two of X7, X8, X9, X10, X11, and X12 are or comprise O or N; R11 is as defined in embodiment 17;
Rx is selected from is independently in each occurrence selected from hydrogen, C(O)R9, C(O)N(R8)2, SO2R9, SO2N(R8)2i P(O)(R8)2i P(O)(OR8)2i B(OR8)2i Ci.6alkyl, C2.6alkenyl, C2. 6alkynyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4-ioheterocycloalkyl; Ry is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R9, C(O)N(R8)2, C(R10)=NR10, SO2R9, SO2N(R8)2i N(R10)C(O)R9, N(R10)SO2R9, N(R10)C(O)N(R8)2i N(R10)SO2N(R8)2i N(R8)2i P(O)(R8)2i P(O)(OR8)2i B(OR8)2i Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, OCi-6alkyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4- -loheterocycloalkyl or two Ry are taken together with their adjacent atom(s) to form a C4- -locycloalkyl or C4-ioheterocycloalkyl group; wherein R8, R9, and R10 are as defined in embodiment 16; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.
Embodiment 19. The compound of embodiment 17 or 18, wherein R11 or Ry is a halogen (e.g. F or Cl) or halogenated Ci_6alkyl (e.g. fluorinated Ci_3alkyl), in at least one occurrence.
Embodiment 20. The compound of embodiment 17 or 18, wherein R11 or Ry is a hydrogen atom in each occurrence.
Embodiment 21. The compound of any one of embodiments 1 to 20, wherein R2 is an optionally substituted C2.6alkyl group.
Embodiment 22. The compound of any one of embodiments 1 to 20, wherein R2 is an optionally substituted Cearyl, C5-6heteroaryl or C5-7heterocycloalkyl group.
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Embodiment 23. The compound of embodiment 22, wherein R2 is of the formula:
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wherein,
R12 is independently in each occurrence selected from halogen, OH, CN, NO2, C(O)R14, C(O)N(R13)2, C(R15)=NR15, SO2R14, SO2N(R13)2, N(R15)C(O)R14, N(R15)SO2R14,
N(R15)C(O)N(R13)2i N(R15)SO2N(R13)2i N(R13)2i P(O)(R13)2i P(O)(OR13)2i B(OR13)2i Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, OCi-6alkyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4- -loheterocycloalkyl;
R13 is independently in each occurrence selected from H, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-iocycloalkyl, C4-ioheterocycloalkyl, Cearyl, and C5-ioheteroaryl, or two R8 are taken together with their adjacent atom(s) to form a C4-ioheterocycloalkyl group; R14 is independently in each occurrence selected from C-i-ealkyl, C2-6alkenyl, C2-6alkynyl, C3- 7cycloalkyl, Cearyl, and C5-6heteroaryl; and R15 is independently in each occurrence selected from H, Ci_6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, Cearyl, and C5-6heteroaryl; and c is 0, 1,2, 3, 4 or 5;
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.
Embodiment 24. The compound of embodiment 22, wherein R2 is of the formula:
xX14 X13' ^ X 15
I I ’
A ' x 1 6
^ x 17
wherein,
X13, X14, X15, X16, and X17 are each independently selected from N and CR16, wherein at most three of X13, X14, X15, X16, and X17 are N.
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R16 is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R14, C(O)N(R13)2, C(R15)=NR15, SO2R14, SO2N(R13)2, N(R15)C(O)R14, N(R15)SO2R14,
N(R15)C(O)N(R13)2i N(R15)SO2N(R13)2i N(R13)2i P(O)(R13)2i P(O)(OR13)2i B(OR13)2, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, OCi-6alkyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4- -loheterocycloalkyl; and c is 0, 1,2, 3, 4 or 5;
wherein R13, R14, and R15 are as defined in embodiment 23; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.
Embodiment 25. The compound of embodiment 22, wherein R2 is of the formula:
wherein,
X18 is selected from N and CR16;
X19, X20, X21, X22, and X23 are each independently selected from O, NRW and C(RZ)2, wherein at most two of X18, X19, X20, X21, X22, and X23 are or comprise O or N; wherein R16 is as defined in embodiment 24; Rw is selected from is independently in each occurrence selected from hydrogen, C(O)R14, C(O)N(R13)2, SO2R14, SO2N(R13)2, P(O)(R13)2i P(O)(OR13)2i B(OR13)2i Ci_6alkyl, C2.6alkenyl, C2-6alkynyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4-ioheterocycloalkyl; Rz is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R14, C(O)N(R13)2, C(R15)=NR15, SO2R14, SO2N(R13)2, N(R15)C(O)R14, N(R15)SO2R14,
N(R15)C(O)N(R13)2i N(R15)SO2N(R13)2i N(R13)2i P(O)(R13)2i P(O)(OR13)2i B(OR13)2i Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, OCi-6alkyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4- -loheterocycloalkyl or two Rz are taken together with their adjacent atom(s) to form a C4- -locycloalkyl or C4-ioheterocycloalkyl group; wherein R13, R14, and R15 are as defined in embodiment 23; and
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wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.
Embodiment 26. The compound of embodiment 24 or 25, wherein R16 or Rz is a hydrogen atom in each occurrence.
5 Embodiment 27. The compound of embodiment 24 or 25, wherein R16 or Rz is a halogen (e.g. F or Cl) or halogenated Ci_6alkyl (e.g. fluorinated Ci_3alkyl), in at least one occurrence.
Embodiment 28. The compound of embodiment 1, wherein the compound is selected from:
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F
F
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or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
Embodiment 29. The compound of embodiment 2, wherein the compound is selected from:
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or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
Embodiment 30. The compound of embodiment 3, wherein the compound is selected from:
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or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
Embodiment 31. A pharmaceutical composition comprising a compound as defined in any one of embodiments 1 to 30, together with a pharmaceutically acceptable carrier, diluent or
excipient.
Embodiment 32. Use of a compound as defined in any one of embodiments 1 to 30 or a pharmaceutical composition as defined in embodiment 31 for the treatment of a disorder related to appetite or one of its complications, a disorder related to glucose regulation or one of its complications, a fibrosis related disorder or one of its complications, a disorder related to metabolism or one of its complications, a disorder related to skin and hair growth and healing, a disorder related to the Gl tract, a disorder related to obesity or one of its complications, or a combination thereof.
Embodiment 33. The use of embodiment 32, wherein said disorder related to appetite or one of its complications is selected from Prader-Willi Syndrome (PWS), hypothalamic obesity, pro­opiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alstrom syndrome.
Embodiment 34. The use of embodiment 32, wherein said disorder related to glucose regulation or one of its complications is selected from diabetes Type I, diabetes Type II, insulin resistance, pre-diabetes, pancreatic diseases (by p-cell protection and/or increased insulin production), and associated nephropathies, neuropathies and retinopathies.
Embodiment 35. The use of embodiment 32, wherein said fibrosis related disorder or one of its complications is selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF),
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cirrhosis and other liver fibrosis disorders (such as nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), fibrotic renal diseases, skin fibrotic disorders (such as scleroderma, and chronic kidney diseases.
Embodiment 36. The use of embodiment 32, wherein said disorder related to metabolism or one of its complications is selected from metabolic syndrome and hyperlipidemia (e.g. hyper­triglyceridemia, hyper-triglyceridemia in the setting of low HDL-cholesterol, elevation of LDL and/or total cholesterol and/or VLDL and/or elevated Apolipoprotein B, atherosclerotic cardiovascular disease, etc.).
Embodiment 37. The use of embodiment 32, wherein said disorder related to obesity or one of its complications is selected from sleep apnea, snoring, asthma, pulmonary hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous statis ulcer, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostate, or gallbladder.
Embodiment 38. The use of embodiment 32, wherein said disorder of the skin and hair is selected from alopecia (male pattern baldness and alopecia associated with metabolic syndrome), excessive scar formation (cicatrix and keloid), and scleroderma.
Embodiment 39. The use of embodiment 32, wherein said disorder related to the Gl tract is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn’s disease.
Embodiment 40. A method for the treatment of a disorder selected from disorders related to appetite or their complications, disorders related to glucose regulation or their complications, fibrosis related disorders or their complications, disorders related to metabolism or their complications, disorders related to skin and hair growth and healing, disorders related to the Gl tract, disorders related to obesity or their complications, or a combination thereof, comprising administering a compound as defined in any one of embodiments 1 to 30 or a pharmaceutical composition as defined in embodiment 31 to a subject in need thereof.
Embodiment 41. The method of embodiment 40, wherein said disorders related to appetite or their complications are selected from Prader-Willi Syndrome (PWS), hypothalamic obesity, pro­opiomelanocortin (POMC) deficiency (including POMC obesity, heterozygous POMC deficiency
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obesity, POMC epigenetic disorders), leptin receptor (LepR) deficiency, Bardet-Biedl (BB) syndrome, and Alstrom syndrome.
Embodiment 42. The method of embodiment 40, wherein said disorders related to glucose regulation or their complications are selected from diabetes Type I, diabetes Type II, insulin resistance, pre-diabetes, pancreatic diseases (by p-cell protection and/or increased insulin production), and associated nephropathies, neuropathies and retinopathies.
Embodiment 43. The method of embodiment 40, wherein said fibrosis related disorders or their complications are selected from progressive fibrosis associated with interstitial lung disease, idiopathic pulmonary fibrosis (IPF), Hermansky-Pudlak syndrome pulmonary fibrosis (HPS-PF), cirrhosis and other liver fibrosis disorders (such as nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis, primary biliary cholangitis), fibrotic renal diseases, skin fibrotic disorders (such as scleroderma, and chronic kidney diseases.
Embodiment 44. The method of embodiment 40, wherein said disorders related to metabolism or their complications are selected from metabolic syndrome and hyperlipidemia (e.g. hyper-triglyceridemia, hyper-triglyceridemia in the setting of low HDL-cholesterol, elevation of LDL and/or total cholesterol and/or VLDL and/or elevated Apolipoprotein B, atherosclerotic cardiovascular disease, etc.).
Embodiment 45. The method of embodiment 40, wherein said disorders related to obesity or their complications are selected from sleep apnea, snoring, obese asthma, pulmonary hypoventilation syndrome, dementia, heart disease, hypertension, gallbladder disease, gastrointestinal disorders, menstrual irregularities, degenerative arthritis, venous statis ulcer, coronary artery disease, arterial sclerotic disease, pseudotumor cerebri, osteoarthritis, high cholesterol, and increased incidence of malignancies of the liver, ovaries, cervix, uterus, breasts, prostate, or gallbladder.
Embodiment 46. The method of embodiment 40, wherein said disorders of the skin and hair is selected from alopecia (male pattern baldness and alopecia associated with metabolic syndrome), excessive scar formation (cicatrix and keloid), and scleroderma.
Embodiment 47. The method of embodiment 40, wherein said disorders related to the Gl tract is selected from constipation, irritable bowel syndrome, and inflammatory bowel syndrome, including ulcerative colitis and Crohn’s disease.
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propionates, butyrates, acrylates and ethylsuccinates of hydroxyl groups, and alkyl esters of an acidic group. Other ester groups include sulfonate or sulfate esters.
The expression “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds formed by the process of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The term “prodrug”, as used herein, means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant description.
Abbreviations may also be used throughout the application, unless otherwise noted, such abbreviations are intended to have the meaning generally understood by the field. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), i-Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), i-Bu (iso-butyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Sue
(succinimide).
The number of carbon atoms in a hydrocarbon substituent can be indicated by the prefix “Cx-Cy” or “Cx-y” where x is the minimum and y is the maximum number of carbon atoms in the substituent.
However, when the prefix “Cx-Cy” or “Cx-y” is associated with a group incorporating one or more heteroatom(s) by definition (e.g. heterocycloalkyl, heteroaryl, etc.), then x and y define respectively the minimum and maximum number of atoms in the cycle, including carbon atoms as well as heteroatom(s).
The term "heteroatom" includes atoms other than carbon and hydrogen, such as, but not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, substituted form of nitrogen, and any quaternized form of a basic nitrogen.
The term “alkyl” as used herein, refers to a saturated, straight- or branched-chain hydrocarbon radical typically containing from 1 to 20 carbon atoms. For example, “Ci-8alkyl” contains from one to eight carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals and the like.
The term “alkenyl” as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms. For example, “C2-
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R5 is selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted
heteroaryl;
R6 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R6 is taken together with R5 and their adjacent atoms to form an optionally substituted heterocycloalkyl or heteroaryl; X1 is selected from SO2 and C=O; and a is 0, 1,2, 3, 4 or 5;
or an isomer and/or tautomer thereof, or a pharmaceutically acceptable salt thereof.
In the above formula, the compounds may be enriched in a particular isomer, for instance of
Formula l(a):
H
Formula l(a)
wherein R1 to R4, X1, and a are as previously defined, or an isomer and/or tautomer thereof, or a pharmaceutically acceptable salt thereof.
In the above formula, the compounds may be enriched is a different isomer, for instance an isomer
of Formula l(b):
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Rz is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R14, C(O)N(R13)2, C(R15)=NR15, SO2R14, SO2N(R13)2, N(R15)C(O)R14, N(R15)SO2R14,
N(R15)C(O)N(R13)2i N(R15)SO2N(R13)2i N(R13)2i P(O)(R13)2i P(O)(OR13)2i B(OR13)2i Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, OCi-6alkyl, C6-ioaryl, C5-ioheteroaryl, C3-iocycloalkyl, and C4-5 wheterocycloalkyl or two Rz are taken together with their adjacent atom(s) to form a C4--locycloalkyl or C4-ioheterocycloalkyl group; wherein R13, R14, R15 and R16 are is as defined herein; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted.
10 In some examples, R16 or Rz is a hydrogen atom in each occurrence. In other examples, R16 or Rz is a halogen (e.g. F or Cl) or halogenated Ci_ealkyl (e.g. fluorinated Ci_3alkyl), in at least one
occurrence.
Non-limiting examples of the compounds of Formula I comprise:
15
Compound 3 Compound 4
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or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
These compounds may be prepared by conventional chemical synthesis such as those described in the Examples section below. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.
The compound as defined herein can be formulated in a pharmaceutical composition for administration to a subject, the compound being usually admixed with a at least one pharmaceutically acceptable carrier, diluent, or excipient.
The expression “pharmaceutically acceptable carrier, diluent, or excipient” and equivalent expressions, refer to a non-toxic carrier, diluent, or excipient that does not destroy the pharmacological activity of the compound with which it is formulated.
Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, and intralesional injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.
For instance, solid dosage forms for oral administration include capsules, tablets, pills, and granules. In a preferred alternative, the composition is a solid dosage form which comprises the compound as described herein and at least one binder as defined in the preceding paragraph, the binder preferably comprising microcrystalline cellulose.
Pharmaceutically acceptable carriers, diluents or excipients that may be used in oral compositions of this disclosure include, but are not limited to, binders, sweeteners, disintegrating agents, diluents, flavorings, coating agents, preservatives, lubricants, and/or polymers. Examples of binders include cellulose-based substances such as microcrystalline cellulose and carboxymethylcellulose, and other binders like gum acacia, gelatin, corn starch, gum tragacanth, sodium alginate, or polyethylene glycol (PEG). Examples of sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Examples of diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or
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Pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of compound that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration.
As used herein, the term “effective amount” means that amount of a compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term “therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disease, disorder, or symptom thereof, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
As used herein, the terms “treatment”, “treat”, and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
The term “patient” or “subject” as used herein refers to an animal such as a mammal. A subject may therefore refer to, for example, mice, rats, dogs, cats, horses, cows, pigs, guinea pigs, primates including humans and the like. Preferably the subject is a human.
The present compounds are useful for the treatment of diseases and disorders where inhibition of the cannabinoid receptor CBi is indicated. Accordingly, here are contemplated a use of the present compounds for the treatment of a disease or disorder as defined herein, a use of the present compounds in the manufacture of a medicament for the treatment of a disease or disorder as defined herein, a compound as herein defined for use in the treatment of the present diseases
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Scheme 1
Step-1: Synthesis of compound A-2
A mixture of sodium hydride (3.5 g, 86.7 mmol, 60% purity, 1 eq.) in dimethylsulfoxide (45 ml.) 5 was added a solution of 1-(4-chlorophenyl)-2-phenyl-ethanone A-1 (20 g, 86.7 mmol, 1 eq.) in dimethylsulfoxide (111 ml_). Then a solution of methyl 2-bromoacetate (13.3 g, 86.7 mmol, 8.2 ml_, 1 eq.) in toluene (68 ml.) was added and the mixture was stirred at 25°C for 16h. The mixture was poured to hydrochloric acid (1M, 200 ml.) and extracted with ethyl acetate 600 ml. (3><200 ml_). Then the organic phase was washed with brine (500 ml_), dried over anhydrous sodium 10 sulfate and concentrated to give the residue. The residue was triturated with petroleum ether (100 ml.) to give the product methyl 4-(4-chlorophenyl)-4-oxo-3-phenyl-butanoate A-2 (17.0 g) as a light yellow solid.
1H NMR (400 MHz, DMSO-de) 6 = 8.08 - 7.99 (m, 2H), 7.57 - 7.51 (m, 2H), 7.36 - 7.27 (m, 4H), 7.24-7.18 (m, 1H), 5.25 (m, 1H), 3.57 (s, 3H), 3.23 (m, 1H), 2.74 (m, 1H).
15 Step-2: Synthesis of compound A-3
To a solution of methyl 4-(4-chlorophenyl)-4-oxo-3-phenyl-butanoate A-2 (17 g, 56.2 mmol, 1 eq.) in ethanol (35 ml.) was added a solution of sodium hydroxide (22.5 g, 561.5 mmol, 10 eq.) in water (35 ml_). Then the mixture was stirred at 25°C for 2h. After evaporation of ethanol, the residue was diluted with water (200 ml.) and washed with ethyl acetate (3 x 50 ml_). The aqueous
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dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product methyl N-(1-piperidylsulfonyl)carbamate (1.8 g, crude) as a yellow oil. 1H NMR (400 MHz, DMSO-de) 5 = 11.23 (s, 1H), 3.64 (s, 3H), 3.23-3.13 (m, 4H), 1.57- 1.44 (m,
6H).
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(c) Procedure 3 (Scheme 4)
Scheme 4
„ MeOH, TEA R3H ---------------------
DCM
R3H: 4,4-F2-1-piperidine 3,3-F2-1 -piperidine
Methyl N-[(4,4-difluoro-1-piperidyl)sulfonyl]carbamate (R3 = 4,4-F2-piperidinyl) To a solution of N-(oxomethylene)sulfamoyl chloride also known as chlorosulfonyl isocyanate (18.2 mmol, 1.6 ml_, 1.1 eq.) in dichloromethane (16 ml.) was added a solution of methanol (18.2 mmol, 0.7 ml_, 1.1 eq.) in dichloromethane (3 ml_)at-10°C under nitrogen, the mixture was stirred at -10°C for 1 h. A solution of 4,4-difluoropiperidine (2 g, 16.5 mmol, 1 eq) and triethylamine (33.0 mmol, 4.6 ml_, 2 eq.) in dichloromethane (3 ml.) was added at -10°C, the mixture was stirred at 25°C for 15h. The mixture was concentrated to give the residue. The residue was purified by silica column (petroleum ether:ethyl acetate=1:1) to give the product methyl N-[(4,4-difluoro-1- piperidyl)sulfonyl]carbamate (1.4 g) as a white solid.
1H NMR (400 MHz, DMSO-de) 6= 11.54 (br s, 1H), 3.67 (s, 3H), 3.40 - 3.35 (m, 4H), 2.19- 1.99
(m, 4H).
ii. Methyl N-[(3,3-difluoro-1-piperidyl)sulfonyl]carbamate (R3 = 3,3-F2-piperidinyl) To a solution of N-(oxomethylene)sulfamoyl chloride (14.0 mmol, 1.2 ml_, 1.1 eq.) in dichloromethane (16 ml.) was added a solution of methanol (14.0 mmol, 0.56 ml_, 1.1 eq.) in dichloromethane (3 ml.) at -10°C under nitrogen, the mixture was stirred at -10°C for 1 h. A solution of 3,3-difluoropiperidine (2.00 g, 12.69 mmol, 1 eq, HCI) and triethylamine (38.1 mmol, 5.3 ml_, 3 eq.) in dichloromethane (3 ml.) was added at -10°C, the the mixture was stirred at 25°C for 15h.
The mixture was concentrated to give the residue. The residue was purified by silica column
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was concentrated to remove acetonitrile and lyophilized to give the racemic Compound 5, i.e. N- [(E)-N'-[(Z)-C-[6-(4-chlorophenyl)-5-phenyl-4,5-dihydro-3H-pyridazin-2-yl]-N-[(3,3-difluoro-1- piperidyl)sulfonyl]carbonimidoyl]carbamimidoyl]acetamide (140 mg) as a yellow solid. iv. Compound 5 (R3 = 3,3-difluoro-1 -piperidinyl) isomers separation The racemic product from step (iii) was separated by SFC (column: DAICEL CHIRALCEL™ OD(250mm x 30mm,10pm); mobile phase: 30% methanol (0.1% ammonia monohydrate) in CO2, 3.0min, 50min) to give Isomers 1 and 2 of Compound 5 having the following properties.
Isomer 1 (35 mg, 99.5% purity) as a white solid.
1H NMR (400 MHz, DMSO-de) 5 = 10.83 (br s, 1H), 8.58 - 7.70 (m, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.35 - 7.28 (m, 4H), 7.26 - 7.17 (m, 3H), 4.39 (d, J = 3.2 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H), 3.28 (t, J= 12.0 Hz, 2H), 3.19 - 3.12 (m, 1H), 3.11 - 3.05 (m, 2H), 2.31 - 2.21 (m, 1H), 2.16 (s, 3H), 2.04 - 1.90 (m, 3H), 1.71 (br s, 2H).
LCMS: (ES+) m/z = 580.1 (M+H), Rt=1.008 min.
SFC: ee value>99%, Rt=1.467 min.
Isomer 2 (48 mg, 99.2% purity) as a white solid.
1H NMR (400 MHz, DMSO-de) 6 = 10.84 (br s, 1H), 8.56-7.72 (m, 2H), 7.58 (d, J= 8.8 Hz, 2H), 7.35 - 7.28 (m, 4H), 7.26 - 7.16 (m, 3H), 4.39 (d, J = 3.2 Hz, 1H), 4.26 (d, J = 13.2 Hz, 1H), 3.28 (t, J= 11.6 Hz, 2H), 3.19 - 3.12 (m, 1H), 3.11 - 3.03 (m, 2H), 2.31 - 2.22 (m, 1H), 2.16 (s, 3H), 2.05 - 1.88 (m, 3H), 1.71 (br s, 2H).
LCMS: (ES+) m/z = 580.1 (M+H), Rt=1.003 min.
SFC: ee value>99%, Rt=1.648 min. (f) Compound 6
Compound 6 (and its isomers), where R3 is a 3,5-difluorophenyl group is prepared according to the following procedures.
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iv. Compound 1 (R3 = 3,5-difluorophenyl) isomers separation The racemic product of step (iii) was separated by SFC (column: DAICEL CHIRALCEL™ OD(250mm x 30mm,10pm); mobile phase: [Neu-MeOH];B%: 40%, 3.5; 35min) to give Isomers 1 and 2 of Compound 6 having the following properties.
Isomer 1 (27 mg, 98.8% purity) as an off-white solid. 1H NMR (400 MHz, Methanol-d4) 6 = 7.57 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 4.8 Hz, 2H), 7.34 - 7.28 (m, 2H), 7.24 (d, J= 7.2 Hz, 1H), 7.21 - 7.12 (m, 5H), 4.59 (s, 2H), 4.44 - 4.29 (m, 2H), 2.37 - 2.25 (m, 1H), 2.14 (s, 3H), 2.09-2.05 (m, 1H). 19F NMR (377 MHz, Methanol-d4) 5 = -110.05 (br s, 1F) LCMS: (ES+) m/z = 573.2 (M+H), Rt=0.895 min.
SFC: ee value 97.88%, Rt=1.445 min.
Isomer 2 (31 mg) as an off-white solid.
1H NMR (400 MHz, Methanol-d4) 6 = 7.57 (d, J = 8.8 Hz, 2H), 7.50-7.49 (m, 2H), 7.33 - 7.28 (m, 2H), 7.24 (d, J = 7.2 Hz, 1H), 7.21 - 7.14 (m, 5H), 4.59 (s, 2H), 4.44 - 4.30 (m, 2H), 2.42 - 2.25 (m, 1H), 2.14 (s, 3H), 2.09-2.05 (m, 1H). 19F NMR (377 MHz, Methanol-d4) 5 = -110.05 (br s, 1F) LCMS: (ES+) m/z = 573.2(M+H), Rt=0.887 min.
SFC: ee value >99%, Rt=1.784 min. (g) Compound 7
Compound 7 (and its isomers), where R3 is a 4-trifluoromethylphenyl group is prepared according to the following procedures.
i. Intermediate I-3 (R3 = 4-trifluoromethylphenyl)
A mixture of Intermediate I-2, methyl N-[4-(trifluoromethyl)phenyl]sulfonylcarbamate (500 mg, 1.8 mmol, 1 eq.) prepared by a known process, and Intermediate 1-1 (Example 1,478 mg, 1.8 mmol, 1 eq.) in toluene (10 mL)was stirred at 120°Cfor 12h. Aftercooling, the mixture was concentrated under reduced pressure to give a residue. The residue was triturated with ethanol (10 mL), then
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filtered and the filter cake was dried to give Intermediate 1-3, i.e. 6-(4-chlorophenyl)-5-phenyl-N- [(4-trifluoromethyl)phenyl]sulfonyl-4,5-dihydro-3H-pyridazine-2-carboxamide (650 mg) as a light
yellow solid.
1H NMR (400 MHz, DMSO-de) 5 = 11.43 (br s, 1H), 8.26 (d, J = 8.4 Hz, 2H), 8.06 (d, J = 8.4 Hz, 2H), 7.89 (d, J= 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.35 - 7.27 (m, 2H), 7.26 - 7.18 (m, 1H), 7.13 (d, J =7.6 Hz, 2H), 4.47 (brd, J = 3.2 Hz, 1H), 3.97 (d, J= 12.8 Hz, 1H), 2.90 (dt, J = 3.6, 13.2 Hz, 1H), 2.12 (m, 1H), 2.00 - 1.89 (m, 1H). ii. Intermediate I-4 (R3 = 4-trifluoromethylphenyl)
To a solution of Intermediate I-3 from step (i) (400 mg, 766.4 pmol, 1 eq.) in acetonitrile (4 ml.) was added phosphorus oxychloride (2.7 mmol, 0.25 ml_, 3.5 eq.), and the mixture was stirred at 25°C for 0.5h. Then 2,6-lutidine (3.07 mmol, 0.36 ml_, 4 eq.) was added and the mixture was stirred at 60 °C for 2.5h. The mixture was poured into water (10 ml.) and extracted with ethyl acetate 15 ml. (3*5 ml_). Then the organic phase was washed with brine (10 ml_), dried over anhydrous sodium sulfate and concentrated to give Intermediate I-4, i.e. (2E)-6-(4-chlorophenyl)- 5-phenyl-N-[4-(trifluoromethyl)phenyl]sulfonyl-4,5-dihydro-3H-pyridazine-2-carboximidoyl chloride (500 mg, crude) a brown solid.
Hi. Compound 7 (R3 = 4-trifluoromethylphenyl) racemate
To a solution of N-carbamimidoylacetamide (337 mg, 3.33 mmol, 4 eq.) and Intermediate I-4 from step (ii) (450 mg, 832 pmol, 1 eq.) in N,N-dimethylformamide (4.5 ml.) was added N,N- diisopropylethylamine (4.16 mmol, 0.72 ml_, 5 eq.). Then the mixture was stirred at 25°C for 1h.
The mixture was purified by prep-HPLC (column: Waters Xbridge™ 150 x 50mm, 10pm; mobile phase: [water(ammonium bicarbonate)-acetonitrile]; B%: 43%-73%, 11 min). The fraction was concentrated to remove acetonitrile and lyophilized to give the racemic Compound 7, i.e. N-[(E)- N'-[(Z)-C-[6-(4-chlorophenyl)-5-phenyl-4,5-dihydro-3H-pyridazin-2-yl]-N-[4- (trifluoromethyl)phenyl]sulfonyl-carbonirnidoyl]carbamimidoyl]acetamide (170 mg) as a yellow
solid.
iv. Compound 7 (R3 = 4-trifluoromethylphenyl) isomers separation The racemic product from step (iii) was separated by SFC (column: DAICEL CHIRALCEL™ OD(250mm x 30mm,10pm); mobile phase: 40% methanol (0.1% ammonia monohydrate) in CO2, 3.5min) to give Isomers 1 and 2 of Compound 7 having the following properties.
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Isomer 1 (38 mg, 99% purity) as a white solid.
1H NMR (400 MHz, Methanol-^) 5 = 8.11 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.34 - 7.29 (m, 2H), 7.25 (d, J= 7.2 Hz, 1H), 7.18 (m, 4H), 4.41 (m, 1H), 4.33 (d, J = 2.8 Hz, 1H), 3.31 - 3.27 (m, 1H), 2.37 - 2.26 (m, 1H), 2.14 (s, 3H), 2.09 (m, 1H).
LCMS: (ES+) m/z = 605.2 (M+H), Rt=0.995 min.
SFC: ee value >99%, Rt=1.551 min.
Isomer 2 (38 mg, 99.6% purity) as a white solid.
1H NMR (400 MHz, DMSO-de) 6 = 8.11 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 7.34 - 7.28 (m, 2H), 7.25 (d, J = 7.2 Hz, 1H), 7.18 (m, 4H), 4.46 - 4.36 (m, 1H), 4.33 (d, J = 3.2 Hz, 1H), 3.32 - 3.26 (m, 1H), 2.37 - 2.26 (m, 1H), 2.14 (s, 3H), 2.08 (m, 1H).
LCMS: (ES+) m/z = 605.2 (M+H), Rt=0.997 min.
SFC: ee value >99%, Rt=1.923 min. (h) Compound 8
Compound 8 (and its isomers), where R3 is a 5-(trifluoromethyl)-2-pyridyl group is prepared according to the following procedures.
i. Intermediate I-3 (R3 = 5-(trifluoromethyl)-2-pyridyl)
A mixture of Intermediate I-2 (Example 2(a)(iii), 1 g, 3.5 mmol, 1 eq.) was dissolved in N,N- dimethylformamide (10 mL) and Intermediate 1-1 (Example 1, 953 mg, 3.5 mmol, 1 eq.) was added. The mixture was stirred at 120°C for 2h. The mixture was poured into water (50 mL) and extracted with ethyl acetate 45 mL (3><15 mL). Then, the organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column (petroleum ether:ethyl acetate, 1:1) and prep-HPLC (formic acid, 0.1%, 30%-50% acetonitrile) to give Intermediate I-3, i.e. 6-(4- chlorophenyl)-5-phenyl-N-[[5-(trifluoromethyl)-2-pyridyl]sulfonyl]-4,5-dihydro-3H-pyridazine-2- carboxamide (520 mg) as a yellow solid.
1H NMR (400 MHz, DMSO-de) 5 = 12.00 (br s, 1H), 9.23 (s, 1H), 8.60 (d, J= 7.6 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.36 - 7.29 (m, 2H), 7.26 - 7.20
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(m, 1H), 7.14 (d, J= 7.2 Hz, 2H), 4.47 (br s, 1H), 3.93 (d, J= 13.2 Hz, 1H), 2.89 (m, 1H), 2.20 - 2.07 (m, 1H), 1.97- 1.87 (m, 1H).
ii. Intermediate I-4 (R3 = 5-(trifluoromethyl)-2-pyridyl)
To a solution of Intermediate I-3 from step (i) (420 mg, 803.2 pmol, 1 eq.) in acetonitrile (4.2 ml.) was added phosphorus oxychloride (2.8 mmol, 0.3 ml_, 3.5 eq.), and the mixture was stirred at 25°C for 0.5h. Then 2,6-lutidine (3.2 mmol, 0.37 ml_, 4 eq.) was added and the mixture was stirred at 60 °C for 2.5h. After cooling, the mixture was poured into water (10 ml.) and extracted with ethyl acetate 15 ml. (3*5 ml_). Then the organic phase was washed with brine (10 ml_), dried over anhydrous sodium sulfate and concentrated to give Intermediate I-4 (2E)-6-(4-chlorophenyl)-5- phenyl-N-[[5-(trifluoromethyl)-2-pyridyl]sulfonyl]-4,5-dihydro-3H-pyridazine-2-carboximidoyl chloride (540 mg, crude) as a yellow solid.
iii. Compound 8 (R3 = 5-(trifluoromethyl)-2-pyridyl) racemate To a solution of N-carbamimidoylacetamide (403 mg, 4 mmol, 4 eq.) and Intermediate I-4 from step (ii) (540 mg, 997.5 pmol, 1 eq.) in N,N-dimethylformamide (5.4 ml.) was added N,N- diisopropylethylamine (5 mmol, 0.87 ml_, 5 eq.). Then, the mixture was stirred at 25°C for 2h. The mixture was poured into water (50 ml_). The aqueous mixture was extracted with ethyl acetate 90 ml. (3><30 ml_). The organic layers were combined and washed with brine (50 ml_), dried over anhydrous sodium sulfate and concentrated under reduce pressure to give a residue.
The residue purified by silica column (petroleum ether:ethyl acetate=1:1) and prep-HPLC (column: Phenomenex™ Luna C18 150 x 25mm, 10pm; mobile phase: [water(formic acid)- acetonitrile];B%: 45%-75%,10min), and then the fraction was concentrated to remove acetonitrile and lyophilized to give the racemic Compound 8, i.e. N-[(NE)-N-[[6-(4-chlorophenyl)-5-phenyl- 4,5-dihydro-3H-pyridazin-2-yl]-[[5-(trifluoromethyl)-2-pyridyl]sulfonylamino]methylene] carbamimidoyljacetamide (95 mg) as a white solid. iv. Compound 8 (R3 = 5-(trifluoromethyl)-2-pyridyl) isomers separation The racemic product of step (iii) was separated by SFC (column: DAICEL CHIRALPAK™ OD(250mm x 30mm, 10pm); mobile phase: 40% methanol (0.1% ammonia monohydrate) in CO2, 4.6min) to give Isomers 1 and 2 of Compound 1 having the following properties.
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Isomer 1 (20 mg, 100% purity) as a white solid.
1H NMR (400 MHz, DMSO-de) 6 = 10.48 (br s, 1H), 9.04 (s, 1H), 8.41 (dd, J= 1.6, 8.4 Hz, 1H), 8.24 - 7.82 (m, 2H), 7.54 (d, J = 4.8 Hz, 2H), 7.38 - 7.14 (m, 8H), 4.44 - 4.30 (m, 2H), 3.28 - 3.20 (m, 1H), 2.29 - 2.21 (m, 1H), 2.05 (s, 3H), 2.02 - 1.96 (m, 1H).
LCMS: (ES+) m/z = 606.2 (M+H), Rt=0.950 min.
SFC: ee value>99%, Rt=1.698 min.
Isomer 2 (35 mg, 100% purity) as a white solid.
1H NMR (400 MHz, DMSO-de) 6 = 10.48 (br s, 1H), 9.04 (s, 1H), 8.41 (dd, J = 2.0, 8.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 2H), 7.53 (m, 2H), 7.37 - 7.15 (m, 8H), 4.44 - 4.30 (m, 2H), 3.28 - 3.20 (m, 1H), 2.31 -2.17(m , 1H), 2.05 (s, 3H), 2.00 (m, 1H).
LCMS: (ES+) m/z = 606.2(M+H), Rt=0.960 min.
SFC: ee value>99%, Rt=2.075 min.
Example 4 - Biological properties a) Design of the assay
Day 1:
Using polyethylenimine (PEI) transfection agent, HEK293 cells were transfected in suspension with the human CB1 or CB1b receptor and one of the following bioSensAII® assays: GAPL-Gi2, or p-arrestin plasma membrane (PM) translocation biosensor (+GRK2). Cells were directly seeded in 96-well plates immediately following transfection.
Day 4 (~ 65 hours post-transfection):
Cells were incubated with coelenterazine (luciferase substrate) and different test compounds prior to the measurement of BRET signals. b) BioSensAlP platform description.
Used in this project are i) Ga plasma membrane (GAPL) biosensors and the ii) p-arrestin plasma membrane translocation biosensor.
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i) GAPL sensors are used to monitor the activation of heterotrimeric G proteins at the plasma membrane upon receptor stimulation. Specifically, these multimolecular BRET sensors detect the plasma membrane recruitment of proteins that interact with active Ga subunits in a G protein family-selective manner. G protein activation following receptor stimulation generally leads to an increase in the BRET signal.
ii) The multimolecular p-arrestin membrane recruitment biosensors allow for real-time spatio­temporal monitoring of p-arrestin 1 and p-arrestin 2 following GPCR activation. Specifically, these P-arrestin sensors were designed to detect the recruitment of proteins to the plasma membrane (P-arrestin PM) with localization to compartment resulting in an increased BRET signal.
c) Cell culture conditions
HEK293 cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) (Wisent; cat# 319- 030-CL: without sodium pyruvate, with 4.5 g/L glucose, without L-glutamine) supplemented with 1% penicillin-streptomycin (Wisent; cat# 450-201-EL) and 2 or 10% fetal bovine serum (Wisent
cat #090150).
d) Transfection and cell platina
HEK293 cells were co-transfected with hCB1 or hCB1b and one of the above-listed bioSensAII® assays. For each transfection condition:
the total amount of transfected DNA was kept constant at 1 pg per mL of cell culture to be transfected; whenever necessary, salmon sperm DNA (Invitrogen, cat# 15632011) was used as ‘carrier’ DNA to supplement plasmid DNA (i.e., biosensor and receptor); the PEI (polyethylenimine 25 kDa linear, PolyScience, cat# 23966) to DNA ratio (ug:ug) was fixed at 3:1.
Transfections were carried out as follows:
DNA and PEI were first diluted separately in 150 mM NaCI. The volume of the diluent in each tube corresponds to 5% of the cell culture volume to be transfected.
Once DNA and PEI were diluted, the PEI-containing solution was added to the DNA solution and the DNA/PEI mixture immediately vortexed for 5 seconds.
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The DNA/PEI mixture was incubated for at least 20 minutes at room temperature to allow for the formation of DNA/PEI complexes.
During the incubation, HEK293 cells were detached, counted and re-suspended in culture medium (composition specified above).
At the end of the incubation period, the DNA/PEI mixture was added to the cells.
Cells were finally distributed in 96-well plates (White Opaque 96-well/Microplates, Greiner, cat# 655083 or CulturPlate-96, White Opaque 96-well Microplate, PerkinElmer, cat# 6005688) at a density of 30 000 cells per well.
e) BRET assay At ~48 hours post-transfection:
Using 450-Select TS Biotek plate washer, culture medium was aspirated and replaced with 100 pl of Hank’s Balanced Salt Solution buffer (HBSS) (Wisent, cat#319-067CL: without red phenol; with sodium bicarbonate, with calcium and magnesium, with HEPES) per well. This process was performed a total of two times (i.e., 2 washes).
After the washing step, the HP D300 digital dispenser (Tecan) was used to inject increasing doses (12) of test compounds (ranging from 0 - 600 nM) to wells. Three to five minutes later, an EC75 of CP-55,940 (0.1 nM for GAPL-Gi2 assay; 100 nM for p-arrestin PM translocation biosensor (+GRK2)) was added to columns 2-12 of each 96-well plate.
The eight wells in column 1 of each plate were consistently reserved for controls (i.e., 3 non-treated wells, 2 wells injected with an EC75 of CP-55,940 and 3 wells injected with an EC100 of CP-55,940).
Plates were then incubated overnight (16-18 hours) at 37degC and 5% CO2 in a humidified
atmosphere.
The following day, BRET experiments were performed according to the following protocol: 10pl of 20pM e-Coelenterazine Prolume Purple (Methoxy e-CTZ) (Nanolight, cat # 369) was added to each well for a final concentration of 2pM.
Plates were incubated for 5 mins at room temperature on an orbital shaker.
BRET readings were then collected with a 0.4sec integration time on a Synergy NEO plate reader (BioTek Instruments, Inc., USA; filters: 400nm/70nm, 515nm/20nm).
67WO 2023/108292 PCT/CA2022/051841
f) Calculations
BRET signals were determined by calculating the ratio of light emitted by GFP-acceptor (515nm) over light emitted by luciferase-donor (400nm). All BRET ratios were standardized using the equation below with pre-established BRET values for positive and negative controls. The 5 standardized BRET ratio is referred to as universal BRET (uBRET). uBRET = ((BRET ratio - A)/(B-A)) * 10 000
Where:
A = BRET ratio obtained from transfection of negative control B = BRET ratio obtained from transfection of positive control
10 Resulting dose-response curves were fitted using the four-parameter logistic non-linear regression model in GraphPad Prism 9.
Invitro assay results for Isomers 1 and 2 of Compounds 1 to 8 as prepared in Example 3 are presented in Table 1.
Table 1 - In vitro assay data Compound Isomer CBi wt Gi2 EC50 (nM)
CB1 wt Parr2 EC50 (nM)
1
1 430 >30,000
1
2
1.2
3.3
2
1 300 23,600
2
2 0.65 1.5
3
1 190 14,100
3
2 0.64 1.3
4
1 >30,000 >30,000
4
2 0.67 1.4
5
1 150 400
5
2 0.43 0.72
6
1
39
380
6
2 0.68 2.6
7
1 200 580
7
2 0.42 2.1
8
1 >30,000 >30,000
8
2
1.9
8.5
68WO 2023/108292 PCT/CA2022/051841
For comparative purposes, the racemic compound identified as compound 3 in J. H. M. Lange et al., Biorg. Med. Chem. Lett., 19 (2009), 5675-5678, was also prepared. The two isomers were separated by SFC as exemplified hereinabove and the two isomers were tested in vitro under the 5 present conditions. The most active isomer was shown to have an Gi2 EC5o of about 5.1 nM and a Parr2 EC5o of 28 nM while the other isomer was inactive in both assays.
Numerous modifications could be made to any of the embodiments described above without departing from the scope of the present invention. Any references, patents or scientific literature documents referred to in the present document are incorporated herein by reference in their 10 entirety for all purposes.
69CLAIMS
1. A compound of Formula I:
N
N
X 1
R 3
N
H
(R1)a
R 4
N
R 2
Formula I
wherein,
R1 is independently in each occurrence selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, halogen, cyano, nitro, hydroxy, optionally substituted alkoxy, amino, optionally substituted alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carboxyl, acyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phosphonyl, optionally substituted phosphinyl, optionally substituted boronate, optionally substituted silyl, and imino; R2 and R3 are each independently selected from optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups; R4 is selected from -C(O)R5, -S(O)2R5, -C(=NR6)R5, and -C(=NR6)NHC(O)R5; R5 is selected from optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R6 is selected from hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylamino or dialkylamino, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, or R6 is taken together with R5 and their adjacent atoms to form an optionally substituted heterocycloalkyl or heteroaryl; X1 is selected from SO2 and C=O; anda is 0, 1, 2, 3, 4 or 5; or an isomer and/or tautomer thereof, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein said compound is of Formula I(a):
N
N
X 1
R 3
N
H
(R1)a
R 4
N
R 2
Formula I(a) wherein R1 to R4, X1, and a are as defined in claim 1. 3. The compound of claim 1, wherein said compound is of Formula I(b):
N
N
X 1
R 3
N
H
(R1)a
R 4
N
R 2
Formula I(b) wherein R1 to R4, X1, and a are as defined in claim 1. 4. The compound of any one of claims 1 to 3, wherein R4 is -C(O)R5, -C(=NR6)R5, or -C(=NR6)NHC(O)R5.
5. The compound of claim 4, wherein R4 is -C(=NR6)NHC(O)R5. 6. The compound of any one of claims 1 to 5, wherein R5 is an optionally substituted C1-6alkyl, optionally substituted C1-6alkoxy, optionally substituted C1-6alkylamino or di C1-6alkylamino. 7. The compound of claim 6, wherein R5 is C1-6alkyl, e.g. methyl.8. The compound of any one of claims 1 to 7, wherein R6 is H. 9. The compound of any one of claims 1 to 8, wherein X1 is SO2. 10. The compound of any one of claims 1 to 9, wherein a is 1 and R1 is halogen. 11. The compound of claim 10, wherein R1 is Cl. 12. The compound of any one of claims 1 to 11, wherein R3 is an optionally substituted C6aryl, C5-6heteroaryl or C5-7heterocycloalkyl group. 13. The compound of claim 12, wherein R3 is of the formula:
(R7)c
wherein,
R7 is independently in each occurrence selected from halogen, OH, CN, NO2, C(O)R9, C(O)N(R8)2, C(R10)=NR10, SO2R9, SO2N(R8)2, N(R10)C(O)R9, N(R10)SO2R9, N(R10)C(O)N(R8)2, N(R10)SO2N(R8)2, N(R8)2,
P(O)(R8)2, P(O)(OR8)2, B(OR8)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, OC1-6alkyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl; R8 is independently in each occurrence selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10heterocycloalkyl, C6aryl, and C5-10heteroaryl, or two R8 are taken together with their adjacent atom(s) to form a C4-10heterocycloalkyl group; R9 is independently in each occurrence selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6aryl, and C5-6heteroaryl; and R10 is independently in each occurrence selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6aryl, and C5-6heteroaryl; and c is 0, 1, 2, 3, 4 or 5; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted. 14. The compound of claim 12, wherein R3 is of the formula:
X 6
X 5
X 4
X 3
X 2
wherein,
X2, X3, X4, X5, and X6 are each independently selected from N and CR11, wherein at most three of X2, X3, X4, X5, and X6 are N.
R11 is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R9, C(O)N(R8)2, C(R10)=NR10, SO2R9, SO2N(R8)2, N(R10)C(O)R9, N(R10)SO2R9, N(R10)C(O)N(R8)2,
N(R10)SO2N(R8)2, N(R8)2, P(O)(R8)2, P(O)(OR8)2, B(OR8)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, OC1-6alkyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl; and c is 0, 1, 2, 3, 4 or 5; wherein R8, R9, and R10 are as defined in claim 16; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted. 15. The compound of claim 12, wherein R3 is of the formula:
X 7
X12
X11
X10
X 9
X 8
wherein, X7 is selected from N and CR11; X8, X9, X10, X11, and X12 are each independently selected from O, NRx and C(Ry)2, wherein at most two of X7, X8, X9, X10, X11, and X12 are or comprise O or N; R11 is as defined in claim 17; Rx is selected from is independently in each occurrence selected from hydrogen, C(O)R9, C(O)N(R8)2, SO2R9, SO2N(R8)2, P(O)(R8)2, P(O)(OR8)2, B(OR8)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl; Ry is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R9, C(O)N(R8)2, C(R10)=NR10, SO2R9, SO2N(R8)2, N(R10)C(O)R9, N(R10)SO2R9, N(R10)C(O)N(R8)2,
N(R10)SO2N(R8)2, N(R8)2, P(O)(R8)2, P(O)(OR8)2, B(OR8)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, OC1-6alkyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl or two Ry are taken together with their adjacent atom(s) to form a C4-10cycloalkyl or C4-10heterocycloalkyl group; wherein R8, R9, and R10 are as defined in claim 16; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted. 16. The compound of claim 14 or 15, wherein R11 or Ry is a halogen (e.g. F or Cl) or halogenated C1-6alkyl (e.g. fluorinated C1-3alkyl), in at least one occurrence. 17. The compound of claim 14 or 15, wherein R11 or Ry is a hydrogen atom in each occurrence. 18. The compound of claims 1-17, wherein R2 is of the formula:
(R12)c
wherein,
R12 is independently in each occurrence selected from halogen, OH, CN, NO2, C(O)R14, C(O)N(R13)2, C(R15)=NR15, SO2R14, SO2N(R13)2, N(R15)C(O)R14, N(R15)SO2R14, N(R15)C(O)N(R13)2,
N(R15)SO2N(R13)2, N(R13)2, P(O)(R13)2, P(O)(OR13)2, B(OR13)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, OC1-6alkyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl; R13 is independently in each occurrence selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C4-10heterocycloalkyl, C6aryl, and C5-10heteroaryl, or two R8 are taken together with their adjacent atom(s) to form a C4-10heterocycloalkyl group;R14 is independently in each occurrence selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6aryl, and C5-6heteroaryl; and R15 is independently in each occurrence selected from H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C6aryl, and C5-6heteroaryl; and c is 0, 1, 2, 3, 4 or 5; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted. 19. The compound of claims 1-17, wherein R2 is of the formula:
X17
X16
X15
X14
X13
wherein,
X13, X14, X15, X16, and X17 are each independently selected from N and CR16, wherein at most three of X13, X14, X15, X16, and X17 are N.
R16 is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R14, C(O)N(R13)2, C(R15)=NR15, SO2R14, SO2N(R13)2, N(R15)C(O)R14, N(R15)SO2R14,
N(R15)C(O)N(R13)2, N(R15)SO2N(R13)2, N(R13)2, P(O)(R13)2, P(O)(OR13)2, B(OR13)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, OC1-6alkyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl; and c is 0, 1, 2, 3, 4 or 5; wherein R13, R14, and R15 are as defined in claim 23; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted. 20. The compound of claims 1-17, wherein R2 is of the formula:
X18
X23
X22
X21
X20
X19wherein, X18 is selected from N and CR16; X19, X20, X21, X22, and X23 are each independently selected from O, NRw and C(Rz)2, wherein at most two of X18, X19, X20, X21, X22, and X23 are or comprise O or N; wherein R16 is as defined in claim 24; Rw is selected from is independently in each occurrence selected from hydrogen, C(O)R14, C(O)N(R13)2, SO2R14, SO2N(R13)2, P(O)(R13)2, P(O)(OR13)2, B(OR13)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl; Rz is independently in each occurrence selected from hydrogen, halogen, OH, CN, NO2, C(O)R14, C(O)N(R13)2, C(R15)=NR15, SO2R14, SO2N(R13)2, N(R15)C(O)R14, N(R15)SO2R14, N(R15)C(O)N(R13)2,
N(R15)SO2N(R13)2, N(R13)2, P(O)(R13)2, P(O)(OR13)2, B(OR13)2, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, OC1-6alkyl, C6-10aryl, C5-10heteroaryl, C3-10cycloalkyl, and C4-10heterocycloalkyl or two Rz are taken together with their adjacent atom(s) to form a C4-10cycloalkyl or C4-10heterocycloalkyl group; wherein R13, R14, and R15 are as defined in claim 23; and wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally further substituted. 21. The compound of claim 19 or 20, wherein R16 or Rz is a hydrogen atom in each occurrence. 22. The compound of claim 19 or 20, wherein R16 or Rz is a halogen (e.g. F or Cl) or halogenated C1-6alkyl (e.g. fluorinated C1-3alkyl), in at least one occurrence. 23. The compound of claim 1, wherein the compound is selected from:
N
N
N N
S
Cl
O O
Cl
N
H
O H2N
N
N
N N
S
Cl
O O
Cl
N
H
O H2NN
N
N N
S
N
O O
Cl
N
H
O H2N
N
N
N N
S
N
O O
Cl
N
H
O H2N
N
N
N N
S
N
O O
Cl
N
H
O H2N
CF3
N
N
N N
S
N
O O
Cl
N
H
O H2N
CF3
N
N
N N
S
N
O O
Cl
F
F
N
H
O H2N
N
N
N N
S
N
O O
Cl
F
F
N
H
O H2N
N
N
N N
S
N
O O
Cl
N
H
O H2N
F
F
N
N
N N
S
N
O O
Cl
N
H
O H2N
F
FN
N
N N
S
O O
Cl
N
H
O H2N
F
F
N
N
N N
S
O O
Cl
N
H
O H2N
F
F
N
N
Cl
N
S
CF3
N N
H
O H2N O O
N
N
Cl
N
S
CF3
N N
H
O H2N O O
N
N
Cl
N
S
CF3
N N
H
O H2N O O
N
N
N
Cl
N
S
CF3
N N
H
O H2N O O
N
;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 23, together with a pharmaceutically acceptable carrier, diluent or excipient. 25. Use of a compound as defined in any one of claims 1 to 23 or a pharmaceutical composition as defined in claim 24 for the treatment of a disorder related to appetite or one of its complications, a disorder related to glucose regulation or one of its complications, a fibrosis related disorder or one of its complications, a disorder related to metabolism or one of its complications, a disorder related to skin and hair growth and healing, a disorder related to the GI tract, a disorder related to obesity or one of its complications, or a combination thereof.