Patent Application
20240182474
Not Applicable
Not Applicable
Not Applicable
The present invention relates to a fused heteroaryl compound having a calcium/calmodulin-dependent protein kinase II (sometimes to be abbreviated as “CaMKII” in the present specification) inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like.
Cardiac diseases include heart failure, arrhythmia, myocardial infarction, angina, valvular heart disease and the like, and they are high-mortality diseases. In treatment of cardiac diseases with a drug, the symptoms are improved by control of each risk factor and symptomatic therapy. However, the satisfaction with treatment remains low level, and there is now no definitive therapy.
Calcium-calmodulin complex binds to Ca2+/calmodulin-dependent protein kinase (CaMK) included in serine/threonine protein kinase, and activates the kinase. The CaMK family includes CaMKII, and four isoforms (α, β, γ and δ) exist as CaMKII. CaMKII α and CaMKII β are expressed mainly in cerebral tissue, and CaMKII γ and CaMKII δ are expressed in many tissues including heart. CaMKII is activated by amino acid-modification due to oxidative stress or hyperglycemia, in addition to the binding of calcium-calmodulin complex. CaMKII regulates cell functions by phosphorylation of a transcription factor which is a substrate, a protein that plays a function in organelle uptake/excretion of Ca2+, a protein that regulates contract and relax of muscles, a channel that regulates an intracellular ion concentration, and the like, due to its kinase activation.
Some documents suggest that CaMKII plays a harmful role in progress of cardiac disease conditions. Expression and activity of CaMKII are increased in heart of human patient or animal with heart failure (Non-Patent Documents 1-4). In transgenic mouse overexpressing CaMKIIδ in heart, onsets of cardiac hypertrophy and heart failure are reported (Non-Patent Document 4). By studies using an inhibitor by a pharmacological method, and studies using a gene deletion by genetic method, protecting effects on heart failure, cardiac hypertrophy, myocardial infarction and arrhythmia by an inhibition of CaMKII and an overexpression of CaMKII inhibitory protein are reported in mouse (Non-Patent Documents 5-7). For catechol aminergic polymorphic ventricular tachycardia, improving effects on disease conditions by CaMKII inhibitor in mutant ryanodine knock-in mouse (RyR2R4496C+/− mouse) are reported (Non-Patent Document 8). These findings suggest avail abilities of CaMKII inhibitors in the prophylaxis and/or treatment of cardiac diseases including heart failure, cardiac hypertrophy, myocardial infarction and cardiac arrhythmia.
Recently, CaMKII exacerbating action on growth or metastasis of a certain type of cancer is suggested (Non-Patent Document 9). In addition, therapeutic effect on acute renal failure, intimal hypertrophy, hepatic fibrosis, stroke, pain, rheumatoid arthritis and the like by CaMKII inhibition are al so indicated (Non-Patent Documents 10-15).
However, genetic methods achieve only deficiency of protein or overexpression of inhibitory protein, and they are different from a mechanism which inhibits temporarily kinase activity, and therefore, effects by kinase inhibitor cannot be al ways expected. In addition, inhibitors which have been al ready reported are not suitable for application as a medicament for a CaMKII selective inhibitor, because they have a low kinase selectivity to CaMKII, or they are not suitable for oral administration or chronic administration.
As a heterocyclic compound, the following compounds are known. Patent Document 1 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in Patent Document 1, is a FLT3 inhibitor and useful for the treatment of acute myelogenous leukemia and the like.
Patent Document 2 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in Patent Document 2, is a Syk (Spleen tyrosine kinase) inhibitor and useful for the treatment of diseases or conditions mediated by Syk (e.g., rheumatism).
Patent Document 3 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in Patent Document 3, is a mGI uR (metabotropic glutamate receptors) 5 modulator and useful for the treatment or prophylaxis of diseases or conditions in which mGI uR5 is involved (e.g., pain disorder, anxiety, depression, Alzheimer's disease, Parkinson's disease, etc.).
Patent Document 4 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in Patent Document 4, is a kinase inhibitor (particularly an inhibitor of kinase domain in VEGF receptor (VEGF receptor tyrosine kinase inhibitor)) and useful for the treatment of vascular abnormality, tumor, diabetic retinopathy, rheumatism, endometriosis, psoriasis and the like.
Patent Document 5 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in Patent Document 5, is a kinase (p38 kinase, etc.) inhibitor and useful for reduction of ischemic cell death (particularly reduction of traumatic neuronal cell death).
Patent Document 6 describes that a compound represented by the following formula (I):
wherein each symbol is as defined in Patent Document 6, is a calcium/calmodulin-dependent protein kinase 11 inhibitor and useful for the prophylaxis or treatment of cardiac diseases.
Non-Patent Document 11: Cell Calcium, vol. 45, p. 284-292
An object of the present invention is to provide a fused heteroaryl compound having a CaMKII inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like.
The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that a compound represented by the following formula (1) has a CaMKII inhibitory action, and therefore, is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
[1] A compound represented by the formula (I):
[2] The compound or pharmaceutically acceptable salt according to the above-mentioned [1], wherein V is O.
[3] The compound or pharmaceutically acceptable salt according to the above-mentioned [1], wherein Ring B1 is an optionally further substituted 5-membered aromatic heterocycle.
[4] The compound or pharmaceutically acceptable salt according to the above-mentioned [1], wherein Z is an optionally substituted ethyl ene group.
[5] The compound or pharmaceutically acceptable salt according to the above-mentioned [1], wherein X5 is N.
[6] The compound or pharmaceutically acceptable salt according to the above-mentioned [1], wherein X6 is CH.
[7] The compound or pharmaceutically acceptable salt according to the above-mentioned [1], wherein at least one of Y1, Y2, Y3 and Y4 are N.
[8] The compound or pharmaceutically acceptable salt according to the above-mentioned [1], which is a compound represented by the formula (1-1):
wherein each symbol is as defined in the above-mentioned [1], or a pharmaceutically acceptable salt thereof (hereinafter sometimes to be referred to as compound (1-1)).
[9] A compound represented by the formula (II):
[10] The compound or pharmaceutically acceptable salt according to the above-mentioned [9], wherein X1 is CH.
[11] The compound or pharmaceutically acceptable salt according to the above-mentioned [9], wherein Ring B2 is tetrazole or triazole, each of which is bonded at its nitrogen.
[12] The compound or pharmaceutically acceptable salt according to the above-mentioned [9], wherein R1 is methyl.
[13] The compound or pharmaceutically acceptable salt according to the above-mentioned [9], wherein Ring A2 is a benzene ring, a 6-membered aromatic heterocycle, or a 6-membered non-aromatic heterocycle, each of which is further substituted by one cyano group and optionally further substituted.
[14] The compound or pharmaceutically acceptable salt according to the above-mentioned [9], wherein at least one of Y1, Y2, Y3 and Y4 are N.
[15] The compound or pharmaceutically acceptable salt according to the above-mentioned [9], which is a compound represented by the formula (II-1):
wherein each symbol is as defined in the above-mentioned [9], or a pharmaceutically acceptable salt thereof (hereinafter sometimes to be referred to as compound (II-1)).
[16] A compound represented by the formula (III):
[17] The compound or pharmaceutically acceptable salt according to the above-mentioned [16], wherein the partial structure represented by the formula;
is a partial structure represented by the formula (A3-1)-(A3-9);
wherein
[18] The compound or pharmaceutically acceptable salt according to the above-mentioned [16], wherein at least one of Y1, Y2, Y3 and Y4 are N.
[19] The compound or pharmaceutically acceptable salt according to the above-mentioned [16], which is a compound represented by the formula (III-1):
wherein each symbol is as defined in the above-mentioned [16], or a pharmaceutically acceptable salt thereof (hereinafter sometimes to be referred to as compound (III-1)).
[20] A compound selected from the group consisting of
[21] A medicament comprising the compound or pharmaceutically acceptable salt according to the above-mentioned [1].
[22] The medicament according to the above-mentioned [21], which is a calcium/calmodulin-dependent protein kinase II inhibitor.
[23] The medicament according to the above-mentioned [21], which is an agent for the prophylaxis or treatment of cardiac diseases.
[24] The medicament according to the above-mentioned [23], wherein the cardiac disease is selected from catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure and fatal arrhythmia.
[25] The compound or pharmaceutically acceptable salt according to the above-mentioned [1] for use in the prophylaxis or treatment of cardiac diseases.
[26] The compound or pharmaceutically acceptable salt according to the above-mentioned [25], wherein the cardiac disease is selected from catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure and fatal arrhythmia.
[27] A method for inhibiting calcium/calmodulin-dependent protein kinase II in a mammal, which comprises administering an effective amount of the compound or pharmaceutically acceptable salt according to the above-mentioned [1] to the mammal.
[28] A method for preventing or treating cardiac diseases in a mammal, which compri ses admini stering an effective amount of the compound or pharmaceutically acceptable salt according to the above-mentioned [1] to the mammal.
[29] The method according to the above-mentioned [28], wherein the cardiac disease is selected from catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure and fatal arrhythmia.
[30] Use of the compound or pharmaceutically acceptable salt according to the above-mentioned [1] for the production of an agent for the prophylaxis or treatment of cardiac diseases.
[31] The use according to the above-mentioned [30], wherein the cardiac disease is selected from catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure and fatal arrhythmia.
Not Applicable
According to the present invention, a fused heteroaryl compound having a superior CaMKII inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like can be provided.
The present invention is explained in detail in the following.
The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition.
In the present specification, examples of the “halogen atom” include fluorine, chlorine, bromine and iodine. In the present specification, examples of the “C1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl propyl, hexyl, isohexyl, 1, 1-dimethyl butyl, 2, 2-dimethyl butyl, 3, 3-dimethyl butyl and 2-ethyl butyl.
In the present specification, examples of the “optionally halogenated C1-6 alkyl group” include a C1-6 alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl, chloromethyl, difluoromethyl, tri chloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2, 2-difluoropropyl, 3, 3, 3-trifluoropropyl, isopropyl, butyl, 4, 4, 4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl and 6, 6, 6-trifluorohexyl.
In the present specification, examples of the “C2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl -3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
In the present specification, examples of the “C2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl.
In the present specification, examples of the “C3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1]heptyl, bicyclo [2.2.2]octyl, bicyclo [3.2.1]octyl and adamantyl.
In the present specification, examples of the “optionally halogenated C3-10 cycloalkyl group” include a C3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2, 2-difluorocyclopropyl, 2, 3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
In the present specification, examples of the “C3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
In the present specification, examples of the “C6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl and 9-anthryl.
In the present specification, examples of the “C7-16 aralkyl group” include benzyl, phenethyl, naphthyl methyl and phenyl propyl.
In the present specification, examples of the “C1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the “optionally halogenated C1-6 alkoxy group” include a C1-6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2, 2, 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4, 4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the “C3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.
In the present specification, examples of the “C1-6 alkyl thio group” include methyl thio, ethyl thio, propyl thio, isopropyl thio, butyl thio, sec-butyl thio, tert-butyl thio, pentyl thio and hexyl thio.
In the present specification, examples of the “optionally halogenated C1-6 alkyl thio group” include a C1-6 alkyl thio group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl thio, difluoromethyl thio, trifluoromethyl thio, ethyl thio, propyl thio, isopropyl thio, butyl thio, 4, 4, 4-trifluorobutyl thio, pentyl thio and hexyl thio.
In the present specification, examples of the “C1-6 alkyl -carbonyl group” include acetyl, propanoyl, butanoyl, 2-methyl propanoyl, pentanoyl, 3-methyl butanoyl, 2-methyl butanoyl, 2, 2-dimethyl propanoyl, hexanoyl and heptanoyl.
In the present specification, examples of the “optionally halogenated C1-6 alkyl-carbonyl group” include a C1-6 alkyl -carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, tri chloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
In the present specification, examples of the “C1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl.
In the present specification, examples of the “C6-14 aryl -carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the “C7-16 aralkyl-carbonyl group” include phenyl acetyl and phenyl propionyl.
In the present specification, examples of the “5- to 14-membered aromatic heterocyclyl carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
In the present specification, examples of the “3- to 14-membered non-aromatic heterocyclyl carbonyl group” include morpholinyl carbonyl, piperidinyl carbonyl and pyrrolidinyl carbonyl.
In the present specification, examples of the “mono- or di -C1-6 alkyl-carbamoyl group” include methyl carbamoyl, ethyl carbamoyl, dimethyl carbamoyl, diethyl carbamoyl and N-ethyl-N-methyl carbamoyl.
In the present specification, examples of the “mono- or di -C7-16 aralkyl-carbamoyl group” include benzyl carbamoyl and phenethyl carbamoyl.
In the present specification, examples of the “C1-6 alkyl sulfonyl group” include methyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, sec-butyl sulfonyl and tert-butyl sulfonyl.
In the present specification, examples of the “optionally halogenated C1-6 alkyl sulfonyl group” include a C1-6 alkyl sulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4, 4, 4-trifluorobutyl sulfonyl, pentyl sulfonyl and hexyl sulfonyl. In the present specification, examples of the “C6-14 aryl sulfonyl group” include phenyl sulfonyl, 1-naphthyl sulfonyl and 2-naphthyl sulfonyl.
In the present specification, examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.
In the present specification, examples of the “hydrocarbon group” (including “hydrocarbon group” of “optionally substituted hydrocarbon group”) include a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group and a C7-16 aralkyl group.
In the present specification, examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent(s) selected from the following Substituent Group A.
The number of the above-mentioned substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
In the present specification, examples of the “heterocyclic group” (including “heterocyclic group” of “optionally substituted heterocyclic group”) include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
In the present specification, examples of the “aromatic heterocyclic group” (including “5- to 14-membered aromatic heterocyclic group”) include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the “aromatic heterocyclic group” include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like; and 8- to 14-membered fused polycyclic (preferably bi or tri cyclic) aromatic heterocyclic groups such as benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrazolotriazinyl, naphtho[2, 3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like.
In the present specification, examples of the “non-aromatic heterocyclic group” (including “3- to 14-membered non-aromatic heterocyclic group”) include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
Preferable examples of the “non-aromatic heterocyclic group” include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisooxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and 9- to 14-membered fused polycyclic (preferably bi or tri cyclic) non-aromatic heterocyclic groups such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho [2, 3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno [2, 3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.
In the present specification, preferable examples of the “7- to 10-membered bridged heterocyclic group” include quinuclidinyl and 7-azabicyclo [2.2.1]heptanyl.
In the present specification, examples of the “nitrogen-containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the “optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent(s) selected from the above-mentioned Substituent Group A.
The number of the substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
In the present specification, examples of the “acyl group” include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group and a phosphono group, each optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C7-16 aralkyl group, a 5- to 14-membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an optionally halogenated C1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group”.
Examples of the “acyl group” al so include a hydrocarbon-sulfonyl group, a heterocyclyl sulfonyl group, a hydrocarbon-sulfinyl group and a heterocyclyl sulfinyl group.
Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclyl sulfonyl group means a heterocyclic group-bonded sulfonyl group, the hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclyl sulfinyl group means a heterocyclic group-bonded sulfinyl group.
Preferable examples of the “acyl group” include a formyl group, a carboxy group, a C1-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl), a C3-10 cycloalkyl -carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), a C3-10 cycloalkenyl -carbonyl group (e.g., 2-cyclohexenecarbonyl), a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclyl carbonyl group, a 3- to 14-membered non-aromatic heterocyclyl carbonyl group, a C1-6 alkoxy-carbonyl group, a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), a C7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), a carbamoyl group, a mono- or di -C1-6 alkyl-carbamoyl group, a mono- or di -C2-6 alkenyl -carbamoyl group (e.g., diallyl carbamoyl), a mono- or di -C3-10 cycloalkyl-carbamoyl group (e.g., cyclopropyl carbamoyl), a mono—or di -C6-14 aryl-carbamoyl group (e.g., phenyl carbamoyl), a mono—or di -C7-16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclyl carbamoyl group (e.g., pyridyl carbamoyl), a thiocarbamoyl group, a mono- or di -C1-6 alkyl -thiocarbamoyl group (e.g., methyl thiocarbamoyl, N-ethyl -N-methyl thiocarbamoyl), a mono- or di -C2-6 alkenyl -thiocarbamoyl group (e.g., diallyl thiocarbamoyl), a mono- or di -C3-10 cycloalkyl -thiocarbamoyl group (e.g., cyclopropyl thiocarbamoyl, cyclohexyl thiocarbamoyl), a mono- or di -C6-14 aryl -thiocarbamoyl group (e.g., phenyl thiocarbamoyl), a mono- or di -C7-16 aralkyl -thiocarbamoyl group (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), a 5- to 14-membered aromatic heterocyclyl thiocarbamoyl group (e.g., pyridyl thiocarbamoyl), a sulfino group, a C1-6 alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), a sulfo group, a C1-6 alkyl sulfonyl group, a C6-14 aryl sulfonyl group, a phosphono group and a mono- or di -C1-6 alkyl phosphono group (e.g., dimethyl phosphono, diethyl phosphono, diisopropyl phosphono, di butyl phosphono).
In the present specification, examples of the “optionally substituted amino group” include an amino group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclyl carbonyl group, a 3- to 14-membered non-aromatic heterocyclyl carbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di -C1-6 alkyl-carbamoyl group, a mono- or di -C7-16 aralkyl -carbamoyl group, a C1-6 alkyl sulfonyl group and a C6-14 aryl sulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”.
Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C1-6 alkyl) amino group (e.g., methyl amino, trifluoromethyl amino, dimethyl amino, ethyl amino, diethyl amino, propyl amino, di butyl amino), a mono- or di -C2-6 alkenyl amino group (e.g., diallyl amino), a mono- or di -C3-10 cycloalkyl amino group (e.g., cyclopropyl amino, cyclohexyl amino), a mono- or di -C6-14 aryl amino group (e.g., phenyl amino), a mono- or di -C7-16 aralkyl amino group (e.g., benzyl amino, di benzyl amino), a mono- or di-(optionally halogenated C1-6 alkyl) -carbonyl amino group (e.g., acetyl amino, propionyl amino), a mono- or di -C6-14 aryl -carbonyl amino group (e.g., benzoyl amino), a mono- or di -C7-16 aralkyl-carbonyl amino group (e.g., benzyl carbonyl amino), a mono—or di-5- to 14-membered aromatic heterocyclyl carbonyl amino group (e.g., nicotinoyl amino, isonicotinoyl amino), a mono- or di-3- to 14-membered non-aromatic heterocyclyl carbonyl amino group (e.g., piperidinyl carbonyl amino), a mono- or di -C1-6 alkoxy-carbonyl amino group (e.g., tert-butoxycarbonyl amino), a 5- to 14-membered aromatic heterocyclyl amino group (e.g., pyridyl amino), a carbamoyl amino group, a (mono- or di -C1-6 alkyl-carbamoyl) amino group (e.g., methyl carbamoyl amino), a (mono- or di -C7-16 aralkyl -carbamoyl) amino group (e.g., benzyl carbamoyl amino), a C1-6 alkyl sulfonyl amino group (e.g., methyl sulfonyl amino, ethyl sulfonyl amino), a C6-14 aryl sulfonyl amino group (e.g., phenyl sulfonyl amino), a (C1-6 alkyl) (C1-6 alkyl-carbonyl) amino group (e.g., N-acetyl -N-methyl amino) and a (C1-6 alkyl) (C6-14 aryl -carbonyl) amino group (e.g., N-benzoyl -N-methyl amino).
In the present specification, examples of the “optionally substituted carbamoyl group” include a carbamoyl group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclyl carbonyl group, a 3- to 14-membered non-aromatic heterocyclyl carbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di -C1-6 alkyl-carbamoyl group and a mono- or di -C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”.
Preferable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di -C1-6 alkyl -carbamoyl group, a mono- or di -C2-6 alkenyl-carbamoyl group (e.g., diallyl carbamoyl), a mono- or di -C3-10 cycloalkyl-carbamoyl group (e.g., cyclopropyl carbamoyl, cyclohexyl carbamoyl), a mono- or di -C6-14 aryl-carbamoyl group (e.g., phenyl carbamoyl), a mono- or di -C7-16 aralkyl-carbamoyl group, a mono- or di -C1-6 alkyl-carbonyl -carbamoyl group (e.g., acetyl carbamoyl, propionyl carbamoyl), a mono- or di -C6-14 aryl-carbonyl-carbamoyl group (e.g., benzoyl carbamoyl) and a 5- to 14-membered aromatic heterocyclyl carbamoyl group (e.g., pyridyl carbamoyl).
In the present specification, examples of the “optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclyl carbonyl group, a 3- to 14-membered non-aromatic heterocyclyl carbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di -C1-6 alkyl-carbamoyl group and a mono- or di -C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”. Preferable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di -C1-6 alkyl -thiocarbamoyl group (e.g., methyl thiocarbamoyl, ethyl thiocarbamoyl, dimethyl thiocarbamoyl, diethyl thiocarbamoyl,
N-ethyl -N-methyl thiocarbamoyl), a mono- or di -C2-6 alkenyl -thiocarbamoyl group (e.g., diallyl thiocarbamoyl), a mono- or di -C3-10 cycloalkyl -thiocarbamoyl group (e.g., cyclopropyl thiocarbamoyl, cyclohexyl thiocarbamoyl), a mono- or di -C6-14 aryl -thiocarbamoyl group (e.g., phenyl thiocarbamoyl), a mono- or di -C7-16 aralkyl -thiocarbamoyl group (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), a mono- or di -C1-6 alkyl-carbonyl -thiocarbamoyl group (e.g., acetyl thiocarbamoyl, propionyl thiocarbamoyl), a mono- or di -C6-14 aryl-carbonyl -thiocarbamoyl group (e.g., benzoyl thiocarbamoyl) and a 5- to 14-membered aromatic heterocyclyl thiocarbamoyl group (e.g., pyridyl thiocarbamoyl).
In the present specification, examples of the “optionally substituted sulfamoyl group” include a sulfamoyl group optionally having “1 or 2 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclyl carbonyl group, a 3- to 14-membered non-aromatic heterocyclyl carbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di -C1-6 alkyl-carbamoyl group and a mono- or di -C7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”.
Preferable examples of the optionally substituted sulfamoyl group include a sulfamoyl group, a mono- or di -C1-6 alkyl -sulfamoyl group (e.g., methyl sulfamoyl, ethyl sulfamoyl, dimethyl sulfamoyl, diethyl sulfamoyl, N-ethyl -N-methyl sulfamoyl), a mono- or di -C2-6 alkenyl -sulfamoyl group (e.g., diallyl sulfamoyl), a mono- or di -C3-10 cycloalkyl -sulfamoyl group (e.g., cyclopropyl sulfamoyl, cyclohexyl sulfamoyl), a mono- or di -C6-14 aryl -sulfamoyl group (e.g., phenyl sulfamoyl), a mono- or di -C7-16 aralkyl -sulfamoyl group (e.g., benzyl sulfamoyl, phenethyl sulfamoyl), a mono- or di -C1-6 alkyl-carbonyl -sulfamoyl group (e.g., acetyl sulfamoyl, propionyl sulfamoyl), a mono- or di -C6-14 aryl-carbonyl -sulfamoyl group (e.g., benzoyl sulfamoyl) and a 5- to 14-membered aromatic heterocyclyl sulfamoyl group (e.g., pyridyl sulfamoyl).
In the present specification, examples of the “optionally substituted hydroxy group” include a hydroxy group optionally having “a substituent selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclyl carbonyl group, a 3- to 14-membered non-aromatic heterocyclyl carbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di -C1-6 alkyl-carbamoyl group, a mono- or di -C7-16 aralkyl -carbamoyl group, a C1-6 alkyl sulfonyl group and a C6-14 aryl sulfonyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”.
Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a C1-6 alkoxy group, a C2-6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy), a C6-14 aryloxy group (e.g., phenoxy, naphthyloxy), a C7-16 aralkyloxy group (e.g., benzyloxy, phenethyloxy), a C1-6 alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), a C6-14 aryl-carbonyloxy group (e.g., benzoyloxy), a C7-16 aralkyl-carbonyloxy group (e.g., benzyl carbonyloxy), a 5- to 14-membered aromatic heterocyclyl carbonyloxy group (e.g., nicotinoyloxy), a 3- to 14-membered non-aromatic heterocyclyl carbonyloxy group (e.g., piperidinyl carbonyloxy), a C1-6 alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy), a carbamoyloxy group, a C1-6 alkyl-carbamoyloxy group (e.g., methyl carbamoyloxy), a C7-16 aralkyl-carbamoyloxy group (e.g., benzyl carbamoyloxy), a C1-6 alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, ethyl sulfonyloxy) and a C6-14 aryl sulfonyloxy group (e.g., phenyl sulfonyloxy).
In the present specification, examples of the “optionally substituted sulfanyl group” include a sulfanyl group optionally having “a substituent selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from Substituent Group A” and a halogenated sulfanyl group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C1-6 alkyl thio group, a C2-6 alkenyl thio group (e.g., allyl thio, 2-butenyl thio, 2-pentenyl thio, 3-hexenyl thio), a C3-10 cycloalkyl thio group (e.g., cyclohexyl thio), a C6-14 aryl thio group (e.g., phenyl thio, naphthyl thio), a C7-16 aralkyl thio group (e.g., benzyl thio, phenethyl thio), a C1-6 alkyl-carbonyl thio group (e.g., acetyl thio, propionyl thio, butyryl thio, isobutyryl thio, pivaloyl thio), a C6-14 aryl-carbonyl thio group (e.g., benzoyl thio), a 5- to 14-membered aromatic heterocyclyl thio group (e.g., pyridyl thio) and a halogenated thio group (e.g., pentafluorothio).
In the present specification, examples of the “optionally substituted silyl group” include a silyl group optionally having “1 to 3 substituents selected from a C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group and a C7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from Substituent Group A”.
Preferable examples of the optionally substituted silyl group include a tri -C1-6 alkyl silyl group (e.g., trimethyl silyl, tert-butyl (dimethyl) silyl).
In the present specification, examples of the “hydrocarbon ring” include a C6-14 aromatic hydrocarbon ring, C3-10 cycloalkane and C3-10 cycloalkene.
In the present specification, examples of the “C6-14 aromatic hydrocarbon ring” include benzene and naphthalene. In the present specification, examples of the “C3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
In the present specification, examples of the “C3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
In the present specification, examples of the “heterocycle” include an aromatic heterocycle and a non-aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
In the present specification, examples of the “aromatic heterocycle” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the “aromatic heterocycle” include 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrol e, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole, 1, 2, 4-thiadiazole, 1, 3, 4-thiadiazole, triazole, tetrazole, triazine and the like; and 8- to 14-membered fused polycyclic (preferably bi or tri cyclic) aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2, 3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxazine and the like.
In the present specification, examples of the “non-aromatic heterocycle” include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the “non-aromatic heterocycle” include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, oxepane and the like; and 9- to 14-membered fused polycyclic (preferably bi or tri cyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2, 3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2, 3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, octahydroisoquinoline and the like.
In the present specification, examples of the “nitrogen-containing heterocycle” include a “heterocycle” containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the “C6-14 aromatic hydrocarbon ring” include anthracene, phenanthrene, acenaphthyl ene, in addition to those exemplified as the above-mentioned “C6-14 aromatic hydrocarbon ring”.
The definition of each symbol in the formula (1) is explained in detail in the following.
X1 is N or CRX1 wherein RX1 is a hydrogen atom, a halogen atom (e.g., a fluorine atom) or a C1-6 alkyl group (e.g., methyl).
The the partial structure represented by the formula:
is specifically represented by the formula (Ia), (Ib) or (Ic):
wherein each symbol is as defined above.
The partial structure represented by the formula:
is preferably a partial structure represented by the formula (Ia1), (Ib1), (Ic1), (Ia2), (Ib2) or (Ic2):
wherein each symbol is as defined above.
In this embodiment, X1 is N or CRX1 wherein RX1 is a hydrogen atom, a halogen atom (e.g., a fluorine atom) or a C1-6 alkyl group (e.g., methyl), preferably CH.
In this embodiment, RX5 is a hydrogen atom.
In this embodiment, RX6 is a hydrogen atom.
The partial structure represented by the formula:
is more preferably a partial structure represented by the formula (Ia1), (Ib1), (Ic1) or (Ib2):
wherein each symbol is as defined above, further more preferably a partial structure represented by the formula (Ia1), (Ib1) or (Ic1):
wherein each symbol is as defined above.
The partial structure represented by the formula:
is still more preferably a partial structure represented by the formula (IIa), (IIb) or (IIc):
wherein each symbol is as defined above, and specifically represented by the formula (IIa1), (IIb1), (IIc1), (IIa2), (IIb2) or (IIc2):
wherein each symbol is as defined above.
In this embodiment, RX1 is a hydrogen atom, a halogen atom (e.g., a fluorine atom) or a C1-6 alkyl group (e.g., methyl), preferably a hydrogen atom.
The partial structure represented by the formula:
is still more preferably a partial structure represented by the formula (IIa1), (IIb1), (IIc1) or (IIb2):
wherein each symbol is as defined above, even more preferably a partial structure represented by the formula (IIa1), (IIb1) or (IIc1):
wherein each symbol is as defined above.
The partial structure represented by the formula:
is particularly preferably a partial structure represented by the formula (IIIa), (IIIb) or (IIIc):
wherein each symbol is as defined above.
The partial structure represented by the formula:
is specifically represented by the formula (Ar-1)-(Ar-12):
wherein each symbol is as defined above.
When Y1, Y2, Y3 and Y4 are all C, then the partial structure is represented by the formula (Ar-1).
When at least one of Y1, Y2, Y and Y4 are N, then the partial structure is represented by the formula (Ar-2)-(Ar-12). These partial structures are collectively represented by the formula:
wherein
The partial structure represented by the formula:
is preferably a partial structure represented by the formula (Ar-1)-(Ar-11):
wherein each symbol is as defined above.
In this embodiment, RY1 is a hydrogen atom.
In this embodiment, RY2 is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom) or a cyano group, preferably is a hydrogen atom or a halogen atom (e.g., a fluorine atom, a chlorine atom), more preferably a hydrogen atom or a fluorine atom, particularly preferably a fluorine atom.
In this embodiment, RY3 is a hydrogen atom or a halogen atom (e.g., a fluorine atom), preferably a hydrogen atom.
In this embodiment, RY4 is a hydrogen atom or a halogen atom (e.g., a fluorine atom), preferably a hydrogen atom.
The partial structure represented by the formula:
is more preferably a partial structure represented by the formula (Ar-1) or (Ar-2):
wherein each symbol is as defined above, further more preferably a partial structure represented by the formula (Ar-1-1) or (Ar-2-1):
wherein each symbol is as defined above.
In this embodiment, RY2 is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom) or a cyano group, preferably is a hydrogen atom or a halogen atom (e.g., a fluorine atom, a chlorine atom), more preferably a hydrogen atom or a fluorine atom, particularly preferably a fluorine atom.
The partial structure represented by the formula:
is particularly preferably a partial structure represented by the formula (Ar-1-1):
wherein each symbol is as defined above.
In this embodiment, RY2 is a hydrogen atom, a halogen atom (e.g., a fluorine atom, a chlorine atom) or a cyano group, preferably is a hydrogen atom or a halogen atom (e.g., a fluorine atom, a chlorine atom), more preferably halogen atom (e.g., a fluorine atom, a chlorine atom), particularly preferably a fluorine atom.
Ring A1 is an optionally further substituted C6-14 aromatic hydrocarbon, an optionally further substituted aromatic heterocycle, or an optionally further substituted non-aromatic heterocycle, each of which is optionally fused with an optionally substituted 5- or 6-membered ring.
The “C6-14 aromatic hydrocarbon” of the “optionally further substituted C6-14 aromatic hydrocarbon” is preferably a benzene ring.
The “aromatic heterocycle” of the “optionally further substituted aromatic heterocycle” is preferably a 5- or 6-membered aromatic heterocycle.
The “non-aromatic heterocycle” of the “optionally further substituted non-aromatic heterocycle” is preferably a 5- or 6-membered non-aromatic heterocycle.
Examples of the “5- or 6-membered ring” of the “optionally substituted 5- or 6-membered ring” include a benzene ring, a C5-6 cycloalkene, a 5- or 6-membered aromatic heterocycle and a 5- or 6-membered non-aromatic heterocycle.
The “C6-14 aromatic hydrocarbon” of the “optionally further substituted C6-14 aromatic hydrocarbon”, the “aromatic heterocycle” of the “optionally further substituted aromatic heterocycle”, the “non-aromatic heterocycle” of the “optionally further substituted non-aromatic heterocycle” and the “5- or 6-membered ring” of the “optionally substituted 5- or 6-membered ring” optionally further have 1 to 5 (preferably 1 to 3) substituents at substitutable position(s), in addition to the partial structure represented by the formula:
Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different. In addition, the above-mentioned Substituent Group A is optionally substituted by substituent(s) selected from Substituent Group A. The number of the substituents is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
Ring A1 is preferably Ring A2, i.e., an optionally further substituted benzene ring, an optionally further substituted 5- or 6-membered aromatic heterocycle, or an optionally further substituted 5- or 6-membered non-aromatic heterocycle, each of which is optionally fused with an optionally substituted 5- or 6-membered ring.
The “5- or 6-membered aromatic heterocycle” of the “optionally further substituted 5- or 6-membered aromatic heterocycle” is preferably a pyridine ring (optionally oxidized), a pyrimidine ring, a pyridazine ring, a pyrazine ring, a pyrazole ring, a thiazole ring, an imidazole ring, a thiophene ring or a furan ring.
The “5- or 6-membered non-aromatic heterocycle” of the “optionally further substituted 5- or 6-membered non-aromatic heterocycle” is preferably a dihydropyridine ring or a dihydropyrimidine ring.
Examples of the “5- or 6-membered ring” of the “optionally substituted 5- or 6-membered ring” include a benzene ring, a C5-6 cycloalkene, a 5- or 6-membered aromatic heterocycle and a 5- or 6-membered non-aromatic heterocycle.
The “benzene ring” of the “optionally further substituted benzene ring”, the “5- or 6-membered aromatic heterocycle” of the “optionally further substituted 5- or 6-membered aromatic heterocycle”, the “5- or 6-membered non-aromatic heterocycle” of the “optionally further substituted 5- or 6-membered non-aromatic heterocycle” and the “5- or 6-membered ring” of the “optionally substituted 5- or 6-membered ring” optionally further have 1 to 5 (preferably 1 to 3) substituents at substitutable position(s), in addition to the partial structure represented by the formula:
Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different. In addition, the above-mentioned Substituent Group A is optionally substituted by substituent (s) selected from Substituent Group A. The number of the substituents is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
Ring A2 is preferably
(I) a benzene ring optionally fused with a 5- to 6-membered monocyclic non-aromatic heterocycle (e.g., dihydrofuran, pyrroline) (i.e., the fused ring is dihydrobenzofuran, isoindoline) optionally substituted by 1 to 3 substituents selected from
In another embodiment, Ring A2 is preferably
In another embodiment, Ring A2 is preferably
Ring A2 is more preferably
In another embodiment, Ring A2 is more preferably
In another embodiment, Ring A2 is more preferably
In another embodiment, Ring A2 is preferably a benzene ring, a 6-membered aromatic heterocycle, or a 6-membered non-aromatic heterocycle, each of which is further substituted by one cyano group and optionally further substituted.
The “6-membered aromatic heterocycle” is preferably a pyridine ring (optionally oxidized), a pyrimidine ring, a pyridazine ring or a pyrazine ring, particularly preferably a pyridine ring.
The “6-membered non-aromatic heterocycle” is preferably a dihydropyridine ring or a dihydropyrimidine ring.
The “benzene ring”, “6-membered aromatic heterocycle” and “6-membered non-aromatic heterocycle” have one cyano group and optionally further have 1 to 5 (preferably 1 to 3) substituents at substitutable position(s), in addition to the partial structure represented by the formula:
Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different. In addition, the above-mentioned Substituent Group A is optionally substituted by substituent (s) selected from Substituent Group A. The number of the substituents is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
Ring A2 is more preferably
In another embodiment, Ring A2 is more preferably
In another embodiment, Ring A2 is more preferably
Ring A2 is further more preferably
In another embodiment, Ring A2 is further more preferably
In another embodiment, Ring A2 is further more preferably
In another embodiment, Ring A2 is more preferably a partial structure represented by the following formula:
wherein Ring A3 is an optionally further substituted benzene ring, an optionally further substituted 6-membered nitrogen-containing aromatic heterocycle, or an optionally further substituted 6-membered nitrogen-containing non-aromatic heterocycle. The cyano group is bonded to the carbon atom adjacent to the carbon atom to which the partial structure represented by the formula:
is bonded.
The “6-membered nitrogen-containing aromatic heterocycle” of the “optionally further substituted 6-membered nitrogen-containing aromatic heterocycle” is preferably a pyridine ring (optionally oxidized), a pyrimidine ring, a pyridazine ring or a pyrazine ring, particularly preferably a pyridine ring. The “6-membered nitrogen-containing non-aromatic heterocycle” of the “optionally further substituted 6-membered nitrogen-containing non-aromatic heterocycle” is preferably a dihydropyridine ring or a dihydropyrimidine ring.
The “benzene ring” of the “optionally further substituted benzene ring”, the “6-membered nitrogen-containing aromatic heterocycle” of the “optionally further substituted 6-membered nitrogen-containing aromatic heterocycle” and “6-membered nitrogen-containing non-aromatic heterocycle” of the “optionally further substituted 6-membered nitrogen-containing non-aromatic heterocycle” optionally further have 1 to 3 substituents at substitutable position(s), in addition to the cyano group and the partial structure represented by the formula:
Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different. In addition, the above-mentioned Substituent Group A is optionally substituted by substituent (s) selected from Substituent Group A. The number of the substituents is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
Ring A3 is preferably
In another embodiment, Ring A3 is preferably
In another embodiment, Ring A3 is preferably
Ring A3 is more preferably
In another embodiment, Ring A3 is more preferably
In another embodiment, Ring A3 is more preferably
The partial structure represented by the formula;
is preferably a partial structure represented by the formula (A3-1) -(A3-9);
wherein
The partial structure represented by the formula;
is more preferably a partial structure represented by the formula (A3-1), (A3-2), (A3-3), (A3-5), (A3-6) or (A3-9);
wherein each symbol is as defined above.
In the formula (A3-1),
In another embodiment, in the formula (A3-1),
In another embodiment, in the formula (A3-1),
In the formula (A3-1),
In another embodiment, in the formula (A3-1),
In the formula (A3-1),
In another embodiment, in the formula (A3-1),
In another embodiment, in the formula (A3-1),
In the formula (A3-1),
In another embodiment, in the formula (A3-1),
In another embodiment, in the formula (A3-1),
In the formula (A3-2),
In the formula (A3-3),
In the formula (A3-5),
In the formula (A3-6),
In the formula (A3-9),
Ring B1 is an optionally further substituted aromatic heterocycle.
The “aromatic heterocycle” of the “optionally further substituted aromatic heterocycle” optionally further has 1 to 5 (preferably 1 to 3) substituents at substitutable position(s), in addition to -V-Z-Ring B1. Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different.
The “aromatic heterocycle” of the “optionally further substituted aromatic heterocycle” is preferably a 5-membered aromatic heterocycle.
Ring B1 is preferably Ring B2, i.e., an optionally further substituted 5-membered aromatic heterocycle.
The “5-membered aromatic heterocycle” of the “optionally further substituted 5-membered aromatic heterocycle” optionally further has 1 to 5 (preferably 1 to 3) substituents at substitutable position(s), in addition to -O—CH(R1) —CH2-Ring B2.
Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different.
The “5-membered aromatic heterocycle” of the “optionally further substituted 5-membered aromatic heterocycle” is preferably a 5-membered nitrogen-containing aromatic heterocycle. Examples of the 5-membered nitrogen-containing aromatic heterocycle include tetrazole, 1, 2, 3-triazole, 1, 2, 4-triazole, pyrazole, imidazole, pyrrol e, thiazole, isothiazole, oxazole, isoxazole, 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole, 1, 2, 4-thiadiazole, 1, 3, 4-thiadiazole and the like;
V is O, S, S(O), S(O)2 or N(RV) wherein RV is a hydrogen atom or an optionally substituted C1-6 alkyl group.
The “C1-6 alkyl group” of the “optionally substituted C1-6 alkyl group” optionally further has 1 to 5 (preferably 1 to 3) substituents at substitutable position(s). Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different.
V is preferably 0.
Z is an optionally substituted C1-6 alkyl ene group.
The “C1-6 alkylene group” of the “optionally substituted C1-6 alkyl ene group” optionally further has 1 to 5 (preferably 1 to 3) substituents at substitutable position(s). Examples of the substituent include substituents selected from the above-mentioned Substituent Group A. When the number of the substituents is two or more, the respective substituents may be the same or different.
Z is preferably an optionally substituted ethyl ene group, more preferably —CH(R1) —CH2— wherein R1 is a C1-6 alkyl group.
R1 is preferably methyl.
Z is particularly preferably —CH(CH3) —CH2—.
Compound (I) is preferably compound (II), more preferably compound (III).
Compound (I) contains a compound represented by the formulas (I-1) and (I-2):
wherein each symbol is as defined above.
Compound (II) contains a compound represented by the formulas (II-1) and (II-2):
wherein each symbol is as defined above.
Compound (111) contains a compound represented by the formulas (III-1) and (III-2):
wherein each symbol is as defined above.
Preferable compounds (1)-(111) are as follows.
Compound (II) wherein
Compound (III) wherein
[Compound B] wherein the partial structure represented by the formula;
is a partial structure represented by the formula (A3-1), (A3-2), (A3-3), (A3-5), (A3-6) or (A3-9);
wherein
In the formula (A3-1),
In the formula (A3-3),
In the formula (A3-5),
In the formula (A3-6),
Specific examples of compound (1) include the compounds of Examples 1 to 486.
When compound (1) is a salt, examples of the salt include metal salts, ammonium salts, salts with organic base, salts with inorganic acid, salts with organic acid, and salts with basic or acidic amino acid. Preferable examples of the metal salt include alkali metal salts such as sodium salts, potassium salts and the like; alkali earth metal salts such as calcium salts, magnesium salts, barium salts and the like; and aluminum salts. Preferable examples of the salt with organic base include salts with trimethyl amine, triethyl amine, pyridine, picoline, 2, 6-lutidine, ethanol amine, di ethanol amine, tri ethanol amine, cyclohexyl amine, dicyclohexyl amine, N, N′-di benzyl ethylenediamine and the like.
Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of the salts with basic amino acid include salts with arginine, lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like. Among them, a pharmaceutically acceptable salt is preferable. For example, when a compound has an acidic functional group, examples of the salt include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt etc.) and the like, ammonium salt etc., and when a compound has a basic functional group, examples of the salt include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
When compound (1) contains isomers such as tautomers, optical isomers, stereoisomers, position isomers and rotational isomers, any of isomers or mixture are also encompassed in the compound of the present invention. Further, when compound (1) contains an optical isomer, the optical isomer separated from the racemate is encompassed in compound (I).
Compound (I) can be obtained in the crystal form. Either single crystalline form or crystalline mixture can be encompassed in compound (I).
Compound (I) can be a pharmaceutically acceptable co-crystal or a co-crystal salt. The co-crystal or co-crystal salt as used herein means a crystal line material composed of two or more unique solids at room temperature, each of which has distinctive physical characteristics such as structure, melting point, and heats of fusion, hygroscopicity, solubility, and stability. A co-crystal or a co-crystal salt can be produced according to co-crystallization method known per se.
Compound (I) may be a solvate (e.g., a hydrate) or a non-solvate and both are encompassed in compound (I).
Compounds labeled with or substituted by isotopes (e.g., 2H, 3H, 11C, 14C, 18F, 35S, 125I, etc.) are also encompassed in compound (1). The compound labeled with or substituted by isotopes can be used as, for example, a tracer used for Positron
Emission Tomography (PET) (PET tracer), and are expected to be useful in the field of medical diagnosis and the like.
The production method of the compound of the present invention is explained below.
The raw material compound and reagent used and the compound obtained in each step in the following production method may be each in a form of a salt, and examples of such salt include those similar to the salts of the compound of the present invention and the like.
When the compound obtained in each step is a free form, it can be converted to the objective salt according to a method known per se. When the compound obtained in each step is a salt, it can be converted to the objective free form or the other salt according to a method known per se.
The compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next reaction. Alternatively, the compound obtained in each step can be isolated and purified from a reaction mixture according to a method known per se, for example, a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, column chromatography and the like.
When the raw material compound and reagent used in each step are commercially available, the commercially available product can also be used directly.
In the reaction in each step, while the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min −48 hr, preferably 10 min -8 hr, unless otherwise specified.
In the reaction in each step, while the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally −78° C.-300° C., preferably -78° C.-150° C., unless otherwise specified.
In the reaction in each step, while the pressure varies depending on the kind of the reagent and solvent to be used, it is generally 1 atm -20 atm, preferably 1 atm -3 atm, unless otherwise specified.
Microwave synthesizer such as Initiator manufactured by Biotage and the like may be used for the reaction in each step. While the reaction temperature varies depending on the kind of the reagent and solvent to be used, it is generally room temperature -300° C., preferably 50° C.-250° C., unless otherwise specified. While the reaction time varies depending on the kind of the reagent and solvent to be used, it is generally 1 min −48 hr, preferably 1 min -8 hr, unless otherwise specified.
In the reaction in each step, the reagent is used in an amount of 0.5 equivalents—20 equivalents, preferably 0.8 equivalents—5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent—1 equivalent, preferably 0.01 equivalent—0.2 equivalent, relative to the substrate. When the reagent is used as a ligand, the reagent is used in an amount of 0.001 equivalent—1 equivalent, preferably 0.01 equivalent—0.2 equivalent, relative to the substrate. When the reagent is used as a reaction solvent, the reagent is used in a solvent amount.
Unless otherwise specified, the reaction in each step is carried out without solvent, or by dissolving or suspending the raw material compound in a suitable solvent. Examples of the solvent include those described in Examples and the following solvents.
The above-mentioned solvent can be used in a mixture of two or more kinds thereof in an appropriate ratio.
When a base is used for the reaction in each step, examples thereof include those described in Examples and the following bases.
inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate and the like;
organic bases: triethyl amine, diethyl amine, pyridine, 4-dimethyl aminopyridine, N, N-dimethyl aniline, 1, 4-di azabicyclo[2.2.2]octane, 1, 8-di azabicyclo[5.4.0]-7-undecene, imidazole, piperidine and the like;
metal alkoxides: sodium ethoxide, potassium tert-butoxide and the like;
alkali metal hydrides: sodium hydride and the like; metal amides: sodium amide, lithium diisopropyl amide, lithium hexamethyl di silazide and the like;
organic lithiums: n-butyl lithium and the like.
When an acid or an acid catalyst is used for the reaction in each step, examples thereof include those described in Examples and the following acids and acid catalysts. inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like;
organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid and the like; Lewi s acid: boron tri fluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
Unless otherwise specified, the reaction in each step is carried out according to a method known per se, for example, the method described in Jikken Kagaku Kouza, 5th Edition, vol. 13-19 (the Chemical Society of Japan ed.); Shin Jikken Kagaku Kouza, vol. 14-15 (the Chemical Society of Japan ed.); Fine Organic Chemistry, Revised 2nd Edition (L. F. Tietze, Th. Eicher, Nankodo); Organic Name Reactions, the Reaction Mechanism and Essence, Revised Edition (Hideo Togo, Kodansha); ORGANIC
SYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (Jie Jack Li, OXFORD UNIVERSITY); Comprehensive Heterocyclic Chemistry III, Vol. 1-Vol. 14 (Elsevier Japan); Strategic Applications of Named
Reactions in Organic Synthesis (translated by Kiyoshi Tomioka, Kagakudojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or the like, or the method described in Examples.
In each step, the protection or deprotection reaction of a functional group is carried out according to a method known per se, for example, the method described in “Protective Groups in Organic Synthesis, 4th Ed”, Wiley-Interscience, Inc., 2007 (Theodora W. Greene, Peter G. M. Wuts); “Protecting Groups 3rd Ed.” Thieme, 2004 (P. J. Kocienski), or the like, or the method described in Examples.
Examples of the protecting group for a hydroxy group of an alcohol and the like and a phenolic hydroxy group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyl dimethyl silyl ether, tetrahydropyranyl ether and the like; carboxylate ester-type protecting groups such as acetate ester and the like; sulfonate ester-type protecting groups such as methanesulfonate ester and the like; carbonate ester-type protecting groups such as tert-butyl carbonate and the like, and the like.
Examples of the protecting group for a carbonyl group of an aldehyde include acetal -type protecting groups such as dimethyl acetal and the like; cyclic acetal -type protecting groups such as 1, 3-di oxane and the like, and the like.
Examples of the protecting group for a carbonyl group of a ketone include ketal -type protecting groups such as dimethyl ketal and the like; cyclic ketal -type protecting groups such as 1, 3-di oxane and the like; oxime-type protecting groups such as O-methyloxime and the like; hydrazone-type protecting groups such as N, N-dimethyl hydrazone and the like, and the like.
Examples of the protecting group for a carboxyl group include ester-type protecting groups such as methyl ester and the like; amide-type protecting groups such as N, N-dimethyl amide and the like, and the like.
Examples of the protecting group for a thiol include ether-type protecting groups such as benzyl thioether and the like; ester-type protecting groups such as thioacetate ester, thiocarbonate, thiocarbamate and the like, and the like. Examples of the protecting group for an amino group and an aromatic heterocycle such as imidazole, pyrrol e, indole and the like include carbamate-type protecting groups such as benzyl carbamate and the like; amide-type protecting groups such as acetamide and the like; alkyl amine-type protecting groups such as N-triphenyl methyl amine and the like; sulfonamide-type protecting groups such as methanesulfonamide and the like, and the like.
The protecting groups can be removed according to a method known per se, for example, by employing a method using acid, base, ultraviolet rays, hydrazine, phenyl hydrazine, sodium N-methyl dithiocarbamate, tetrabutyl ammonium fluoride, palladium acetate, trialkyl silyl halide (e.g., trimethyl silyl iodide, trimethyl silyl bromide) and the like, a reduction method, and the like.
When reduction reaction is carried out in each step, examples of the reducing agent to be used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, di isobutyl aluminum hydride (DIBAL-H), sodium borohydride, tetramethyl ammonium triacetoxyborohydride and the like; boranes such as borane tetrahydrofuran complex and the like; Raney nickel; Raney cobalt; hydrogen; formic acid; triethyl silane and the like. When carbon-carbon double bond or triple bond or a nitro group or a benzyloxycarbonyl group is reduced, a method using a catalyst such as palladium-carbon, Lindlar's catalyst and the like may be employed.
When oxidation reaction is carried out in each step, examples of the oxidizing agent to be used include peroxides such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide and the like; perchlorates such as tetrabutyl ammonium perchlorate and the like; chlorates such as sodium chlorate and the like; chlorites such as sodium chlorite and the like; periodates such as sodium periodate and the like; hypervalent iodine reagents such as iodosylbenzene and the like; reagents containing manganese such as manganese dioxide, potassium permanganate and the like; leads such as lead tetraacetate and the like; reagents containing chromium such as pyridinium chlorochromate (PCC), pyridinium di chromate (PDC), Jones reagent and the like; halogen compounds such as N-bromosuccinimide (NBS) and the like; oxygen; ozone; sulfur trioxide-pyridine complex; osmium tetroxide; selenium dioxide; 2, 3-dichloro-5, 6-di cyano-1, 4-benzoquinone (DDQ), oxone and the like.
When radical reaction is carried out in each step, examples of the radical initiator to be used include azo compounds such as azobisisobutyronitrile (AIBN) and the like; water-soluble radical initiators such as 4-4′-azobis-4-cyanopentanoic acid (ACPA) and the like; triethyl boron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reagent to be used include tributyl stannane, tristrimethylsilyl silane, 1, 1, 2, 2-tetraphenyl disilane, diphenyl silane, samarium iodide and the like.
When nucleophilic substitution reaction is carried out in each step, examples of the base to be used include organic lithiums (e.g., lithium bis(trimehyl silyl) amide), metal alkoxides (e.g., potassium tert-butoxide), alkali metal hydrides (e.g., sodium hydride), inorganic bases, organic bases and the like.
When aromatic nucleophilic substitution reaction is carried out in each step, a combination of a nucleophile (e.g., a hydroxy, an amine, imidazole etc.) and a base (e.g., an organic base etc.), or a combination of a nucleophile and an acid (e.g., an organic acid etc.) is used as a reagent.
When nucleophilic addition reaction by a carbo anion, nucleophilic 1, 4-addition reaction (Michael addition reaction) by a carbo anion or nucleophilic substitution reaction by a carbo anion is carried out in each step, and examples of the base to be used for generation of the carbo anion include organic lithiums, metal alkoxides, inorganic bases, organic bases and the like.
When Grignard reaction is carried out in each step, examples of the Grignard reagent to be used include aryl magnesium halides such as phenyl magnesium bromide and the like; and alkyl magnesium halides such as methyl magnesium bromide and the like. The Grignard reagent can be prepared according to a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metal magnesium in an ether or tetrahydrofuran as a solvent.
When azidation reaction of an alcohol, an alkyl halide or a sulfonate is carried out in each step, examples of the azidating agent to be used include diphenyl phosphoryl azide (DPPA), trimethyl silyl azide, sodium azide and the like. For example, for the azidation reaction of an alcohol, a method using diphenyl phosphoryl azide and 1, 8-di azabicyclo [5.4.0]undec-7-ene (DBU), a method using trimethyl silyl azide and a Lewis acid, and the like are employed.
When reductive amination reaction is carried out in each step, examples of the reducing agent to be used include sodium triacetoxyborohydride, sodium cyanoborohydride, borane-2-methyl pyridine complex, hydrogen, formic acid and the like. When the substrate is an amine compound, examples of the carbonyl compound to be used include paraformaldehyde, aldehydes such as acetaldehyde and the like, and ketones such as cyclohexanone and the like. When the substrate is a carbonyl compound, examples of the amine to be used include ammonia, primary amines such as methyl amine and the like; secondary amines such as dimethyl amine and the like, and the like.
When Mitsunobu reaction is carried out in each step, a combination of an azodi carboxylate (e.g., diethyl azodi carboxylate (DEAD), diisopropyl azodi carboxylate (DI AD) etc.) and triphenyl phosphine, or a phosphorane reagent (e.g., cyanomethyl enetributyl phosphorane (Tsunoda reagent) is used as a reagent.
When esterification reaction, amidation reaction or urea formation reaction is carried out in each step, examples of the reagent to be used include acyl halides such as acid chlorides, acid bromides and the like; activated carboxylic acids such as anhydrides, activated esters, sulfates and the like. Examples of the activating agent of the carboxylic acid include carbodiimide condensing agents such as 1-ethyl -3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (WSCD) and the like; triazine condensing agents such as 4-(4, 6-di methoxy-1, 3, 5-triazin-2-yl)-4-methyl morpholinium chloride n-hydrate (DMT-MM) and the like; carbonate condensing agents such as 1, 1-carbonyl di imidazole (CDI) and the like; diphenyl phosphoryl azide (DPPA); benzotriazol -1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl -pyridinium iodide (Mukai yama reagent); thionyl chloride; lower alkylhaloformates such as ethyl chloroformate and the like; 0-(7-azabenzotriazol -1-yl) -N, N, N′, N′-tetramethyl uronium hexafluorophosphorate (HATU); sulfuric acid; combinations thereof and the like. When carbodiimide condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethyl aminopyridine (DMAP) and the like may be added to the reaction system.
When coupling reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as palladium(II) acetate, tetrakis (triphenyl phosphine) palladium(0), dichlorobis (triphenyl phosphine) palladium(II), tris (di benzylideneacetone) dipalladium(0), [1,1′-bis (diphenyl phosphino) ferrocene]dichioropalladium(II), bis(di -tert-butyl (4-dimethyl aminophenyl) phosphine) dichioropalladium(II), (tri -tert-butyl phosphine) palladium(0) and the like; nickel compounds such as tetrakis(triphenyl phosphine) nickel (0) and the like; rhodium compounds such as
When thiocarbonylation reaction is carried out in each step, phosphorus pentasulfide is typically used as the thiocarbonylating agent. Alternatively, a reagent having a 1, 3, 2, 4-dithiadiphosphetane-2, 4-disulfide structure (e.g., 2, 4-bis(4-methoxyphenyl) -1, 3, 2, 4-dithiadiphosphetane-2, 4-disulfide
(Lawesson reagent) etc.) can also be used instead of phosphorus pentasulfide.
When halogenation reaction of a hydroxy group is carried out in each step, examples of the halogenating agent to be used include hydrohalic acids and acid halides of inorganic acids, specifically, hydrochloric acid, thionyl chloride, phosphorus oxychloride and the like for chlorination, 48% hydrobromic acid and the like for bromination. In addition, a method of producing an alkyl halide by reacting an alcohol with triphenyl phosphine and carbon tetrachloride or carbon tetrabromide or the like can be employed. Alternatively, a method of producing an alkyl halide via two steps comprising converting an alcohol to the corresponding sulfonate, and then reacting the sulfonate with lithium bromide, lithium chloride or sodium iodide can also be employed.
When sulfonate esterification reaction is carried out in each step, examples of the sulfonating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride and the like.
When hydrolysis reaction is carried out in each step, an acid or a base is used as a reagent. For acid hydrolysis reaction of tert-butyl ester, formic acid, triethyl silane and the like may be added to reductively-trap tert-butyl cation which is by-produced.
When dehydration reaction is carried out in each step, examples of the dehydrating agent to be used include sulfuric acid, di phosphorus pentaoxide, phosphorus oxychloride, N, N′-dicyclohexyl carbodiimide, alumina, polyphosphoric acid and the like.
When cyanation reaction is carried out in each step, examples of the metal catalyst to be used include palladium compounds such as chloro(2-dicyclohexyl phosphino-2′, 4′, 6′-tri -1-propyl -1, 1′-biphenyl) (2′-amino-1, 1′-biphenyl -2-yl) palladium(II), palladium(II) acetate, tetrakis(triphenyl phosphine) palladium(0), dichlorobis (triphenyl phosphine) palladium(II), tris (di benzylideneacetone)dipalladium(0), 1, 1′-bis (diphenyl phosphino) ferrocene palladium(II) chloride, (tri -tert-butyl phosphine) palladium(0) and the like; nickel compounds such as tetrakis (triphenyl phosphine) nickel (0) and the like; rhodium compounds such as tris (triphenyl phosphine) rhodium (III) chloride and the like; cobalt compounds; copper compounds such as copper oxide, copper(I) iodide, copper(II) diacetate and the like; platinum compounds and the like. Examples of the cyano compound to be used include potassium hexacyanoferrate (II) tri hydrate, copper(I) cyanide, zinc cyanide, potassium cyanide, sodium cyanide and the like. In addition, a base can be added to the reaction system, and examples thereof include organic bases, inorganic bases and the like. Moreover, a ligand can be added to the reaction system, and examples thereof include organic amines such as N, N′-dimethyl ethylenediamine, N, N′-dimethyl -cyclohexane-1, 2-di amine, 2, 2-bi pyridyl and the like; organophosphorus compounds such as 2-dicyclohexyl phosphino-2′, 4′, 6′-tri isopropyl biphenyl, triphenyl phosphine, tri -tert-butyl phosphine, tri cyclohexyl phosphine, BI NAP (2, 2′-bis (diphenyl phosphino) -1, 1-bi naphthyl) and the like; and the like.
When nitration reaction is carried out in each step, examples of the nitrating agent to be used include mineral acids such as mixed acid, nitric acid and the like; nitrates such as potassium nitrate, sodium nitrate, tetramethyl ammonium nitrate, silver nitrate and the like.
When 0-alkylation reaction or N-alkylation reaction is carried out in each step, a combination of an alkylating agent (e.g., an alkyl halide, an alkyl sulfonate ester etc.) and a base (e.g., an organic base, an inorganic base, alkali metal hydrides etc.) is used as a reagent.
Compound (I) of the present invention can be produced according to the methods explained below.
A1, B1, V, X1-X6, Y1-Y4 and Z in the following schemes are as defined above.
Compound (I) wherein X2 is C, one of X3 and X4 is N, and the other is C can be produced from compound (2) according to the method shown in Scheme 1-1.
wherein L1-L4 are each independently a leaving group, M1 and M2 are each independently a metal group, T1 is a leaving group or metal group, and the other symbol s are as defined above.
Examples of the “leaving group” for L1-L4 and T1 include a halogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom, an iodine atom etc.), an optionally halogenated C1-6 alkyl sulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy etc.), an optionally substituted C6-14 aryl sulfonyloxy group [e.g., a C6-14 aryl sulfonyloxy group optionally having 1 to 3 substituents selected from a C1-6 alkyl group (e.g., methyl, etc.)], an optionally halogenated C1-6 alkyl sulfide group, an optionally substituted C6-14 aryl sulfide group, a C1-6 alkoxy group (e.g., methoxy, etc.), a nitro group, m-nitrobenzene sulfonyloxy and naphthyl sulfonyloxy and the like.
Examples of the “metal group” for M1, M2 and T1 include a boronic acid group (—B(OH)2), or a boronate ester group (—B(OR)2; R is a C1-6 alkyl group) or a cyclic group thereof (e.g., a 4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborol an-2-yl, etc.), or trialkyl stannyl group and the like.
Compounds (2), (3), (7) and (9) may be a commercially available product, or can be produced according to a method known per se.
Compound (I) wherein X1 is CH, X2 and X4 are C, X6 is CH, and X3 and X5 are N, can also be produced from compound (9) according to the method shown in Scheme 1-2.
wherein T2 is a leaving group or a metal group, and the other symbol s are as defined above.
Examples of the “leaving group” for T2 include those exemplified as the “leaving group” for T1.
Examples of the “metal group” for T2 include those exemplified as the “metal group” for T1.
Compounds (3′), (9) and (II) may be a commercially available product, or can be produced according to a method known per se.
Compound (I) wherein X1 is CRX1a, X3 and X4 are C, and X6 is CRX6, and X2 and X5 are N, can be produced from compound (12) according to the method shown in Scheme 1-3.
wherein L5 is a leaving group, M3 is a metal group, RX1a is a hydrogen atom or a C1-2 alkyl group, R is a C1-2 alkyl group, and the other symbol s are as defined above.
Examples of the “leaving group” for L5 include those exemplified as the “leaving group” for L1-L4.
Examples of the “metal group” for M3 include those exemplified as the “metal group” for M1 and M2.
Compounds (2), (12), (13) and (16) may be a commercially available product, or can be produced according to a method known per se. Compound (5) can be produced according to Scheme 1-1.
Compound (2′), which is compound (2) wherein -V-Z-Ring B1 is —O—CH(R1) —CH2-Ring B2, can be produced from compound (19) according to the method shown in Scheme 2-1 or a similar method known per se (WO 2018/183112 A1 and WO 2020/068854 A1).
wherein L6 is a leaving group, and the other symbols are as defined above.
Examples of the “leaving group” for L6 include those exemplified as the “leaving group” for L1-L4.
Compounds (19), (20), (22) and (23) may be a commercially available product, or can be produced according to a method known per se.
The starting compound and/or production intermediate for compound (1) may form a salt. While the salt is not particularly limited as long as the reaction can be performed, examples thereof include those similar to the salts optionally formed by compound (1) and the like, and the like.
As for the configurational isomers (E, Z forms) of compound (1), they can be isolated and purified when isomerization occurs, for example, according to a conventional separation means such as extraction, recrystallization, distillation, chromatography and the like to obtain a pure compound. In addition, the corresponding pure isomer can al so be obtained by isomerizing a double bond using heating, an acid catalyst, a transition metal complex, a metal catalyst, a radical catalyst, light irradiation, a strong base catalyst and the like, according to the method described in Shin Jikken Kagaku Kouza 14 (The Chemical Society of Japan ed.), pages 251 to 253, 4th Edition Jikken Kagaku Kouza 19 (The Chemical Society of Japan ed.), pages 273 to 274 or a method analogous thereto.
Compound (I) contains a stereoisomer depending on the kind of a substituent, and each stereoisomer and a mixture thereof are encompassed in the present invention.
Compound (I) may be a hydrate or a non-hydrate.
When desi red, compound (1) can be synthesized by performing deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, reaction of carbon chain extension, halogenation reaction, substituent exchange reaction, coupling reaction, reductive amination, nucleophilic addition reaction by a carbo anion, Grignard reagent and deoxofluorination reaction singly or two or more thereof in combination.
When the objective product is obtained as a free form by the above-mentioned reaction, it can be converted to a salt according to a conventional method, or when the objective product is obtained as a salt, it can be converted to a free form or other salt according to a conventional method. The thus-obtained compound (1) can also be isolated and purified from a reaction mixture according to a known method such as phase transfer, concentration, solvent extraction, distillation, crystallization, recrystallization, chromatography and the like.
When compound (1) contains a configurational isomer, a diastereomer, a conformer and the like, each can be isolated according to the above-mentioned separation and purification methods, if desired. In addition, when compound (1) is racemic, d-form and I-form can be isolated according to a conventional optical resolution.
The thus-obtained compound (1), other reaction intermediate therefor and starting compounds thereof can be isolated and purified from a reaction mixture according to a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC), moderate-pressure preparative liquid chromatography (moderate-pressure preparative LC) and the like.
A salt of compound (1) can be produced according to a method known per se. For example, when compound (1) is a basic compound, it can be produced by adding an inorganic acid or organic acid, or when compound (1) is an acidic compound, by adding an organic base or inorganic base.
When compound (1) contains an optical isomer, each optical isomer and a mixture thereof are encompassed in the scope of the present invention, and these isomers can be subjected to optical resolution or can be produced respectively, according to a method known per se, if desired.
When compound (1) contains a configurational isomer, a diastereomer, a conformer and the like, each can be isolated according to the above-mentioned separation and purification methods, if desired. In addition, when compound (1) is racemic, S-form and R-form can be isolated according to a conventional optical resolution.
When compound (1) contains a stereoisomer, each isomer and a mixture thereof are encompassed in the present invention.
Compound (I) may be a prodrug. A prodrug of compound (1) means a compound which is converted to compound (I) with a reaction due to an enzyme, a gastric acid, etc. under the physiological condition in the living body, that is, a compound which is converted to compound (1) with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound which is converted to compound (1) by hydrolysis etc. due to gastric acid, etc.
A prodrug for compound (1) may be a compound obtained by subjecting an amino group in compound (1) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in compound (1) to an eicosanoylation, alanylation, pentyl amino carbonylation, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidyl methylation, pivaloyloxymethylation or tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in compound (1) to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in compound (1) to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethyl aminomethyl carbonylation, etc.); a compound obtained by subjecting a carboxyl group in compound (1) to an esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in compound (1) to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethyl aminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1, 3-dioxolen-4-yl)methyl esterification, cyclohexyloxy carbonylethyl esterification or methyl amidation, etc.) and the like. Any of these compounds can be produced from compound (1) by a method known per se. The prodrug of compound (1) may be a compound that converts to compound (1) under physiological conditions as described in Development of Pharmaceutical Products, vol. 7, Molecule Design, 163-198, Hirokawa Shoten (1990).
Compound (I) or a prodrug thereof (to be abbreviated as the compound of the present invention) is superior in vivo kinetics (e.g., plasma drug half-life, intracerebral transferability, metabolic stability), shows low toxicity (e.g., more superior as a medicament in terms of liver/hepatotoxicity, acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, cytotoxicity, drug interaction, carcinogenicity etc.; especially liver/hepatotoxicity). The compound of the present invention is directly used as a medicament or a pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like to be orally or parenterally administered to mammals (e.g., humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep and goats) in safety. Examples of the “parenteral” include intravenous, intramuscular, subcutaneous, intra-organ, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal and intratumor administrations, administration to the vicinity of tumor etc. and direct administration to the lesion.
Since the compound of the present invention has a superior CaMKII inhibitory action, it is expected to be useful for the prophylaxis or treatment of, for example, cardiac diseases (cardiac hypertrophy, acute heart failure and chronic heart failure including congestive heart failure, cardiomyopathy, angina, myocarditis, atrial/ventricular arrhythmia, tachycardia, myocardial infarction, etc.), myocardial ischemia, venous insufficiency, post-myocardial infarction transition to heart failure, hypertension, corpulmonale, arteriosclerosis including atherosclerosis (aneurysm, coronary arterial sclerosis, cerebral arterial sclerosis, peripheral arterial sclerosis, etc.), vascular thickening, vascular thickening/occlusion and organ damages after intervention (percutaneous coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound, coronary thrombolytic therapy, etc.), vascular reocclusion/restenosis after bypass surgery, cardiac hypofunction after artificial heart lung surgery, respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus/pulmonary embolism, etc.), bone disorders (nonmetabolic bone disorders such as bone fracture, refracture, bone malformation/spondylosis deformans, osteosarcoma, myeloma, dysostosis and scoliosis, bone defect, osteoporosis, osteomalacia, rickets, osteitis fibrosis, renal osteodystrophy, Paget's disease of bone, myelitis with rigidity, chronic rheumatoid arthritis, gonarthrosis and articular tissue destruction in similar disorders thereof, etc.), inflammatory diseases (diabetic complication such as retinopathy, nephropathy, nerve damage, macroangiopathy etc.; arthritis such as chronic rheumatoid arthritis, osteoarthritis, rheumatoid myelitis, periostitis etc.; inflammation after surgery/trauma; reduction of swelling; pharyngitis; cystitis; pneumonia; atopic dermatitis; inflammatory enteric diseases such as Crohn's disease, ulcerative colitisetc.; meningitis; inflammatory eye diseases; inflammatory pulmonary diseases such as pneumonia, silicosis, pulmonary sarcoidosis, pulmonary tuberculosis etc, and the like), allergic diseases (allergic rhinitis, conjunctivitis, gastrointestinal allergy, pollen allergy, anaphylaxis, etc.), drug dependence, neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, AIDS encephalopathy, etc.), central nervous system damage (disorders such as cerebral hemorrhage and cerebral infarction and aftereffects and complications thereof, head injury, spinal damage, cerebral edema, sensory dysfunction, sensory abnormality, autonomic dysfunction, abnormal autonomic function, multiple sclerosis etc.), dementia, disturbed memory, disturbed consciousness, amnesia, anxiety symptoms, nervous symptoms, unpleasant condition, mental disorders (depression, epilepsy, alcohol dependency, etc.), ischemic peripheral circulatory disorder, deep-vein thrombosis, occlusive peripheral circulatory disorder, arteriosclerosis obliterans (ASO), occlusive thromboangiitis, diabetes (type 1 diabetes, type 2 diabetes, pregnancy diabetes etc.), diabetic complications (nerve damage, nephropathy, retinopathy, cataract, macroangiopathy, osteopenia, diabetic hyperosmolar diabetic coma, infectious diseases, diabetic gangrene, xerostomia, deterioration in hearing, cerebrovascular damage, peripheral circulatory disorder, etc.), urinary incontinence, metabolic/nutritional disorders (obesity, hyperlipidemia, hypercholesterolemia, diabetes, impaired glucose tolerance, hyperuricemia, hyperkalemia, hypernatremia etc.), metabolic syndrome, vesceral obesity syndrome, male or female sexual dysfunction and the like, and
for the prophylaxis or treatment of dysgeusia, smell disturbance, abnormal circadian rhythm of blood pressure, cerebrovascular damage (asymptomatic cerebrovascular damage, transient cerebral ischemia attack, stroke, cerebrovascular dementia, hypertensive encephalopathy, cerebral infarction, etc.), cerebral edema, cerebral circulatory disturbance, recurrence and aftereffects of cerebrovascular damages (neurological symptoms, mental symptoms, subjective symptoms, impairment of activities of daily living, etc.), kidney diseases (nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, diabetic nephropathy, nephrotic syndrome, hypertensive nephrosclerosis, complications of dialysis, organ damage including nephropathy by irradiation, etc.), erythrocytosis/hypertension/organ damage/vascular thickening after transplantation, rejection after transplantation, ocular disorders (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, hypertensive tinnitus, other circulatory diseases (ischemic cerebral circulatory disturbance, Raynaud's disease, Buerger's disease, etc.), chronic occlusive pulmonary diseases, interstitial pneumonia, carinii pneumonia, connective tissue disorders (e.g., systemic erythematosus, scleroderma, polyarteritis, etc.), liver disorders (hepatitis and cirrhosis including chronic types, etc.), portal hypertension, digestive disorders (gastritis, gastric ulcer, gastric cancer, disorder after gastric surgery, poor digestion, esophageal ulcer, pancreatitis, col on polyp, cholelithiasis, hemorrhoidal problem, esophageal and gastric variceal rupture, etc.), hematological/hematopoietic disorders (erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelosis, etc.), solid tumor, tumors (malignant melanoma, malignant lymphoma, digestive organs (e.g., stomach, intestine, etc.) cancers, etc.), cancers and cachexia associated therewith, cancer metastases, endocrine disorders (Addison's disease, Cushing's syndrome, pheochromocytoma, primary aldosteronism, etc.), Creutzfeldt-Jakob disease, urological/male genital diseases (cystitis, prostatic enlargement, prostate cancer, sexually transmitted diseases, etc.), gynecological disorders (menopausal disorders, pregnancy toxemia, endometriosis, uterine fibroid, ovarian diseases, mammary gland diseases, sexually transmitted diseases, etc.), diseases caused by environmental/occupational factor (e.g., radiation damage, damage from ultraviolet/infrared/laser beam, altitude sickness etc.), infectious diseases (viral infectious diseases of, for example, cytomegalovirus, influenza virus and herpesvirus, rickettsial infectious diseases, bacterial infectious diseases, etc.), toxemia (septicemia, septic shock, endotoxic shock, gram-negative septicemia, toxin shock syndrome, etc.), ear nose throat diseases (Meni ère's disease, tinnitus, dysgeusia, vertigo, balance disorder, deglutition disorder etc.), cutaneous diseases (keloid, hemangioma, psoriasis, etc.), dialysis hypotension, myasthenia gravis, systemic diseases such as chronic fatigue syndrome, and the like, particularly cardiac diseases (particularly catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like, in animals, particularly mammals (e.g., humans, monkeys, cats, pigs, horses, bovines, mice, rats, guinea pigs, dogs, rabbits etc.).
Herein, the concept of prophylaxis of cardiac diseases include treatment of prognosis of myocardial infarction, angina attack, cardiac bypass surgery, thrombolytic therapy, coronary revascularization and the like, and the concept of treatment of cardiac diseases include suppress of progress or severity of heart failure (including both contractile failure HFrEF, and heart failure HFpEF with maintained ejection fraction), and maintenance of cardiac function when performing non-drug therapies (e.g., an implantable defibrillator, resection of cardiac sympathetic nerve, catheter ablation, cardiac pacemaker, intra aortic balloon pumping, auxiliary artificial heart, Batista operation, cell transplantation, gene therapy, heart transplantation and the like) for severe heart failure/arrhythmia, and the like. When the compound of the present invention is applied to prophylaxis or treatment of heart failure, improvement of heart contractility or atonicity is expected to be achieved by short-ti me administration, without side effects such as pressure decrease, tachycardia, reduced renal blood flow and the like, regardless of differences in causative diseases such as ischemic cardiac disease, cardiomyopathy, hypertension and the like and symptoms such as contractile failure, diastolic failure and the like. Moreover, long-term improvement of prognosis (survival rate, readmission rate, cardiac event rate etc.) is expected to be achieved, in addition to short-term improvement of cardiac function. When the compound of the present invention is applied to prophylaxis or treatment of arrhythmia, improvement or remission of the symptom is expected to be achieved, regardless of differences in etiology and atrial/ventricular. In addition, long-term improvement of prognosis (survival rate, readmission rate, cardiac event rate etc.) is expected to be achieved.
While the dose of the compound of the present invention varies depending on the administration route, symptom and the like, when, for example, the compound is orally administered to a patient with cardiac disease (adult, body weight 40-80 kg, for example, 60 kg), it is, for example, 0.001-1000 mg/kg body weight/day, preferably 0.01-100 mg/kg body weight/day, more preferably 0.1-10 mg/kg body weight/day. This amount can be administered in 1 to 3 portions per day.
A medicament containing the compound of the present invention can be used alone or as a pharmaceutical composition containing the compound of the present invention and a pharmaceutically acceptable carrier according to a method known per se as a production method of a pharmaceutical preparation (e.g., the method described in the Japanese Pharmacopoeia etc.). A medicament containing the compound of the present invention can be safely administered in the form of, for example, tablet (including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal and the like), pill, powder, granule, capsule (including soft capsule, microcapsule), troche, syrup, liquid, emulsion, suspension, release control preparation (e.g., immediate-release preparation, sustained-release preparation, sustained-release microcapsule), aerosol, film (e.g., orally disintegrating film, oral mucosa-adhesive film), injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drip infusion, transdermal absorption type preparation, ointment, lotion, adhesive preparation, suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like, orally or parenterally (e.g., intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal administrations, and administration to the lesion).
As the aforementioned “pharmaceutically acceptable carrier”, various organic or inorganic carriers conventionally used as preparation materials (starting materials) can be used. For example, excipient, lubricant, binder, disintegrant and the like are used for solid preparations, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffer, soothing agent and the like are used for liquid preparations. Where necessary, preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can also be used.
Examples of the excipient include lactose, sucrose, D-manntol, starch, corn starch, crystal line cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binding agent include crystal line cellulose, white sugar, D-manntol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, carboxymethyl cellulose sodium and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-manntol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like; and the like.
Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-manntol and the like.
Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like. Examples of the soothing agent include benzyl alcohol and the like.
Examples of the preservative include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopheroland the like.
While the pharmaceutical composition varies according to the dosage form, administration method, carrier and the like, it can be produced according to a conventional method by adding the compound of the present invention in a proportion of generally 0.01-100% (w/w), preferably 0.1-95% (w/w), of the total amount of the preparation.
When the compound of the present invention is applied to each of the above-mentioned diseases, it can be used in appropriate combination with a pharmaceutical agent (hereinafter to be abbreviated as a concomitant drug) or a treatment method generally employed for such diseases. For heart failure, for example, it can be used concurrently with angiotensin converting enzyme (ACE) inhibitors (e.g., alacepril, captopril, cilazapril, delapril, enalapril, lisinopril, temocapril, trandolapril, quinapril, imidapril, benazepril, perendopril and the like), angiotensin II receptor antagonists (e.g., losartan, candesartan cillexetil, valsartan, termisartan, irbesartan, forasartan and the like), angiotensin II receptor antagonist/NEP inhibitor combination agent (entresto), β receptor antagonists (e.g., propranolol, nadolol, timolol, nipradilol, bunitorolol, indenolol, penbutolol, carteolol, carvedilol, pindolol, acebutolol, atenolol, bisoprolol, metoprolol, labetalol, amosulalol, arotinolol and the like), Ca antagonists (e.g., manidipine, nicardipine, nilvadipine, nisoldipine, nitrendipine, benidipine, amiodipine, aranidipine and the like), diuretics (e.g., thiazide diuretics such as benzyl hydrochlorothiazide, cyclopentiazide, ethiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, penfluthiazide, polythiazide, trichlormethiazide and the like; loop diuretics such as chlorthalidone, clofenamide, indapamide, mefruside, meticrane, sotolazone, tribamide, quinetazone, metolazone, furosemide, mefruside and the like; potassium retention diuretics such as spironolactone, triamterene and the like; and the like), digital is preparations (e.g., di gi toxin, digoxin, methyl digoxin, lanatoside C, proscillaridin and the like), ANP or BNP preparations, Casensitizers (e.g., pimobendan and the like), anti coagulants (e.g., warfarin, sodium citrate, activated protein C, tissue factor pathway inhibitor, anti thrombin III, dalteparin sodium, aragatroban, gabexate, sodium ozagrel, ethyl icosapentate, beraprost sodium, alprostadil, pentoxifyline, tisokinase, streptokinase and the like), anti arrhythmic drugs (e.g., sodium channel blockers such as quinidine, procainamide, disopyramide, ajmaline, cibenzoline, lidocain, diphenyl hydantoin, mexiletine, propafenone, flecainide, pilsicainide, phenytoin and the like; potassium channel blockers such as amiodarone and the like; calcium channel blockers such as verapamil, diltiazem and the like; and the like), PDE inhibitors (e.g., amrinone, milrinone, olprinone hydrochloride and the like), therapeutic drugs for diabetes (e.g., sulfonyl ureas such as tolbutamide, chlorpropamide, glyclopyramide, acetohexamide, tolazamide, glibenclamide, glybuzole and the like; biguanides such as metformin hydrochloride, buformin hydrochloride and the like; α-glucosidase inhibitors such as voglibose, acarbose and the like, insulin sensitizers such as pioglitazone, troglitazone and the like; SGLT2 inhibitors such as ipragliflozin, dapagliflozin, ruseogurifurojin, tofogliflozin, canagliflozin, empagliflozin and the like; insulin, glucagon; therapeutic drugs for diabetic complications such as epalrestat and the like; and the like), anti-obesity drugs and the like, and is al so applicable when an implantable artificial heart, an implantable defibrillator, a ventricular pacing, Batista operation, heart transplantation or cell transplantation is performed. In addition, for arrhythmia, for example, it can be used concurrently with other anti arrhythmic drugs (e.g., sodium channel blockers such as flecainide, quinidine, procainamide, disopyramide, ajmaline, cibenzoline, lidocain, diphenyl hydantoin, mexiletine, propafenone, pilsicainide, phenytoin and the like; potassium channel blockers such as amiodarone and the like; calcium channel blockers such as verapamil, diltiazem and the like, and the like) and B receptor antagonists, non-drug therapies (e.g., an implantable defibrillator, resection of cardiac sympathetic nerve, catheter ablation, cardiac pacemaker and the like). In addition, after acute myocardial infarction or during myocardial infarction prognosis, for example, the compound can be used in combination with anti thrombotics (e.g., anticoagulants such as heparin sodium, heparin calcium, warfarin and the like; thrombolytic agents such as urokinase and the like; anti-platelet drugs such as aspirin, sulfinpyrazone (anturan), dipyridamole (persantin), ticropidine (panaldine), cilostazol (pletal), clopidogrel and the like; and the like), angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, β receptor antagonists, therapeutic drugs for diabetes, therapeutic drugs for hyperlipidemia (e.g., HMG-COA reductase inhibitors such as pravastatine, fluvastatine, cerivastatine, atorvastatine and the like; fibrate drugs such as sinfibrate, clofibrate aluminum, clinofibrate, fenofibrate and the like; and the like), coronary vessel reconstructive surgery such as PTCA, CABG and the like; and the like. Furthermore, in chronic rheumatoid arthritis, for example, the compound can be used in combination with non-steroidal anti inflammatory agents (e.g., acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenyl butazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostat mesilate, ulinastatine, colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol, sodium aurothiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen, oxymorphone or a salt thereof and the like), immunomodulators or immunosuppressants (e.g., methotrexate, cyclosporine, tacrolimus, gusperimus, azathioprine, anti lymphocyte serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like), steroids (e.g., dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinoloneacetonide, fluocinonide, fluocinoloneacetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclometasone dipropionate, estriol and the like), p38 MAP kinase inhibitors, anti-TNF-α drugs (e.g., etanercept, infliximab, D2E7, CDP-571, PASS TNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-α anti body and the like), cyclooxygenase inhibitors (e.g., salicylic acid derivatives such as celecoxib, rofecoxib, aspirin and the like, MK-663, valdecoxib, SC-57666, tiracoxib, S-2474, diclofenac, indomethacin, Ioxoprofen and the like) and the like.
Moreover, it is possible to use the compound of the present invention in combination with biological products (e.g.: anti body, vaccine preparation and the like) when applying to the above-mentioned respective diseases, and it is also possible to apply the compound in combination with a gene therapy and the like as a combination therapy. As anti body and vaccine preparation, for example, vaccine preparation to angiotensin II, vaccine preparation to CETP, CETP anti body, TNF α anti body, anti body to other cytokine, amiloid β vaccine preparation, type 1 diabetes vaccine (DIAPEP-277 of Peptor Ltd. and the like), anti-HIV anti body, HIV vaccine preparation and the like, anti body and vaccine preparation to cytokine, renin-angiotensin enzyme and products thereof, anti body and vaccine preparation to enzyme and protein involved in blood lipid metabolism, anti body and vaccine preparation to enzyme and protein involved in blood coagulation-fibrinolytic system, anti body and vaccine preparation to protein involved in glucose metabolism and insulin resistance and the like can be mentioned. In addition, a combined use with biological products involved in growth factors such as GH, IGF and the like is possible. As a gene therapy, for example, a treatment method using a gene relating to cytokine, renin-angiotensin enzyme and products thereof, G protein, G protein-coupled receptor and phosphorylation enzyme thereof, a therapeutic method using a DNA decoy such as NFκB decoy and the like, a therapeutic method using anti sense, a therapeutic method using a gene relating to enzyme and protein involved in blood lipid metabolism (e.g., gene relating to metabolism, excretion and absorption of cholesterol or triglyceride or HDL-cholesterol or blood phospholipid, and the like), a therapeutic method using a gene relating to enzyme and protein (e.g., growth factors such as HGF, VEGF and the like, and the like) involved in angiogenetic therapy aiming at obstruction of peripheral vessel and the like, a therapeutic method using a gene relating protein involved in glucose metabolism and insulin resistance, anti sense to cytokine such as TNF-α and the like, and the like can be mentioned. In addition, it is possible to use the compound in combination with various organ regeneration methods such as heart regeneration, kidney regeneration, pancreas regeneration, blood vessel regeneration and the like, cell transplantation therapy using bone marrow cells (bone marrow mononuclear cell, bone marrow mesenchymal stem cell and the like), and artificial organs (artificial blood vessels and cardiac muscle cell sheet) using tissue engineering.
By combining the compound of the present invention and a concomitant drug, a superior effect such as
Hereinafter the compound of the present invention and a concomitant drug used in combination are referred to as the “combination agent of the present invention”.
When using the combination agent of the present invention, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or a pharmaceutical composition thereof and the concomitant drug or a pharmaceutical composition thereof can be administered to an administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be appropriately selected depending on an administration subject, administration route, disease, combination and the like.
The administration mode of the concomitant drug of the present invention is not particularly restricted, and it is sufficient that the compound of the present invention and the concomitant drug are combined in administration. Examples of such administration mode include the following methods:
(1) administration of a single preparation obtained by simultaneously processing the compound of the present invention and the concomitant drug, (2) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (for example, administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like.
The combination agent of the present invention exhibits low toxicity. For example, the compound of the present invention or (and) the aforementioned concomitant drug can be combined with a pharmacologically acceptable carrier according to the known method to prepare a pharmaceutical composition such as tablets (including sugar-coated tablet and film-coated tablet), powders, granules, capsules (including soft capsule), liquids, injections, suppositories, sustained-release agents, etc. These compositions can be administered safely orally or non-orally (e.g., topical, rectal, intravenous administration etc.). Injection can be administered intravenously, intramuscularly, subcutaneously, or by intraorgan administration or directly to the lesion.
Examples of the pharmacologically acceptable carriers usable for the production of a combination agent of the present invention, various organic or inorganic carrier substances conventionally used as preparation materials can be mentioned.
For solid preparations, for example, excipient, lubricant, binder and disintegrant can be used. For liquid preparations, for example, solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like can be used. Where necessary, an appropriate amount of conventional preservative, antioxidant, colorant, sweetening agent, adsorbent, wetting agent and the like can be used as appropriate.
Examples of the excipient include lactose, sucrose, D-manntol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binding agent include crystal line cellulose, white sugar, D-manntol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, carboxymethyl cellulose sodium and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-manntol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like; and the like.
Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin, D-manntol and the like.
Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates, citrates and the like.
Examples of the soothing agent include benzyl alcohol and the like.
Examples of the preservative include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfite, ascorbic acid, α-tocopheroland the like.
The mixing ratio of the compound of the present invention to the concomitant drug in the combination agent of the present invention can be appropriately selected depending on an administration subject, administration route, diseases and the like.
For example, the content of the compound of the present invention in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt %, preferably from about 0.1 to about 50 wt %, further preferably from about 0.5 to about 20 wt %, based on the preparation.
The content of the concomitant drug in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 0.01 to about 100 wt %, preferably from about 0.1 to about 50 wt %, further preferably from about 0.5 to about 20 wt %, based on the preparation.
The content of additives such as a carrier and the like in the combination agent of the present invention differs depending on the form of a preparation, and usually from about 1 to about 99.99 wt %, preferably from about 10 to about 90 wt %, based on the preparation.
When the compound of the present invention and a concomitant drug are separately formulated into preparations, the contents thereof are similar to the above.
The present invention is explained in detail in the following by referring to Examples, Experimental Examples and Formulation Examples, which are not to be construed as limitative, and the invention may be changed within the scope of the present invention.
In the following Examples, the “room temperature” generally means about 10° C. to about 35° C.. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. % means wt %, unless otherwise specified.
Unless particularly specified, the elution in column chromatography in Example was performed under observation by TLC (Thin Layer Chromatography). For TLC observation, 60F254 manufactured by Merck was used as a TLC plate, and the solvent used as an elution solvent for column chromatography was used as a developing solvent. For detection, a UV detector was adopted.
In silica gel column chromatography, NH means use of aminopropyl silane-bonded silica gel, and Diol means use of 3-(2,3-dihydroxypropoxy)propyl silane-bonded silica gel. In preparative HPLC (high performance liquid chromatography), C18 means use of octadecyl-bonded silica gel. The ratios indicated for elution solvents are volume mixing ratios, unless otherwise specified.
For 1H NMR analysis, ACD/SpecManager (trade name) software and the like were used. Peaks of a hydroxy group, an amino group and the like, which having very mild protons, may not be described.
MS was measured by LC/MS. As ionization method, ESI method or APCI method was used. The data indicates actual measured value (found). Generally, molecular ion peaks are observed, and may be observed as a fragment ion. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.
The unit of sample concentration (c) for optical rotation ([α]D) is g/100 mL.
Elemental analysis value (Anal.) was described as calculated value (Cal cd) and actual measured value (Found).
The peak by powder X-RAY diffraction in Example means the peak measured using Cu Kα-ray as a source by Ultima IV (Rigaku Corporation, Japan) at room temperature. The measurement conditions are as follows.
Electric pressure/Electric current: 40 kV/50 mA Scan speed: 6 degree/min
Scan range of 2 Theta: 2-35 degree
The crystallinity by powder X-RAY diffraction in Example was calculated by Hermans method.
In Examples, the following abbreviations are used.
To a mixture of 4-bromo-2-hydroxybenzonitrile (14.5 g), methyl(2R)-2-hydroxypropanoate (15.3 g), PPh3 (57.6 g) and THF (150 mL) was added 2.2M DEAD toluene solution (120 mL) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature overnight. The mixture was diluted with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (20.0 g). 1H NMR (300 MHZ, DMSO-d6) δ 7.72 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.6 Hz, 1H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 5.40 (q, J=6.8 Hz, 1H), 3.71 (s, 3H), 1.57 (d, J=6.8 Hz, 3H).
To a mixture of methyl(2S)-2-(5-bromo-2-cyanophenoxy) propanoate (72.0 g) in MeOH (200 mL) and THF (100 mL) was added NaBH4 (4.76 g) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 10 hr. The mixture was quenched with saturated aqueous NH4Cl solution at 0° C. and concentrated under reduced pressure. The residue was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (65.0 g). 1H NMR (300 MHZ, DMSO-d6) δ 7.66 (d, J=8.3 Hz, 1H), 7.60 (S, 1H), 7.28 (d, J=8.3 Hz, 1H), 4.97 (t, J=5.5 Hz, 1H), 4.65-4.78 (m, 1H), 3.54 (t, J=5.4 Hz, 2H), 1.24 (d, J=6.1 Hz, 3H).
To a solution of 4-bromo-2-(((2S)-1-hydroxypropan-2-yl)oxy) benzonitrile (21.0 g) and TEA (23 mL) in THF (100 mL) was added MsCl (8.9 mL) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 1 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was filtered through an NH silica gel pad and concentrated under reduced pressure to give the titled compound (26.0 g). 1H NMR (300 MHZ, DMSO-d6) δ 7.70 (d, J=8.3 Hz, 1H), 7.66 (d, J=1.6 Hz, 1H), 7.34 (dd, J=8.3, 1.7 Hz, 1H), 5.07 (td, J=6.2, 3.0 Hz, 1H), 4.42-4.48 (m, 1H), 4.31-4.39 (m, 1H), 3.22 (s, 3H), 1.33 (d, J=6.3 Hz 3H); m/z 335.2 [M+H]+.
To a mixture of (2S)-2-(5-bromo-2-cyanophenoxy) propyl methanesulfonate (25.0 g), 1H-tetrazole (10.5 g) and DMF (100 mL) was added K2CO3 (20.7 g) at room temperature and the mixture was stirred at 80° C. overnight. The mixture was diluted with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (10.3 g). 1H NMR (300 MHZ, CDCl3) δ 8.88-9.02 (m, 1H), 7.42 (d, J=8.2 Hz, 1H), 7.21 (dd, J=8.3, 1.7 Hz, 1H), 7.01 (d, J=1.6 Hz, 1H), 4.79-4.89 (m, 2H), 4.64-4.77 (m, 1H), 1.44-1.51 (m, 3H); MS m/z 308.2 [M+H]+.
To a mixture of 4-bromo-2-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}benzonitrile (5.00 g), (Bpin)2 (4.52 g), KOAc (7.93 g) and DMF (50 mL) was added Pd(dppf)Cl2—CH2Cl2 (594 mg). After being stirred under nitrogen atmosphere at 100° C. for 4 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (3.30 g).
MS m/z 356.2 [M+H]+.
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (120 mg), 4-(4, 4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-2-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}benzonitrile (666 mg) and CS2CO3 (508 mg) in THF (10 mL) and water (2.0 mL) was added Pd(tBu3P)2 (39.9 mg) and the mixture was stirred under nitrogen atmosphere at 70° C. for 10 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the titled compound (80.0 mg). 1H NMR (300 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.31 (d, J=7.4 Hz, 1H), 8.31 (s, 1H), 7.85-7.97 (m, 3H), 7.80 (d, J=7.2 Hz, 1H), 6.85 (s, 1H), 5.36-5.48 (m, 1H), 4.84-5.01 (m, 2H), 1.39 (d, J=6.1 Hz, 3H); MS m/z 347.2 [M+H]+.
To a mixture of 4-{pyrazolo[1,5-a]pyrimidin-5-yl}-2-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}benzonitrile (180 mg) in DMF (5.0 mL) was added NBS (101 mg) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 10 hr. The mixture was quenched with saturated aqueous NaHCO3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the crude titled compound. The crude product was used for the next step without further purification.
MS m/z 425.0 [M+H]+.
To a mixture of 4-{3-bromopyrazolo[1,5-a]pyrimidin-5-yl}-2-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}benzonitrile (220 mg) and [3-(methoxycarbonyl)phenyl]boronic acid (111 mg) in THF (20 mL) and water (4.0 mL) were added CS2CO3(252 mg) and Pd(tBu3P)2 (26.4 mg) and the mixture was stirred under nitrogen atmosphere at 80° C. for 14 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the titled compound (160 mg). 1H NMR (300 MHZ, DMSO-d6) δ 9.36-9.40 (m, 2H), 9.10 (s, CH), 8.96 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 8.05-8.14 (m, 2H), 7.84-8.02 (m, 3H), 7.60-7.70 (m, 1H), 5.45-5.59 (m, 1H), 4.87-5.07 (m, 2H), 3.93 (s, 3H), 1.44 (d, J=5.8 Hz, 3H); MS m/z 481.2 [M+H]+.
To a mixture of methyl 3-[5-(4-cyano-3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl) pyrazolo[1,5-a]pyrimidin-3-yl]benzoate (150 mg) in MeOH (10 mL) and THF (10 mL) was added 2M aqueous NaOH solution (0.16 mL). The mixture was stirred under nitrogen atmosphere at 50° C. for 10 hr. The mixture was acidified with 6M aqueous HCl solution (pH 2-3). The precipitate was collected by filtration and dried under reduced pressure to give the crude titled compound. The crude product was used for the next step without further purification.
MS m/z 467.2 [M+H]+.
To a mixture of 3-[5-(4-cyano-3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoic acid (145 mg), WSC-HCl (178 mg) and HOBt-H2O (125 mg) in DMF (5.0 mL) were added (2-aminoethyl) diethyl amine (72.2 mg) and TEA (0.13 mL). The mixture was stirred under nitrogen atmosphere for 16 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane), and then preparative HPLC (water/CH3CN containing 0.1% TFA). The desired fraction was azeotroped with toluene under reduced pressure. The residue was dissolved in MeOH (5.0 mL) and Amberlyst® A21 was added to the mixture. The mixture was stirred at room temperature for 15 min and then the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the titled compound (15.0 mg) as a yellow solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.34-9.40 (m, 2H), 8.91 (s, 1H), 8.87 (s, 1H), 8.46-8.53 (m, 1H), 8.35 (d, J=7.0 Hz, 1H), 8.15 (s, 1H), 8.03-8.08 (m, 1H), 7.87-7.98 (m, 2H), 7.74 (d, J=7.3 Hz, 1H), 7.55-7.62 (m, 1H), 5.52-5.65 (m, 1H), 4.87-5.06 (m, 2H), 3.33-3.46 (m, 4H), 2.52-2.67 (m, 4H), 1.43 (d, J=5.8 Hz, 3H), 0.98 (t, J=5.8 Hz, 6H); MS m/z 565.4 [M+H]+.
To a solution of 5-bromo-2-fluorophenol (74.0 g), methyl(2R)-2-hydroxypropanoate (80.7 g) and PPh3 (152 g) in THF (1000 mL) was added portionwise DIAD (118 g) at 0° C. The mixture was stirred under nitrogen atmosphere at 25° C. for 12 hr. The mixture was diluted with water (1000 mL) and extracted with EtOAc (800 mL×3). The combined organic layer was washed with brine (1000 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (85.0 g). 1H NMR (400 MHZ, CDCl3) δ 6.93-7.07 (m, 3H), 4.76 (q, J=7.2 Hz, 1H), 3.77 (s, 3H), 1.65 (d, J=6.8 Hz, 3H).
To a solution of methyl(2S)-2-(5-bromo-2-fluorophenoxy)propanoate (85.0 g) in THF (330 mL) and MeOH (660 mL) was added portionwise NaBH4 (17.4 g) at 0° C. over 0.5 hr. The mixture was stirred under nitrogen atmosphere at 25° C. for 12 hr. The mixture was diluted with saturated aqueous NH4Cl solution (500 mL) and water (500 mL) at 0° C. The organic solvent was removed under reduced pressure. The residue was extracted with EtOAc (400 mL×3). The combined organic layer was washed with brine (800 mL), dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (75.0 g). 1H NMR (400 MHZ, CDCl3) δ 7.16 (dd, J=7.2, 2.0 Hz, 1H), 7.04-7.10 (m, 1H), 6.92-6.97 (m, 1H), 4.42-4.46 (m, 1H), 3.74-3.80 (m, 2H), 2.58 (brs, 1H), 1.29 (d, J=6.0 Hz, 3H).
C) (2S)-2-(5-bromo-2-fluorophenoxy) propyl methanesulfonate
To a solution of (2S)-2-(5-bromo-2-fluorophenoxy)propan-1-ol (75.0 g) and TEA (60.9 g) in THF (1000 mL) was added dropwise
MsCl (48.3 g) at 0° C. The mixture was stirred under nitrogen atmosphere at 25° C. for 1 hr. The mixture was diluted with water (800 mL) and extracted with EtOAc (1000 mL×3). The combined organic layer was washed with brine (800 mL), dried over Na2SO4 and concentrated under reduced pressure to give the titled compound (97.0 g). 1H NMR (400 MHZ, CDCl3) δ 7.15 (dd, J=7.2, 2.4 Hz, 1H), 7.06-7.10 (m, 1H), 6.94-6.99 (m, 1H), 4.59-4.63 (m, 1H), 4.35-4.36 (m, 2H), 3.05 (s, 3H), 1.38 (d, J=6.4 Hz, 3H).
To a mixture of (2S)-2-(5-bromo-2-fluorophenoxy) propyl methanesulfonate (97.0 g) and 1H-tetrazole (41.5 g) in DMF (1000 mL) was added K2CO3 (82.0 g). The mixture was stirred at 80° C. for 12 hr. The mixture was diluted with saturated aqueous NH4Cl solution (600 mL) and extracted with EtOAc (200 mL×3). The combined organic layer was washed with brine (600 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (31.0 g). 1H NMR (400 MHZ, CDCl3) δ 8.80 (s, 1H), 7.05-7.17 (m, 1H), 6.90-7.04 (m, 2H), 4.75-4.85 (m, 1H), 4.65-4.74 (m, 1H), 4.54-4.64 (m, 1H), 1.38 (d, J=6.4 Hz, 3H).
A mixture of 1-[(2S)-2-(5-bromo-2-fluorophenoxy) propyl]-1H-tetrazole (29.3 g), (Bpin)2 (37.1 g), Pd(dppf)Cl2—CH2Cl2 (7.95 g) and KOAc (19.1 g) in DMSO (300 mL) was stirred under nitrogen atmosphere at 100° C. for 2 hr. The mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL×3). The combined organic layer was washed with brine (300 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (33.0 g). 1H NMR (400 MHZ, CDCl3) δ 8.44 (s, 1H), 7.33-7.35 (m, 1H), 7.26-7.29 (m, 1H), 6.94-6.99 (m, 1H), 4.89-4.93 (m, 2H), 4.70-4.76 (m, 1H), 1.35 (d, J=5.2 Hz, 3H), 1.27 (s, 12H).
The reaction and purification were performed according to Example 1 Step F to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.87 (s, 1H), 8.59 (d, J=7.3 Hz, 1H), 7.72 (dd, J=2.2, 8.0 Hz, 1H), 7.61 (ddd, J=2.2, 4.4, 8.5 Hz, 1H), 7.20 (dd, J=8.5, 10.5 Hz, 1H), 7.08 (d, J=7.3 Hz, 1H), 6.48 (s, 1H), 4.87-4.95 (m, 1H), 4.80-4.86 (m, 1H), 4.65-4.73 (m, 1H), 2.53 (s, 3H), 1.45 (d, J=6.2 Hz, 3H); MS m/z 354.3 [M+H]+.
The reaction and purification were performed according to Example 1 Step G to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.88 (s, 1H), 8.56 (d, J=7.3 Hz, 1H), 7.77 (dd, J=2.2, 7.9 Hz, 1H), 7.69 (ddd, J=2.2, 4.4, 8.6 Hz, 1H), 7.21 (dd, J=8.6, 10.5 Hz, 1H), 7.14 (d, J=7.4 Hz, 1H), 4.81-4.92 (m, 2H), 4.66-4.74 (m, 1H), 2.52 (s, 3H), 1.46 (d, J=6.2 Hz, 3H); MS m/z 432.2, 434.2 [M+H]+.
The reaction and purification were performed according to Example 1 Step H to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.43 (s, 1H), 9.14 (d, J=7.3 Hz, 1H), 8.01-8.10 (m, 1H), 7.97 (ddd, J=1.9, 4.4, 8.5 Hz, 1H), 7.71 (d, J=7.4 Hz, 1H), 7.53-7.64 (m, 2H), 7.42 (dd, J=8.7, 10.9 Hz, 1H), 7.22 (dd, J=3.6, 5.1 Hz, 1H), 5.07-5.18 (m, 1H), 4.89-4.98 (m, 1H), 4.79-4.89 (m, 1H), 2.66 (s, 3H), 1.41 (d, J=6.2 Hz, 3H); MS m/z 436.4 [M+H]+.
To a mixture of (2S)-2-(3-bromophenoxy)propan-1-ol (35.0 g), (Bpi n)2 (45.9 g) and KOAc (44.3 g) in toluene (100 mL) was added Pd(dppf)Cl2 (5.53 g). After being stirred under argon atmosphere at 100° C. for 3 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (36.0 g).
MS m/z 279.1 [M+H]+.
The reaction and purification were performed according to Example 1 Step F to give the titled compound.
MS m/z 270.4 [M+H]+.
The reaction and purification were performed according to Example 1 Step G to give the titled compound.
MS m/z 348.2 [M+H]+.
The reaction and purification were performed according to Example 1 Step H to give the titled compound.
MS m/z 352.1 [M+H]+.
To a mixture of (2S)-2-{3-[3-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidin-5-yl]phenoxy}propan-1-ol (1.80 g) and TEA (777 mg) in THF (10 mL) was added MsCl (644 mg). The mixture was stirred at room temperature for 30 min. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the crude titled compound (2.20 g). The crude product was used for the next step without further purification. MS m/z 430.1 [M+H]+.
To a mixture of (2S)-2-{3-[3-(thiophen-2-yl) pyrazolo[1,5-alpyrimidin-5-yl]phenoxy}propyl methanesulfonate (100 mg), K2CO3 (64.3 mg) in DMF (5.0 mL) was added 1, 2,4-triazole (32.1 mg). The mixture was stirred at 100° C. for 15 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the titled compound (75.0 mg) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.20 (d, J=7.4 Hz, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 7.97 (s, 1H), 7.92 (d, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.73 (d, J=7.4 Hz, 1H), 7.66 (dd, J=5.1, 3.6 Hz, 1H), 7.45-7.30 (m, 2H), 7.17 (dd, J=3.6, 1.1 Hz, 1H), 7.08 (dd, J=8.1, 2.2 Hz, 1H), 4.95-5.05 (m, 1H), 4.59 (d, J=5.6 Hz, 2H), 1.36 (d, J=6.2 Hz, 3H); MS m/z 403.1 [M+H]+.
To a solution of 1-[(2S)-2-[2-fluoro-5-(4, 4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenoxy]propyl]-1H-tetrazole (33.0 g) and 6-chloroimidazo[1,2-b]pyridazine (14.6 g) in THF (320 mL) and water (80 mL) were added CS2CO3 (61.8 g) and Pd(dppf) Cl2—CH2Cl2 (7.74 g). The mixture was stirred under nitrogen atmosphere at 70° C. for 1 hr. The mixture was diluted with water (300 mL) and extracted with EtOAc (400 mL×3). The combined organic layer was washed with brine (500 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the titled compound (13.0 g). 1H NMR (400 MHZ, CDCl3) δ 8.51 (s, 1H), 7.99-8.01 (m, 2H), 7.79 (s, 1H), 7.55-7.57 (m, 2H), 7.39 (d, J=8.0 Hz, 1H), 7.16-7.20 (m, 1H), 5.01-5.06 (m, 2H), 4.83-4.85 (m, 1H), 1.51 (d, J=6.0 Hz, 3H).
To a mixture of 1-[(2S)-2-(2-fluoro-5-{imidazo[1,2-b]pyridazin-6-yl}phenoxy) propyl]-1H-tetrazole (20.0 g) in DMF (300 mL) was added NBS (10.5 g). The mixture was stirred under nitrogen atmosphere at 25° C. for 12 hr. The mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL×3). The combined organic layer was washed with brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to give the titled compound (15.1 g). 1H NMR (400 MHZ, CDCl3) δ 8.54 (s, 1H), 7.99-8.01 (m, 1H), 7.80 (s, 1H), 7.62-7.64 (m, 2H), 7.46 (d, J=6.4 Hz, 1H), 7.21-7.23 (m, 1H), 5.04-5.07 (m, 2H), 4.84-4.86 (m, 1H), 1.52 (d, J=6.0 Hz, 3H).
Pd(PPh3)2Cl2 (4.33 mg) was added to a mixture of 1-[(2S)-2-(5-{3-bromoimidazo[1,2-b]pyridazin-6-yl}-2-fluorophenoxy) propyl]-1H-tetrazole (50.0 mg), (2-cyanophenyl)boronic acid (19.3 mg), CS2CO3 (77.8 mg) in THF (5.0 mL) and water (1.0 mL). The mixture was stirred under nitrogen atmosphere at 70° C. for 1 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized from EtOAc to give the titled compound (28.0 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.40 (s, 1H), 8.39 (d, J=5.8 Hz, 1H), 8.23 (s, 1H), 8.07-8.13 (m, 2H), 7.97 (d, J=5.8 Hz, 1H), 7.90-7.97 (m, 1H), 7.81 (dd, J=5.8, 3.0 Hz, 1H), 7.68-7.72 (m, 2H), 7.35-7.38 (m, 1H), 5.01-5.09 (m, 1H), 4.78-4.94 (m, 2H), 1.36 (d, J=6.0 Hz, 3H); MS m/z 441.2 [M+H]+.
To a mixture of 5-chloro-3H-imidazo[4,5-b]pyridine (3.90 g) and DI PEA (6.53 g) in DMF (40 mL) was added SEMCl (3.6 mL). After being stirred under nitrogen atmosphere at 80° C. for 14 hr, additional SEMCl (1.3 mL) was added to the mixture. After being stirred under nitrogen atmosphere at 80° C. for 4 hr, the mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give a mixture of the titled compounds (4.93 g). MS m/z 284.2 [M+H]+.
The reaction and purification were performed according to Example 284 Step D to give the titled compound.
MS m/z 470.3 [M+H]+.
To a mixture of a mixture of 1-[(2S)-2-[2-fluoro-5-(3-{[2-(trimethyl silyl) ethoxy]methyl}-3H-imidazo[4,5-b]pyridin-5-yl) phenoxy]propyl]-1H-tetrazole and 1-[(2S)-2-[2-fluoro-5-(1-{[2-(trimethyl silyl) ethoxy]methyl}-1H-imidazo[4,5-b]pyridin-5-yl) phenoxy]propyl]-1H-tetrazole (7.48 g) in THF (40 mL) was added 1M TBAF THF solution (14 mL). The mixture was stirred under nitrogen atmosphere at 80° C. for 4 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the crude titled compound (2.60 g). The crude product was used for the next step without further purification. 1H NMR (300 MHZ, DMSO-d6) δ 12.62-13.31 (m, 1H), 9.42 (s, 1H), 8.39-8.51 (m, 1H), 7.98-8.18 (m, 1H), 7.68-7.86 (m, 3H), 7.25-7.36 (m, 1H), 5.01-5.12 (m, 1H), 4.75-4.93 (m, 2H), 1.36 (d, J=6.1 Hz, 3H); MS m/z 340.3 [M+H]+.
A mixture of 1-[(2S)-2-(2-fluoro-5-{3H-imidazo[4,5-b]pyridin-5-yl}phenoxy) propyl]-1H-tetrazole (250 mg), 2-chloropyridine-3-carbonitrile (152 mg), K3PO4 (233 mg), tBuXPhos (62.5 mg) and Pd2(dba)3 (67.4 mg) in DMA (15 mL) was stirred under microwave irradiation at 100° C. for 1 hr. The mixture was quenched with water at room temperature and extracted with EtOAc.
The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) and silica gel column chromatography (NH, EtOAc/hexane) to give the titled compound (8.00 mg) as a white solid. 1H NMR (300 MHZ, CDCl3) δ 8.91 (s, 1H), 8.83 (dd, J=1.8, 4.9 Hz, 1H), 8.65 (s, 1H), 8.48 (dd, J=1.8, 7.8 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.97 (dd, J=2.1, 8.2 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.61 (dd, J=4.9, 7.9 Hz, 1H), 7.53-7.58 (m, 1H), 7.18 (dd, J=8.5, 11 Hz, 1H), 4.92 (dt, J=2.9, 6.6 Hz, 1H), 4.80-4.87 (m, 1H), 4.65-4.74 (m, 1H), 1.42 (d, J=6.2 Hz, 3H); MS m/z 442.3 [M+H]+.
The reaction and purification were performed according to Example 284 Step A to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 10.15 (s, 1H), 8.57 (d, J=8.5 Hz, 1H), 7.72 (s, 1H), 7.13 (d, J=8.5 Hz, 1H), 3.59 (s, 3H); MS m/z 279.0 [M+H]+.
The reaction and purification were performed according to Example 284 Step B and C to give the titled compound.
MS m/z 259.1 [M+H]+.
The reaction and purification were performed according to Example 284 Step D to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.41 (s, 1H), 8.83 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.24 (s, 1H), 8.08 (dd, J=2.0, 8.3 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.84 (ddd, J=2.0, 4.4, 8.6 Hz, 1H), 7.32 (dd, J=8.6, 11 Hz, 1H), 5.08-5.19 (m, 1H), 4.88-4.96 (m, 1H), 4.76-4.87 (m, 1H), 3.97 (s, 3H), 1.37 (d, J=6.1 Hz, 3H); MS m/z 445.2 [M+H]+.
To a mixture of 3-bromophenol (75.0 g), methyl(2R)-2-hydroxypropanoate (90.3 g) and PPh3 (171 g) in THF (1000 mL) was added DIAD (131 g) at 0° C. The mixture was stirred under nitrogen atmosphere at 20° C. for 12 hr. The mixture was diluted with water (1000 mL) and extracted with EtOAc (500 ml×3). The combined organic layer was washed with brine (1000 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with 15% EtOAc in PE (500 mL) and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (41.0 g). 1H NMR (400 MHZ, CDCl3) δ 7.09-7.19 (m, 2H), 7.04 (d, J=2.0 Hz, 1H), 6.75-6.81 (m, 1H), 4.74 (q, J=6.8 Hz, 1H), 3.77 (s, 3H), 1.61 (d, J=6.8 Hz, 3H).
To a mixture of methyl(2S)-2-(3-bromophenoxy)propanoate (41.0 g) in THF (200 mL) and MeOH (400 mL) was added portionwise NaBH4 (8.98 g) at 0° C. The mixture was stirred under nitrogen atmosphere at 20° C. for 12 hr. Saturated aqueous NH4Cl solution (500 mL) and water (500 mL) were added to the mixture at 0° C. The organic solvent was removed under reduced pressure. The residue was extracted with EtOAc (400 mL×3). The combined organic layer was washed with brine (800 mL), dried over Na2SO4 and concentrated under reduced pressure to give the titled compound (35.0 g). 1H NMR (400 MHZ, CDCl3) δ 7.01-7.16 (m, 3H), 6.80-6.90 (m, 1H), 4.41-4.52 (m, 1H), 3.64-3.75 (m, 2H), 2.06 (brs, 1H), 1.26 (d, J=6.0 Hz, 3H).
To a mixture of (2S)-2-(3-bromophenoxy)propan-1-ol (64.0 g) and TEA (56.1 g) in THF (700 mL) was added dropwise MsCl (44.4 g) at 0° C. in 0.5 hr. The mixture was stirred under nitrogen atmosphere at 20° C. for 1 hr. The mixture was diluted with water (1000 mL) and extracted with EtOAc (500 mL×3). The combined organic layer was washed with brine (1000 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the titled compound (82.0 g). 1H NMR (400 MHZ, CDCl3) δ 7.06-7.19 (m, 3H), 6.81-6.92 (m, 1H), 4.59-4.70 (m, 1H), 4.25-4.36 (m, 2H), 3.03 (s, 3H), 1.36 (d, J=6.0 Hz, 3H).
To a mixture of (2S)-2-(3-bromophenoxy) propyl methanesulfonate (82.0 g) in DMF (800 mL) were added K2CO3 (73.3 g) and 1H-tetrazole (37.2 g). The mixture was stirred under nitrogen atmosphere at 80° C. for 12 hr. The mixture was concentrated under reduced pressure. The residue was poured into water (1500 mL) and extracted with EtOAc (800 mL×3). The combined organic layer was washed with brine (1000 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (72.0 g). 1H NMR (400 MHZ, CDCl3) δ 8.71 (s, 1H), 7.09-7.18 (m, 2H), 6.95-7.03 (m, 1H), 6.67-6.73 (m, 1H), 4.66-4.79 (m, 2H), 4.53-4.65 (m, 1H), 1.36 (d, J=6.0 Hz, 3H).
To a mixture of 1-[(2S)-2-(3-bromophenoxy) propyl]-1H-tetrazole (36.0 g), (Bpin)2 (48.4 g) and KOAc (25.0 g) in DMSO (500 mL) was added Pd(dppf)Cl2—CH2Cl2 (10.4 g). The mixture was stirred at 100° C. for 2 hr. The mixture was diluted with water (2000 mL) and extracted with EtOAc (1000 mL×3). The combined organic layer was washed with water (1000 mL×2), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (63.0 g). 1H NMR (400 MHZ, CDCl3) δ 8.75 (s, 1H), 7.43 (d, J=7.2 Hz, 1H), 7.25-7.34 (m, 2H), 6.90-6.97 (m, 1H), 4.74-4.86 (m, 2H), 4.56-4.65 (m, 1H), 1.30-1.42 (m, 15H); MS m/z 331.0 [M+H]+.
To a solution of 1-[(2S)-2-[3-(4, 4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenoxy]propyl]-1H-tetrazole (11.0 g), CS2CO3 (21.7 g) and 6-chloroimidazo[1,2-b]pyridazine (5.12 g) in THF (100 mL) and water (25 mL) was added Pd(dppf)Cl2—CH2Cl2 (2.72 g). The mixture was stirred under nitrogen atmosphere at 70° C. for 1 hr. The mixture was diluted with water (100 mL) and extracted with EtOAc (150 mL×3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (8.00 g). 1H NMR (400 MHZ, CDCl3) δ 8.78 (s, 1H), 7.99-8.05 (m, 2H), 7.83 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.39-7.46 (m, 3H), 6.93 (dd, J=8.4, 2.8 Hz, 1H), 4.87-4.93 (m, 1H), 4.79-4.83 (m, 1H), 4.62-4.67 (m, 1H), 1.43 (d, J=6.0 Hz, 3H).
To a solution of 1-[(2S)-2-(3-{imidazo[1,2-b]pyridazin-6-yl}phenoxy) propyl]-1H-tetrazole (8.00 g) in DMF (70 mL) was added NBS (4.43 g). The mixture was stirred under nitrogen atmosphere at 25° C. for 12 hr. The mixture was diluted with water (60 mL) and extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to give the titled compound (8.75 g) 1H NMR (400 MHZ, CDCl3) δ 8.79 (s, 1H), 7.98 (d, J=9.6 Hz, 1H), 7.78 (s, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.47-7.52 (m, 2H), 7.41 (t, J=8.0 Hz, 1H), 6.92-6.94 (dd, J=8.4, 2.0 Hz, 1H), 4.85-4.91 (m, 1H), 4.78-4.82 (m, 1H), 4.62-4.68 (m, 1H), 1.43 (d, J=6.4 Hz, 3H).
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.76 (s, 1H), 8.18 (s, 1H), 8.13 (d, J=9.6 Hz, 1H), 7.96 (d, J=7.6 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.74-7.79 (m, 1H), 7.51-7.58 (m, 4H), 7.41 (t, J=8.0 Hz, 1H), 6.94 (dd, J=8.4, 2.4 Hz, 1H), 4.86-4.90 (m, 1H), 4.76-4.83 (m, 1H), 4.60-4.70 (m, 1H), 1.41 (d, J=6.0 Hz, 3H). MS m/z 423.2 [M+H]+.
The reaction and purification were performed according to Example 57 Step A to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.26 (d, J=1.6 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H), 7.29-7.30 (m, 1H), 4.75 (q, J=6.8 Hz, 1H), 3.74 (s, 3H), 1.60 (d, J=6.8 Hz, 3H).
The reaction and purification were performed according to Example 57 Step B to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.25 (d, J=1.6 Hz, 1H), 8.22 (d, J=2.8 Hz, 1H), 7.40-7.41 (m, 1H), 4.47-4.54 (m, 1H), 3.75-3.77 (m, 2H), 2.52 (brs, 1H), 1.29 (d, J=6.4 Hz, 3H).
The reaction and purification were performed according to Example 57 Step C to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.29 (d, J=1.6 Hz, 1H), 8.22 (d, J=2.4 Hz, 1H), 7.39-7.40 (m, 1H), 4.66-4.70 (m, 1H), 4.32 (d, J=5.2 Hz, 2H), 3.02 (s, 3H), 1.37 (d, J=6.4 Hz, 3H).
The reaction and purification were performed according to Example 57 Step D to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.69 (s, 1H), 8.31 (d, J=1.6 Hz, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.26 (s, 1H), 4.73-4.82 (m, 2H), 4.58-4.63 (m, 1H), 1.40 (d, J=6.0 Hz, 3H).
The reaction and purification were performed according to Example 57 Step E and Example 121 Step A to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.76-8.82 (m, 2H), 8.37 (d, J=2.7 Hz, 1H), 8.03-8.12 (m, 2H), 7.85 (s, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.47 (d, J=9.6 Hz, 1H), 4.94-5.02 (m, 1H), 4.81-4.88 (m, 1H), 4.65-4.73 (m, 1H), 1.49 (d, J=6.2 Hz, 3H); MS m/z 323.1 [M+H]+.
The reaction and purification were performed according to Example 121 Step B to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.85 (d, J=1.4 Hz, 1H), 8.78 (s, 1H), 8.38 (d, J=2.8 Hz, 1H), 8.06 (d, J=9.4 Hz, 1H), 7.84 (s, 1H), 7.78-7.83 (m, 1H), 7.53 (d, J=9.5 Hz, 1H), 4.94-5.03 (m, 1H), 4.80-4.88 (m, 1H), 4.65-4.74 (m, 1H), 1.50 (d, J=6.1 Hz, 3H); MS m/z 401.1, 403.1 [M+H]+.
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.47 (s, 1H), 8.86 (d, J -1.7 Hz, 1H), 8.45 (d, J=9.4 Hz, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.27 (s, 1H), 8.09-8.14 (m, 2H), 8.04 (d, J=9.5 Hz, 1H), 7.91-7.99 (m, 2H), 7.70 (dt, J=1.2, 7.7 Hz, 1H), 5.13 (dt, J=3.6, 6.6 Hz, 1H), 4.87-4.95 (m, 1H), 4.76-4.85 (m, 1H), 1.35 (d, J=6.2 Hz, 3H); MS m/z 424.2 [M+H]+.
To a mixture of 1-[(2S)-2-(5-{3-bromoimidazo[1,2-b]pyridazin-6-yl}-2-fluorophenoxy) propyl]-1H-tetrazole (400 mg), 2-chloropyridine-3-carbonitrile (238 mg) and CsF (726 mg) in MeOH (10 mL) and water (1.0 mL) was added (Bpin)2 (485 mg). After being stirred at room temperature for 10 min, a mixture of Pd(0Ac) 2 (21.4 mg) and cataCXium® A (68.5 mg) in toluene (0.50 mL) was added to the mixture. The mixture was stirred under nitrogen atmosphere at 60° C. for 30 min and then at 90° C. for 14 hr. The insoluble material was removed by filtration and washed with MeOH and THF. The filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane), and then preparative HPLC (water/CH3CN containing 0.1% TFA). The desired fraction was neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized from EtOAc/IPE to give the titled compound (42.0 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.40 (s, CH), 9.05 (dd,J-1.74, 4.86 Hz, 1H), 8.59 (dd, J=1.70, 7.93 Hz, 1H), 8.43 (d, J=9.63 Hz, 1H), 8.31 (s, 1H), 8.03 (d, J=9.63 Hz, 1H), 7.86 (dd, J=2.02, 8.16 Hz, 1H), 7.68-7.77 (m, 2H), 7.39 (dd, J=8.57, 11.05 Hz, 1H), 5.05 (dt, J=3.76, 6.56 Hz, 1H), 4.77-4.96 (m, 2H), 1.37 (d, J=6.14 Hz, 3H); MS m/z 442.1 [M+H]+.
To a solution of 3-bromopyridine-4-carbonitrile (200 mg) in toluene (5.0 mL) were added hexabutyl di tin (1.27 g) and Pd(PPh3)4 (126 mg). The mixture was stirred under nitrogen atmosphere for 110° C. for 16 hr. The mixture was concentrated under reduced pressure to give the crude titled compound (860 mg). The crude product was used for next step without purification.
A mixture of 3-(tri butyl stannyl)pyridine-4-carbonitrile (196 mg), 1-[(2S)-2-(3-{3-bromoimidazo[1,2-b]pyridazin-6-yl}phenoxy) propyl]-1H-tetrazole (200 mg), Pd(PPh3)4 (58.0 mg) and 1,4-di oxane (5.0 mL) was stirred under nitrogen atmosphere at 100° C. for 16 hr. The mixture was diluted with saturated aqueous KF solution (50 mL) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (water/CH3CN containing 0.05% NH3—H2O). Most of CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the titled compound (54.0 mg) as a light yellow solid. 1H NMR (400 MHZ, CDCl3) δ 9.36 (s, 1H), 8.82 (d, J=5.2 Hz, 1H), 8.78 (s, 1H), 8.28 (s, 1H), 8.16 (d, J=9.6 Hz, 1H), 7.79 (d, J=4.8 Hz, 1H), 7.60 (d, J=9.6 Hz, 1H), 7.49-7.55 (m, 2H), 7.36-7.45 (m, 1H), 6.91-6.98 (m, 1H), 4.86-4.90 (m, 1H), 4.76-4.83 (m, 1H), 4.61-4.70 (m, 1H), 1.42 (d, J=6.0 Hz, 3H). MS m/z 424.2 [M+H]+.
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (400 MHZ, DMSO-d6) δ 12.06 (brs, 1H), 9.48 (s, 1H), 8.98 (dd, J=7.2, 2.0 Hz, 1H), 8.71 (s, 1H), 8.31 (d, J=9.6 Hz, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.61 (s, 1H), 7.40-7.52 (m, 2H), 7.09 (dd, J=8.4, 2.4 Hz, 1H), 6.51 (t, J=7.2 Hz, 1H), 5.01-5.11 (m, 1H), 4.81-4.91 (m, 1H), 4.69-4.79 (m, 1H), 1.36 (d, J=6.4 Hz, 3H); MS m/z 415.3 [M+H]+.
To a solution of 3-[6-(3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl)imidazo[1,2-b]pyridazin-3-yl]-1,2-dihydropyridin-2-one (100 mg) in DMF (3.0 mL) were added K2CO3 (67.0 mg) and iodomethane (41.0 mg). The mixture was stirred at 30° C. for 12 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (water/CH3CN containing 0.225% FA). The eluent was concentrated under reduced pressure to remove organic solvent. The residual aqueous solution was lyophilized to give the titled compound (18.0 mg) as a yellow solid. 1H NMR (400 MHZ, DMSO-d6) δ 9.48 (s, 1H), 8.96 (dd, J=7.2, 2.0 Hz, 1H), 8.71 (s, 1H), 8.30 (d, J=9.6 Hz, 1H), 7.81-7.95 (m, 2H), 7.68 (d, J=7.6 Hz, 1H), 7.60 (s, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 6.54 (t, J=7.2 Hz, 1H), 5.00-5.11 (m, 1H), 4.81-4.91 (m, 1H), 4.69-4.79 (m, 1H), 3.61 (s, 3H), 1.36 (d, J=6.0 Hz, 3H); MS m/z 429.2 [M+H]+.
The reaction and purification were performed according to Example 253 Step B to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 7.53 (d, J=7.6 Hz, 1H), 6.07 (d, J=7.6 Hz, 1H), 3.99 (s, 3H), 3.55 (s, 3H); MS m/z 164.8 [M+H]+.
To a solution of 4-methoxy-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.10 g) in THF (3.0 mL) was added 5% aqueous NaOH solution (12 mL). The mixture was stirred at 110° C. for 2 hr. The mixture was cooled to room temperature and acidified with 2N aqueous HCl solution (pH 3). The resulting precipitate was collected by filtration and dried in air to give the titled compound (640 mg). 1H NMR (400 MHZ, DMSO-d6) δ 12.58 (brs, 1H), 7.82 (d, J=7.6 Hz, 1H), 6.02 (d, J=7.6 Hz, 1H), 3.36 (s, 3H); MS m/z 150.8 [M+H]+.
To a solution of 4-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (440 mg) in DMF (8.0 mL) was added POBr3 (1.68 g). The mixture was stirred at 110° C. for 3 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the titled compound (520 mg). 1H NMR (400 MHZ, CDCl3) δ 7.40 (d, J=7.2 Hz, 1H), 6.50 (d, J=7.2 Hz, 1H), 3.58 (s, 3H); MS m/z 214.8 [M+H]+.
The reaction and purification were performed according to Example 251 Step A to give the crude titled compound. The crude product was used for the next step without further purification. MS m/z 425.1 [M+H]+.
The reaction and purification were performed according to Example 251 Step B to give the titled compound. 1H NMR (400 MHZ, DMSO-d6) δ 9.48 (s, 1H), 8.46 (s, 1H), 8.42 (d, J=9.6 Hz, 1H), 8.23 (d, J=7.2 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.63 (s, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.15 (d, J=6.8 Hz, 1H), 7.10 (d, J=10.4 Hz, 1H), 4.95-5.05 (m, 1H), 4.81-4.91 (m, 1H), 4.69-4.79 (m, 1H), 3.58 (s, 3H), 1.34 (d, J=6.0 Hz, 3H); MS m/z 454.2 [M+H]+.
To a stirred solution of 5-bromopyrimidine (4.00 g) in CHCl3 (40 mL) was added a solution of mCPBA (6.13 g) in DCM (40 mL) at 0° C. The mixture was stirred at 60° C. for 8 hr. The mixture was diluted with saturated aqueous NaHCO3 solution (150 mL) and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
The residue was triturated with 15% EtOAc in PE (50 mL). The resulting precipitate was collected by filtration and dried to give the tilted compound (1.40 g). 1H NMR (400 MHZ, CDCl3) δ 8.89 (s, 1H), 8.50-8.52 (m, 1H), 8.28 (d, J=1.6 Hz, 1H).
To a mixture of 5-bromopyrimidine N-oxide (1.60 g), CH3CN (30 mL) and TEA (3.70 g) was added trimethyl silyl cyanide (1.81 g). The mixture was stirred under nitrogen atmosphere at 25° C. for 2 hr. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (770 mg). 1H NMR (400 MHZ, CDCl3) δ 9.26 (s, 1H), 9.08 (s, 1H).
To a solution of 1-[(2S)-2-(3-{3-bromoimidazo[1,2-b]pyridazin-6-yl}phenoxy) propyl]-1H-tetrazole (100 mg) in toluene (3.0 mL) was added hexabutyl di tin (290 mg). The mixture was degassed with nitrogen gas and then Pd(PPh3)4 (29.0 mg) was added to the mixture. The mixture was stirred under nitrogen atmosphere at 110° C. for 16 hr. The mixture was concentrated under reduced pressure to give the crude titled compound (200 mg). The crude product was used for the next step without purification. MS m/z 612.1 [M+H]+.
A solution of 5-bromopyrimidine-4-carbonitrile (46.0 mg), 1-[(2S)-2-{3-[3-(tri butyl stannyl)imidazo[1,2-b]pyridazin-6-yl]phenoxy}propyl]-1H-tetrazole (200 mg) and Pd(PPh3)2Cl2 (18.0 mg) in 1,4-di oxane (5.0 mL) was stirred under nitrogen atmosphere at 100° C. for 12 hr. The mixture was diluted with saturated aqueous KF solution (100 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE), and then preparative HPLC (water/CH3CN containing 0.05% NH3—H2O). Most of CH3CN was removed under reduced pressure and the remaining solvent was removed by lyophilization to give the titled compound (3.0 mg) as an off-white solid. 1H NMR (400 MHZ, DMSO-d6) δ 9.63 (s, 1H), 9.35 (s, 1H), 8.75 (s, 1H), 8.40 (s, 1H), 8.20 (d, J=9.6 Hz, 1H), 7.65 (d, J=9.6 Hz, 1H), 7.50-7.55 (m, 1H), 7.46-7.50 (m, 1H), 7.39-7.46 (m, 1H), 6.96 (dd, J=7.6, 2.0 Hz, 1H), 4.84-4.94 (m, 1H), 4.78-4.84 (m, 1H), 4.61-4.70 (m, 1H), 1.46 (d, J=6.4 Hz, 3H); MS m/z 425.2 [M+H]+.
To a mixture of 3-[6-(4-fluoro-3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl)imidazo[1,2-b]pyridazin-3-yl]pyridine-4-carbonitrile (44.0 mg) in CH3CN (4.0 mL) was added mCPBA (24.0 mg) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 14 hr (Additional mCPBA was added to the mixture until the starting material was consumed). The mixture was quenched with Na2S203-5H2O at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (water/CH3CN containing 0.1% TFA). The desired fraction was neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to give the titled compound (20.0 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.40 (s, 1H), 9.08 (d, J=1.47 Hz, 1H), 8.42-8.50 (m, 2H), 8.39 (s, 1H), 8.16 (d, J=6.79 Hz, 1H), 8.05 (d, J=9.63 Hz, 1H), 7.85 (dd, J=2.15, 8.21 Hz, 1H), 7.72 (ddd, J=2.16, 4.42, 8.55 Hz, 1H), 7.42 (dd, J=8.62, 11.00 Hz, 1H), 5.05-5.15 (m, 1H), 4.87-4.95 (m, 1H), 4.77-4.86 (m, 1H), 1.38 (d, J=6.33 Hz, 3H); MS m/z 458.1 [M+H]+.
In a sealed tube, a mixture of 1-[(2S)-2-(3-{3-bromoimidazo[1,2-b]pyridazin-6-yl}phenoxy) propyl]-1H-tetrazole (200 mg), 2-chloropyridine-3-carbonitrile (206 mg), cataCXium® A (71.6 mg), CsF (226 mg), Pd(0Ac)2 (22.4 mg) and (Bpin)2 (253 mg) in THF (5.0 mL) and water (0.50 mL) was stirred at 120° C. for 4 hr. The mixture was diluted with EtOAc (50 mL) and water (10 mL) and then the insoluble material was removed by filtration. The organic layer was separated, washed with aqueous NH4Cl solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/EtOAc) and crystallized from EtOAc four times to give the titled compound (72.0 mg) as a white solid. 1H NMR (300 MHZ, CDCl3) δ 9.00-8.94 (m, 1H), 8.89-8.86 (m, 1H), 8.36-8.33 (m, 1H), 8.31-8.24 (m, 1H), 8.18-8.11 (m, 1H), 8.06-7.99 (m, 1H), 7.87-7.79 (m, 1H), 7.56-7.49 (m, 2H), 7.25-7.17 (m, 1H), 4.95-4.81 (m, 3H), 4.75-4.63 (m, 1H), 1.44 (d, J=6.4 Hz, 3H); MS m/z 424.2 [M+H]+.
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 9.29 (d, J=0.73 Hz, 1H), 8.87 (s, 1H), 8.82-8.86 (m, 1H), 8.23-8.28 (m, 1H), 8.12-8.20 (m, 1H), 7.77-7.83 (m, 1H), 7.62-7.67 (m, 1H), 7.49-7.59 (m, 2H), 7.18-7.25 (m, 1H), 4.80-4.91 (m, 2H), 4.65-4.75 (m, 1H), 1.45 (d, J=6.24 Hz, 3H); MS m/z 442.2 [M+H]+.
To a cold mixture of 2,6-di bromo-3-nitropyridine (3.02 g) and 2-aminopyridine-3-carbonitrile (1.27 g) in THF (30 mL) was added portionwise 60% NaH in oil (638 mg) at 5° C. The mixture was stirred under argon atmosphere at room temperature for 1 hr. The mixture was poured into water at 0° C. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was crystallized from THE/EtOAc to give the titled compound (2.43 g). 1H NMR (300 MHZ, CDCl3) δ 10.07-10.19 (m, 1H), 8.62-8.68 (m, 1H), 8.32-8.41 (m, 1H), 8.03-8.10 (m, 1H), 7.28-7.34 (m, 1H), 7.17-7.22 (m, 1H); MS m/z 320.9 [M+H]+.
B) 2-[(3-amino-6-bromopyridin-2-yl)amino]pyridine-3-carbonitrile
To a mixture of 2-[(6-bromo-3-nitropyridin-2-yl)amino]pyridine-3-carbonitrile (2.42 g) and saturated aqueous NH4Cl solution (15 mL) in THF (20 mL) and EtOH (10 mL) was added iron powder (8.43 g). The mixture was stirred at 50° C. for 4 hr.
The mixture was filtered through a Celite® pad and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the crude titled compound (2.20 g). The crude product was used for the next step without further purification. 1H NMR (300 MHZ, CDCl3) δ 8.32-8.38 (m, 1H), 7.80-7.89 (m, 1H), 7.16-7.25 (m, 2H), 7.00-7.08 (m, 1H), 6.86-6.92 (m, 1H), 4.00-4.09 (m, 2H); MS m/z 290.9 [M+H]+.
A mixture of 2-[(3-amino-6-bromopyridin-2-yl)amino]pyridine-3-carbonitrile (2.18 g), triethyl orthoformate (55.5 g) and TsOH-H2O (570 mg) in THF (7.0 mL) was stirred at 100° C. for 1 hr. The mixture was concentrated under reduced pressure at 50-60° C. The residue was dissolved in hot water (100 mL), EtOAc (100 mL) and THF (100 mL). The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure and crystallized from EtOAc to give the titled compound (1.98 g). 1H NMR (300 MHZ, DMSO-d6) δ 9.00 (dd, J=1.8, 4.9 Hz, 1H), 8.94 (s, 1H), 8.74 (dd, J=1.8, 7.8 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.89 (dd, J=5.0, 7.9 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H); MS m/z 300.0 [M+H]+.
To a mixture of 2-{5-bromo-3H-imidazo[4,5-b]pyridin-3-yl}pyridine-3-carbonitrile (200 mg), 1-[(2S)-2-[3-(4, 4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenoxy]propyl]-1H-tetrazole (264 mg) and CS2CO3 (325 mg) in THF (5.0 mL) and water (1.0 mL) was added Pd(dppf) Cl2 (54.5 mg). The mixture was stirred under microwave irradiation at 100° C. for 1 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) and crystallized from EtOAc to give the titled compound (112 mg) as an off-white solid. 1H NMR (300 MHZ, CDCl3) δ 8.79-8.87 (m, 2H), 8.64-8.68 (m, 1H), 8.44-8.50 (m, 1H), 8.19-8.27 (m, 1H), 7.84-7.90 (m, 1H), 7.74-7.81 (m, 1H), 7.56-7.64 (m, 2H), 7.33-7.43 (m, 1H), 6.87-6.96 (m, 1H), 4.88-5.05 (m, 1H), 4.76-4.86 (m, 1H), 4.61-4.71 (m, 1H), 1.39 (d, J=6.2 Hz, 3H); MS m/z 424.2 [M+H]+.
2N aqueous HCl solution (0.40 mL) was added to a suspension of 4-fluoro-2-[6-(5-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl]benzonitrile (157 mg) in EtOH (5.0 mL) at room temperature. The mixture was slightly warmed for a while. The resulting mixture was cooled to room temperature and then concentrated under reduced pressure to give the titled compound (139 mg) as a light yellow solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.47 (s, 1H), 8.89 (d, J=1.7 Hz, 1H), 8.50 (d, J=9.5 Hz, 1H), 8.45 (d, J=2.7 Hz, 1H), 8.37 (s, 1H), 8.22 (dd, J=5.7, 8.8 Hz, 1H), 8.16-8.08 (m, 2H), 8.08-8.04 (m, 1H), 7.59 (dt, J=2.7, 8.5 Hz, 1H), 5.16 (dt, J=3.2, 6.3 Hz, 1H), 4.96-4.89 (m, 1H), 4.85-4.77 (m, 1H), 1.36 (d, J=6.1 Hz, 3H); MS m/z 442.2 [M+H]+.
To a mixture of 6-methoxypyridine-3-carbonitrile (500 mg) in THF (10 mL) was added 2M lithium diisopropyl amide heptane solution (2.2 mL) at −78° C. After being stirred at −78° C. for 30 min, triisopropyl borate (1.40 g) was added to the mixture. The mixture was stirred at 20° C. for 30 min. The mixture was quenched with water and washed with PE. The aqueous layer was adjusted to pH 6 by addition of 1M aqueous HCl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the titled compound (422 mg).
MS m/z 179.0 [M+H]+.
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.78 (s, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J=9.6 Hz, 1H), 7.56-7.62 (m, 1H), 7.48-7.55 (m, 1H), 7.45 (t, J=8.0 Hz, 1H), 6.98 (dd, J=8.4, 2.0 Hz, 1H), 4.89-4.99 (m, 1H), 4.75-4.87 (m, 1H), 4.61-4.72 (m, 1H), 4.08 (s, 3H), 1.45 (d, J=6.0 Hz, 3H); MS m/z 454.3 [M+H]+.
To a mixture of 2-amino-4-fluorobenzonitrile (1.05 g) and 2, 6-di bromo-3-nitropyridine (2.60 g) in THF (20 mL) was added 60% NaH in oil (1.10 g) at 5° C. The mixture was stirred under nitrogen atmosphere at room temperature for 1 hr. The mixture was quenched with saturated aqueous NH4Cl solution (50 mL) at 5° C. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the titled compound (1.29 g). 1H NMR (300 MHZ, CDCl3) δ 10.97-10.83 (m, 1H), 8.43 (d, J=8.5 Hz, 1H), 8.39-8.30 (m, 1H), 7.73-7.64 (m, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.01-6.91 (m, 1H).
B) 2-[(3-amino-6-bromopyridin-2-yl)amino]-4-fluorobenzonitrile
To a mixture of 2-[(6-bromo-3-nitropyridin-2-yl)amino]-4-fluorobenzonitrile (1.28 g) and saturated aqueous NH4Cl solution (15 mL) in THF (10 mL) and EtOH (5.0 mL) was added iron (4.23 g). The mixture was stirred at 50° C. for 3 hr. The mixture was filtered through a Celite® pad and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the crude titled compound (1.16 g). The crude product was used for the next step without further purification.
MS m/z 307.0 [M+H]+.
A mixture of 2-[(3-amino-6-bromopyridin-2-yl)amino]-4-fluorobenzonitrile (1.16 g), triethyl orthoformate (16.7 g) and TsOH-H2O (0.290 g) in THF (4.0 mL) was stirred at 100° C. for 1 hr. The mixture was concentrated under reduced pressure at 50-60° C.
The residue was dissolved in hot water and EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (0.440 g). 1H NMR (300 MHZ, CDCl3) δ 8.40-8.36 (m, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.96-7.88 (m, 1H), 7.56 (s, 2H), 7.40-7.31 (m, 1H).
The reaction and purification were performed according to Example 284 Step D to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.77 (s, 1H), 8.45 (s, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.06-7.95 (m, 1H), 7.84-7.76 (m, 1H), 7.70-7.56 (m, 3H), 7.43-7.31 (m, 2H), 6.94-6.83 (m, 1H), 4.96-4.74 (m, 2H), 4.69-4.58 (m, 1H), 1.41 (d, J=6.1 Hz, 3H); MS m/z 441.1 [M+H]+.
The reaction and purification were performed according to Example 326 Step B to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.78 (d, J=2.7 Hz, 1H), 8.73 (s, 1H), 6.90 (d, J=2.7 Hz, 1H), 5.03 (ttd, J=3.3, 6.5, 10.0 Hz, 1H), 4.86-4.65 (m, 2H), 1.51 (d, J=6.2 Hz, 3H); MS m/z 241.1 [M+H]+.
A mixture of 3-chloro-5-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}pyridazine (70.0 mg), 6-chloroimidazo[1, 2-b]pyridazine (100 mg), CsF (314 mg), Pd(0Ac)2 (18.6 mg), cataCXium® A (59.5 mg) and (Bpin)2 (525 mg) in water (0.30 mL) and THF (3.0 mL) was stirred under microwave irradiation at 100° C. for 2 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. To a solution of the residue in acetone (6.0 mL) was added manganese dioxide (360 mg). The mixture was stirred at room temperature for 14 hr. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the titled compound (29.0 mg).
MS m/z 324.0 [M+H]+.
The reaction and purification were performed according to Example 121 Step B to give the titled compound.
MS m/z 402.1, 404.1 [M+H]+.
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (300 MHZ, CD3OD) δ 9.31 (s, 1H), 9.02 (d, J=2.9 Hz, 1H), 8.52-8.44 (m, 1H), 8.40-8.32 (m, 2H), 8.16-7.98 (m, 3H), 7.48 (dt, J=2.7, 8.3 Hz, 1H), 5.38-5.24 (m, 1H), 5.02-4.92 (m, 2H), 1.53 (d, J=6.2 Hz, 3H); MS m/z 443.2 [M+H]+.
A mixture of 1-[(2S)-2-(3-{3-bromoimidazo[1, 2-b]pyridazin-6-yl}phenoxy) propyl]-1H-tetrazole (120 mg), 2-chloro-4-methoxypyridine-3-carbonitrile (151 mg), cataCXium® A (42.9 mg), CsF (136 mg), Pd(0Ac)2 (13.4 mg) and (Bpi n)2 (228 mg) in water (0.50 mL) and THF (5.0 mL) was stirred under microwave irradiation at 120° C. for 4 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NH4Cl solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/EtOAc) and crystallized from EtOAc/IPE to give the crude titled compound. The crude product was further purified by silica gel column chromatography (NH, MeOH/EtOAc) to the titled compound (40.0 mg) as a white solid. 1H NMR (300 MHZ, CDCl3) δ 8.80 (s, 1H), 8.78-8.73 (m, 1H), 8.33-8.29 (m, 1H), 8.18-8.11 (m, 1H), 7.86-7.82 (m, 1H), 7.60-7.54 (m, 1H), 7.53-7.46 (m, 1H), 7.45-7.38 (m, 1H), 7.02-6.94 (m, 2H), 5.06-4.92 (m, 1H), 4.89-4.80 (m, 1H), 4.75-4.65 (m, 1H), 4.13 (s, 3H), 1.41 (d, J=6.2 Hz, 3H); MS m/z 454.1 [M+H]+.
A mixture of 4-chloro-6-{[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]oxy}pyrimidine (113 mg), 2-{5-bromo-3H-imidazo[4, 5-b]pyridin-3-yl}-4-fluorobenzonitrile (30.0 mg), cataCXium® A (13.5 mg), CsF (71.8 mg), Pd(0Ac)2 (4.2 mg) and (Bpi n)2 (120 mg) in water (0.20 mL) and THF (2.5 mL) was stirred under microwave irradiation at 80° C. for 2 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NH4Cl solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the titled compound (10.0 mg) as an off-white solid. 1H NMR (300 MHZ, CDCl3) δ 8.81 (d, J=0.80 Hz, 1H), 8.68 (s, 1H), 8.64-8.57 (m, 1H), 8.49 (s, 1H), 8.36-8.30 (m, 1H), 8.04-7.96 (m, 1H), 7.67-7.58 (m, 2H), 7.47-7.35 (m, 1H), 5.87-5.72 (m, 1H), 4.88-4.79 (m, 1H), 4.78-4.67 (m, 1H), 1.43 (d, J=6.4 Hz, 3H); MS m/z 443.1 [M+H]+.
The reaction and purification were performed according to Example 326 Step B to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.43 (s, 1H), 8.18 (d, J=5.8 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 6.98 (dd, J=2.3, 5.8 Hz, 1H), 5.20-5.07 (m, 1H), 4.91-4.83 (m, 1H), 4.81-4.70 (m, 1H), 1.29 (d, J=6.1 Hz, 3H); MS m/z 240.0 [M+H]+.
The reaction and purification were performed according to Example 298 Step B to give the titled compound.
MS m/z 323.0 [M+H]+.
The reaction and purification were performed according to Example 121 Step B to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.58 (d, J=5.8 Hz, 1H), 8.32-8.27 (m, 1H), 8.19-8.14 (m, 1H), 8.01 (s, 1H), 7.79 (d, J=2.5 Hz, 1H), 7.20 (dd, J=2.6, 5.8 Hz, 1H), 5.30-5.16 (m, 1H), 4.98-4.89 (m, 1H), 4.88-4.78 (m, 1H), 1.38 (d, J=6.1 Hz, 3H); MS m/z 401.0, 403.0 [M+H]+.
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.73 (s, 1H), 8.54 (d, J=5.7 Hz, 1H), 8.39-8.28 (m, 2H), 8.23-8.13 (m, 1H), 7.98-7.90 (m, 2H), 7.85 (d, J=2.5 Hz, 1H), 7.32-7.27 (m, 1H), 6.85 (dd, J=2.6, 5.7 Hz, 1H), 5.11-4.97 (m, 1H), 4.87-4.78 (m, 1H), 4.76-4.65 (m, 1H), 1.50 (d, J=6.2 Hz, 3H); MS m/z 442.1 [M+H]+.
To a solution of 2, 6-dichloronicotinonitrile (2.50 g) in MeOH (65 mL) was added slowly a solution of NaOMe (781 mg) in MeOH (15 mL). The mixture was stirred at 15° C. for 16 hr. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (675 mg). 1H NMR (400 MHZ, CDCl3) δ 7.79 (d, J=8.4 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 4.01 (s, 3H); MS m/z 169.1 [M+H]+.
The reaction and purification were performed according to Example 321 to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.79 (s, 1H), 8.32 (s, 1H), 8.14 (d, J=9.5 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.79-7.73 (m, 1H), 7.61-7.52 (m, 2H), 7.46-7.36 (m, 1H), 7.00-6.92 (m, 1H), 6.91-6.84 (m, 1H), 5.03-4.89 (m, 1H), 4.87-4.76 (m, 1H), 4.71-4.59 (m, 1H), 4.04 (s, 3H), 1.41 (d, J=6.1 Hz, 3H); MS m/z 454.2 [M+1]+.
Sodium (0.170 g, cube) was added to MeOH (10 mL) at room temperature. After completely dissolved, the solution was slowly added to a mixture of 4, 6-dichloropyrimidine-5-carbonitrile (1.30 g) in MeOH (10 mL) and THF (10 mL) at 5° C. The mixture was stirred under argon atmosphere at 5° C. to room temperature for 4 hr. The mixture was poured into EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with saturated aqueous NH4Cl solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was washed with IPE to give the crude titled compound (0.560 g). The crude product was used for the next step without further purification. 1H NMR (300 MHZ, CDCl3) δ 8.73-8.67 (m, 1H), 4.17 (s, 3H).
The reaction and purification were performed according to Example 321 to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.98 (s, 1H), 8.81 (s, 1H), 8.47 (s, 1H), 8.17 (d, J=9.5 Hz, 1H), 7.89-7.84 (m, 1H), 7.68-7.62 (m, 1H), 7.56-7.49 (m, 1H), 7.46-7.39 (m, 1H), 7.03-6.94 (m, 1H), 5.07-4.94 (m, 1H), 4.89-4.81 (m, 1H), 4.75-4.64 (m, 1H), 4.24 (s, 3H), 1.43 (d, J=6.2 Hz, 3H); MS m/z 455.1 [M+H]+.
A mixture of 1-[(2S)-2-(5-{3-bromoimidazo[1, 2-b]pyridazin-6-yl}-2-fluorophenoxy) propyl]-1H-tetrazole (380 mg), 2-chloro-4-methoxypyridine-3-carbonitrile (305 mg), cataCXium® A (130 mg), CsF (413 mg), Pd(OAc)2 (40.7 mg) and (Bpi n)2 (690 mg) in water (2.0 mL) and THF (20 mL) was stirred at 120° C. for 4 hr in a sealed tube. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NH4Cl solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, MeOH/EtOAc) and crystallized from EtOAc/IPE to give the titled compound (97.0 mg) as an off-white solid. 1H NMR (300 MHZ, CDCl3) δ 8.89 (s, 1H), 8.76 (d, J=6.1 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.97 (dd, J=2.0, 8.1 Hz, 1H), 7.53 (d, J=9.5 Hz, 1H), 7.49-7.42 (m, 1H), 7.23-7.16 (m, 1H), 6.99 (d, J=6.1 Hz, 1H), 5.03-4.91 (m, 1H), 4.90-4.81 (m, 1H), 4.80-4.66 (m, 1H), 4.13 (s, 3H), 1.45 (d, J=6.2 Hz, 3H); MS m/z 472.1 [M+H]+.
To a mixture of tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (22.6 g) in pyridine (100 mL) was added TsCl (26.6 g) at 25° C. The mixture was stirred at room temperature for 14 hr. The mixture was poured into water (500 mL) at room temperature and the stirring was continued for 2 hr. The precipitate was collected by filtration. The solid was dissolved in EtOAc (200 mL) and washed with water and saturated aqueous NH4Cl solution, dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with hexane to give the titled compound (30.6 g). 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.3 Hz, 2H), 7.39-7.31 (m, 2H), 4.85-4.72 (m, 1H), 4.70-4.60 (m, 1H), 3.45-3.29 (m, 1H), 3.21-3.09 (m, 1H), 2.45 (s, 3H), 1.41 (s, 9H), 1.22 (d, J=6.4 Hz, 3H).
A mixture of 6-bromopyridin-2-ol (200 mg), tert-butyl N-[(2R)-2-[(4-methyl benzenesulfonyl)oxy]propyl]carbamate (751 mg) and K2CO3 (472 mg) in DMA (1.2 mL) was stirred at 65° C. for 14 hr.
The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NH4Cl solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (341 mg). 1H NMR (300 MHz, CDCl3) δ 7.41 (dd, J=7.6, 8.1 Hz, 1H), 7.08-7.01 (m, 1H), 6.68-6.60 (m, 1H), 5.32-5.16 (m, 1H), 4.97-4.82 (m, 1H), 3.54-3.41 (m, 1H), 3.39-3.23 (m, 1H), 1.43 (s, 9H), 1.32 (d, J=6.3 Hz, 3H).
To a mixture of tert-butyl N-[(2S)-2-[(6-bromopyridin-2-yl)oxy]propyl]carbamate (0.680 g) in EtOAc (2.0 mL) was added 4M HCl in EtOAc solution (2.0 mL). The mixture was stirred at 55° C. for 1 hr. After cooling, the precipitate was collected by filtration to give the titled compound (360 mg). The filtrate was concentrated under reduced pressure to give the crude titled product (300 mg). 1H NMR (300 MHZ, DMSO-d6) δ 8.26-8.00 (m, 3H), 7.77-7.66 (m, 1H), 7.32-7.21 (m, 1H), 6.87 (s, 1H), 5.34-5.16 (m, 1H), 3.24-3.00 (m, 2H), 1.31 (d, J=6.2 Hz, 3H).
To a mixture of (2S)-2-[(6-bromopyridin-2-yl)oxy]propan-1-amine hydrochloride (350 mg) in ethyl formate (3.5 mL) was added TEA (0.27 mL). The mixture was stirred under argon atmosphere at 45° C. for 4 hr. After cooling, EtOH (1.0 mL) and water (3.5 mL) were added thereto. The mixture was concentrated under reduced pressure and partitioned with EtOAc and water. The organic layer was separated, washed with saturated aqueous NH4Cl solution and brine, dried over MgSO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (320 mg). 1H NMR (300 MHZ, CDCl3) δ 8.20 (s, 1H), 7.43 (d, J=0.6 Hz, 1H), 7.11-7.02 (m, 1H), 6.70-6.64 (m, 1H), 6.46-6.29 (m, 1H), 5.26 (dt, J=3.4, 6.6 Hz, 1H), 3.74-3.60 (m, 1H), 3.54-3.41 (m, 1H), 1.38-1.30 (m, 3H).
E) 2-bromo-6-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyridine
To a mixture of N-[(2S)-2-[(6-bromopyridin-2-yl)oxy]propyl] formamide (4.70 g) and TEA (7.6 mL) in THF (45 mL) was added POCl3 (2.7 mL) at 5° C. The mixture was stirred at 5° C. for 2 hr. The mixture was quenched with saturated aqueous NaHCO3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. To a mixture of the residue in TFE (45 mL) was added trimethyl silyl azide (3.6 mL) at room temperature. The mixture was stirred at 60° C. for 2 hr. Additional trimethyl silyl azide (1.2 mL) was added to the mixture at room temperature. The mixture was stirred at 60° C. for 1 hr. The mixture was quenched with saturated aqueous NaHCO3 solution at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (5.13 g). 1H NMR (300 MHZ, CDCl3) δ 8.67 (s, 1H), 7.51-7.41 (m, 1H), 7.11 (dd, J=0.6, 7.5 Hz, 1H), 6.67 (dd, J=0.6, 8.2 Hz, 1H), 5.63-5.50 (m, 1H), 4.84-4.60 (m, 2H), 1.39 (d, J=6.4 Hz, 3H).
The reaction and purification were performed according to Example 298 Step B to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.41-8.35 (m, 1H), 8.31-8.23 (m, 1H), 8.11-7.99 (m, 1H), 7.94-7.81 (m, 3H), 6.99-6.85 (m, 1H), 5.92-5.72 (m, 1H), 5.02-4.72 (m, 2H), 1.44-1.33 (m, 3H).
The reaction and purification were performed according to Example 121 Step B to give the crude titled compound. The crude product was used to the next step without further purification. H) 4-fluoro-2-[6-(6-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyridin-2-yl)imidazo[1, 2-b]pyridazin-3-yl]benzonitrile
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.45 (s, 1H), 8.46 (d, J=9.6 Hz, 1H), 8.83 (s, 1H), 8.18-8.25 (m, 2H), 8.04 (dd, J=10.0, 2.7 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.58 (dt, J=8.0, 2.7 Hz, H), 6.93 (d, J=8.0 Hz, 1H), 5.80-5.87 (m, 1H), 4.78-4.97 (m, 2H), 1.40 (d, J=6.0 Hz, 3H); MS m/z 442.1 [M+H]+.
To a mixture of 1H-tetrazole (30.0 g) and THF (30 mL) was added (S)-propylene oxide (50.0 g). After being stirred at 40° C. for 72 hr, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give a colorless oil. To a mixture of the oil and THF (100 mL), were added TBSCl (7.05 g) and imidazole (3.18 g). After being stirred at room temperature for 15 hr, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (22.7 g). 1H NMR (300 MHZ, DMSO-d6) δ 9.30 (s, 1H), 5.13 (d, J=5.0 Hz, 1H), 4.46 (dd, J=13.8, 3.8 Hz, 1H), 4.30 (dd, J=13.8, 5.0 Hz, 1H), 3.94-4.04 (m, 1H), 1.09 (d, J=6.3 Hz, 3H).
To a mixture of (2S)-1-(1H-tetrazol-1-yl) propan-2-ol (2.14 g) in THF (50 mL) was added 60% NaH in oil (798 mg). After being stirred at room temperature for 10 min, 2, 6-dichloropyrazine (2.48 g) was added to the mixture. After being stirred at room temperature for 1 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (2.65 g).
MS m/z 241.0 [M+H]+.
The reaction and purification were performed according to Example 298 Step B to give the titled compound.
MS m/z 324.0 [M+H]+.
The reaction and purification were performed according to Example 121 Step B to give the titled compound. 1H NMR (400 MHZ, DMSO-d6) δ 9.48 (s, 1H), 9.06 (s, 1H), 8.44 (s, 1H), 8.39 (d, J=9.5 Hz, 1H), 8.09 (d, J=9.5 Hz, 1H), 8.06 (s, 1H), 5.90-5.78 (m, 1H), 5.02-4.94 (m, 1H), 4.91-4.82 (m, 1H), 1.43 (d, J=6.4 Hz, 3H); MS m/z 402.0, 403.9 [M+H]+.
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.48 (s, 1H), 8.97 (s, 1H), 8.52 (d, J=9.6 Hz, 1H), 8.40 (d, J=13.3 Hz, 2H), 8.16-8.25 (m, 2H), 8.08 (dd, J=10.0, 2.7 Hz, 1H), 7.59 (dt, J=8.5, 2.7 Hz, 1H), 5.81-5.89 (m, 1H), 4.83-5.02 (m, 2H), 1.41 (d, J=6.0 Hz, 3H). MS m/z 443.1 [M+H]+.
The reaction and purification were performed according to Example 326 Step B to give the titled compound.
MS m/z 313.2 [M+H]+.
A mixture of 4-(benzyloxy)-2-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyrimidine (2.93 g) and 10% palladium-carbon (0.300 g) in EtOH (50 mL) was stirred under hydrogen atmosphere at room temperature for 14 hr. The catalyst was removed by filtration and then the filtrate was concentrated under reduced pressure to give the titled compound (2.00 g).
MS m/z 223.2 [M+H]+.
To a mixture of 2-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyrimidin-4-ol (1.71 g) in DMF (15 mL) was added 60% NaH in oil (368 mg). After being stirred at room temperature for 10 mi n, N-phenyl trifluoromethanesulfonimide (3.01 g) was added to the mixture. After being stirred at room temperature for 30 min, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the titled compound (2.57 g). 1H NMR (300 MHZ, DMSO-d6) δ 9.40 (s, 1H), 8.96-8.60 (m, 1H), 7.45-7.07 (m, 2H), 5.78-5.35 (m, 1H), 5.16-4.49 (m, 2H), 1.67-0.66 (m, 3H).
Pd(dppf) CI 2 (64.3 mg) was added to a mixture of 2-{5-bromo-3H-imidazo[4, 5-b]pyridin-3-yl}-4-fluorobenzonitrile (250 mg), (Bpin)2 (398 mg) and KOAc (154 mg) in toluene (5.0 mL). After being stirred under nitrogen atmosphere at 100° C. for 2 hr, the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure to give the crude titled compound (220 mg). The crude product was used for the next step without further purification.
MS m/z 282.9 [M+H]+.
The reaction and purification were performed according to Example 393 Step F to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.43 (s, 1H), 9.02 (s, 1H), 8.66 (d, J=5.0 Hz, 1H), 8.47 (d, J=1.1 Hz, 2H), 8.33 (dd, J=8.7, 5.9 Hz, 1H), 8.05 (dd, J=8.5, 2.5 Hz, 1H), 7.84 (d, J=5.0 Hz, 1H), 7.74 (dd, J=9.3, 2.5 Hz, 1H), 5.71-5.78 (m, 1H), 4.82-4.98 (m, 2H), 1.42 (d, J=6.3 Hz, 3H). MS m/z 443.1 [M+H]+.
To a mixture of [3-(2-cyano-5-fluorophenyl)-3H-imidazo[4, 5-b]pyridin-5-yl]boronic acid (180 mg), 2-bromo-6-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyridine (199 mg), CS2CO3 (413 mg), THF (10 mL) and water (2.0 mL) was added Pd(dppf) Cl2—CH2Cl2 (52.2 mg). After being stirred under nitrogen atmosphere at 70° C. for 1 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (60.0 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.92 (s, 1H), 8.40 (s, 2H), 8.32 (dd, J=7.8, 5.8 Hz, 1H), 8.03 (dd, J=9.4, 2.6 Hz, 1H), 7.79-7.87 (m, 2H), 7.72 (dt, J=8.5, 2.6 Hz, 1H), 6.81 (dd, J=7.6, 1.3 Hz, 1H), 5.77-5.87 (m, 1H), 4.79-4.98 (m, 2H), 1.40 (d, J=6.3 Hz, 3H); MS m/z 442.1 [M+H]+.
To a mixture of 5-chloropyridazin-3-ol (5.00 g), (2R)-1-(1H-tetrazol-1-yl) propan-2-ol (4.90 g) and PPh3 (15.0 g) in THF (100 mL) was added DIAD (11.6 g). After being stirred under nitrogen atmosphere at room temperature for 1 hr, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) and silica gel column chromatography (NH, EtOAc/hexane) to give the titled compound (640 mg). 1H NMR (300 MHZ, DMSO-d6) δ 9.45 (s, 1H), 9.03 (d, J=2.0 Hz, 1H), 7.51-7.61 (m, 1H), 5.73-5.83 (m, 1H), 4.79-4.97 (m, 2H), 1.34 (d, J=6.3 Hz, 3H).
The reaction and purification were performed according to Example 393 Step F to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.61-9.53 (m, 1H), 9.49-9.42 (m, 1H), 9.04-8.97 (m, 1H), 8.51-8.43 (m, 1H), 8.40-8.26 (m, 2H), 8.11-8.03 (m, 1H), 7.79-7.68 (m, 2H), 5.96-5.80 (m, 1H), 5.02-4.82 (m, 2H), 1.41-1.36 (m, 3H); MS m/z 443.2 [M+H]+.
To a mixture of 2, 2-difluoroethan-1-ol (94.3 mg) in THF (2.0 mL) was added 60% NaH in oil (55.1 mg) at 0° C. The mixture was stirred under nitrogen atmosphere at 0° C. for 5 min. A solution of 2, 4-dichloropyridine-3-carbonitrile (200 mg) in THF (2.0 mL) was added to the mixture at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 4 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (185 mg).
MS m/z 219.1 [M+H]+.
The reaction and purification were performed according to Example 321 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.90 (d, J=6.0 Hz, 1H), 8.41 (d, J=9.5 Hz, 1H), 8.28 (s, 1H), 7.99 (d, J=9.6 Hz, 1H), 7.68-7.61 (m, 2H), 7.54 (d, J=6.1 Hz, 1H), 7.44 (t, J=8.2 Hz, 1H), 7.06 (dd, J=1.9, 8.2 Hz, 1H), 6.77-6.32 (m, 1H), 5.07-4.93 (m, 1H), 4.91-4.68 (m, 4H), 1.34 (d, J=6.1 Hz, 3H); MS m/z 504.1 [M+H]+.
A solution of 2N methyl amine THF solution (2.4 mL) was added to a solution of 2, 4-dichloropyridine-3-carbonitrile (400 mg) in DMF (6.0 mL) at 0° C. The mixture was stirred at 0° C. for 5 min and at room temperature for 2 hr. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by recrystallization from EtOAc/hexane to give the titled compound (283 mg) as a white solid. 1H NMR (300 MHZ, CDCl3) δ 8.12 (dd, J=0.5, 6.1 Hz, 1H), 6.50 (d, J=6.1 Hz, 1H), 5.46-5.15 (m, 1H), 3.01 (d, J=5.0 Hz, 3H); MS m/z 168.1 [M+1]+.
The reaction and purification were performed according to Example 321 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.45 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.36 (d, J=9.5 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J=9.6 Hz, 1H), 7.65 (d, J=7.7 Hz, 1H), 7.61 (d, J=2.2 Hz, 1H), 7.43 (t, J=8.0 Hz, 1H), 7.33 (q, J=4.3 Hz, 1H), 7.06 (dd, J=2.5, 7.9 Hz, 1H), 6.80 (d, J=6.1 Hz, 1H), 5.05-4.95 (m, 1H), 4.91-4.83 (m, 1H), 4.83-4.71 (m, 1H), 2.92 (d, J=4.7 Hz, 3H), 1.32 (d, J=6.1 Hz, 3H); MS m/z 455.3 [M+1]+.
To a solution of methyl(2E)-3-methoxyprop-2-enoate (313 mg), 3-fluoro-1H-pyrazol-5-amine (300 mg) in THF (3.0 mL) was added CS2CO3 (1.32 g) and the mixture was stirred at 80° C. for 12 hr. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (370 mg). 1H NMR (400 MHZ, CDCl3) δ 12.0 (brs, 1H), 7.99 (d, J=8.0 Hz, 1H), 6.06 (d, J=8.0 Hz, 1H), 5.63 (d, J=5.2 Hz, 1H).
To a solution of 2-fluoropyrazolo[1,5-a]pyrimidin-5-ol (370 mg) in CH3CN (5.0 mL) was added POCl3 (1.48 g) and the mixture was stirred under nitrogen atmosphere at 80° C. for 12 hr. The mixture was concentrated under reduced pressure. The residue was poured into water and basified with 4M aqueous NaOH solution (pH 8). The resulting precipitate was collected by filtration and dried to give the crude titled compound (350 mg). The crude product was used for the next step without further purification.
The reaction and purification were performed according to Example 1 Step F to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.77 (s, 1H), 8.52 (d, J=7.2 Hz, 1H), 7.61-7.63 (m, 2H), 7.40 (t, J=8.0 Hz, 1H), 7.24-7.26 (m, 1H), 6.93-6.96 (m, 1H), 6.22 (d, J=5.2 Hz, 1H), 4.88-4.95 (m, 1H), 4.77-4.82 (m, 1H), 4.60-4.67 (m, 1H), 1.42 (d, J=6.4 Hz, 3H).
The reaction and purification were performed according to Example 1 Step G to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.78 (s, 1H), 8.51 (d, J=7.2 Hz, 1H), 7.66-7.69 (m, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.30 (d, J=7.2 Hz, 1H), 6.96 (dd, J=8.0, 2.0 Hz, 1H), 4.87-4.95 (m, 1H), 4.79-4.83 (m, 1H), 4.63-4.68 (m, 1H), 1.44 (d, J=6.4 Hz, 3H).
The reaction and purification were performed according to Example 1 Step H to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.76 (s, 1H), 8.62 (d, J=7.3 Hz, 1H), 7.94-7.85 (m, 1H), 7.85-7.81 (m, 1H), 7.66-7.60 (m, 1H), 7.50-7.37 (m, 3H), 7.24-7.15 (m, 1H), 7.01-6.96 (m, 1H), 5.01-4.89 (m, 1H), 4.85-4.77 (m, 1H), 4.71-4.61 (m, 1H), 1.43 (d, J=6.2 Hz, 3H); MS m/z 459.1 [M+H]+
The reaction and purification were performed according to Example 413 Step A to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.26-8.31 (m, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.82 (dt, J=8.3, 0.9 Hz, 1H), 7.16 (d, J=57.0 Hz, 1H).
To a mixture of 1-bromo-4-(difluoromethyl)-2-nitrobenzene (4.00 g) in DMF (100 mL) were added Pd(PPh3)4 (1.82 g) and Zn(CN)2 (5.56 g). After being stirred under argon atmosphere at 110° C. for 15 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (1.80 g). 1H NMR (300 MHZ, DMSO-d6) δ 8.56 (s, 1H), 8.35 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.29 (t, J=57.0 Hz, 1H).
The reaction and purification were performed according to Example 413 Step C to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 7.53 (d, J=8.1 Hz, 1H), 6.96 (s, 1H), 6.95 (t, J=54.0 Hz, 1H), 6.70-6.73 (m, 1H), 6.37 (brs, 2H).
The reaction and purification were performed according to Example 284 Step A to give the titled compound.
MS m/z 369.0 [M+H]+.
The reaction and purification were performed according to Example 284 Step B to give the titled compound.
MS m/z 339.0 [M+H]+.
The reaction and purification were performed according to Example 284 Step C to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.35 (s, 1H), 8.09-7.99 (m, 2H), 7.91 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.81 (t, J=1.0 Hz, 1H); MS m/z 349.0 [M+H]+.
The reaction and purification were performed according to Example 284 Step D to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.75 (s, 1H), 8.47 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.13-8.06 (m, 2H), 7.86-7.74 (m, 2H), 7.64-7.57 (m, 2H), 7.41-7.32 (m, 1H), 7.06-6.66 (m, 2H), 4.91-4.74 (m, 2H), 4.69-4.58 (m, 1H), 1.40-1.35 (m, 3H); MS m/z 473.1 [M+H]+.
To a mixture of 2-bromo-4-fluoro-6-methoxybenzonitrile (110 mg), (Bpin)2 (182 mg), KOAc (140 mg) and toluene (10 mL) was added Pd(dppf)Cl2—CH2Cl2 (39.0 mg). After being stirred under nitrogen atmosphere at 100° C. for 3 hr, the mixture was filtered and concentrated under reduced pressure.
To a mixture of the residue, 2-{3-bromoimidazo[1, 2-b]pyridazin-6-yl}-6-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyrazine (92.0 mg), CS2CO3 (151 mg), DME (5.0 mL) and water (1.0 mL) was added Pd(amphos)Cl2 (16.0 mg). After being stirred under nitrogen atmosphere at 80° C. for 1 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane), silica gel column chromatography (NH, EtOAc/hexane) and recrystallization from EtOAc/hexane to give the titled compound (52.0 mg) as a pale yellow solid. 1H NMR (300 MHZ, DMSO-d6) ¿ 9.48 (s, 1H), 8.95 (s, 1H), 8.50 (d, J=9.5 Hz, 1H), 8.43 (s, 1H), 8.34 (s, 1H), 8.16 (d, J=9.5 Hz, 1H), 7.60 (dd, J=2.3, 9.6 Hz, 1H), 7.39 (dd, J=2.3, 10.9 Hz, 1H), 5.90-5.77 (m, 1H), 5.04-4.94 (m, 1H), 4.92-4.82 (m, 1H), 4.04 (s, 3H), 1.42 (d, J=6.4 Hz, 3H); MS m/z 473.1 [M+H]+.
To a solution of 2, 4, 6-trifluorobenzonitrile (10.5 g) in CH3CN (80 mL) was added 28% aqueous NH3 solution (45 mL). After being stirred under nitrogen atmosphere at room temperature for 72 hr, the mixture was concentrated under reduced pressure. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (4.58 g). 1H NMR (300 MHZ, CDCl3) δ 6.31-6.18 (m, 2H), 4.68 (brs, 2H); m/z 153.1 [M−H]−.
To a solution of 2-amino-4, 6-difluorobenzonitrile (4.58 g) in DMF (50 mL) was added 28% NaOMe in MeOH solution (7.9 mL) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 72 hr. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give 2-amino-4-fluoro-6-methoxybenzonitrile (1.92 g) and 2-amino-6-fluoro-4-methoxybenzonitrile (1.04 g).
Data of 2-amino-4-fluoro-6-methoxybenzonitrile 1H NMR (300 MHZ, DMSO-d6) δ 6.32 (s, 2H), 6.14 (dt, J=2.2, 11.6 Hz, 2H), 3.80 (s, 3H).
Data of 2-amino-6-fluoro-4-methoxybenzonitrile 1H NMR (300 MHZ, DMSO-d6) δ 6.38 (s, 2H), 6.20-6.09 (m, 2H), 3.73 (s, 3H).
To a mixture of 2-amino-4-fluoro-6-methoxybenzonitrile (1.93 g) and 2, 6-di bromo-3-nitropyridine (3.91 g) in THF (60 mL) was added 60% NaH in oil (1.85 g) at 0° C. The mixture was stirred under nitrogen atmosphere at room temperature for 1 hr.
The mixture was quenched with water at 0° C. and the precipitating solid was collected by filtration. The solid was washed with water and dried under reduced pressure to give the crude titled compound (4.95 g). The crude product was used for the next step without further purification. 1H NMR (300 MHZ, DMSO-d6) δ 10.50 (s, 1H), 8.49 (d, J=8.6 Hz, 1H), 7.60 (dd, J=2.3, 11.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 1H), 7.07 (dd, J=2.2, 10.9 Hz, 1H), 3.97 (s, 3H); m/z 366.9 [M+H]+.
To a mixture of crude 2-[(6-bromo-3-nitropyridin-2-yl)amino]-4-fluoro-6-methoxybenzonitrile (1.90 g) and saturated aqueous NH4Cl solution (30 mL) in THF (60 mL) and EtOH (10 mL) was added iron (3.46 g). The mixture was stirred at 50° C. for 14 hr.
The mixture was filtered through a Celite® pad and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure.
To a mixture of the residue and TsOH-H2O (391 mg) in THF (40 mL) was added triethyl orthoformate (18 mL). After being stirred at 100° C. for 3 hr, the mixture was concentrated under reduced pressure at 60° C.. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (640 mg). 1H NMR (300 MHZ, DMSO-d6) δ 8.84 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.57-7.47 (m, 2H), 4.05 (s, 3H); m/z 346.9 [M+H]+.
To a mixture of 2-{5-bromo-3H-imidazo[4, 5-b]pyridin-3-yl}-4-fluoro-6-methoxybenzonitrile (100 mg), (Bpin) 2 (87.6 mg), KOAc (84.7 mg) in toluene (8.0 mL) was added Pd(dppf)Cl2—CH2Cl2 (23.5 mg). After being stirred under nitrogen atmosphere at 100° C. for 1 hr, the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to give the crude titled compound (90.0 mg). The crude product was used for the next step without further purification.
MS m/z 312.9 [M+H]+.
To a mixture of crude[3-(2-cyano-5-fluoro-3-methoxyphenyl)-3H-imidazo[4, 5-b]pyridin-5-yl]boronic acid (90.0 mg), 2-bromo-6-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyridine (98.0 mg) and CS2CO3 (187 mg) in THF (5.0 mL) and water (0.50 mL) was added Pd(amphos) Cl2 (20.3 mg). After being stirred under nitrogen atmosphere at 70° C. for 1 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) and recrystallized from EtOAc/IPE to give the titled compound (45.0 mg) as an off-white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.87 (s, 1H), 8.39 (s, 2H), 7.89-7.78 (m, 2H), 7.58-7.46 (m, 2H), 6.85-6.76 (m, 1H), 5.90-5.76 (m, 1H), 5.00-4.76 (m, 2H), 4.07 (s, 3H), 1.40 (d, J=6.3 Hz, 3H); MS m/z 472.2 [M+H]+.
To a cold mixture of diisopropyl amine (3.30 g) in THF (50 mL) under argon atmosphere was added dropwise 1.6M n-BuLi hexane solution (20 mL) at −78° C. The mixture was stirred under argon atmosphere at −78° C. for 30 min. Then a mixture of 2-methoxypyridine-3-carbonitrile (4.00 g) in THF (25 mL) was added to the mixture. After being stirred under argon atmosphere at −78° C. for 1 hr, a mixture of hexachloroethane (14.1 g) in THF (50 mL) was added to the mixture. The mixture was warmed to −40° C. and stirred for 15 min. The mixture was quenched with water (100 mL) at the same temperature and extracted with EtOAc. The organic layer was separated, washed with saturated aqueous NH4Cl solution, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (0.850 g). 1H NMR (300 MHZ, CDCl3) δ 8.24 (d, J=5.5 Hz, 1H), 7.06 (d, J=5.6 Hz, 1H), 4.09-4.06 (m, 3H).
The reaction and purification were performed according to Example 321 to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.90-8.83 (m, 1H), 8.45 (s, 1H), 8.38-8.34 (m, 1H), 8.20-8.13 (m, 1H), 7.80-7.72 (m, 1H), 7.59-7.52 (m, 2H), 7.52-7.46 (m, 1H), 7.26-7.18 (m, 1H), 4.98-4.82 (m, 2H), 4.78-4.63 (m, 1H), 4.16 (s, 3H), 1.48 (d, J=6.2 Hz, 3H); MS m/z 472.1 [M+H]+.
To a mixture of benzyl alcohol (2.55 g) in DMF (30 mL) was added 60% NaH in oil (1.03 g). After being stirred at room temperature for 10 min, 2-amino-4, 6-difluorobenzonitrile (3.64 g) was added to the mixture. After being stirred at 100° C. for 3 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EOAc/hexane) to give the titled compound (660 mg) as a white solid.
MS m/z 241.1 [M−H]−.
DMAP (16.6 mg) was added to a mixture of 2-amino-6-(benzyloxy)-4-fluorobenzonitrile (0.660 g), TEA (825 mg) and (Boc)2O (1.30 g) in THF (10 mL). The mixture was stirred at room temperature for 15 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (1.05 g).
MS m/z 441.2 [M−H]−.
A mixture of tert-butyl N-[3-(benzyloxy)-2-cyano-5-fluorophenyl]-N-[(tert-butoxy) carbonyl]carbamate (1.05 g) and 10% palladium-carbon (100 mg) in EtOH (10 mL) was stirred under hydrogen atmosphere at room temperature for 4 hr. The catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give the crude titled compound (840 mg). The crude product was used for the next step without further purification.
MS m/z 351.1 [M−H]−.
To a mixture of tert-butyl N-[(tert-butoxy) carbonyl]-N-(2-cyano-5-fluoro-3-hydroxyphenyl) carbamate (840 mg), ethyl bromodifluoroacetate (966 mg) in DMF (10 mL) and water (2.0 mL) was added K2CO3 (12.4 g). After being stirred at 100° C. for 1 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was diluted with THF (2.0 mL) and TFA (2.0 mL) was added to the mixture. After being stirred at 50° C. for 15 hr, the mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (342 mg).
MS m/z 201.1 [M−H]−.
To a mixture of 2-amino-6-(di fluoromethoxy)-4-fluorobenzonitrile (672 mg), CuBr (1.42 g) in CH3CN (10 mL) was added amylnitrite (1.35 g). The mixture was stirred under nitrogen atmosphere at room temperature for 2 hr. The mixture was quenched with water at room temperature, diluted with EtOAc and filtered through a Celite® pad. The filtrate was partitioned two layers and the organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (550 mg). 1H NMR (300 MHZ, DMSO-d6) δ 7.86 (dd, J=8.3, 2.3 Hz, 2H), 7.58 (dd, J=9.8, 2.2 Hz, 1H), 7.47 (t, J=79.0 Hz, 1H).
The reaction and purification were performed according to Example 392 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.47 (d, J=9.5 Hz, 1H), 7.90-7.97 (m, 2H), 7.79-7.82 (m, 1H), 7.60-7.66 (m, 1H), 7.47 (t, J=72.0 Hz, 1H), 6.92-6.94 (m, 1H), 5.78-5.90 (m, 1H), 4.78-4.97 (m, 2H), 1.41 (d, J=6.4 Hz, 3H); MS m/z 508.1 [M+H]+.
The reaction and purification were performed according to Example 392 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.44 (d, J=9.6 Hz, 1H), 8.29 (s, 1H), 8.21 (d, J=9.5 Hz, 1H), 7.97-7.88 (m, 1H), 7.79 (d, J=7.0 Hz, 1H), 7.56 (dd, J=2.3, 9.6 Hz, 1H), 7.37 (dd, J=2.2, 10.9 Hz, 1H), 6.94 (d, J=7.8 Hz, 1H), 5.89-5.76 (m, 1H), 5.00-4.89 (m, 1H), 4.88-4.76 (m, 1H), 4.03 (s, 3H), 1.40 (d, J=6.3 Hz, 3H); MS m/z 472.1 [M+H]+.
To a mixture of 2-amino-6-(di fluoromethoxy)-4-fluorobenzonitrile (2.67 g), CuBr (5.66 g) in CH3CN (30 mL) was added amyl nitrite (1.35 g). The mixture was stirred under nitrogen atmosphere at room temperature for 2 hr. The mixture was quenched with water, diluted with EtOAc and filtered through a Celite® pad. The filtrate was partitioned two layers and the organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (2.28 g). 1H NMR (300 MHZ, DMSO-d6) δ 7.69-7.78 (m, 2H), 7.47-7.51 (m, 1H), 7.47 (t, J=72.0 Hz, 1H).
The reaction and purification were performed according to Example 392 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.43 (s, 1H), 8.38-8.41 (m, 1H), 8.27 (s, 1H), 7.95-7.99 (m, 3H), 7.63-7.65 (m, 3H), 7.63 (t, J=72 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.06 (dd, J=2.0, 8.3 Hz, 1H), 4.95-5.03 (m, 1H), 4.70-4.89 (m, 2H), 1.36 (d, J=6.1 Hz, 3H); MS m/z 489.1 [M+H]+.
Deoxo-Fluor® (9.60 g) was added to a mixture of 2-bromo-3-nitrobenzaldehyde (5.00 g) in toluene (50 mL). The mixture was stirred at room temperature for 1 hr. The mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was separated, washed with brine, dried over
MgSO4 and concentrated under reduced pressure to give the crude titled compound (5.40 g). The crude product was used for the next step without further purification. 1H NMR (300 MHZ, DMSO-d6) δ 8.15-8.19 (m, 1H), 7.94-7.97 (m, 1H), 7.77-7.82 (m, 1H), 7.26 (t, J=84.0 Hz, 1H).
To a mixture of 2-bromo-1-(difluoromethyl)-3-nitrobenzene (2.00 g) in NMP (20 mL) were added Li Br (688 mg) and CuCN (851 mg). The mixture was stirred under microwave irradiation at 200° C. for 1 hr. The mixture was poured into water and the insoluble material was removed by filtration through a Celite® pad. The filtrate was extracted with EtOAc. The organic layer was separated, washed with brine dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (540 mg). 1H NMR (300 MHZ, DMSO-d6) δ 8.54-8.57 (m, 1H), 8.23-8.26 (m, 1H), 8.10-8.16 (m, 1H), 7.41 (t, J=56.0 Hz, 1H).
A mixture of 2-(difluoromethyl)-6-nitrobenzonitrile (540 mg) and 10% palladium-carbon (60.0 mg) in EtOH (5.0 mL) was stirred under hydrogen atmosphere at room temperature for 14 hr. The catalyst was removed by filtration, and then the filtrate was concentrated under reduced pressure to give the titled compound (460 mg).
MS m/z 167.2 [M−H]−.
The reaction and purification were performed according to Example 409 Step E to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.08-8.12 (m, 1H), 7.75-7.88 (m, 2H), 7.27 (t, J=54.0 Hz, 1H).
The reaction and purification were performed according to Example 392 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.42 (s, 1H), 8.38-8.41 (m, 1H), 8.28 (s, 1H), 8.22-8.28 (m, 1H), 8.06-8.11 (m, 1H), 7.95-8.01 (m, 2H), 7.61-7.64 (m, 1H), 7.55-7.58 (m, 1H), 7.40-7.45 (m, 1H), 7.63 (t, J=54.0 Hz, 1H), 7.04-7.08 (m, 1H), 4.95-5.03 (m, 1H), 4.70-4.89 (m, 2H), 1.30 (d, J=6.1 Hz, 3H); MS m/z 473.1 [M+H]+.
A mixture of 2-bromo-6-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyridine (510 mg), 5-chloropyrazolo[1,5-a]pyrimidine (549 mg), (Bpi n)2 (2.27 g), cataCXium® A (256 mg), Pd(OAc)2 (80.3 mg) and CsF (1.35 g) in THF (10 mL) and water (2.5 mL) was stirred under microwave irradiation at 120° C. for 2 hr. The mixture was partitioned between EtOAc and aqueous NaHCO3 solution. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the titled compound (133 mg). 1H NMR (300 MHZ, CDCl3) δ 8.76 (dd, J=0.9, 7.3 Hz, 1H), 8.69 (s, 1H), 8.19-8.14 (m, 2H), 7.83-7.75 (m, 2H), 6.83 (dd, J=0.8, 8.2 Hz, 1H), 6.75 (dd, J=0.8, 2.4 Hz, 1H), 5.86-5.76 (m, 1H), 4.89-4.82 (m, 1H), 4.77-4.70 (m, 1H), 1.49 (d, J=6.4 Hz, 3H); MS m/z 323.1 [M+1]+.
The reaction and purification were performed according to Example 1 Step G to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.71 (d, J=7.3 Hz, 1H), 8.67 (s, 1H), 8.30 (dd, J=0.7, 7.5 Hz, 1H), 8.14 (s, 1H), 7.87-7.78 (m, 2H), 6.85 (dd, J=0.7, 8.2 Hz, 1H), 5.82 (dt, J=3.6, 6.6 Hz, 1H), 4.89-4.81 (m, 1H), 4.78-4.70 (m, 1H), 1.49 (d, J=6.3 Hz, 3H); MS m/z 401.1, 403.1 [M+1]+.
The reaction and purification were performed according to Example 1 Step H to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.45 (s, 1H), 9.40 (d, J=7.3 Hz, 1H), 8.83 (s, 1H), 8.12-8.04 (m, 4H), 7.99-7.93 (m, 1H), 7.42 (dt, J=2.7, 8.4 Hz, 1H), 6.98 (dd, J=0.7, 8.2 Hz, 1H), 5.87 (dt, J=3.5, 6.6 Hz, 1H), 5.00-4.91 (m, 1H), 4.88-4.79 (m, 1H), 1.42 (d, J=6.3 Hz, 3H); MS m/z 442.2 [M+1]+.
To a mixture of 1-bromo-2-(difluoromethyl)-4-fluorobenzene (4.70 g) and sulfuric acid (30 mL) was added nitric acid (2.7 mL) at 0° C. After being stirred at 0° C. for 4 hr, the mixture was poured into iced water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound containing a regioisomer (4.10 g). 1H NMR (300 MHZ, DMSO-d6) δ 8.33 (dd, J=2.9, 7.8 Hz, 1H), 7.94 (dd, J=3.0, 8.5 Hz, 1H), 7.26 (t, J=53.5 Hz, 1H).
The reaction and purification were performed according to Example 413 Step B to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.58 (dd, J=2.6, 8.3 Hz, 1H), 8.24 (dd, J=2.5, 8.0 Hz, 1H), 7.40 (t, J=53.4 Hz, 1H).
The reaction and purification were performed according to Example 413 Step C to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 7.04 (t, J=54.3 Hz, 1H), 6.77-6.63 (m, 4H); m/z 185.1 [M+H]+.
The reaction and purification were performed according to Example 409 Step E to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.20 (dd, J=2.5, 8.2 Hz, 1H), 7.82 (dd, J=2.3, 8.7 Hz, 1H), 7.26 (t, J=53.9 Hz, 1H).
The reaction and purification were performed according to Example 392 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.47 (d, J=9.6 Hz, 1H), 8.37 (s, 1H), 8.30-8.18 (m, 2H), 7.94-7.86 (m, 2H), 7.82-7.76 (m, 1H), 7.39 (t, J=53.8 Hz, 1H), 6.99-6.90 (m, 1H), 5.92-5.73 (m, 1H), 4.98-4.90 (m, 1H), 4.88-4.77 (m, 1H), 1.41 (d, J=6.3 Hz, 3H); m/z 492.1 [M+H]+.
To a mixture of 2-amino-6-bromobenzonitrile (1.00 g) and tri butyl(1-ethoxyvinyl) tin (2.19 g) in toluene (20 mL) was added Pd(PPh3) 2Cl2 (177 mg). After being stirred under argon atmosphere at 100° C. for 4 hr, 1N aqueous HCl solution was added to the mixture at room temperature. After being stirred for 2 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the crude titled compound (820 mg). The crude product was used for the next step without further purification.
MS m/z 161.0 [M+H]+.
The reaction and purification were performed according to Example 409 Step E to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.15-8.18 (m, 1H), 8.10-8.14 (m, 1H), 7.75-7.80 (m, 1H), 2.65 (s, 3H).
To a mixture of 2-acetyl-6-bromobenzonitrile (510 mg), (Bpin)2 (1.15 g), KOAc (445 mg) in toluene (10 mL) was added Pd(dppf) Cl2 (185 mg). The mixture was stirred under nitrogen atmosphere at 100° C. for 4 hr. The mixture was passed through a Celite® pad to remove insoluble materials and the filtrate was concentrated under reduced pressure to give the crude titled compound (620 mg). The crude product was used for the next step without further purification.
MS m/z 272.0 [M+H]+(detected as the boronic acid). D) 2-acetyl-6-[6-(3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl)imidazo[1, 2-b]pyridazin-3-yl]benzonitrile
The reaction and purification were performed according to Example 121 Step C to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.37-8.40 (m, 1H), 8.26-8.29 (m, 1H), 8.21 (s, 1H), 8.00-8.06 (m, 1H), 7.92-7.95 (m, 1H), 7.56-7.61 (m, 2H), 7.36-7.45 (m, 1H), 7.02-7.07 (m, 1H), 4.95-5.03 (m, 1H), 4.70-4.89 (m, 2H), 2.75 (s, 3H), 1.31 (d, J=6.1 Hz, 3H); MS m/z 465.1 [M+H]+.
The reaction and purification were performed according to Example 413 Step A to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.42 (s, 1H), 8.39 (d, J=9.5 Hz, 1H), 8.26 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.89-8.01 (m, 3H), 7.59-7.63 (m, 1H), 7.51-7.56 (m, 1H), 7.40-7.45 (m, 1H), 7.04-7.09 (m, 1H), 4.95-5.03 (m, 1H), 4.70-4.89 (m, 2H), 2.18 (t, J=19.1 Hz, 3H), 1.31 (d, J=6.1 Hz, 3H); MS m/z 487.1 [M+H]+.
A mixture of 2-[6-(4-fluoro-3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl)imidazo[1, 2-b]pyridazin-3-yl]-4-methoxypyridine-3-carbonitrile (604 mg), TMSCl (2.78 g) and Nal (959 mg) in CH3CN (30 mL) was stirred at 80° C. for 6 hr. Then 5% aqueous Na2S2O3 solution was added to the mixture. The mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and water. The mixture was stirred at room temperature for a while and then the precipitate was collected by filtration to give the titled compound (373 mg). 1H NMR (300 MHZ, DMSO-d6) 12.58 (brs, 1H), 9.40 (s, 1H), 8.47 (d, J=9.6 Hz, 1H), 8.41 (s, 1H), 8.08 (d, J=9.6 Hz, 1H), 7.97 (brs, 1H), 7.88 (dd, J=2.0, 8.1 Hz, 1H), 7.74 (ddd, J=2.1, 4.4, 8.6 Hz, 1H), 7.42 (dd, J=8.6, 11.0 Hz, 1H), 6.44 (brs, 1H), 5.07 (dt, J=3.5, 6.7 Hz, 1H), 4.96-4.88 (m, 1H), 4.87-4.79 (m, 1H), 1.38 (d, J=6.1 Hz, 3H); MS m/z 458.3 [M+1]+.
A mixture of 2-[6-(4-fluoro-3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl)imidazo[1, 2-b]pyridazin-3-yl]-4-oxo-1, 4-dihydropyridine-3-carbonitrile (200 mg), fluoromethyl 4-methyl benzenesulfonate (445 mg) and CS2CO3 (426 mg) in DMF (6.0 mL) was stirred at 70° C. for 16.5 hr. The mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) and recrystallization from EtOAc to give the titled compound (108 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.39 (s, 1H), 8.96 (d, J=5.9 Hz, 1H), 8.44 (d, J=9.5 Hz, 1H), 8.32 (s, 1H), 8.03 (d, J=9.6 Hz, 1H), 7.88 (dd, J=2.1, 8.1 Hz, 1H), 7.71 (ddd, J=2.0, 4.3, 8.6 Hz, 1H), 7.60 (d, J=5.2 Hz, 1H), 7.40 (dd, J=8.6, 11.0 Hz, 1H), 6.36-6.11 (m, 2H), 5.11-5.00 (m, 1H), 4.94-4.88 (m, 1H), 4.86-4.78 (m, 1H), 1.38 (d, J=6.1 Hz, 3H); MS m/z 490.3 [M+1]+.
The reaction and purification were performed according to Example 326 Step B to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.75 (s, 1H), 7.29-7.20 (m, 4H), 7.06 (dd, J=2.8, 8.2 Hz, 1H), 5.57 (dquin, J=3.7, 6.4 Hz, 1H), 4.84-4.77 (m, 1H), 4.74-4.67 (m, 1H), 1.45 (d, J=6.3 Hz, 3H); MS m/z 302.0, 304.0 [M+1]+.
The reaction and purification were performed according to Example 298 Step B to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.79 (s, 1H), 8.06-7.97 (m, 3H), 7.92-7.88 (m, 1H), 7.81 (d, J=1.2 Hz, 1H), 7.52 (dd, J=8.3, 9.4 Hz, 1H), 5.83-5.72 (m, 1H), 4.91-4.85 (m, 1H), 4.81-4.73 (m, 1H), 1.56 (d, J=6.3 Hz, 3H); MS m/z 341.2 [M+1]+.
The reaction and purification were performed according to Example 1 Step G to give the titled compound. 1H NMR (300 MHZ, CDCl3) δ 8.78 (s, 1H), 8.13 (dd, J=3.2, 8.3 Hz, 1H), 8.05-8.01 (m, 1H), 7.98-7.94 (m, 1H), 7.81 (s, 1H), 7.55 (dd, J=8.3, 9.4 Hz, 1H), 5.82-5.73 (m, 1H), 4.92-4.84 (m, 1H), 4.82-4.73 (m, 1H), 1.56 (d, J=6.3 Hz, 3H); MS m/z 419.0, 421.0 [M+1]+.
The reaction and purification were performed according to Example 321 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.42 (s, 1H), 8.44 (d, J=9.5 Hz, 1H), 8.28 (s, 1H), 8.16 (d, J=9.5 Hz, 1H), 7.97-7.87 (m, 1H), 7.84-7.76 (m, 1H), 7.55 (dd, J=2.1, 9.4 Hz, 1H), 7.37 (dd, J=1.8, 10.9 Hz, 1H), 5.99-5.86 (m, 1H), 5.03-4.92 (m, 1H), 4.92-4.81 (m, 1H), 4.03 (s, 3H), 1.45 (d, J=6.3 Hz, 3H); MS m/z 490.3 [M+1]+.
To a mixture of 4-chloro-2-methoxy-6-nitroaniline (23.4 g) in CH3CN (200 mL) was added 48% aqueous HBr solution (96.8 g). Then a solution of NaNO2 (8.69 g) in water (100 mL) was added portionwise to the mixture. The mixture was stirred at room temperature for 1 hr. CuBr (19.7 g) was added portinowise to the mixture. After being stirred at room temperature for 1 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was passed through an NH silica gel pad to give the titled compound (23.5 g). 1H NMR (300 MHZ, DMSO-d6) δ 7.78 (d, J=2.3 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 3.98 (s, 3H).
The reaction and purification were performed according to Example 413 Step B to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.02 (d, J=1.8 Hz, 1H), 7.89 (d, J=1.8 Hz, 1H), 4.06 (s, 3H).
To a mixture of 4-chloro-2-methoxy-6-nitrobenzonitrile (7.46 g) and in AcOH (100 mL) was added iron (19.5 g). The mixture was stirred at 80° C. for 1 hr. The mixture was filtered through a Celite® pad and the filtrate was extracted with EtOAc.
The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give the titled compound (4.60 g). 1H NMR (300 MHZ, DMSO-d6) δ 6.42 (d, J=1.7 Hz, 1H), 6.32 (brs, 2H), 6.31 (d, J=1.7 Hz, 1H), 3.82 (s, 3H).
The reaction and purification were performed according to Example 284 Step A to give the titled compound.
MS m/z 384.9 [M+H]+.
The reaction and purification were performed according to Example 284 Step B and C to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.83 (s, 1H), 8.23 (d, J=8.3 Hz, 1H), 7.68 (s, 2H), 7.63 (d, J=8.3 Hz, 1H), 4.07 (s, 3H); MS m/z 364.8 [M+H]+.
The reaction and purification were performed according to Example 326 Step B to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.68 (s, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 5.56-5.59 (m, 1H), 4.75-4.83 (m, 1H), 4.66-4.74 (m, 1H), 1.44 (d, J=6.4 Hz, 3H); MS m/z=285.2, 286.7 [M+H]+.
The reaction and purification were performed according to Example 393 Step E and F to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.48 (s, 1H), 8.95 (d, J=8.1 Hz, 2H), 8.44 (d, J=8.3 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.30 (s, 1H), 7.74 (d, J=1.7 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 5.89-5.79 (m, 1H), 5.02-4.83 (m, 2H), 4.18-4.06 (m, 3H), 1.42 (d, J=6.3 Hz, 3H); MS m/z 489.1 [M+H]+
To a mixture of 2-bromo-4fluoro-6-methoxybenzoltrile (301 mg), 6-chloroimidazo[1, 2-b]pyridazine (205 mg), KOAc (256 mg) and xylene (30 mL) was added Pd(PPh3)4 (151 mg). After being stirred under nitrogen atmosphere at 130° C. for 14 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) and washed with IPE to give the titled compound (236 mg). 1H NMR (300 MHZ, DMSO-d6) δ 8.38 (d, J=9.5 Hz, 1H), 8.25 (s, 1H), 7.54 (d, J=9.5 Hz, 1H), 7.43 (dd, J=2.3, 9.4 Hz, 1H), 7.38 (dd, J=2.3, 10.9 Hz, 1H), 4.02 (s, 3H); MS m/z 302.9 [M+H]+.
A mixture of 1, 2, 4-triazole (2.00 g,) and (S)-(−)-propylene oxide (1.85 g) was stirred at 32° C. for 24 hr. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the titled compound (2.40 g). 1H NMR (400 MHZ, CDCl3) δ 8.09 (s, 1H), 7.89 (s, 1H), 4.15-4.30 (m, 2H), 4.00-4.10 (m, 1H), 3.45 (d, J=4.0 Hz, 1H), 1.26 (d, J=6.4 Hz, 3H).
To a mixture of (2S)-1-(1H-1, 2, 4-triazol-1-yl) propan-2-ol (271 mg) and THF (5.0 mL) was added 60% NaH in oil (92.0 mg). After being stirred at room temperature for 10 min, 2, 6-dibromopyridine (499 mg) was added to the mixture. After being stirred at room temperature for 3 days, 60% NaH in oil (92.0 mg) was added to the mixture. After being stirred at 70° C. for 2 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (287 mg). 1H NMR (300 MHZ, DMSO-d6) δ 8.49 (s, 1H), 7.92 (s, 1H), 7.62 (dd, J=7.6, 8.1 Hz, 1H), 7.19 (dd, J=0.6, 7.5 Hz, 1H), 6.78 (dd, J=0.6, 8.2 Hz, 1H), 5.46-5.36 (m, 1H), 4.51-4.44 (m, 2H), 1.28 (d, J=6.4 Hz, 3H); MS m/z 282.9, 284.9 [M+H]+.
The reaction and purification were performed according to Example 298 Step B to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 8.52 (s, 1H), 8.44 (d, J=9.5 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J=9.5 Hz, 1H), 7.96-7.87 (m, 2H), 7.79 (d, J=6.8 Hz, 1H), 7.56 (dd, J=2.2, 9.5 Hz, 1H), 7.37 (dd, J=2.3, 10.9 Hz, 1H), 6.92 (dd, J=0.6, 8.1 Hz, 1H), 5.82-5.67 (m, 1H), 4.60-4.52 (m, 2H), 4.03 (s, 3H), 1.39 (d, J=6.4 Hz, 3H); m/z 471.1 [M+H]+.
The reaction and purification were performed according to Example 435 Step A to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.46 (s, 1H), 8.45 (d, J=9.5 Hz, 1H), 8.39 (s, 1H), 8.06 (d, J=9.5 Hz, 1H), 8.03-7.94 (m, 1H), 7.71-7.65 (m, 2H), 7.46 (t, J=7.9 Hz, 1H), 7.09 (dd, J=2.1, 7.8 Hz, 1H), 6.54-6.36 (m, 1H), 5.10-4.96 (m, 1H), 4.92-4.83 (m, 1H), 4.82-4.72 (m, 1H), 1.34 (d, J=6.1 Hz, 3H), NH was not assigned; m/z 440.3 [M+H]+.
The reaction and purification were performed according to Example 435 Step B to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.96 (d, J=6.0 Hz, 1H), 8.42 (d, J=9.6 Hz, 1H), 8.31 (s, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.68-7.59 (m, 3H), 7.44 (t, J=8.1 Hz, 1H), 7.10-7.03 (m, 1H), 6.24 (d, J=51.5 Hz, 2H), 5.05-4.94 (m, 1H), 4.92-4.83 (m, 1H), 4.81-4.73 (m, 1H), 1.34 (d, J=6.1 Hz, 3H); m/z 472.3 [M+H]+.
To a mixture of 2, 6-dichloropyridine-3-carbonitrile (1.68 g) in DMSO (15 mL) was added portionwise KF (1.81 g) at 0° C. The mixture was stirred at room temperature for 48 hr. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (175 mg). 1H NMR (300 MHZ, DMSO-d6) δ 8.63 (dd, J=8.1, 8.8 Hz, 1H), 7.80 (dd, J=1.2, 8.1 Hz, 1H).
The reaction and purification were performed according to Example 321 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.78 (dd, J=7.6, 8.5 Hz, 1H), 8.43 (d, J=9.6 Hz, 1H), 8.38 (s, 1H), 8.05 (d, J=9.6 Hz, 1H), 7.73-7.63 (m, 2H), 7.56 (dd, J=3.0, 8.6 Hz, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.10-7.03 (m, 1H), 5.06-4.95 (m, 1H), 4.91-4.71 (m, 2H), 1.34 (d, J=6.1 Hz, 3H); m/z 442.2 [M+H]+.
To a solution of 1-dodecanethiol (858 mg) in DCM (12 mL) was added AlCl3 (565 mg) was added at 0° C. After being stirred at room temperature for 5 min, 4-fluoro-2-methoxy-6-[5-(6-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}pyridin-2-yl)-3H-imidazo[4, 5-b]pyridin-3-yl]benzonitrile (100 mg) was added. After being stirred at room temperature for 14.5 hr, the mixture was concentrated under reduced pressure. The mixture was partitioned between EtOAc and 0.1N aqueous HCl solution. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) and then preparative HPLC (water/CH3CN containing 0.1% TFA). The desi red fraction was neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to give the titled compound (10.7 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.76 (s, 1H), 8.38-8.31 (m, 2H), 7.91-7.87 (m, 1H), 7.85-7.79 (m, 1H), 6.81 (dd, J=1.1, 7.9 Hz, 1H), 6.79-6.65 (m, 1H), 6.62-6.46 (m, 1H), 5.88-5.76 (m, 1H), 4.99-4.90 (m, 1H), 4.87-4.79 (m, 1H), 1.40 (d, J=6.4 Hz, 3H) (The OH proton was not observed.); MS m/z 458.2 [M+H]+.
A mixture of 2-[6-(4-fluoro-3-{[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]oxy}phenyl)imidazo[1, 2-b]pyridazin-3-yl]-4-oxo-1, 4-dihydropyridine-3-carbonitrile (161 mg), iodomethane-d3 (152 mg) and K2CO3 (97.1 mg) in DMF (5.0 mL) was stirred at room temperature for 1 hr. Then the mixture was partitioned between EtOAc and water. The organic layer was washed with 5% aqueous Na2S2O3 solution and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the titled compound (23.8 mg) as a light yellow solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.40 (s, 1H), 8.85 (d, J=6.1 Hz, 1H), 8.42 (d, J=9.4 Hz, 1H), 8.27 (s, 1H), 8.01 (d, J=9.5 Hz, 1H), 7.88 (d, J=7.3 Hz, 1H), 7.76-7.67 (m, 1H), 7.48-7.36 (m, 2H), 5.03 (dd, J=3.2, 6.0 Hz, 1H), 4.97-4.88 (m, 1H), 4.87-4.77 (m, 1H), 1.38 (d, J=5.9 Hz, 3H); MS m/z 475.2 [M+H]+.
The reaction and purification were performed according to example 473 to give the titled compound. 1H NMR (300 MHZ, DMSO-d6) δ 9.44 (s, 1H), 8.87 (s, 1H), 8.39 (s, 2H), 7.87-7.80 (m, 2H), 7.59-7.47 (m, 2H), 6.86-6.78 (m, 1H), 5.91-5.77 (m, 1H), 5.00-4.89 (m, 1H), 4.87-4.78 (m, 1H), 1.40 (d, J=6.0 Hz, 3H); MS m/z 475.2 [M+H]+.
A mixture of (2R)-2-(5-bromo-2-fluorophenoxy)-3-(1H-tetrazol-1-yl) propan-1-ol (386 mg), nonafluorobutanesulfonyl fluoride (2.19 g), triethyl amine tri hydrofluoride (1.16 g) and TEA (1.46 g) in THF (15 mL) was stirred at room temperature for 1.5 hr. Then the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the titled compound (376 mg). 1H NMR (300 MHZ, CDCl3) δ 8.77 (s, 1H), 7.20-7.14 (m, 1H), 7.09 (dd, J=2.3, 7.3 Hz, 1H), 6.98 (dd, J=8.8, 10.7 Hz, 1H), 4.96-4.80 (m, 2H), 4.79-4.63 (m, 2H), 4.61-4.46 (m, 1H); MS m/z 319.1, 321.1 [M+H]+.
A mixture of 1-[(2R)-2-(5-bromo-2-fluorophenoxy)-3-fluoropropyl]-1H-tetrazole (124 mg), (Bpi n)2 (118 mg), Pd(dppf) Cl2—CH2Cl2 (15.8 mg) and KOAc (76.2 mg) in DME (4.0 mL) was stirred under argon atmosphere at 100° C. for 2 hr. Then the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
A mixture of the residue, 2-{6-chloroimidazo[1, 2-b]pyridazin-3-yl}-4-methoxypyridine-3-carbonitrile (100 mg), Pd(PPh3) 4 (20.2 mg) and K2CO3 (143 mg) in THF (10 mL) and water (1.0 mL) was stirred under argon atmosphere at 70° C. for 4 hr. Then the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the titled compound (13.9 mg) as a white solid. 1H NMR (300 MHZ, DMSO-d6) δ 9.43 (s, 1H), 8.86 (d, J=6.1 Hz, 1H), 8.44 (d, J=9.6 Hz, 1H), 8.27 (s, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.86 (dd, J=2.0, 8.1 Hz, 1H), 7.74 (ddd, J=2.1, 4.4, 8.5 Hz, 1H), 7.45-7.38 (m, 2H), 5.33-5.19 (m, 1H), 5.09-4.96 (m, 2H), 4.96-4.64 (m, 2H), 4.11 (s, 3H); MS m/z 490.0 [M+H]+.
To a mixture of methyl(2R)-2, 3-dihydroxypropanoate (6.88 g) in DCM (45 mL) were added imidazole (7.80 g) and TBSCl (9.50 g) at 0° C. After being stirred under nitrogen atmosphere at room temperature for 2 hr, the mixture was poured into water and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (9.19 g). 1H NMR (400 MHZ, DMSO-d6) δ 4.20-4.24 (m, 1H), 3.87-3.92 (m, 1H), 3.84-3.86 (m, 1H), 3.78 (s, 3H), 3.02 (d, J=7.6 Hz, 1H), 0.87 (s, 9H), 0.05 (d, J=6.0 Hz, 6H).
To a mixture of methyl(2R)-3-[(tert-butyl dimethyl silyl)oxy]-2-hydroxypropanoate (9.10 g), 5-bromo-2-fluorophenol (4.94 g), PPh3 (10.2 g) in THF (100 mL) was added DIAD (7.85 g) at 0° C. After being stirred under nitrogen atmosphere at 10° C. for 12 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (10.0 g). 1H NMR (400 MHZ, CDCl3) δ 7.06-7.12 (m, 2H), 6.96 (dd, J=8.8, 2.0 Hz, 1H), 4.73 (d, J=4.8 Hz, 1H), 4.09 (d, J=4.8 Hz, 2H), 3.79 (s, 3H), 0.88 (s, 9H), 0.08 (d, J=7.6 Hz, 6H).
To a solution of (2S)-2-(5-bromo-2-fluorophenoxy)-3-[(tert-butyl dimethyl silyl)oxy]propanoate (10.0 g) in THF (40 mL) and
MeOH (60 mL) was portionwise added NaBH4 (2.49 g) at 0° C. After being stirred at 10° C. for 12 hr, the mixture was quenched with saturated aqueous NH4Cl solution and water at 0° C. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (8.90 g). 1H NMR (400 MHZ, CDCl3) δ 7.29 (dd, J=7.6, 2.4 Hz, 1H), 7.02-7.08 (m, 1H), 6.91-6.98 (m, 1H), 4.30-4.38 (m, 1H), 3.82-3.92 (m, 4H), 0.88 (s, 9H), 0.62 (d, J=6.8 Hz, 6H). (The OH proton was not observed.)
To a solution of (2R)-2-(5-bromo-2-fluorophenoxy)-3-[(tert-butyl dimethyl silyl)oxy]propan-1-ol (8.90 g) and TEA (4.75 g) in THF (80 mL) was dropwise added MsCl (5.27 g) at 0° C. After being stirred under nitrogen atmosphere at 10° C. for 1 hr, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the titled compound (9.77 g). 1H NMR (400 MHZ, CDCl3) δ 7.24 (dd, J=7.2, 2.4 Hz, 1H), 7.06-7.12 (m, 1H), 6.97 (dd, J=10.8, 8.8 Hz, 1H), 4.42-4.55 (m, 3H), 3.80-3.89 (m, 2H), 3.05 (s, 3H), 0.88 (s, 9H), 0.61 (d, J=6.4 Hz, 6H).
To a mixture of (2S)-2-(5-bromo-2-fluorophenoxy)-3-[(tert-butyl dimethyl silyl)oxy]propyl methanesulfonate (9.77 g) and 1H-tetrazole (2.99 g) in DMF (80 mL) was added K2CO3 (5.90 g). After being stirred under nitrogen atmosphere at 80° C. for 12 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (3.30 g). 1H NMR (400 MHZ, CDCl3) δ 8.76 (s, 1H), 7.08-7.13 (m, 2H), 6.91-6.97 (m, 1H), 4.84-4.89 (m, 1H), 4.72-4.79 (m, 1H), 4.56-4.64 (m, 1H), 3.71-3.82 (m, 2H), 0.90 (s, 9H), 0.62 (d, J=7.6 Hz, 6H).
To a mixture of 1-[(2R)-2-(5-bromo-2-fluorophenoxy)-3-[(tert-butyl dimethyl silyl)oxy]propyl]-1H-tetrazole (3.30 g) in THF (30 mL) was added 1M TBAF THE solution (15 mL) at 0° C. After being stirred under nitrogen atmosphere at 10° C. for 12 hr, the mixture was diluted with saturated aqueous NaHCO3 solution and water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (2.16 g). 1H NMR (400 MHZ, CDCl3) δ 8.78 (s, 1H), 7.10-7.15 (m, CH), 7.08 (dd, J=7.2, 2.0 Hz, 1H), 6.97 (dd, J=10.8, 8.8 Hz, 1H), 4.86-4.90 (m, 2H), 4.60-4.68 (m, 1H), 3.76-3.89 (m, 2H), 2.36 (brs, 1H); MS m/z 317.1, 319.1 [M+H]+.
To a mixture of (2R)-2-(5-bromo-2-fluorophenoxy)-3-(1H-tetrazol-1-yl) propan-1-ol (300 mg) and (Bpi n)2 (360 mg) in DMSO (4.0 mL) were added KOAc (186 mg) and Pd(dppf)Cl2 (35.0 mg). After being stirred under nitrogen atmosphere at 100° C. for 2 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (262 mg). 1H NMR (400 MHZ, CDCl3) δ 8.79 (s, CH), 7.45-7.49 (m, 1H), 7.34 (dd, J=8.8, 1.2 Hz, 1H), 7.09 (dd, J=11.2, 8.0 Hz, 1H), 4.83-4.93 (m, 2H), 4.66-4.71 (m, 1H), 3.73-3.85 (m, 2H), 1.33 (s, 12H). (The OH proton was not observed.)
To a mixture of (2R)-2-[2-fluoro-5-(4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenoxy]-3-(1H-tetrazol-1-yl) propan-1-ol (262 mg) and 2-{6-chloroimidazo[1, 2-b]pyridazin-3-yl}-4-methoxypyridine-3-carbonitrile (137 mg) in DME (3.0 mL) and water (0.30 mL) were added Cs2CO3 (313 mg) and Pd(PPh3)4 (55.0 mg). After being stirred under nitrogen atmosphere at 70° C. for 4 hr, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/EtOAc) to give the titled compound (170 mg) as a yellow solid. 1H NMR (400 MHZ, DMSO-d6) δ 9.39 (s, 1H), 8.85 (d, J=6.0 Hz, 1H), 8.42 (d, J=9.2 Hz, 1H), 8.26 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.86 (dd, J=8.4, 2.0 Hz, 1H), 7.67-7.72 (m, 1H), 7.43 (d, J=6.0 Hz, 1H), 7.38 (dd, J=10.8, 8.4 Hz, 1H), 5.25 (t, J=5.2 Hz, 1H), 4.90-4.94 (m, 3H), 4.11 (s, 3H), 3.74-3.80 (m, 1H), 3.65-3.71 (m, 1H); MS m/z 488.0 [M+H]+.
To a mixture of 4-nitrobenzenesulfonyl chloride (6.41 g) in DCM (55 mL) were added 5-bromo-2-fluoroaniline (5.00 g) and pyridine (2.50 g) at 0° C. After being stirred under nitrogen atmosphere at 10° C. for 12 hr, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (9.00 g). 1H NMR (400 MHZ, CDCl3) δ 8.31-8.34 (m, 2H), 7.96-7.99 (m, 2H), 7.79 (dd, J=6.8, 2.4 Hz, 1H), 7.27-7.29 (m, 1H), 6.91 (dd, J=10.0, 8.8 Hz, 1H), 6.77 (s, 1H).
To a mixture of N-(5-bromo-2-fluorophenyl)-4-nitrobenzene-1-sulfonamide (5.00 g), tert-butyl N-[(2R)-2-hydroxypropyl]carbamate (2.57 g) and PPh3 (5.24 g) in THF (50 mL) was added DIAD (4.04 g) at 0° C., After being stirred under nitrogen atmosphere at 10° C. for 12 hr, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (3.20 g). 1H NMR (400 MHZ, CDCl3) δ 8.31-8.36 (m, 2H), 7.86-7.99 (m, 2H), 7.54-7.27 (m, 1H), 7.25-7.01 (m, 2H), 6.81-6.91 (m, 1H), 3.02-3.31 (m, 2H), 2.53-2.85 (m, 1H), 1.45 (s, 9H), 1.02-1.11 (m, 3H).
The reaction and purification were performed according to Example 325 Step C to give the titled compound. 1H NMR (400 MHZ, DMSO-d6) δ 8.47 (d, J=8.8 Hz, 2H), 8.05-8.19 (m, 5H), 7.76-7.81 (m, 1H), 7.31-7.55 (m, 2H), 4.46-4.63 (m, 1H), 2.91-3.05 (m, 1H), 2.71-2.81 (m, 1H), 0.95-1.11 (m, 3H); MS m/z 432.0, 434.0 [M+H]+.
The reaction and purification were performed according to Example 325 Step D to give the titled compound.
MS m/z 460.0, 462.0 [M+H]+.
The reaction and purification were performed according to Example 325 Step E to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.72 (s, 1H), 8.34 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 7.56-7.60 (m, 1H), 6.96-7.24 (m, 2H), 4.66-4.76 (m, 2H), 4.35-4.42 (m, 1H), 1.15-1.31 (m, 3H).
The reaction and purification were performed according to Example 57 Step E to give the titled compound. 1H NMR (400 MHZ, CDCl3) δ 8.71 (s, 1H), 8.31 (d, J=9.2 Hz, 2H), 7.82-7.91 (m, 3H), 7.43-7.71 (m, 1H), 7.19 (s, 1H), 4.56-4.91 (m, 2H), 4.30-4.41 (m, 1H), 1.33 (s, 12H), 1.24-1.28 (m, 3H); MS m/z 533.2 [M+H]+.
To a mixture of mercaptoacetic acid (125 mg), N-[2-fluoro-5-(4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)phenyl]-4-nitro-N-[(2S)-1-(1H-tetrazol-1-yl)propan-2-yl]benzene-1-sulfonamide (240 mg) in DMF (4.0 mL) was added Li OH (49.0 mg). After being stirred under nitrogen atmosphere at 10° C. for 4 hr, the mixture was quenched with saturated aqueous NaHCO3 solution and water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/PE) to give the titled compound (65.0 mg). 1H NMR (400 MHZ, CDCl3) δ 8.57 (s, 1H), 7.18-7.22 (m, 1H), 7.10 (d, J=9.2 Hz, 1H), 7.02 (dd, J=12.0, 8.0 Hz, 1H), 4.51-4.67 (m, 2H), 4.09-4.14 (m, 1H), 1.34 (s, 12H), 1.27 (d, J=6.4 Hz, 3H) (The NH proton was not observed.); MS m/z 348.1 [M+H]+.
To a mixture of 2-fluoro-5-(4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-N-[(2S)-1-(1H-tetrazol-1-yl) propan-2-yl]aniline (65.0 mg) and 2-{6-chloroimidazo[1, 2-b]pyridazin-3-yl}-4-methoxypyridine-3-carbonitrile (36.0 mg) in DME (1.0 mL) and water (0.10 mL) were added Pd(PPh3)4 (14.0 mg) and CS2CO3 (81.0 mg). After being stirred under nitrogen atmosphere at 70° C. for 4 hr, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM) and then preparative TLC (MeOH/DCM) to give the titled compound (13.0 mg) as a yellow solid. 1H NMR (400 MHZ, DMSO-de) 9.32 (s, 1H), 8.85 (d, J=6.0 Hz, 1H), 8.38 (d, J=9.6 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J=9.6 Hz, 1H), 7.40-7.49 (m, 2H), 7.17-7.28 (m, 2H), 5.74 (d, J=8.0 Hz, 1H), 4.61-4.73 (m, 2H), 4.16-4.25 (m, 1H), 4.01 (s, 3H), 1.21 (d, J=6.4 Hz, 3H); MS m/z 471.1 [M+H]+.
The compounds of the Examples 1 to 486 in the following Table 1 were produced according to the methods described in the above-mentioned Examples, or methods analogous thereto. The MS of the compounds of Examples 1 to 486 are shown in the following Table 1. MS in the tables means actual measured val ue.
In vitro CaMKIIδ inhibitory activity was evaluated by a binding assay.
Full-length, glutathione-S-transferase(GST)-tagged, human CaMKIIδ was purchased from Carna Biosciences (product #02-111, Kobe, Japan). Full-length bovine calmodulin was purchased from Wako Pure Chemical Industries (Osaka, Japan). Terbium-labeled anti-GST anti body (Tb-anti-GST Ab) was purchased from Life Technologies (Carlsbad, CA, USA). Fluorescent probe ligand, 5, 5-difluoro-7, 9-dimethyl-3-(3-oxo-3-((3-((4-(3-(piperazin-1-yl)phenyl) pyrimidin-2-yl)amino) phenyl)amino) propyl)-5H-dipyrrolo[1, 2-c: 2′, 1′-f] [1, 3, 2]diazaborinin-4-ium-5-uide, was described in WO 2018/183112 A1.
(iii) Methods
Time-resolved fluorescence resonance energy transfer (TR-FRET) assay
All assays were conducted using 384-well, white, flat-bottomed plates (product #784075, Greiner Bio-One, Frickenhausen, Germany) in kinase assay buffer, which consists of 50 mM HEPES pH 7.2-7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Brig-35, 0.1 mM DTT). The fluorescent probe ligand, 5, 5-difluoro-7, 9-dimethyl-3-(3-oxo-3-((3-((4-(3-(piperazin-1-yl)phenyl)pyrimidin-2-yl)amino) phenyl)amino) propyl)-5H-dipyrrolo[1, 2-c: 2′, 1′-f] [1, 3, 2]diazaborinin-4-ium-5-uide was added at a final concentration of 300 nM to solutions containing 0.21 nM Tb-anti-GST Ab, 1 mM CaCl2, 10 μg/mL calmodulin, and 0.5 nM GST-tagged CaMKIIδ. After shaded incubation of the protein-probe mixture on ice for 30 min, the premix was dispensed in the assay plate including test inhibitors with 4 fold dilution series of eight concentrations. After 1 hr incubation at room temperature, TR-FRET signals were measured in duplicate using an EnVision microplate reader (Perkin Elmer, Waltham, MA, USA). The solution in each well was excited with a laser (λ=340 nm) reflected by a dichroic mirror (D400/D505 (Perkin Elmer) through an excitation filter (UV (TRF) 340, (Perkin Elmer)), and fluorescence from Tb and BODIPY were detected through two emission filters (CFP 495 (Perkin Elmer) for Tb, Emission 520 (Perkin Elmer) for BODIPY). The percentage of inhibition of test compounds was calculated according to equation (1)
Inhibition(%)=100×(μH-T)/(μH-μL) (1)
Where T is the value of the wells containing test compounds and μH and μL are the mean values of the 0% and 100% inhibition control wells, respectively. The values of the 0 and 100% inhibition controls were the signals obtained in the absence and presence of high concentration (3 μM) of a parent compound of the fluorescent probe ligand (without the fluorophore), respectively. The half maximal inhibitory concentration (IC50) of test compounds was calculated by fitting the data with the logistic equation using XLfit (IDBS, Guildford, UK). The IC50 was classified according to the following activity ranks.
The results are shown in Table 1.
Evaluation of in vivo cardiac CaMKII inhibition (oral administration)
To evaluate potency of test compounds to inhibit cardiac CaMKII in vivo, phosphorylation levels of the CaMKII-specific phosphorylation site of phosphol amban (Thr17, P-PLN) were measured in the heart of rats administered orally with test compounds.
Test compounds were suspended in 0.5% [w/v] methyl cellulose/water solution and administered (30 mg/kg) to male CD (SD) IGS rats (6-8 weeks old, n=4) by oral gavage (5 ml/kg). At 2 hours after the administration, rats were sacrificed and the hearts were harvested. After washing the isolated hearts with ice-cold saline, connective tissues were removed on ice, and the isolated left ventricle were frozen into liquid nitrogen gas and stored at −80° C.
The left ventricle samples were homogenized in RIPA-buffer containing phosphatase inhibitors and protease inhibitors. Samples were analyzed by Western blotting using anti-P-PLN (Thr17) anti body (Santa Cruz Biotechnology, sc-17024-R). The band intensities were quantified using an imaging system and were normalized relative to the vehicle-treated group.
(iii) Results
Four compounds from the examples were tested two hours after administration at a dose of 30 mg/kg and each compound had a P-PLN reduction rate of >25% compared to the vehicle-treated group.
Medicaments containing the compound of the present invention as an active ingredient can be produced, for example, by the following formulations.
1. capsule
The total amount of the above-mentioned (1), (2) and (3) and 5 mg of (4) are blended and granulated, and 5 mg of the remaining (4) is added. The whole mixture is sealed in a gelatin capsule.
2. tablet
The total amount of the above-mentioned (1), (2) and (3), 20 mg of (4) and 2.5 mg of (5) are blended and granulated, and 10 mg of the remaining (4) and 2.5 mg of the remaining (5) are added and the mixture is compression formed to give a tablet.
According to the present invention, a fused heteroaryl compound having a superior CaMKII inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of cardiac diseases (particularly catechol aminergic polymorphic ventricular tachycardia, postoperative atrial fibrillation, heart failure, fatal arrhythmia) and the like can be provided.
The present application claims priority to and the benefit of U. S. Provisional Application No. 63/084,217, filed on Sep. 28, 2020, which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63084217 | Sep 2020 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 17485137 | Sep 2021 | US |
| Child | 18238949 | US |
