WO2021190616A1 - Methods for inhibiting casein kinases - Google Patents
Methods for inhibiting casein kinases Download PDFInfo
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- WO2021190616A1 WO2021190616A1 PCT/CN2021/083135 CN2021083135W WO2021190616A1 WO 2021190616 A1 WO2021190616 A1 WO 2021190616A1 CN 2021083135 W CN2021083135 W CN 2021083135W WO 2021190616 A1 WO2021190616 A1 WO 2021190616A1
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- WIPO (PCT)
- Prior art keywords
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- fluorophenyl
- hydrocarbyl
- mmol
- compound
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- 238000000034 method Methods 0.000 title claims abstract description 79
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 17
- 108010031425 Casein Kinases Proteins 0.000 title description 2
- 102000005403 Casein Kinases Human genes 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 274
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- 230000000694 effects Effects 0.000 claims abstract description 16
- 125000001424 substituent group Chemical group 0.000 claims description 137
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 95
- 125000003118 aryl group Chemical group 0.000 claims description 76
- 229910052757 nitrogen Inorganic materials 0.000 claims description 68
- -1 hydroxy, mercapto, hydroxycarbonyl Chemical group 0.000 claims description 62
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
- 125000005842 heteroatom Chemical group 0.000 claims description 58
- 125000004432 carbon atom Chemical group C* 0.000 claims description 55
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 55
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 125000001145 hydrido group Chemical group *[H] 0.000 claims description 49
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 47
- 229910052799 carbon Inorganic materials 0.000 claims description 44
- 125000001072 heteroaryl group Chemical group 0.000 claims description 44
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- 238000000338 in vitro Methods 0.000 claims description 14
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- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 12
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Definitions
- the circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation of the clock is implicated in a number of human disorders, including depression, seasonal affective disorder, and metabolic disorders.
- the circadian clock may regulate multiple downstream rhythms, such as those in sleep and awakening, body temperature, and hormone secretion (Ko and Takahashi, Hum Mol Gen 15: R271-R277. ) .
- diseases such as depression, seasonal affective disorder, and metabolic disorders, may have a circadian origin (Barnard and Nolan, PLoS Genet. 2008 May; 4 (5) : e1000040. ) .
- circadian clock proteins Phosphorylation of circadian clock proteins is an essential element in controlling the cyclical rhythm of the clock.
- Casein kinase I delta (CK1 ⁇ ) or CK1 epsilon (CK1 ⁇ ) are closely related Ser-Thr protein kinases that serve as key clock regulators as demonstrated by mammalian mutations in each that dramatically alter the circadian period. Therefore, inhibitors of CK1 ⁇ / ⁇ may be used for treating circadian disorders and other related disorders.
- the present application provides methods for inhibiting CK1 ⁇ and/or CK1 ⁇ , as well as methods and compositions for treating related diseases and/or disorders.
- the present application provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof:
- Ar l is an aryl group that is optionally substituted by one or more (e.g., 1-2, or more) R 1 substituents, and each R 1 is independently selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxido, wherein the substituent on the sulfur atom is hydrocarbyl, sulfonylamide,
- substituents on the sulfonamido nitrogen atom are hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl-hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl,
- substituent (s) on the aminohydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- substituent (s) on the amino nitrogen are selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group;
- X 1 , X 2 and X 3 are each independently C or N;
- R 7 is absent or -CN
- A is absent, or ring A
- R 2 is -NH 2 , -CN or Z
- Z is independently selected from the group consisting of: hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and -X-Y,
- -X is -O, -S or -NQ
- -Y is hydrido, hydrocarbyl or hydrocarbylaryl
- Q is hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl,
- R 3 is a halogen or -CN
- R 5 is independently selected from the group consisting of: -COO-C 1 -C 6 alkyl, -CO-R 10 and R 52 ,
- R 52 is independently selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that is substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydro
- substituent (s) on the aminohydrocarbyl nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- R 6 is C 1 -C 6 alkyl or R 61 ,
- R 61 is independently selected from the group consisting of: an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that is optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclo
- substituent (s) on the amino-hydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- R 1 is F
- the compound of Formula I comprises one of said R 1 substituent.
- R 3 is F or -CN.
- A is one of the followings:
- R 5 is -COO-CH 2 CH 3 or -CO-R 10 .
- R 10 is
- R 8 is -CH 3 .
- R 6 is -CH 3 .
- B is one of the followings:
- the compound of Formula I is selected from the group consisting of:
- X 1 is C
- X 2 is C
- X 3 is N
- R 7 is absent
- A is and B is
- R 2 is Z
- Z is -NR 23 R 24
- R 23 is hydrido, or C 1 -C 6 hydrocarbyl
- R 24 is independently selected from a group consisting of hydrido, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2 -pyridyl lower hydrocarbyl, 3 -pyridyl lower hydrocarbyl and 4-pyridyl lower hydrocarbyl,
- Ar 1 is an aryl group that is substituted by a halogen or halo group, lower hydrocarbyl, or hydrocarbyloxy group,
- R 6 is R 61 , R 61 is hydrido, or C 1 -C 6 hydrocarbyl, and
- R 5 is R 52 , R 52 is hydrido, or lower hydrocarbyl.
- X 1 is C
- X 2 is C
- X 3 is N
- R 7 is absent
- A is and B is
- R 2 is Z
- Z is -OR 25
- R 25 is hydrido, C 1 -C 6 hydrocarbyl, or aryl lower hydrocarbyl,
- Ar 1 is an aryl group that is independently substituted with a halogen, lower hydrocarbyl, or hydrocarbyloxy group,
- R 6 is R 61 , R 61 is C 1 -C 6 hydrocarbyl,
- R 5 is R 52 , R 52 is hydrido.
- X 1 is C
- X 2 is C
- X 3 is N
- R 7 is absent
- A is and B is
- R 2 is -CN
- Ar 1 is an aryl group that is substituted by a halogen, lower hydrocarbyl or a hydrocarbyloxy group,
- R 6 is R 61 , R 61 is lower hydrocarbyl, and
- R 5 is R 52 , R 52 is hydrido or lower hydrocarbyl.
- the present application provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula II, or a pharmaceutically acceptable salt thereof:
- R 1 is a halogen
- n 0, 1 or 2
- X 1 , X 2 , X 3 , X 4 , X 5 and X 6 are each independently C or N,
- R 3 is absent or -CN
- A is absent, or ring A
- R 4 is a halogen
- R 5 is selected from the group consisting of: -NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH and C 1 -C 6 alkyl-O-CO-C 1 -C 6 alkyl,
- R 1 is F
- n 1
- n 2
- R 4 is F
- R 5 is selected from the group consisting of: -NH 2 , -CH 3 , -CH 2 -NH-CH 3 , -CH 2 -OH and -CH 2 -O-CO-CH 3 .
- A is selected from the group consisting of:
- the number of R 7 is 1 or 2.
- B is selected from the group consisting of:
- the compound of Formula II is selected from the group consisting of:
- the present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula III, or a pharmaceutically acceptable salt thereof:
- R 1 is a halogen
- n 0, 1, or 2
- X 1 and X 2 are each independently C or N,
- A is absent, or ring A
- R 2 is C 1 -C 6 alkyl
- R 4 is -CN, -COO-C 1 -C 6 alkyl, or amido group
- R 5 is C 1 -C 6 alkyl
- R 1 is F
- n 1
- R 2 is -CH 3 .
- R 4 is -CN, -CO-NH 2 , or -COO-CH 3 .
- R 5 is -CH 3 .
- C is selected from the group consisting of:
- the compound of Formula III is selected from the group consisting of:
- the present application provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula IV, or a pharmaceutically acceptable salt thereof:
- R 1 is a halogen
- n 0, 1 or 2
- R 1 is F
- n 1
- R 2 is
- the compound of Formula IV is selected from the group consisting of:
- the method is an in vitro method, an ex vivo method, or an in vivo method.
- the present application also provides a method for treating a neurological and/or psychiatric disease or disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of any one of Formula I ⁇ IV or a pharmaceutically acceptable salt thereof.
- the disease or disorder is a mood disorder, a sleep disorder or a circadian disorder.
- the mood disorder is selected from the group consisting of a depressive disorder and a bipolar disorder.
- a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, is administered:
- FIG. 1 illustrates the synthetic scheme of compound 2-1.
- FIG. 2 illustrates the synthetic scheme of compound 3-8.
- FIG. 3 illustrates the synthetic scheme of compounds 2-5, 2-6, 2-7 and 2-8.
- FIG. 4 illustrates the synthetic scheme of compound 1-2.
- FIG. 5 illustrates the synthetic scheme of compounds 2-12, 2-13 and 2-14.
- FIG. 6 illustrates the synthetic scheme of compound 1-4.
- FIG. 7 illustrates the synthetic scheme of compound 2-16.
- FIG. 8 illustrates the synthetic scheme of compounds 3-4, 3-5, 3-2 and 3-1.
- FIG. 9 illustrates the synthetic scheme of compound 1-10.
- FIG. 10 illustrates the synthetic scheme of compound 3-7.
- FIG. 11 illustrates the synthetic scheme of compound 2-27.
- FIG. 12 illustrates the synthetic scheme of compound 2-28.
- FIG. 13 illustrates the synthetic scheme of compounds 2-29 and 2-31.
- FIG. 14 illustrates the synthetic scheme of compound 2-30.
- FIG. 15 illustrates the synthetic scheme of compound 2-33.
- FIG. 16 illustrates the synthetic scheme of compound 2-34.
- FIG. 17 illustrates the synthetic scheme of compound 2-32.
- FIG. 18 illustrates the synthetic scheme of compound 2-36.
- FIG. 19 illustrates the synthetic scheme of compound 1-5.
- FIG. 20 illustrates the synthetic scheme of compound 1-13.
- FIGs. 21 -24 illustrate the synthetic schemes of compounds 2-37 to 2-40.
- FIG. 25 illustrates the synthetic scheme of compound 3-11.
- FIG. 26 illustrates the synthetic scheme of compound 2-41.
- FIG. 27 illustrates the synthetic scheme of compound 3-12.
- FIGs. 28 -29 illustrate the synthetic schemes of compounds 2-42 to 2-43.
- FIG. 30 illustrates the synthetic scheme of compound 3-13.
- FIGs. 31 -36 illustrate the synthetic schemes of compounds 2-44 to 2-49.
- FIG. 37 illustrates the synthetic scheme of compound 3-14.
- FIGs. 38 -49 illustrate the synthetic schemes of compounds 2-50 to 2-61.
- alkyl generally refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; for example, from one to twelve carbon atoms; in another example, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms (such as 1, 2, 3 or more carbon atoms) .
- substituents include e.g., methyl, ethyl, propyl (including n-propyl and isopropyl) , butyl (including n-butyl, isobutyl, sec-butyl and terf-butyl) , pentyl, isoamyl, hexyl and the like.
- the number of carbon atoms in a hydrocarbyl substituent i.e., alkyl, alkenyl, cycloalkyl, aryl, etc.
- C 1 -C 6 alkyl refers to an alkyl substituent containing from 1 to 6 carbon atoms.
- alkyl may be optionally further substituted.
- cycloalkyl generally refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Cycloalkyl may be a single ring, which typically contains from 4 to 7 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- cycloalkyl may be 2 or 3 rings fused together, such as bicyclo [4.2.0] octane and decalinyl and may also be referred to as “bicycloalkyl” .
- cycloalkyl may be optionally further substituted.
- cycloalkyl also includes substituents that are fused to a C 6 -C 10 aromatic ring or to a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group.
- a fused cycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyl group.
- the fused C 6 -C 10 aromatic ring or 5-10-membered heteroaromatic ring may be optionally further substituted.
- cycloalkyl may be optionally further substituted.
- halogen generally refers to fluorine (which may be depicted as -F) , chlorine (which may be depicted as -Cl) , bromine (which may be depicted as -Br) , or iodine (which may be depicted as -I) .
- the halogen is chlorine.
- the halogen is fluorine.
- the halogen is bromine.
- heterocycloalkyl generally refers to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g., an atom other than C) , such as oxygen, nitrogen or sulfur.
- a heteroatom e.g., an atom other than C
- oxygen, nitrogen or sulfur such as oxygen, nitrogen or sulfur.
- 4-to 7-membered heterocycloalkyl means the substituent is a single ring with 4 to 7 total members.
- a heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen or sulfur) .
- the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
- heterocycloalkyl substituent is in turn substituted with a group or substituent
- the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
- heterocycloalkyl may be optionally further substituted.
- heterocycloalkyl also includes substituents that are fused to a C 6-10 aromatic ring or to a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group.
- a fused heterocycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group.
- the fused C 6 -C 10 aromatic ring or 5-to 10-membered heteroaromatic ring may be optionally further substituted.
- heterocycloalkyl may be optionally further substituted.
- heteroaryl generally refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (for example, oxygen, nitrogen, or sulfur) , with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
- a heteroaryl may be a single ring or 2 or 3 fused rings.
- heteroaryl substituents include but are not limited to: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2, 3-, 1, 2, 4-, 1, 2, 5-, or 1, 3, 4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-
- the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
- the heteroaryl substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom.
- heteroaryl may be optionally further substituted.
- heteroaryl also includes substituents such as pyridyl and quinolinyl that are fused to a C 4-10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4-10-mennbered heterocyclic ring, wherein a group having such a fused heteroaryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group.
- the one or more substituents are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group.
- the fused C 4-10 carbocyclic or 4-10-membered heterocyclic ring may be optionally further substituted.
- heteroaryl may be optionally further substituted.
- aryl generally refers to an aromatic substituent containing one ring or two or three fused rings.
- the aryl substituent may have six to eighteen carbon atoms.
- the aryl substituent may have six to fourteen carbon atoms.
- the term “aryl” may refer to substituents such as phenyl, naphthyl and anthracenyl.
- aryl may also include substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4-10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4-to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
- substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4-10 carbocyclic ring, such as a C 5 or a C 6 carbocyclic ring, or to a 4-to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group.
- substituents such as phenyl, naphthyl and anthracenyl that are fused to a C 4-10
- the fused C 4-10 carbocyclic or 4-to 10-membered heterocyclic ring may optionally be further substituted.
- aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl” ) , indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as “phenalenyl” ) , and fluorenyl.
- aryl may be optionally further substituted.
- the number of atoms in a cyclic substituent containing one or more heteroatoms is indicated by the prefix "X-Y-membered” , wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent.
- 5-to 8-membered heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one or more heteroatoms, in the cyclic moiety of the heterocycloalkyl.
- hydrogen generally refers to a hydrogen substituent, and may be depicted as -H.
- hydroxy or “hydroxyl” generally refers to -OH.
- the prefix “hydroxy” generally indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents.
- Compounds bearing a carbon to which one or more hydroxy substituents are attached include, for example, alcohols, enols and phenol. For example, hydroxy may be optionally further substituted.
- cyano (also referred to as “nitrile” ) generally means -CN.
- a substituent is “substitutable” or can be “substituted” if it comprises at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms.
- hydrogen, halogen, and cyano do not fall within this definition.
- a substituent is described as being “substituted, ” a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon or nitrogen of the substituent.
- a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent.
- monofluoroalkyl is alkyl substituted with a fluoro substituent
- difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated) .
- substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent.
- R’ and R together with the nitrogen atom to which they are attached may form a heterocyclic ring comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted.
- the heterocyclic ring formed from R’ and R” together with the nitrogen atom to which they are attached may be partially or fully saturated, or aromatic. In one embodiment, the heterocyclic ring consists of 4 to 10 atoms.
- each substituent is selected independent of the other (s) .
- Each substituent therefore may be identical to or different from the other substituent (s) .
- Form I (or Formula II, Formula III, or Formula IV) may be hereinafter referred to as a “compound (s) of the invention” .
- Such terms are also defined to include all forms of the compound of Formula I (or Formula II, Formula III, or Formula IV) , including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof.
- the compounds of Formula I, or pharmaceutically acceptable salts thereof may exist in unsolvated and solvated forms.
- the solvent or water When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
- the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
- the compounds of “Formula I” may have asymmetric carbon atoms.
- the carbon-carbon bonds of the compounds of Formula I may be depicted herein using a solid line, a solid wedge, or a dotted wedge.
- the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc. ) at that carbon atom are included.
- the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the present application may contain more than one asymmetric carbon atom.
- a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
- the compounds of Formula I (or Formula II, Formula III, or Formula IV) can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
- the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of Formula I (or Formula II, Formula III, or Formula IV) and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
- the compounds of the present application may exist as clathrates or other complexes. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of Formula I (or Formula II, Formula III, or Formula IV) containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts.
- the resulting complexes may be ionized, partially ionized, or non-ionized.
- J. Pharm. Sci., 64 (8) , 1269-1288 by Haleblian (August 1975) See J. Pharm. Sci., 64 (8) , 1269-1288 by Haleblian (August 1975) .
- Stereoisomers of Formula I include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of Formula I (or Formula II, Formula III, or Formula IV) , including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs) .
- acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
- the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
- the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
- the compounds of Formula I may exhibit the phenomena of tautomerism and structural isomerism.
- the compounds of Formula I may exist in several tautomeric forms, including the enol and imine forms, and the keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of Formula I (or Formula II, Formula III, or Formula IV) .
- Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the compounds of Formula I (or Formula II, Formula III, or Formula IV) .
- the present application also includes isotopically-labeled compounds, which are identical to those recited in Formula I (or Formula II, Formula III, or Formula IV) above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that may be incorporated into compounds of Formula I (or Formula II, Formula III, or Formula IV) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl.
- isotopically-labeled compounds of Formula I for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
- Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes may be used for their ease of preparation and detectability.
- substitution with heavier isotopes such as deuterium, i.e., 2 H can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances.
- Isotopically-labeled compounds of Formula I may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
- the compounds of the present application may be used in the form of salts derived from inorganic or organic acids.
- a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidity, or a desirable solubility in water or oil.
- a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
- treating generally means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
- treatment generally refers to the act of treating as “treating” is defined immediately above.
- treating may also include adjuvant and neo-adjuvant treatment of a subject.
- salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context)
- pharmaceutically acceptable salt generally refers to a salt prepared by combining a compound of the present application (e.g., a compound of any of Formula I -IV) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption.
- Pharmaceutically acceptable salts are particularly useful as products of the methods of the present application because of their greater aqueous solubility relative to the parent compound.
- the salts of the compounds of this application are non-toxic “pharmaceutically acceptable salts. ”
- Salts encompassed within the term “pharmaceutically acceptable salts” generally refer to non-toxic salts of the compounds of the present application which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
- a compound of the present application is administered in an amount effective to treat a condition as described herein.
- the compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
- Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts.
- the term “therapeutically effective amount” as used herein generally refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
- the present application provides a method for inhibiting CK1 delta or CK1 epsilon activity.
- the method may comprise administering an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof:
- Ar l may be an aryl group that may be optionally substituted by one or more (e.g., 1-2, or more) R 1 substituents, and each R 1 may be independently selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl and sulfoxido, wherein the substituent on the sulfur atom may be hydrocarbyl, sulfonylamide,
- substituents on the sulfonamido nitrogen atom may be hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl- hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl,
- substituent (s) on the aminohydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- substituent (s) on the amino nitrogen may be selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group;
- X 1 , X 2 and X 3 each may independently be C or N;
- R 7 may be absent or -CN
- A may be absent, or ring A,
- R 2 may be -NH 2 , -CN or Z
- Z may be independently selected from the group consisting of: hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and -X-Y,
- -X may be -O, -S or -NQ
- -Y may be hydrido, hydrocarbyl or hydrocarbylaryl
- Q may be hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl,
- R 3 may be a halogen or -CN
- B may be absent, or ring B,
- R 5 may be independently selected from the group consisting of: -COO-C 1 -C 6 alkyl, -CO-R 10 and R 52 ,
- R 52 may be independently selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that may be substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl
- substituent (s) on the aminohydrocarbyl nitrogen may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- R 6 may be C 1 -C 6 alkyl or R 61 ,
- R 61 may be independently selected from the group consisting of: an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that may be optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy,
- substituent (s) on the amino-hydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- the compound of Formula I may comprise a compound of Formula Ia:
- each R 1 may be independently selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl and sulfoxido, wherein the substituent on the sulfur atom may be hydrocarbyl, sulfonylamide,
- substituents on the sulfonamido nitrogen atom may be hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl-hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl,
- substituent (s) on the aminohydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- substituent (s) on the amino nitrogen may be selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group;
- X 1 , X 2 and X 3 each may independently be C or N;
- R 7 may be absent or -CN
- A may be absent, or ring A,
- R 2 may be -NH 2 , -CN or Z
- Z may be independently selected from the group consisting of: hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and -X-Y,
- -X may be -O, -S or -NQ
- -Y may be hydrido, hydrocarbyl or hydrocarbylaryl
- Q may be hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl,
- R 3 may be a halogen or -CN
- B may be absent, or ring B,
- R 5 may be independently selected from the group consisting of: -COO-C 1 -C 6 alkyl, -CO-R 10 and R 52 ,
- R 52 may be independently selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that may be substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl
- substituent (s) on the aminohydrocarbyl nitrogen may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- R 6 may be C 1 -C 6 alkyl or R 61 ,
- R 61 may be independently selected from the group consisting of: an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that may be optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy,
- substituent (s) on the amino-hydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
- the compound of Formula I may comprise a compound of Formula Ia:
- each R 1 may independently be a halogen
- n may be 0, 1, or 2
- X 1 , X 2 and X 3 may each independently be C or N;
- R 7 may be absent or -CN
- A may be absent, or ring A,
- R 2 may be -NH 2 , or -CN,
- R 3 may be a halogen or -CN
- B may be absent, or ring B,
- R 5 may independently be selected from the group consisting of: -COO-C 1 -C 6 alkyl, and -CO-R 10 ,
- R 6 may be C 1 -C 6 alkyl
- R 1 may be F.
- n 1
- R 3 may be F or -CN.
- A in the compound of Formula I or Formula Ia, A may be one of the followings:
- R 5 may be -COO-CH 2 CH 3 or -CO-R 10 .
- R 10 may be any organic compound of Formula I or Formula Ia.
- R 8 may be -CH 3 .
- R 6 may be -CH 3 .
- B in the compound of Formula I or Formula Ia, B may be one of the followings:
- the compound of Formula I or Formula Ia may be a compound in table 1.
- X 1 may be C
- X 2 may be C
- X 3 may be N
- R 7 may be absent
- A may be and B may be
- R 2 may be Z
- Z may be -NR 23 R 24 ,
- R 23 may be hydrido, or C 1 -C 6 hydrocarbyl
- R 24 may be independently selected from a group consisting of hydrido, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2 -pyridyl lower hydrocarbyl, 3 -pyridyl lower hydrocarbyl and 4-pyridyl lower hydrocarbyl;
- Ar 1 may be an aryl group that may be substituted by a halogen or halo group, lower hydrocarbyl, or hydrocarbyloxy group;
- R 6 may be R 61 , R 61 may be hydrido, or C 1 -C 6 hydrocarbyl;
- R 5 may be R 52 , R 52 may be hydrido, or lower hydrocarbyl.
- X 1 may be C
- X 2 may be C
- X 3 may be N
- R 7 may be absent
- A may be and B may be
- R 2 may be Z
- Z may be -OR 25
- R 25 may be hydrido, C 1 -C 6 hydrocarbyl, or aryl lower hydrocarbyl;
- Ar 1 may be an aryl group that may be independently substituted with a halogen, lower hydrocarbyl, or hydrocarbyloxy group;
- R 6 may be R 61 , R 61 may be C 1 -C 6 hydrocarbyl; and
- R 5 may be R 52 , R 52 may be hydrido.
- X 1 may be C
- X 2 may be C
- X 3 may be N
- R 7 may be absent
- A may be and B may be
- R 2 may be -CN
- Ar 1 may be an aryl group that may be substituted by a halogen, lower hydrocarbyl or a hydrocarbyloxy group;
- R 6 may be R 61 , R 61 may be lower hydrocarbyl;
- R 5 may be R 52 , R 52 may be hydrido or lower hydrocarbyl.
- the compound of Formula I may also include any of the compounds described in WO 99/58523, which is incorporated herein by reference in its entirety.
- the present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula II, or a pharmaceutically acceptable salt thereof:
- R 1 may be a halogen
- n may be 0, 1 or 2;
- X 1 , X 2 , X 3 , X 4 , X 5 and X 6 may each independently be C or N;
- R 3 may be absent or -CN
- A may be absent, or ring A,
- R 4 may be a halogen
- R 5 may be selected from the group consisting of: -NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-NH-C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH and C 1 -C 6 alkyl-O-CO-C 1 -C 6 alkyl,
- R 1 may be F.
- n 1
- n may be 2.
- R 4 may be F.
- R 5 may be selected from the group consisting of: -NH 2 , -CH 3 , -CH 2 -NH-CH 3 , -CH 2 -OH and -CH 2 -O-CO-CH 3 .
- A in the compound of Formula II, A may be selected from the group consisting of:
- the number of R 7 may be 1 or 2.
- B may be selected from the group consisting of:
- X 1 may be C.
- X 6 may be N.
- R 1 may be F
- n may be 1
- X 1 and X 3 may be C
- X 2 and X 6 may be N
- R 2 and R 3 may be absent
- R n1 and R n2 may independently be optionally substituted
- R 1 may be F
- n may be 1
- X 1 and X 3 may be C
- X 2 and X 6 may be N
- R 2 and R 3 may be absent
- R 1 may be F
- n may be 1
- X 1 and X 3 may be C
- X 2 and X 6 may be N
- R 2 and R 3 may be absent
- B may be selected from the group consisting of: and said B may be optionally substituted.
- R 1 may be F
- n may be 1
- X 1 and X 3 may be C
- X 2 and X 6 may be N
- R 2 and R 3 may be absent
- B may be and said B may be optionally substituted with C 1 -C 6 alkyl or CO-C 1 -C 6 alkyl
- the compound of Formula II may be one of the compounds in tables 2-1 ⁇ 2-2.
- the present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula III, or a pharmaceutically acceptable salt thereof:
- R 1 may be a halogen
- n may be 0, 1, or 2;
- X 1 and X 2 may each independently be C or N;
- A may be absent, or ring A
- R 2 may be C 1 -C 6 alkyl
- C may be or ring C
- R 4 may be -CN, -COO-C 1 -C 6 alkyl, or amido group
- R 5 may be C 1 -C 6 alkyl
- R 1 may be F.
- n 1
- R 2 may be -CH 3 .
- the compound may have a structure of wherein, R 1 may be a halogen, n may be 0, 1, or 2, R A1 , R A2 and R A3 may independently be selected from C and N.
- R A1 may be N.
- A in the compound of Formula III, A may be
- R 4 may be -CN, -CO-NH 2 , or -COO-CH 3 .
- R 5 may be -CH 3 .
- C may be selected from the group consisting of:
- the compound of Formula III may be one of the compounds in table 3.
- the present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula IV, or a pharmaceutically acceptable salt thereof:
- R 1 may be a halogen
- n may be 0, 1 or 2;
- R 1 in the compound of Formula IV, R 1 may be F.
- n 1
- R 2 may be
- the compound of Formula IV may be one of the ompounds in table 4.
- the method may be an in vitro method, an ex vivo method, or an in vivo method.
- the compounds of the present application e.g., the compounds of Formula I –Formula IV
- the compounds of the present application e.g., the compounds of Formula I –Formula IV
- the present application also provides a method for treating a neurological and/or psychiatric disease or disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of any one of Formula I ⁇ IV or a pharmaceutically acceptable salt thereof.
- the disease or disorder is a mood disorder, a sleep disorder or a circadian disorder.
- the mood disorder is selected from the group consisting of a depressive disorder and a bipolar disorder.
- the method of the present application may also comprise administering to a subject in need thereof a pharmaceutical composition comprising one or more compounds of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
- the compounds of the present application may be administered orally.
- Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
- the compounds of the present application may also be administered directly into the blood stream, into muscle, or into an internal organ.
- Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
- Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
- the compounds of the present application may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the present application can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present application may be administered rectally or vaginally. In another embodiment, the compounds of the present application may also be administered directly to the eye or ear.
- the dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg, such as from about 0.1 to about 50 mg/kg, from about 0.5 to about 30 mg/kg (i.e., mg compound of the present application per kg body weight) .
- dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound may be repeated a plurality of times in a day (typically no greater than 4 times) . Multiple doses per day typically may be used to increase the total daily dose, if desired.
- compositions may be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1 . 0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient.
- a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient.
- doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
- Suitable subjects according to the present application may include mammalian subjects. Mammals according to the present application include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
- the present application comprises the use of one or more compounds of the present application for the preparation of a medicament for the treatment of the conditions recited herein.
- the compounds of the present application can be administered as compound per se.
- pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
- the present application comprises pharmaceutical compositions.
- Such pharmaceutical compositions comprise a compound of the present application presented with a pharmaceutically acceptable carrier.
- the carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05%to 95%by weight of the active compounds.
- a compound of the present application may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
- the compounds of the present application may be administered by any suitable route, may be in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
- the active compounds and compositions for example, may be administered orally, rectally, parenterally, or topically.
- the compounds of the present application can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states.
- the compound (s) of the present application and other therapeutic agent (s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
- the administration of two or more compounds “in combination” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other.
- the two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
- Standard abbreviations may be used, e.g., bp, base pair (s) ; kb, kilobase (s) ; pl, picoliter (s) ; s or sec, second (s) ; min, minute (s) ; h or hr, hour (s) ; aa, amino acid (s) ; nt, nucleotide (s) ; i.m., intramuscular (ly) ; i.p., intraperitoneal (ly) ; s.c., subcutaneous (ly) ; and the like.
- FIG. 1 illustrates the synthetic scheme of compound 2-1. As shown in FIG. 1, the specific synthesis steps are as follows:
- Step 1 methyl 2-bromo-3- (4-fluorophenyl) -3-oxopropanoate
- Step 2 methyl 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine-3-carboxylate
- Step 3 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine-3-carboxylic acid
- Step 4 2- (4-fluorophenyl) -N-methoxy-N-methylimidazo [1, 2-a] pyrazine-3-carboxamide
- Step 5 1- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) ethan-1-one
- Step 6 4- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) pyrimidin-2-amine
- FIG. 2 illustrates the synthetic scheme of compound 3-8. As shown in FIG. 2, the specific synthesis steps are as follows:
- Step 1 (Z) -3- ( (allyloxy) imino) -3- (4-fluorophenyl) propanenitrile
- FIG. 3 illustrates the synthetic scheme of compounds 2-5, 2-6, 2-7 and 2-8. As shown in FIG. 3, the specific synthesis steps are as follows:
- Step 1 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine
- Step 2 3-bromo-2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine
- Step 3 2- (4-fluorophenyl) -3- (pyridin-4-yl) imidazo [1, 2-a] pyrazine
- Step 4 2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazine
- Step 5 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6-dihydroimidazo [1, 2-a] pyrazin-7 (8H) -yl) ethan-1-one
- Step 6 2- (4-fluorophenyl) -3- (tributylstannyl) imidazo [1, 2-a] pyrazine
- Step 7 4- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) furo [3, 4-b] pyridin-5 (7H) -one
- FIG. 4 illustrates the synthetic scheme of compound 1-2. As shown in FIG. 4, the specific synthesis steps are as follows:
- Step 1 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3, 4-b] pyridin-5 (7H) -one
- FIG. 5 illustrates the synthetic scheme of compounds 2-12, 2-13 and 2-14. As shown in FIG. 5, the specific synthesis steps are as follows:
- Step 1 ethyl 3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
- Step 2 ethyl 1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
- Step 3 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
- Phenylmethanamine (4.7 g) and NaHCO 3 (3.7 g) were added to a solution of ethyl 2- (2-bromoethyl) -5- (4-fluorophenyl) pyrazole-3-carboxylate (13.5 g) and potassium iodide (13 g) in acetonitrile (200 mL) at room temperature.
- the resulting mixture was stirred at 90 °C for 16 h.
- the reaction mixture was cooled to room temperature and concentrated under pressure, diluted with water (100 mL) .
- the reaction mixture was extracted with DCM (30 mL*3) , filtered and concentrated under pressure.
- Step 4 5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 5 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 6 5-benzyl-2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 7 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 8 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- FIG. 6 illustrates the synthetic scheme of compound 1-4. As shown in FIG. 6, the specific synthesis steps are as follows:
- Step 1 2- (4-fluorophenyl) -2, 3a, 4, 5, 6, 7-hexahydro-3H-indazol-3-one
- Step 2 3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-2H-indazole
- Step 3 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-2H-indazole
- FIG. 7 illustrates the synthetic scheme of compound 2-16. As shown in FIG. 7, the specific synthesis steps are as follows:
- Step 1 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazole
- Step 2 2- (4-fluorophenyl) -1- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazole
- FIG. 8 illustrates the synthetic scheme of compounds 3-1, 3-2, 3-4 and 3-5. As shown in FIG. 8, the specific synthesis steps are as follows:
- Step 1 (E) -3- (4-fluorophenyl) -2- (pyridin-4-yl) acrylonitrile
- Step 2 methyl 3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate
- Step 3 methyl 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate
- Step 4 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid
- Step 5 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide
- Step 6 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile
- FIG. 9 illustrates the synthetic scheme of compound 1-10. As shown in FIG. 9, the specific synthesis steps are as follows:
- Step 2 4- ( (trimethylsilyl) ethynyl) pyridine
- Step 3 4- (1- (4-fluorophenyl) -1H-1, 2, 3-triazol-5-yl) pyridine
- FIG. 10 illustrates the synthetic scheme of compound 3-7. As shown in FIG. 10, the specific synthesis steps are as follows:
- Step 1 methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate
- Methyl 2-isocyanoacetate (6.18 g, 62.4 mmol) and Ag2CO3 (1.15 g, 4.2 mmol) were added to a solution of 1-ethynyl-4-fluorobenzene (5 g, 42 mmol) in NMP (20 mL) . The mixture was stirred at 80 °C for 1 h under nitrogen atmosphere. The mixture was extracted with EtOAc. The solvents were evaporated in vacuo and crude material was added to a silica gel column, was eluted with PE/EA (20: 1) . Chemical Formula: calculated for (M+H+) C12H10FNO2: 219.22, Found: 219.9.
- Step 2 methyl 3- (4-fluorophenyl) -1-methyl-1H-pyrrole-2-carboxylate
- Step 3 methyl 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylate
- Step 4 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylic acid
- Step 7 3- (4-fluorophenyl) -1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile
- Step 8 3- (4-fluorophenyl) -1-methyl-4- (5-oxo-5, 7-dihydrofuro [3, 4-b] pyridin-4-yl) -1H-pyrrole-2-carbonitrile
- FIG. 11 illustrates the synthetic scheme of compound 2-27. As shown in FIG. 11, the specific synthesis steps are as follows:
- Step 1 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) propan-1-one
- FIG. 12 illustrates the synthetic scheme of compound 2-28. As shown in FIG. 12, the specific synthesis steps are as follows:
- Step 1 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) -2-methylpropan-1-one
- FIG. 13 illustrates the synthetic scheme of compounds 2-29 and 2-31. As shown in FIG. 13, the specific synthesis steps are as follows:
- Step 1 ethyl 3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
- Step 2 ethyl 1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
- Step 3 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
- Phenylmethanamine and NaHCO 3 were added to a solution of ethyl 1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate and potassium iodide in acetonitrile (200 mL) at room temperature, the resulting mixture was stirred at 90 °C for 16 h. The mixture was cooled to room temperature. The reaction mixture was concentrated under pressure. The crude material was added to a flash chromatography and was eluted with PE/EA (3: 1) . Chemical Formula: calculated for (M+H + ) C 19 H 16 FN 3 O: 324.36, Found: 321.9.
- Step 4 5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 5 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 6 5-benzyl-2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 7 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 8 1- (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 9 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine-3-yl) -2-methylpyridine-1-oxide
- FIG. 14 illustrates the synthetic scheme of compound 2-30. As shown in FIG. 14, the specific synthesis steps are as follows:
- Step 1 methyl 1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
- Step 2 (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol
- FIG. 15 illustrates the synthetic scheme of compound 2-33. As shown in FIG. 15, the specific synthesis steps are as follows:
- Step 1 (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone
- FIG. 16 illustrates the synthetic scheme of compound 2-34. As shown in FIG. 16, the specific synthesis steps are as follows:
- CDI 500 mg, 3.08 mmol
- methenamine 95.6 mg, 3.08 mmol
- acetonitrile 3 mL
- Step 2 2- (4-fluorophenyl) -N-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazine-5 (4H) -carboxamide
- N-methyl-1H-imidazole-1-carboxamide (8.7 mg, 0.07 mol) and TEA (7.78 mg, 0.077 mol) were added to a solution of 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (20 mg, 0.07 mol) in DCM (2 mL) .
- the reaction mixture was stirred at 25 °C for 2 h.
- the mixture was concentrated, then was purified by prep-TLC and prep-HPLC to provide the product.
- FIG. 17 illustrates the synthetic scheme of compound 2-32. As shown in FIG. 17, the specific synthesis steps are as follows:
- Step 1 (4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) methyl acetate
- FIG. 18 illustrates the synthetic scheme of compound 2-36. As shown in FIG. 18, the specific synthesis steps are as follows:
- Step 1 5-benzyl-2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 2 2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 3 1- (2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- FIG. 19 illustrates the synthetic scheme of compound 1-5. As shown in FIG. 19, the specific synthesis steps are as follows:
- Step 1 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine
- FIG. 20 illustrates the synthetic scheme of compound 1-13. As shown in FIG. 20, the specific synthesis steps are as follows:
- NBS (48 mg, 0.27 mmol) was added to a solution of 1- (4-fluorophenyl) pyrrole-2-carbonitrile (50 mg, 0.27 mmol) in THF (3 mL) at 0 °C.
- the reaction mixture was stirred at 25 °C for 3 h.
- the reaction mixture was concentrated under pressure.
- Step 3 1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile
- Step 1 ethyl 3- (4-fluorophenyl) -1- (oxiran-2-ylmethyl) -1H-pyrazole-5-carboxylate
- Step 2 1- (3- (4-fluorophenyl) -5- (hydroxymethyl) -1H-pyrazol-1-yl) propan-2-ol
- Step 4 3-bromo-2- (4-fluorophenyl) -6-methyl-6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
- Step 5 2- (4-fluorophenyl) -6-methyl-3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
- Compound 2-38 was purified by HPLC (Gemini-C18 150 x 21.2 mm, 5um, ACN –H 2 O 0.1%FA, gradient 10% ⁇ 40%) to give Compound 2-38 (44.8 mg, HPLC: 100%) .
- Step 1 ethyl (R) -1- (1- ( (tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (2)
- Step 2 ethyl (R) -1- (1- ( (tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (3)
- Step 3 (R) -2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (4)
- Step 4 (R) -3-bromo-2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (5)
- Step 5 (R) -2- (4-fluorophenyl) -7-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
- Example 21 As shown in FIG. 23, the specific synthesis steps are similar to Example 21.
- Step 1 ethyl 1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
- Step 2 (1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol and 3- (3- (4-fluorophenyl) -5- (hydroxymethyl) -1H-pyrazol-1-yl) propan-1-ol
- Step 1 3- (4-fluorophenyl) -1-methyl-4- (1H-pyrazolo [3, 4-b] pyridin-4-yl) -1H-pyrrole-2-carbonitrile
- Step 2 (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol (3)
- Step 4 3-bromo-2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine (5)
- Step 1 3- (4-fluorophenyl) -1-methyl-4- (1H-pyrrolo [2, 3-b] pyridin-4-yl) -1H-pyrrole-2-carbonitrile
- Step 1 4- (2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazin-3-yl) pyridin-2-amine
- Step 1 4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
- Step 2 4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
- Step 3 1- (3- (2-aminopyridin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 1 3- (4-fluorophenyl) -4- (3H-imidazo [4, 5-b] pyridin-7-yl) -1-methyl-1H-pyrrole-2-carbonitrile
- Step1 1- (2- (4-fluorophenyl) -3- (2-methylpyrimidin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step1 1- (3- (2-ethylpyridin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 1 1- (3- (6-aminopyrimidin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 2 6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazole
- Step 3 7-bromo-6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazole
- Step 4 4- (6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazol-7-yl) pyridin-2-amine
- Step 1 (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone
- Step 1 2- (4-fluorophenyl) -5-methyl-3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
- Step 1 methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate
- Step 2 methyl 3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate
- Step 3 methyl 1- (2- ( (tert-butoxycarbonyl) amino) ethyl) -3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate
- Step 4 methyl 1- (2-aminoethyl) -3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate
- Step 5 8- (4-fluorophenyl) -7-iodo-3, 4-dihydropyrrolo [1, 2-a] pyrazin-1 (2H) -one
- Step 6 8- (4-fluorophenyl) -7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrrolo [1, 2-a] pyrazin-1 (2H) -one
- Step 7 4- (8- (4-fluorophenyl) -1-oxo-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a] pyrazin-7-yl) furo [3, 4-b] pyridin-5 (7H) -one
- Step 1 1- (4-fluorophenyl) -6-hydroxyhexane-1, 3-dione
- Step 2 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propan-1-ol
- Step 3 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propyl methanesulfonate
- Step 5 3-bromo-2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazole
- Step 6 4- (2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazol-3-yl) pyridin-2-amine
- Step 1 4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
- Step 2 4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
- Step 1 tert-butyl (4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate
- Step 2 tert-butyl (4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate
- Step 3 tert-butyl (4- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate
- Step 4 4- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
- Step 1 1- (2- (4-fluorophenyl) -3- (1H-pyrrolo [2, 3-b] pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 2 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -3, 3-dibromo-1, 3-dihydro-2H-pyrrolo [2, 3-b] pyridin-2-one
- Step 3 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -1, 3-dihydro-2H-pyrrolo [2, 3-b] pyridin-2-one
- Step 2 methyl 2- ⁇ 4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridin-2-yl ⁇ acetate
- Step 3 methyl 2- (4- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) acetate
- Step 2 1- (4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) propan-2-one
- Step 3 1- (4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) propan-2-ol
- Step 4 1- (2- (4-fluorophenyl) -3- (2- (2-hydroxypropyl) pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 1 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2, 3-dihydrofuro [3, 2-b] pyridine
- Step 2 1- (3- (2, 3-dihydrofuro [3, 2-b] pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step1 1- (3- (2, 3-dihydrofuro [3, 2-b] pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 1 1- (3-bromo-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
- Step 2 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine
- Step 1 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine
- Step 2 7- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine
- Step 1 7- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) furo [3, 2-b] pyridin-2 (3H) -one
- Step 1 7- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) furo [3, 2-b] pyridin-2 (3H) -one
- Example 50 Biological activity
- the CK1 ⁇ kinase assay was performed with a buffer (40 ⁇ L, pH 7.5) containing 50 mM Tris, 10 mM MgCl 2 , 1 mM dithiothreitol, 100 ⁇ g/mL BSA with 10 ⁇ M ATP, 2nM wild type CK1 ⁇ , and 42 ⁇ M peptide substrate PLSRTLpSVASLPGL (Flotow et al., 1990) in the presence of 1 ⁇ L of a CK1 ⁇ inhibitor (e.g., a compound of the present application) or 4%DMSO (e.g., as control) .
- a CK1 ⁇ inhibitor e.g., a compound of the present application
- 4%DMSO e.g., as control
- reaction mixture was incubated for 85 min at 25 °C; detection was carried out as described for the Kinase-Glo Assay (Promega) .
- Luminescent output was measured on the Perkin Elmer Envision plate reader (PerkinElmer, Waltham, MA) .
- Bmal1-dLuc or Per2-dLuc U2OS cells were suspended in the culture medium (DMEM supplemented with 10%fetal bovine serum, 0.29 mg/mL L-glutamine, 100 units/mL penicillin, and 100 mg/mL streptomycin) and plated onto 96-well white solid-bottom plates at 200 ⁇ L (10, 000 cells) per well.
- DMEM fetal bovine serum
- 0.29 mg/mL L-glutamine 100 units/mL penicillin
- streptomycin 100 mg/mL
- the “*” in Table 5 indicates that the value exceeds the measurement range, for example, the value is >100000.
- the “*” in Table 6 indicates that the value exceeds the measurement range, for example, the value is >30.
- Caco-2 cells were diluted to 6.86 ⁇ 10 5 cells/mL with culture medium and 50 ⁇ L of cell suspension were dispensed into the filter well of the 96-well HTS Transwell plate. Cells were cultivated for 14-18 days in a cell culture incubator at 37 °C, 5%CO 2 , 95%relative humidity. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating.
- Transepithelial electrical resistance (TEER) across the monolayer was measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA) .
- the Plate was returned to the incubator once the measurement was done.
- the TEER value was calculated according to the following equation:
- TEER measurement (ohms) *Area of membrane (cm 2 ) TEER value (ohm ⁇ cm 2 )
- TEER value should be greater than 230 ohm ⁇ cm 2 , which indicates the well-qualified Caco-2 monolayer.
- the Caco-2 plate was removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4) , and then incubated at 37 °C for 30 minutes.
- control compounds and test compounds were diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) get 5 ⁇ M working solutions.
- HBSS 10 mM HEPES, pH 7.4
- the final concentration of DMSO in the incubation system was 0.5%.
- the plates were incubated at 37 °C for 2 hours.
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Abstract
The present disclosure provides methods for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula (I) to (IV), or a pharmaceutically acceptable salt thereof.
Description
The circadian clock links our daily cycles of sleep and activity to the external environment. Deregulation of the clock is implicated in a number of human disorders, including depression, seasonal affective disorder, and metabolic disorders. For example, the circadian clock may regulate multiple downstream rhythms, such as those in sleep and awakening, body temperature, and hormone secretion (Ko and Takahashi, Hum Mol Gen 15: R271-R277. ) . Furthermore, diseases such as depression, seasonal affective disorder, and metabolic disorders, may have a circadian origin (Barnard and Nolan, PLoS Genet. 2008 May; 4 (5) : e1000040. ) .
Phosphorylation of circadian clock proteins is an essential element in controlling the cyclical rhythm of the clock. Casein kinase I delta (CK1δ) or CK1 epsilon (CK1ε) are closely related Ser-Thr protein kinases that serve as key clock regulators as demonstrated by mammalian mutations in each that dramatically alter the circadian period. Therefore, inhibitors of CK1δ/ε may be used for treating circadian disorders and other related disorders.
SUMMARY OF THE INVENTION
The present application provides methods for inhibiting CK1δ and/or CK1ε, as well as methods and compositions for treating related diseases and/or disorders.
In one aspect, the present application provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein Ar
l is an aryl group that is optionally substituted by one or more (e.g., 1-2, or more) R
1 substituents, and each R
1 is independently selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxido, wherein the substituent on the sulfur atom is hydrocarbyl, sulfonylamide,
wherein the substituents on the sulfonamido nitrogen atom are hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl-hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the aminohydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,
amino, and a N-monosubstituted or N, N-disubstituted amino group,
wherein the substituent (s) on the amino nitrogen are selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group;
wherein X
1, X
2 and X
3 are each independently C or N;
R
7 is absent or -CN;
wherein R
2 is -NH
2, -CN or Z,
wherein Z is independently selected from the group consisting of: hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and -X-Y,
wherein -X is -O, -S or -NQ,
-Y is hydrido, hydrocarbyl or hydrocarbylaryl,
Q is hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl,
wherein R
3 is a halogen or -CN,
wherein ring A is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring A is optionally substituted with a R
4 substituent, and R
4 is =O;
wherein R
5 is independently selected from the group consisting of: -COO-C
1-C
6 alkyl, -CO-R
10 and R
52,
wherein R
10 is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said R
10 is optionally substituted with a R
8 substituent, said R
8 substituent is C
1-C
6 alkyl,
wherein R
52 is independently selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that is substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarby-amino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyl-oxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroaryl-sulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclo-hydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the aminohydrocarbyl nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,
wherein R
6 is C
1-C
6 alkyl or R
61,
wherein R
61 is independently selected from the group consisting of: an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that is optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the amino-hydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,
wherein ring B is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring B is optionally substituted with a R
9 substituent, and said R
9 is PMB.
In some embodiments, in the compound of Formula I, R
1 is F.
In some embodiments, the compound of Formula I comprises one of said R
1 substituent.
In some embodiments, in the compound of Formula I, R
3 is F or -CN.
In some embodiments, in the compound of Formula I, R
5 is -COO-CH
2CH
3 or -CO-R
10.
In some embodiments, in the compound of Formula I, R
8 is -CH
3.
In some embodiments, in the compound of Formula I, R
6 is -CH
3.
In some embodiments, the compound of Formula I is selected from the group consisting of:
In some embodiments, in the compound of Formula I, X
1 is C, X
2 is C, X
3 is N, R
7 is absent, A is
and B is
wherein R
2 is Z, Z is -NR
23R
24,
R
23 is hydrido, or C
1-C
6 hydrocarbyl, R
24 is independently selected from a group consisting of hydrido, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2 -pyridyl lower hydrocarbyl, 3 -pyridyl lower hydrocarbyl and 4-pyridyl lower hydrocarbyl,
Ar
1 is an aryl group that is substituted by a halogen or halo group, lower hydrocarbyl, or hydrocarbyloxy group,
R
6 is R
61, R
61 is hydrido, or C
1-C
6 hydrocarbyl, and
R
5 is R
52, R
52 is hydrido, or lower hydrocarbyl.
In some embodiments, in the compound of Formula I, X
1 is C, X
2 is C, X
3 is N, R
7 is absent, A is
and B is
wherein R
2 is Z, Z is -OR
25,
R
25 is hydrido, C
1-C
6 hydrocarbyl, or aryl lower hydrocarbyl,
Ar
1 is an aryl group that is independently substituted with a halogen, lower hydrocarbyl, or hydrocarbyloxy group,
R
6 is R
61, R
61 is C
1-C
6 hydrocarbyl,
R
5 is R
52, R
52 is hydrido.
In some embodiments, in the compound of Formula I, X
1 is C, X
2 is C, X
3 is N, R
7 is absent, A is
and B is
wherein R
2 is -CN,
Ar
1 is an aryl group that is substituted by a halogen, lower hydrocarbyl or a hydrocarbyloxy group,
R
6 is R
61, R
61 is lower hydrocarbyl, and
R
5 is R
52, R
52 is hydrido or lower hydrocarbyl.
In another aspect, the present application provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula II, or a pharmaceutically acceptable salt thereof:
wherein R
1 is a halogen,
n is 0, 1 or 2,
X
1, X
2, X
3, X
4, X
5 and X
6 are each independently C or N,
R
2 is absent, or =O,
R
3 is absent or -CN,
wherein R
4 is a halogen,
wherein R
5 is selected from the group consisting of: -NH
2, C
1-C
6 alkyl, C
1-C
6 alkyl-NH-C
1-C
6 alkyl, C
1-C
6 alkyl-OH and C
1-C
6 alkyl-O-CO-C
1-C
6 alkyl,
wherein ring A is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring A is optionally substituted with a R
6 substituent, the R
6 is =O,
B is a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said B is optionally substituted with one or more R
7 substituents, and
wherein each R
7 is independently selected from the group consisting of: CO-C
1-C
6 alkyl, Bn, =O, C
1-C
6 alkyl, CO-NH-C
1-C
6 alkyl, CO-C
1-C
6 alkyl-CN, R
8, R
8-C
1-C
6 alkyl, and CO-R
8-C
1-C
6 alkyl, wherein R
8 is a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-.
In some embodiments, in the compound of Formula II, R
1 is F.
In some embodiments, in the compound of Formula II, n is 1.
In some embodiments, in the compound of Formula II, n is 2.
In some embodiments, in the compound of Formula II, R
4 is F.
In some embodiments, in the compound of Formula II, R
5 is selected from the group consisting of: -NH
2, -CH
3, -CH
2-NH-CH
3, -CH
2-OH and -CH
2-O-CO-CH
3.
In some embodiments, in the compound of Formula II, R
7 is selected from the group consisting of: -Bn, =O, -CH
3, -CO-CH
3, -CO-CH
2-CH
3, -CO-CH- (CH
3)
2, -CO-NH-CH
3, -CO-CH
2-CN, R
8, R
8-CH
3 and -CO-R
8-CH
3, wherein R
8 is
In some embodiments, in the compound of Formula II, the number of R
7 is 1 or 2.
In some embodiments, in the compound of Formula II, B is selected from the group consisting of:
In some embodiments, the compound of Formula II is selected from the group consisting of:
In another aspect, the present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula III, or a pharmaceutically acceptable salt thereof:
wherein R
1 is a halogen,
n is 0, 1, or 2,
X
1 and X
2 are each independently C or N,
wherein R
2 is C
1-C
6 alkyl,
ring A is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring C is optionally substituted with a R
3 substituent, R
3 is =O,
wherein R
4 is -CN, -COO-C
1-C
6 alkyl, or amido group,
R
5 is C
1-C
6 alkyl, and
ring C is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring C is optionally substituted with a R
6 substituent, R
6 is =O.
In some embodiments, in the compound of Formula III, R
1 is F.
In some embodiments, in the compound of Formula III, n is 1.
In some embodiments, in the compound of Formula III, R
2 is -CH
3.
In some embodiments, in the compound of Formula III, R
4 is -CN, -CO-NH
2, or -COO-CH
3.
In some embodiments, in the compound of Formula III, R
5 is -CH
3.
In some embodiments, the compound of Formula III is selected from the group consisting of:
In another aspect, the present application provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula IV, or a pharmaceutically acceptable salt thereof:
wherein R
1 is a halogen,
n is 0, 1 or 2,
R
2 is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said R
2 is optionally substituted with a R
3 substituent, and R
3 is =O.
In some embodiments, in the compound of Formula IV, R
1 is F.
In some embodiments, in the compound of Formula IV, n is 1.
In some embodiments, the compound of Formula IV is selected from the group consisting of:
In some embodiments, the method is an in vitro method, an ex vivo method, or an in vivo method.
In another aspect, the present application also provides a method for treating a neurological and/or psychiatric disease or disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of any one of Formula I~IV or a pharmaceutically acceptable salt thereof.
In some embodiments, the disease or disorder is a mood disorder, a sleep disorder or a circadian disorder.
In some embodiments, the mood disorder is selected from the group consisting of a depressive disorder and a bipolar disorder.
In some embodiments, in a method of the present application, a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof, is administered:
4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-2H-indazol-3-yl) pyrimidin-2-amine,
4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3, 4-b] pyridin-5 (7H) -one,
4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3, 4-b] pyridin-7 (5H) -one,
2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-2H-indazole,
4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine,
2- (4-fluorophenyl) -3- (pyridin-4-yl) -2, 4, 5, 6-tetrahydrocyclopenta [c] pyrazole,
2- (4-fluorophenyl) -5- (4-methoxybenzyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-2H-pyrazolo [4, 3-c] pyridine,
3-fluoro-4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) picolinonitrile,
4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine-2, 3-dicarbonitrile,
4- (1- (4-fluorophenyl) -1H-1, 2, 3-triazol-5-yl) pyridine,
ethyl 1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-1, 2, 3-triazole-4-carboxylate,
(1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-1, 2, 3-triazol-4-yl) (4-methylpiperazin-1-yl) methanone,
1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile,
4- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) pyrimidin-2-amine,
4- (2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazin-3-yl) pyrimidin-2-amine,
4- (2- (4-fluorophenyl) -7- (1-methylpiperidin-4-yl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazin-3-yl) pyrimidin-2-amine,
1- (3- (2-aminopyrimidin-4-yl) -2- (4-fluorophenyl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazin-7-yl) ethan-1-one,
2- (4-fluorophenyl) -3- (pyridin-4-yl) imidazo [1, 2-a] pyrazine,
2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazine,
1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6-dihydroimidazo [1, 2-a] pyrazin-7 (8H) -yl) ethan-1-one,
4- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) furo [3, 4-b] pyridin-5 (7H) -one,
4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyrimidin-2-amine,
4- (2- (4-fluorophenyl) -5- (1-methylpiperidin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyrimidin-2-amine,
1- (3- (2-aminopyrimidin-4-yl) -2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one,
5-benzyl-2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine,
2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine,
1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one,
4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazol-1-yl) pyrimidin-2-amine,
2- (4-fluorophenyl) -1- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazole,
1- (2- (4-fluorophenyl) -3- (2- ( (methylamino) methyl) pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-5-yl) ethan-1-one,
1- (2- (4-fluorophenyl) -3- (2- (hydroxymethyl) pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-5-yl) ethan-1-one,
(4- (2- (4-fluorophenyl) -5- (piperazin-1-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) methanol,
1- (2- (4-fluorophenyl) -3- (pyrimidin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-5-yl) ethan-1-one,
1- (2- (4-fluorophenyl) -3- (pyridazin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one,
1- (2- (3, 4-difluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one,
(R) -1- (2- (4-fluorophenyl) -7-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one,
2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydro-5H-pyrazolo [5, 1-b] [1, 3] oxazin-5-one,
2- (4-fluorophenyl) -5-methyl-3- (pyridin-4-yl) -4, 5-dihydropyrazolo [1, 5-a] pyrazin-6 (7H) -one,
2-acetyl-7- (4-fluorophenyl) -8- (pyridin-4-yl) -1, 2, 3, 4-tetrahydropyrrolo [1, 2-a] pyrazine-6-carbonitrile,
1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) propan-1-one,
1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) -2-methylpropan-1-one,
1- (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one,
2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine,
4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methylpyridine-1-oxide,
(4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) methyl acetate,
(2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone,
2- (4-fluorophenyl) -N-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazine-5 (4H) -carboxamide,
3- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) -3-oxopropanenitrile,
1- (2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one,
3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile,
3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide,
8- (4-fluorophenyl) -7- (pyridin-4-yl) -3, 4-dihydropyrrolo [1, 2-a] pyrazin-1 (2H) -one,
methyl 3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate,
methyl 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate,
2- (4-fluorophenyl) -4-methyl-1- (5-oxo-5, 7-dihydrofuro [3, 4-b] pyridin-4-yl) -1H-pyrrole-3-carbonitrile,
3- (4-fluorophenyl) -1-methyl-4- (5-oxo-5, 7-dihydrofuro [3, 4-b] pyridin-4-yl) -1H-pyrrole-2-carbonitrile,
2- (4-fluorophenyl) -4-methyl-1- (pyridin-4-yl) -1H-pyrrole-3-carbonitrile,
2- (4-fluorophenyl) -4-methyl-1- (2-methylpyridin-4-yl) -1H-pyrrole-3-carboxamide,
3- (4-fluorophenyl) -2- (2-methylpyridin-4-yl) -2, 5, 6, 7-tetrahydro-4H-pyrrolo [3, 4-c] pyridin-4-one,
(R) -5- (3- (4-fluorophenyl) -4- (pyridin-4-yl) isoxazol-5-yl) dihydrofuran-2 (3H) -one, and
(R) -4- (3- (4-fluorophenyl) -4- (pyridin-4-yl) isoxazol-5-yl) dihydrofuran-2 (3H) -one.
Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present application will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are employed, and the accompanying drawings (also “figure” and “FIG. ” herein) , of which:
FIG. 1 illustrates the synthetic scheme of compound 2-1.
FIG. 2 illustrates the synthetic scheme of compound 3-8.
FIG. 3 illustrates the synthetic scheme of compounds 2-5, 2-6, 2-7 and 2-8.
FIG. 4 illustrates the synthetic scheme of compound 1-2.
FIG. 5 illustrates the synthetic scheme of compounds 2-12, 2-13 and 2-14.
FIG. 6 illustrates the synthetic scheme of compound 1-4.
FIG. 7 illustrates the synthetic scheme of compound 2-16.
FIG. 8 illustrates the synthetic scheme of compounds 3-4, 3-5, 3-2 and 3-1.
FIG. 9 illustrates the synthetic scheme of compound 1-10.
FIG. 10 illustrates the synthetic scheme of compound 3-7.
FIG. 11 illustrates the synthetic scheme of compound 2-27.
FIG. 12 illustrates the synthetic scheme of compound 2-28.
FIG. 13 illustrates the synthetic scheme of compounds 2-29 and 2-31.
FIG. 14 illustrates the synthetic scheme of compound 2-30.
FIG. 15 illustrates the synthetic scheme of compound 2-33.
FIG. 16 illustrates the synthetic scheme of compound 2-34.
FIG. 17 illustrates the synthetic scheme of compound 2-32.
FIG. 18 illustrates the synthetic scheme of compound 2-36.
FIG. 19 illustrates the synthetic scheme of compound 1-5.
FIG. 20 illustrates the synthetic scheme of compound 1-13.
FIGs. 21 -24 illustrate the synthetic schemes of compounds 2-37 to 2-40.
FIG. 25 illustrates the synthetic scheme of compound 3-11.
FIG. 26 illustrates the synthetic scheme of compound 2-41.
FIG. 27 illustrates the synthetic scheme of compound 3-12.
FIGs. 28 -29 illustrate the synthetic schemes of compounds 2-42 to 2-43.
FIG. 30 illustrates the synthetic scheme of compound 3-13.
FIGs. 31 -36 illustrate the synthetic schemes of compounds 2-44 to 2-49.
FIG. 37 illustrates the synthetic scheme of compound 3-14.
FIGs. 38 -49 illustrate the synthetic schemes of compounds 2-50 to 2-61.
While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.
Definitions
As used herein, the term “alkyl” generally refers to a linear or branched-chain saturated hydrocarbyl substituent (i.e., a substituent obtained from a hydrocarbon by removal of a hydrogen) containing from one to twenty carbon atoms; for example, from one to twelve carbon atoms; in another example, from one to ten carbon atoms; in another embodiment, from one to six carbon atoms; and in another embodiment, from one to four carbon atoms (such as 1, 2, 3 or more carbon atoms) . Examples of such substituents include e.g., methyl, ethyl, propyl (including n-propyl and isopropyl) , butyl (including n-butyl, isobutyl, sec-butyl and terf-butyl) , pentyl, isoamyl, hexyl and the like. In some instances, the number of carbon atoms in a hydrocarbyl substituent (i.e., alkyl, alkenyl, cycloalkyl, aryl, etc. ) is indicated by the prefix “C
a-C
b” wherein a is the minimum and b is the maximum number of carbon atoms in the substituent. Thus, for example, “C
1-C
6 alkyl” refers to an alkyl substituent containing from 1 to 6 carbon atoms. For example, alkyl may be optionally further substituted.
As used herein, the term “cycloalkyl” generally refers to a carbocyclic substituent obtained by removing a hydrogen from a saturated carbocyclic molecule and having three to fourteen carbon atoms. In one embodiment, a cycloalkyl substituent has three to ten carbon atoms. Cycloalkyl may be a single ring, which typically contains from 4 to 7 ring atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, cycloalkyl may be 2 or 3 rings fused together, such as bicyclo [4.2.0] octane and decalinyl and may also be referred to as “bicycloalkyl” . For example, cycloalkyl may be optionally further substituted.
As used herein, the term “cycloalkyl” also includes substituents that are fused to a C
6-C
10 aromatic ring or to a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused cycloalkyl group as a substituent is bound to a carbon atom of the cycloalkyl group. When such a fused cycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a carbon atom of the cycloalkyl group. The fused C
6-C
10 aromatic ring or 5-10-membered heteroaromatic ring may be optionally further substituted. For example, cycloalkyl may be optionally further substituted.
As used herein, the term “halogen” generally refers to fluorine (which may be depicted as -F) , chlorine (which may be depicted as -Cl) , bromine (which may be depicted as -Br) , or iodine (which may be depicted as -I) . In one embodiment, the halogen is chlorine. In another embodiment, the halogen is fluorine. In another embodiment, the halogen is bromine.
As used herein, the term “heterocycloalkyl” generally refers to a substituent obtained by removing a hydrogen from a saturated or partially saturated ring structure containing a total of 4 to 14 ring atoms, wherein at least one of the ring atoms is a heteroatom (e.g., an atom other than C) , such as oxygen, nitrogen or sulfur. For example, as used herein, the term “4-to 7-membered heterocycloalkyl” means the substituent is a single ring with 4 to 7 total members. A heterocycloalkyl alternatively may comprise 2 or 3 rings fused together, wherein at least one such ring contains a heteroatom as a ring atom (i.e., nitrogen, oxygen or sulfur) . In a group that has a heterocycloalkyl substituent, the ring atom of the heterocycloalkyl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heterocycloalkyl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. For example, heterocycloalkyl may be optionally further substituted.
As used herein, the term “heterocycloalkyl” also includes substituents that are fused to a C
6-10 aromatic ring or to a 5-to 10-membered heteroaromatic ring, wherein a group having such a fused heterocycloalkyl group as a substituent is bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group. When such a fused heterocycloalkyl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to a heteroatom of the heterocycloalkyl group or to a carbon atom of the heterocycloalkyl group. The fused C
6-C
10 aromatic ring or 5-to 10-membered heteroaromatic ring may be optionally further substituted. For example, heterocycloalkyl may be optionally further substituted.
As used herein, the term “heteroaryl” generally refers to an aromatic ring structure containing from 5 to 14 ring atoms in which at least one of the ring atoms is a heteroatom (for example, oxygen, nitrogen, or sulfur) , with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include but are not limited to: 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl; 5-membered ring substituents such as triazolyl, imidazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1, 2, 3-, 1, 2, 4-, 1, 2, 5-, or 1, 3, 4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused ring substituents such as quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1, 4-benzoxazinyl. In a group that has a heteroaryl substituent, the ring atom of the heteroaryl substituent that is bound to the group may be the at least one heteroatom, or it may be a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. Similarly, if the heteroaryl substituent is in turn substituted with a group or substituent, the group or substituent may be bound to the at least one heteroatom, or it may be bound to a ring carbon atom, where the ring carbon atom may be in the same ring as the at least one heteroatom or where the ring carbon atom may be in a different ring from the at least one heteroatom. For example, heteroaryl may be optionally further substituted.
As used herein, the term “heteroaryl” also includes substituents such as pyridyl and quinolinyl that are fused to a C
4-10 carbocyclic ring, such as a C
5 or a C
6 carbocyclic ring, or to a 4-10-mennbered heterocyclic ring, wherein a group having such a fused heteroaryl group as a substituent is bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. When such a fused heteroaryl group is substituted with one or more substituents, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the heteroaryl group or to a heteroatom of the heteroaryl group. The fused C
4-10 carbocyclic or 4-10-membered heterocyclic ring may be optionally further substituted. For example, heteroaryl may be optionally further substituted.
As used herein, the term “aryl” generally refers to an aromatic substituent containing one ring or two or three fused rings. The aryl substituent may have six to eighteen carbon atoms. As an example, the aryl substituent may have six to fourteen carbon atoms. The term “aryl” may refer to substituents such as phenyl, naphthyl and anthracenyl. The term “aryl” may also include substituents such as phenyl, naphthyl and anthracenyl that are fused to a C
4-10 carbocyclic ring, such as a C
5 or a C
6 carbocyclic ring, or to a 4-to 10-membered heterocyclic ring, wherein a group having such a fused aryl group as a substituent is bound to an aromatic carbon of the aryl group. When such a fused aryl group is substituted with one more substituent, the one or more substituents, unless otherwise specified, are each bound to an aromatic carbon of the fused aryl group. The fused C
4-10 carbocyclic or 4-to 10-membered heterocyclic ring may optionally be further substituted. Examples of aryl groups include accordingly phenyl, naphthalenyl, tetrahydronaphthalenyl (also known as “tetralinyl” ) , indenyl, isoindenyl, indanyl, anthracenyl, phenanthrenyl, benzonaphthenyl (also known as “phenalenyl” ) , and fluorenyl. For example, aryl may be optionally further substituted.
In some instances, the number of atoms in a cyclic substituent containing one or more heteroatoms (i.e., heteroaryl or heterocycloalkyl) is indicated by the prefix "X-Y-membered" , wherein wherein x is the minimum and y is the maximum number of atoms forming the cyclic moiety of the substituent. Thus, for example, 5-to 8-membered heterocycloalkyl refers to a heterocycloalkyl containing from 5 to 8 atoms, including one or more heteroatoms, in the cyclic moiety of the heterocycloalkyl.
As used herein, the term “hydrogen” generally refers to a hydrogen substituent, and may be depicted as -H.
As used herein, the term “hydroxy” or “hydroxyl” generally refers to -OH. When used in combination with another term (s) , the prefix “hydroxy” generally indicates that the substituent to which the prefix is attached is substituted with one or more hydroxy substituents. Compounds bearing a carbon to which one or more hydroxy substituents are attached include, for example, alcohols, enols and phenol. For example, hydroxy may be optionally further substituted.
As used herein, the term “cyano” (also referred to as “nitrile” ) generally means -CN.
A substituent is “substitutable” or can be “substituted” if it comprises at least one carbon or nitrogen atom that is bonded to one or more hydrogen atoms. Thus, for example, hydrogen, halogen, and cyano do not fall within this definition.
If a substituent is described as being “substituted, ” a non-hydrogen substituent is in the place of a hydrogen substituent on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro substituent, and difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent may be identical or different (unless otherwise stated) .
As used herein, the terms “substituent, ” “radical, ” and “group” may be used interchangeably.
If a substituent is described as being “optionally substituted, ” the substituent may be either (1) not substituted, or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the carbon (to the extent there are any) may separately and/or together be replaced with an independently selected optional substituent. If a nitrogen of a substituent is described as being optionally substituted with one or more of a list of substituents, one or more of the hydrogens on the nitrogen (to the extent there are any) may each be replaced with an independently selected optional substituent. One exemplary substituent may be depicted as –NR’R” , wherein R’ and R” together with the nitrogen atom to which they are attached may form a heterocyclic ring comprising 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein said heterocycloalkyl moiety may be optionally substituted. The heterocyclic ring formed from R’ and R” together with the nitrogen atom to which they are attached may be partially or fully saturated, or aromatic. In one embodiment, the heterocyclic ring consists of 4 to 10 atoms.
If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other (s) . Each substituent therefore may be identical to or different from the other substituent (s) .
As used herein, the term “Formula I” (or Formula II, Formula III, or Formula IV) may be hereinafter referred to as a “compound (s) of the invention” . Such terms are also defined to include all forms of the compound of Formula I (or Formula II, Formula III, or Formula IV) , including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, and metabolites thereof. For example, the compounds of Formula I, or pharmaceutically acceptable salts thereof, may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
The compounds of “Formula I” (or Formula II, Formula III, or Formula IV) may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of Formula I may be depicted herein using a solid line, a solid wedge, or a dotted wedge. The use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc. ) at that carbon atom are included. The use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included. It is possible that compounds of the present application may contain more than one asymmetric carbon atom. In those compounds, the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included. For example, unless stated otherwise, it is intended that the compounds of Formula I (or Formula II, Formula III, or Formula IV) can exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of Formula I (or Formula II, Formula III, or Formula IV) and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of diastereomers is present.
The compounds of the present application (e.g., the compounds of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI) may exist as clathrates or other complexes. Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of Formula I (or Formula II, Formula III, or Formula IV) containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J. Pharm. Sci., 64 (8) , 1269-1288 by Haleblian (August 1975) .
Stereoisomers of Formula I (or Formula II, Formula III, or Formula IV) include cis and trans isomers, optical isomers such as R and S enantiomers, diastereomers, geometric isomers, rotational isomers, conformational isomers, and tautomers of the compounds of Formula I (or Formula II, Formula III, or Formula IV) , including compounds exhibiting more than one type of isomerism; and mixtures thereof (such as racemates and diastereomeric pairs) . Also included are acid addition or base addition salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
When any racemate crystallizes, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
The compounds of Formula I (or Formula II, Formula III, or Formula IV) may exhibit the phenomena of tautomerism and structural isomerism. For example, the compounds of Formula I may exist in several tautomeric forms, including the enol and imine forms, and the keto and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of compounds of Formula I (or Formula II, Formula III, or Formula IV) . Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present application includes all tautomers of the compounds of Formula I (or Formula II, Formula III, or Formula IV) .
The present application also includes isotopically-labeled compounds, which are identical to those recited in Formula I (or Formula II, Formula III, or Formula IV) above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be incorporated into compounds of Formula I (or Formula II, Formula III, or Formula IV) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to,
2H,
3H,
13C,
14C,
15N,
18O,
17O,
31P,
32P,
35S,
18F, and
36Cl. Certain isotopically-labeled compounds of Formula I (or Formula II, Formula III, or Formula IV) , for example those into which radioactive isotopes such as
3H and
14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,
3H, and carbon-14, i.e.,
14C, isotopes may be used for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,
2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances. Isotopically-labeled compounds of Formula I (or Formula II, Formula III, or Formula IV) may generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting an isotopically-labeled reagent for a non-isotopically-labeled reagent.
The compounds of the present application may be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidity, or a desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.
As used herein, the term “treating” , unless otherwise indicated, generally means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term “treatment” , as used herein, unless otherwise indicated, generally refers to the act of treating as "treating" is defined immediately above. The term “treating” may also include adjuvant and neo-adjuvant treatment of a subject.
Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context) , the salt maybe pharmaceutically acceptable. The term “pharmaceutically acceptable salt” generally refers to a salt prepared by combining a compound of the present application (e.g., a compound of any of Formula I -IV) with an acid whose anion, or a base whose cation, is generally considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present application because of their greater aqueous solubility relative to the parent compound. For use in medicine, the salts of the compounds of this application are non-toxic “pharmaceutically acceptable salts. ” Salts encompassed within the term “pharmaceutically acceptable salts” generally refer to non-toxic salts of the compounds of the present application which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
Typically, a compound of the present application is administered in an amount effective to treat a condition as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. Therapeutically effective doses of the compounds required to treat the progress of the medical condition are readily ascertained by one of ordinary skill in the art using preclinical and clinical approaches familiar to the medicinal arts. The term “therapeutically effective amount” as used herein generally refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disorder being treated.
Use and Methods
The present application provides a method for inhibiting CK1 delta or CK1 epsilon activity. The method may comprise administering an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof:
wherein Ar
l may be an aryl group that may be optionally substituted by one or more (e.g., 1-2, or more) R
1 substituents, and each R
1 may be independently selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl and sulfoxido, wherein the substituent on the sulfur atom may be hydrocarbyl, sulfonylamide,
wherein the substituents on the sulfonamido nitrogen atom may be hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl- hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the aminohydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
amino, and a N-monosubstituted or N, N-disubstituted amino group,
wherein the substituent (s) on the amino nitrogen may be selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group;
wherein X
1, X
2 and X
3 each may independently be C or N;
R
7 may be absent or -CN;
wherein R
2 may be -NH
2, -CN or Z,
wherein Z may be independently selected from the group consisting of: hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and -X-Y,
wherein -X may be -O, -S or -NQ,
-Y may be hydrido, hydrocarbyl or hydrocarbylaryl,
Q may be hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl,
wherein R
3 may be a halogen or -CN,
wherein ring A may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring A may be optionally substituted with a R
4 substituent, and R
4 may be =O;
wherein R
5 may be independently selected from the group consisting of: -COO-C
1-C
6 alkyl, -CO-R
10 and R
52,
wherein R
10 may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said R
10 may be optionally substituted with a R
8 substituent, said R
8 substituent may be C
1-C
6 alkyl,
wherein R
52 may be independently selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that may be substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarby-amino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyl-oxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroaryl-sulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclo-hydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the aminohydrocarbyl nitrogen may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
wherein R
6 may be C
1-C
6 alkyl or R
61,
wherein R
61 may be independently selected from the group consisting of: an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that may be optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the amino-hydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
wherein ring B may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring B may be optionally substituted with a R
9 substituent, and said R
9 may be PMB.
In some cases, the compound of Formula I may comprise a compound of Formula Ia:
wherein each R
1 may be independently selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl and sulfoxido, wherein the substituent on the sulfur atom may be hydrocarbyl, sulfonylamide,
wherein the substituents on the sulfonamido nitrogen atom may be hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl-hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the aminohydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
amino, and a N-monosubstituted or N, N-disubstituted amino group,
wherein the substituent (s) on the amino nitrogen may be selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group;
wherein X
1, X
2 and X
3 each may independently be C or N;
R
7 may be absent or -CN;
wherein R
2 may be -NH
2, -CN or Z,
wherein Z may be independently selected from the group consisting of: hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and -X-Y,
wherein -X may be -O, -S or -NQ,
-Y may be hydrido, hydrocarbyl or hydrocarbylaryl,
Q may be hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl,
wherein R
3 may be a halogen or -CN,
wherein ring A may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring A may be optionally substituted with a R
4 substituent, and R
4 may be =O;
wherein R
5 may be independently selected from the group consisting of: -COO-C
1-C
6 alkyl, -CO-R
10 and R
52,
wherein R
10 may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said R
10 may be optionally substituted with a R
8 substituent, said R
8 substituent may be C
1-C
6 alkyl,
wherein R
52 may be independently selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that may be substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarby-amino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyl-oxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclo- hydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroaryl-sulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclo-hydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the aminohydrocarbyl nitrogen may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
wherein R
6 may be C
1-C
6 alkyl or R
61,
wherein R
61 may be independently selected from the group consisting of: an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that may be optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,
wherein the substituent (s) on the amino-hydrocarbyl nitrogen atom may be selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto may form a 5-to 8-membered heterocyclic or heteroaryl ring group,
wherein ring B may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring B may be optionally substituted with a R
9 substituent, and said R
9 may be PMB.
In some cases, the compound of Formula I may comprise a compound of Formula Ia:
wherein each R
1 may independently be a halogen,
n may be 0, 1, or 2,
X
1, X
2 and X
3 may each independently be C or N;
R
7 may be absent or -CN,
R
2 may be -NH
2, or -CN,
R
3 may be a halogen or -CN,
ring A may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring A may optionally be substituted with a R
4 substituent, and R
4 is =O;
R
5 may independently be selected from the group consisting of: -COO-C
1-C
6 alkyl, and -CO-R
10,
wherein R
10 may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said R
10 may optionally be substituted with a R
8 substituent, said R
8 substituent may be C
1-C
6 alkyl,
wherein R
6 may be C
1-C
6 alkyl,
wherein ring B may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring B may optionally be substituted with a R
9 substituent, and said R
9 may be PMB.
In some cases, in the compound of Formula I or Formula Ia, R
1 may be F.
In some cases, in the compound of Formula Ia, n may be 1.
In some cases, in the compound of Formula I or Formula Ia, R
3 may be F or -CN.
In some cases, in the compound of Formula I or Formula Ia, R
5 may be -COO-CH
2CH
3 or -CO-R
10.
In some cases, in the compound of Formula I or Formula Ia, R
8 may be -CH
3.
In some cases, in the compound of Formula I or Formula Ia, R
6 may be -CH
3.
In some cases, the compound of Formula I or Formula Ia may be a compound in table 1.
Table 1. The compounds of Formula I or Formula Ia
In some cases, in the compound of Formula I, X
1 may be C, X
2 may be C, X
3 may be N, R
7 may be absent, A may be
and B may be
wherein R
2 may be Z, Z may be -NR
23R
24,
R
23 may be hydrido, or C
1-C
6 hydrocarbyl, R
24 may be independently selected from a group consisting of hydrido, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2 -pyridyl lower hydrocarbyl, 3 -pyridyl lower hydrocarbyl and 4-pyridyl lower hydrocarbyl;
Ar
1 may be an aryl group that may be substituted by a halogen or halo group, lower hydrocarbyl, or hydrocarbyloxy group;
R
6 may be R
61, R
61 may be hydrido, or C
1-C
6 hydrocarbyl; and
R
5 may be R
52, R
52 may be hydrido, or lower hydrocarbyl.
In some cases, in the compound of Formula I, X
1 may be C, X
2 may be C, X
3 may be N, R
7 may be absent, A may be
and B may be
wherein R
2 may be Z, Z may be -OR
25,
R
25 may be hydrido, C
1-C
6 hydrocarbyl, or aryl lower hydrocarbyl;
Ar
1 may be an aryl group that may be independently substituted with a halogen, lower hydrocarbyl, or hydrocarbyloxy group;
R
6 may be R
61, R
61 may be C
1-C
6 hydrocarbyl; and
R
5 may be R
52, R
52 may be hydrido.
In some cases, in the compound of Formula I, X
1 may be C, X
2 may be C, X
3 may be N, R
7 may be absent, A may be
and B may be
wherein R
2 may be -CN;
Ar
1 may be an aryl group that may be substituted by a halogen, lower hydrocarbyl or a hydrocarbyloxy group;
R
6 may be R
61, R
61 may be lower hydrocarbyl; and
R
5 may be R
52, R
52 may be hydrido or lower hydrocarbyl.
The compound of Formula I may also include any of the compounds described in WO 99/58523, which is incorporated herein by reference in its entirety.
The present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula II, or a pharmaceutically acceptable salt thereof:
wherein R
1 may be a halogen;
n may be 0, 1 or 2;
X
1, X
2, X
3, X
4, X
5 and X
6 may each independently be C or N;
R
2 may be absent or =O;
R
3 may be absent or -CN;
wherein R
4 may be a halogen,
wherein R
5 may be selected from the group consisting of: -NH
2, C
1-C
6 alkyl, C
1-C
6 alkyl-NH-C
1-C
6 alkyl, C
1-C
6 alkyl-OH and C
1-C
6 alkyl-O-CO-C
1-C
6 alkyl,
wherein ring A may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring A may be optionally substituted with a R
6 substituent, R
6 may be =O;
B may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said B may be optionally substituted with one or more R
7 substituents,
wherein each R
7 substituent may be independently selected from the group consisting of: CO-C
1-C
6 alkyl, Bn, =O, C
1-C
6 alkyl, CO-NH-C
1-C
6 alkyl, CO-C
1-C
6 alkyl-CN, R
8, R
8-C
1-C
6 alkyl, and CO-R
8-C
1-C
6 alkyl, wherein R
8 may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-.
In some cases, in the compound of Formula II, R
1 may be F.
In some cases, in the compound of Formula II, n may be 1.
In some cases, in the compound of Formula II, n may be 2.
In some cases, in the compound of Formula II, R
4 may be F.
In some cases, in the compound of Formula II, R
5 may be selected from the group consisting of: -NH
2, -CH
3, -CH
2-NH-CH
3, -CH
2-OH and -CH
2-O-CO-CH
3.
In some cases, in the compound of Formula II, each R
7 may be independently selected from the group consisting of: -Bn, =O, -CH
3, -CO-CH
3, -CO-CH
2-CH
3, -CO-CH- (CH
3)
2, -CO-NH-CH
3, -CO-CH
2-CN, R
8, R
8-CH
3 and -CO-R
8-CH
3, wherein R
8 may be
In some cases, in the compound of Formula II, the number of R
7 may be 1 or 2.
In some cases, in the compound of Formula II, B may be selected from the group consisting of:
In some cases, wherein X
1 may be C.
In some cases, wherein X
6 may be N.
In some cases, wherein, R
1 may be F, n may be 1, X
1 and X
3 may be C, X
2 and X
6 may be N, R
2 and R
3 may be absent, R
n1 and R
n2 may independently be optionally substituted, B may be a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said B may be optionally substituted.
In some cases, wherein, R
1 may be F, n may be 1, X
1 and X
3 may be C, X
2 and X
6 may be N, R
2 and R
3 may be absent, B may be a 4-to 7-membered cycloalkyl or heterocycloalkyl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said B may be optionally substituted.
In some cases, wherein, R
1 may be F, n may be 1, X
1 and X
3 may be C, X
2 and X
6 may be N, R
2 and R
3 may be absent, B may be selected from the group consisting of:
and said B may be optionally substituted.
In some cases, wherein, R
1 may be F, n may be 1, X
1 and X
3 may be C, X
2 and X
6 may be N, R
2 and R
3 may be absent, B may be
and said B may be optionally substituted with C
1-C
6 alkyl or CO-C
1-C
6 alkyl
In some cases, the compound of Formula II may be one of the compounds in tables 2-1~2-2.
Table 2-1. The compounds of Formula II
Table 2-2. The compounds of Formula II
The present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula III, or a pharmaceutically acceptable salt thereof:
wherein R
1 may be a halogen;
n may be 0, 1, or 2;
X
1 and X
2 may each independently be C or N;
wherein R
2 may be C
1-C
6 alkyl,
ring A may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring C may be optionally substituted with a R
3 substituent, R
3 may be =O;
wherein R
4 may be -CN, -COO-C
1-C
6 alkyl, or amido group,
R
5 may be C
1-C
6 alkyl, and
ring C may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms may be replaced with a heteroatom selected from =N-and -O-, and said ring C may be optionally substituted with a R
6 substituent, R
6 may be =O.
In some cases, in the compound of Formula III, R
1 may be F.
In some cases, in the compound of Formula III, n may be 1.
In some cases, in the compound of Formula III, R
2 may be -CH
3.
In some cases, in the compound of Formula III, wherein said ring A may be a 5-membered heteroaryl.
In some cases, in the compound of Formula III, wherein 2 carbon atoms of said A may be replaced with a heteroatom selected from =N-and -O-.
In some cases, wherein the compound may have a structure of
wherein, R
1 may be a halogen, n may be 0, 1, or 2, R
A1, R
A2 and R
A3 may independently be selected from C and N.
In some cases, wherein R
A1 may be N.
In some cases, in the compound of Formula III, R
4 may be -CN, -CO-NH
2, or -COO-CH
3.
In some cases, in the compound of Formula III, R
5 may be -CH
3.
In some cases, the compound of Formula III may be one of the compounds in table 3.
Table 3. The compounds of Formula III
The present application also provides a method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula IV, or a pharmaceutically acceptable salt thereof:
wherein R
1 may be a halogen;
n may be 0, 1 or 2;
R
2 may be a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said R2 may be optionally substituted with R
3 substituent, R
3 may be =O.
In some cases, in the compound of Formula IV, R
1 may be F.
In some cases, in the compound of Formula IV, n may be 1.
In some cases, the compound of Formula IV may be one of the ompounds in table 4.
Table 4. The compounds of Formula IV
In some cases, the method may be an in vitro method, an ex vivo method, or an in vivo method. For example, the compounds of the present application (e.g., the compounds of Formula I –Formula IV) may be administered in vitro to one or more cells (or a cell line) , to control the growth or activity of these cells. In another example, the compounds of the present application (e.g., the compounds of Formula I –Formula IV) may be administered to a patient (e.g., a mammal, such as a human patient) in need thereof.
The present application also provides a method for treating a neurological and/or psychiatric disease or disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound of any one of Formula I~IV or a pharmaceutically acceptable salt thereof.
In some cases, the disease or disorder is a mood disorder, a sleep disorder or a circadian disorder.
In some cases, the mood disorder is selected from the group consisting of a depressive disorder and a bipolar disorder.
The method of the present application may also comprise administering to a subject in need thereof a pharmaceutical composition comprising one or more compounds of Formula I, II, III, or IV or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.
The compounds of the present application may be administered orally. Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
In another embodiment, the compounds of the present application may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
In another embodiment, the compounds of the present application may also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the present application can also be administered intranasally or by inhalation. In another embodiment, the compounds of the present application may be administered rectally or vaginally. In another embodiment, the compounds of the present application may also be administered directly to the eye or ear.
The dosage regimen for the compounds and/or compositions containing the compounds is based on a variety of factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. Dosage levels of the order from about 0.01 mg to about 100 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions. In one embodiment, the total daily dose of a compound of the invention (administered in single or divided doses) is typically from about 0.01 to about 100 mg/kg, such as from about 0.1 to about 50 mg/kg, from about 0.5 to about 30 mg/kg (i.e., mg compound of the present application per kg body weight) . In one embodiment, dosing is from 0.01 to 10 mg/kg/day. In another embodiment, dosing is from 0.1 to 1.0 mg/kg/day. Dosage unit compositions may contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound may be repeated a plurality of times in a day (typically no greater than 4 times) . Multiple doses per day typically may be used to increase the total daily dose, if desired.
For oral administration, the compositions may be provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1 . 0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 75.0, 100, 125, 150, 175, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, or in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenously, doses may range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
Suitable subjects according to the present application may include mammalian subjects. Mammals according to the present application include, but are not limited to, canine, feline, bovine, caprine, equine, ovine, porcine, rodents, lagomorphs, primates, and the like, and encompass mammals in utero. In one embodiment, humans are suitable subjects. Human subjects may be of either gender and at any stage of development.
In another embodiment, the present application comprises the use of one or more compounds of the present application for the preparation of a medicament for the treatment of the conditions recited herein.
For the treatment of the conditions referred to above, the compounds of the present application can be administered as compound per se. Alternatively, pharmaceutically acceptable salts are suitable for medical applications because of their greater aqueous solubility relative to the parent compound.
In another embodiment, the present application comprises pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the present application presented with a pharmaceutically acceptable carrier. The carrier can be a solid, a liquid, or both, and may be formulated with the compound as a unit-dose composition, for example, a tablet, which can contain from 0.05%to 95%by weight of the active compounds. A compound of the present application may be coupled with suitable polymers as targetable drug carriers. Other pharmacologically active substances can also be present.
The compounds of the present application may be administered by any suitable route, may be in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The active compounds and compositions, for example, may be administered orally, rectally, parenterally, or topically.
The compounds of the present application can be used, alone or in combination with other therapeutic agents, in the treatment of various conditions or disease states. The compound (s) of the present application and other therapeutic agent (s) may be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.
The administration of two or more compounds “in combination” means that the two compounds are administered closely enough in time that the presence of one alters the biological effects of the other. The two or more compounds may be administered simultaneously, concurrently or sequentially. Additionally, simultaneous administration may be carried out by mixing the compounds prior to administration or by administering the compounds at the same point in time but at different anatomic sites or using different routes of administration.
The phrases “concurrent administration, ” “co-administration, ” “simultaneous administration, ” and “administered simultaneously” mean that the compounds are administered in combination.
Examples
The following examples are set forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present application, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc. ) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair (s) ; kb, kilobase (s) ; pl, picoliter (s) ; s or sec, second (s) ; min, minute (s) ; h or hr, hour (s) ; aa, amino acid (s) ; nt, nucleotide (s) ; i.m., intramuscular (ly) ; i.p., intraperitoneal (ly) ; s.c., subcutaneous (ly) ; and the like.
Example 1. Preparation of Compound 2-1
FIG. 1 illustrates the synthetic scheme of compound 2-1. As shown in FIG. 1, the specific synthesis steps are as follows:
Step 1: methyl 2-bromo-3- (4-fluorophenyl) -3-oxopropanoate
NBS (9.98 g, 56.1 mmol) and AIBN (0.73 g, 5.1 mmol) were added to a solution of methyl 3- (4-fluorophenyl) -3-oxopropanoate (10 g, 51 mmol) in 130 mL of CHCl
3. The mixture was stirred at 62℃ for 15 hours (h) . The reaction mixture was concentrated under pressure. The crude material was then added to a silica gel column and was eluted with PE/EA (20: 1) . Chemical Formula: calculated for (M+H
+) C
10H
8BrFO
3: 275.07, Found: 274.7.
Step 2: methyl 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine-3-carboxylate
Methyl 2-bromo-3- (4-fluorophenyl) -3-oxopropanoate (14 g, 50.9 mmol) and pyrazin-2-amine (9.68 g, 101.8 mmol) were dissolved in 100 mL of EtOH. The mixture was heated to reflux for 18 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel and was eluted with DCM/MeOH (50: 1) . Chemical Formula: calculated for (M+H
+) C
14H
10FN
3O
2: 271.25, Found: 271.8.
Step 3: 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine-3-carboxylic acid
Methyl 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine-3-carboxylate (0.7 g, 2.6 mmol) was dissolved in MeOH (40 mL) . LiOH (0.31 g, 13 mmol) , dissolved in 10 mL water, was added. The reaction mixture was stirred at room temperature for 15 h. The reaction mixture was adjusted to pH =5-6 with HCl (1mol/L) and then concentrated under reduced pressure, and the crude product was dissolved in ethyl acetate and washed with water. The solvent was concentrated, and the crude material was added to a silica gel column and was eluted with DCM/MeOH (20: 1) . Chemical Formula: calculated for (M+H
+) C
13H
8FN
3O
2: 257.22, Found: 257.8.
Step 4: 2- (4-fluorophenyl) -N-methoxy-N-methylimidazo [1, 2-a] pyrazine-3-carboxamide
2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine-3-carboxylic acid (0.7g, 2.7 mmol) and SOCl
2 (0.026 mL, 3.5 mmol) were heated to reflux in anhydrous DCE (30 mL) for 1 h, after which the mixture was evaporated and distilled. The resulting acid chloride was dissolved in toluene and added dropwise over a period of 20 min to a stirred solution of N, O-dimethylhydroxylamine (0.17 g, 2.7 mmol) and K
2CO
3 (0.82 g, 5.8 mmol) in a mixture of H
2O–toluene (1: 1, 100 mL) at 0 ℃. After stirring for 2 h, the organic phase was washed with dilute aqueous NaOH and H2O. The solvents were evaporated in vacuo. The crude material was added to a silica gel column and was eluted with PE/EA (10: 1) . Chemical Formula: calculated for (M+H
+) C
15H
13FN
4O
2: 300.29, Found: 300.8.
Step 5: 1- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) ethan-1-one
A 3 M solution of CH3MgBr in tetrahydrofuran (THF) (0.26 g, 2.2 mmol) was added to a stirred solution of 2- (4-fluorophenyl) -N-methoxy-N-methylimidazo [1, 2-a] pyrazine-3-carboxamide (0.5 g, 1.7 mmol) in THF (20 mL) at -78℃. The mixture was allowed to rest at room temperature and then stirred for 16 h. A saturated solution of ammonium chloride was added, and the mixture was extracted with EtOAc. The solvents were evaporated in vacuo and crude material was added to a silica gel column and was eluted with PE/EA (1: 2) . Chemical Formula: calculated for (M+H
+) C
14H
10FN
3O: 255.25, Found: 255.8.
Step 6: 4- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) pyrimidin-2-amine
1, 1-dimethoxy-N, N-dimethylmethanamine (0.31 g, 2.5 mmol) were added successively to a solution of 1- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) ethan-1-one (100 mg, 0.4 mmol) in n-propanol (20 mL) . The reaction mixture was heated at 92 ℃ for 3 h. And then, guanidine (0.12 g, 1.9 mmol) and K2CO3 (0.25 g, 1.8 mmol) were added. The reaction mixture was stirred at 92 ℃ for 16 h. Hydroxide sodium solution (5 N, 50 mg) was added, the reaction mixture was stirred at 92 ℃ for 8 h. Then, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed with water. The residue was purified by PTLC to obtain the product. Chemical Formula: calculated for (M+H
+) C
16H
11FN
6: 306.3, Found: 306.9.
1H NMR (400 MHz, CDCl
3) δ 9.35 (dd, J= 4.7 Hz, 1.4 Hz, 1H) , 9.22 (s, 1H) , 8.22 (d, J = 5.2 Hz, 1H) , 8.05 (d, J = 4.7 Hz, 1H) , 7.71-7.67 (m, 2H) , 7.18 (t, J = 8.7 Hz, 2H) , 6.60 (d, J = 5.3 Hz, 1H) .
Example 2. Preparation of Compound 3-8
FIG. 2 illustrates the synthetic scheme of compound 3-8. As shown in FIG. 2, the specific synthesis steps are as follows:
Step 1: (Z) -3- ( (allyloxy) imino) -3- (4-fluorophenyl) propanenitrile
O-allylhydroxylammonium chloride (1.35 g, 12.3 mmol) and KOAc (1.2 g, 12.3 mmol) were decentralized in MeOH (5 mL) . The mixture was allowed to stir at 25 ℃ for 30 min. Meanwhile, 3- (4-fluorophenyl) -3-oxopropanenitrile (2 g, 12.3 mmol) dissolved in MeOH (15 mL) was added dropwise over a 5 min time period. The reaction mixtures were then allowed to stir at 60 ℃ for 16 h. Then, the solvent was concentrated in vacuo. The crude material was added to a silica gel column and was eluted with PE/EA (20: 2) . Chemical Formula: calculated for (M+H
+) C
12H
11FN
2O: 218.23, Found: 218.9.
Step 2: 2- (4-fluorophenyl) -4-methyl-1H-pyrrole-3-carbonitrile
[ (cod) IrCl]
2 (0.31 g, 0.4 mmol) , AgOTf (0.24g, 0.9 mmol) and NaBH
4 (35 mg, 0.9 mmol) were decentralized in THF (10 mL) . This mixture was then allowed to stir at 25 ℃ for 20 min under nitrogen atmosphere. (Z) -3- ( (allyloxy) imino) -3- (4-fluorophenyl) propanenitrile (2 g, 9.2 mmol) , dissolved in THF (20 mL) , was added. The reaction mixture was then allowed to stir at 25 ℃ for 18 h, and then heated to 50 ℃ for 24 h. Then, the solvent was concentrated in vacuo. The crude material was added to a silica gel column and was eluted with PE/EA (10: 2) . Chemical Formula: calculated for (M+H
+) C
12H
9FN
2: 200.22, Found: 200.9.
Step 3: 2- (4-fluorophenyl) -4-methyl-1- (pyridin-4-yl) -1H-pyrrole-3-carbonitrile
A mixture of 2- (4-fluorophenyl) -4-methyl-1H-pyrrole-3-carbonitrile (100 mg, 0.49 mmol) , 4-iodopyridine (204 mg, 1.00 mmol) , K
2CO
3 (207 mg, 1.50 mmol) , and CuI (9.5 mg, 0.05 mmol) were mixed with NMP (4 mL) . The system was evacuated and replaced with an argon atmosphere. Then, the mixture was stirred at 200 ℃ for 2.5 h on microwave. The mixture was extracted with EtOAc, the solvents were evaporated in vacuo and the crude material was purified by PTLC to obtain the product. Chemical Formula: calculated for (M+H
+) C
17H
12FN
3: 277.30, Found: 277.8.
1H NMR (400 MHz, CDCl
3) δ 8.60 (s, 2H) , 7.28 –7.20 (m, 2H) , 7.12 –7.05 (m, 2H) , 7.02 (d, J = 5.5 Hz, 2H) , 6.79 (d, J =1.0 Hz, 1H) , 2.30 (d, J = 0.9 Hz, 3H) .
Example 3. Preparation of Compounds 2-5, 2-6, 2-7 and 2-8
FIG. 3 illustrates the synthetic scheme of compounds 2-5, 2-6, 2-7 and 2-8. As shown in FIG. 3, the specific synthesis steps are as follows:
Step 1: 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine
2-bromo-1- (4-fluorophenyl) ethanone (10 g, 46.1 mmol) and NaHCO
3 (11.6 g, 138.3 mmol) were added to a stirred solution of pyrazin-2-amine (4.38 g, 46.1 mmol) in 300 mL of EtOH. The mixture was heated to reflux for 4 h. Then, the solvent was concentrated in vacuo. The crude material was added to a silica gel column and was eluted with DCM/MeOH (10: 1) . Chemical Formula: calculated for (M+H
+) C
12H
8FN
3: 213.22, Found: 213.9.
Step 2: 3-bromo-2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine
NBS (1 g, 4.7mmol) was dissolved in CH
3CN (30 mL) , the solution was stirred at 0 ℃. Then, 2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine (1 g, 5.6 mmol) was added. The mixture was stirred at 0 ℃ for 2 h. The solvent was concentrated and dissolved in EA, washed with water and the solvent was concentrated in vacuo. The crude material was added to a silica gel column and was eluted with PE/EA (1:2) . Chemical Formula: calculated for (M+H
+) C
12H
7BrFN
3: 292.11, Found: 291.7.
Step 3: 2- (4-fluorophenyl) -3- (pyridin-4-yl) imidazo [1, 2-a] pyrazine
Pyridin-4-ylboronic acid (63 mg, 0.51 mmol) and Pd (PPh
3)
4 (79 mg, 0.068 mmol) were added to a solution of 3-bromo-2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine (100 mg, 0.34 mmol) in EtOH (3 mL) . Toluene (1 mL) and Sodium carbonate solution (2 N, 0.5 mL) were added. Then, the mixture was swept degas by nitrogen. The mixture was stirred at 100 ℃ for 3 h on microwave. The solvents were evaporated in vacuo and the crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
17H
11FN
4: 290.30, Found: 290.8.
1H NMR (400 MHz, CDCl
3) δ 9.22 (d, J = 1.2 Hz, 1H) , 8.85 (d, J = 5.9 Hz, 2H) , 8.05 (dd, J = 4.7, 1.4 Hz, 1H) , 7.97 (d, J =4.7 Hz, 1H) , 7.70 –7.58 (m, 2H) , 7.44 (dd, J = 4.5, 1.5 Hz, 2H) , 7.09 (t, J = 8.7 Hz, 2H) .
Step 4: 2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyrazine
NaBH
4 (26 mg, 0.69 mmol) was added to a solution of 4- [2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl] pyridine (100 mg, 0.35 mmol) in EtOH (5 mL) . The mixture was stirred at 80 ℃ for 16 h. Then, the solvent was concentrated, and the crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
17H
15FN
4: 294.33, Found: 294.9.
1H NMR (400 MHz, CDCl
3) δ 8.68 (dd, J = 4.5, 1.5 Hz, 2H) , 7.50 –7.34 (m, 2H) , 7.26 (dd, J = 4.5, 1.6 Hz, 2H) , 6.97 (dd, J = 9.7, 7.8 Hz, 2H) , 4.28 (s, 2H) , 3.86 (t, J = 5.4 Hz, 2H) , 3.29 (t, J = 5.4 Hz, 2H) .
Step 5: 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -5, 6-dihydroimidazo [1, 2-a] pyrazin-7 (8H) -yl) ethan-1-one
To a solution of 4- [2- (4-fluorophenyl) -5H, 6H, 7H, 8H-imidazo [1, 2-a] pyrazin-3-yl] pyridine (20 mg) in THF (5 mL) , acetic anhydride (14 mg) was added. The reaction mixture was stirred at 25 ℃for 6 h. Then, the solvent was concentrated and the crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
19H
17FN
4O: 336.37, Found: 336.9.
1H NMR (400 MHz, CDCl
3) δ 8.70 (d, J = 5.7 Hz, 2H) , 7.49 –7.33 (m, 2H) , 7.28 –7.18 (m, 2H) , 6.98 (dd, J =12.0, 5.5 Hz, 2H) , 4.91 (s, 2H) , 4.06 (t, J = 5.3 Hz, 2H) , 3.90 (t, J = 5.3 Hz, 2H) , 2.26 (s, 3H) .
Step 6: 2- (4-fluorophenyl) -3- (tributylstannyl) imidazo [1, 2-a] pyrazine
A solution of 3-bromo-2- (4-fluorophenyl) imidazo [1, 2-a] pyrazine (100 mg, 0.34 mmol) and n-BuLi (39 mg, 0.34 mmol) in THF (5 mL) was stirred at -78 ℃ under nitrogen atmosphere, then, 2.4 N TMEDA (0.43 mL) was added, the reaction mixture was stirred at -78 ℃ for 1 h. Then, tributylchlorostannane (166 mg, 0.51 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated solution of ammonium chloride and washed for several times with diethyl ether, the crude material was then purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
24H
34FN
3Sn: 502.27, Found: 503.7.
Step 7: 4- (2- (4-fluorophenyl) imidazo [1, 2-a] pyrazin-3-yl) furo [3, 4-b] pyridin-5 (7H) -one
4-bromofuro [3, 4-b] pyridin-5 (7H) -one (8.5 mg, 0.04 mmol) and Pd (PPh
3)
4 (9 mg, 0.008 mmol) were added to a solution of 2- (4-fluorophenyl) -3- (tributylstannyl) imidazo [1, 2-a] pyrazine (20 mg, 0.04 mmol) in 1, 4-dioxane (5 mL) . The reaction mixture was stirred at 80 ℃ for 16 h under nitrogen atmosphere. The mixture was extracted with EtOAc and the solvents were evaporated in vacuo and the crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
19H
11FN
4O
2: 346.32, Found: 346.8.
1H NMR (400 MHz, CDCl
3) δ 9.15 (d, J = 5.0 Hz, 1H) , 7.93 (dd, J = 8.8, 5.4 Hz, 2H) , 7.81 –7.69 (m, 2H) , 7.66 (s, 1H) , 7.55 (dd, J = 5.7, 3.3 Hz, 1H) , 7.15 (t, J = 8.7 Hz, 2H) , 5.52 (s, 2H) .
Example 4. Preparation of Compound 1-2
FIG. 4 illustrates the synthetic scheme of compound 1-2. As shown in FIG. 4, the specific synthesis steps are as follows:
Step 1: 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3, 4-b] pyridin-5 (7H) -one
4-bromo-7H-furo [3, 4-b] pyridin-5-one (169.5007 mg, 0.792 mmol) , Na
2CO
3 (139.9200 mg, 1.32 mmol) , and Pd (dppf) Cl
2 (48.2460 mg, 0.066 mmol) were added to a solution of 1- (4-fluorophenyl) -3-methyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (200 mg, 0.66 mmol) in MePh/H
2O (11 mL) . The reaction mixture was stirred at 100℃ for 16h. The reaction mixture was filtered and concentrated to provide the crude product. The residue was purified by combi-flash with PE/EA (1: 1) to provide 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) furo [3, 4-b] pyridin-5 (7H) -one (170 mg, 79.1%yield) as a white solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
17H
12FN
3O
2 309.1, m/z found 310.0 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.87 (d, J = 5.1 Hz, 1H) , 7.35 (d, J = 5.1 Hz, 1H) , 7.25-7.14 (m, 4H) , 6.68 (s, 1H) , 5.38 (s, 2H) , 2.33 (s, 3H) .
Example 5. Preparation of Compounds 2-12, 2-13 and 2-14
FIG. 5 illustrates the synthetic scheme of compounds 2-12, 2-13 and 2-14. As shown in FIG. 5, the specific synthesis steps are as follows:
Step 1: ethyl 3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
2-ethoxy-2-oxoethanediazonium (19.2 g, 0.167 mmol) was added to a solution of Intermediate 1 (20.0 g, 0.167 mol) in toluene (200 mL) at room temperature and the resulting mixture was stirred at 130 ℃ for 3 h, The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (3: 1) to provide the 15.6 g (40%) of white solid product. Chemical Formula: calculated for (M+H
+) C
12H
11FN
2O
2: 235.08, Found: 234.9.
Step 2: ethyl 1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
1, 2-dibromoethaneand (15 g) was added to a solution of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (15.6 g) and potassium carbonate (18.4 g) in acetonitrile (200 mL) at room temperature, the resulting mixture was stirred at 90℃ for 4h. The reaction mixture was cooled to room temperature and concentrated under pressure, diluted with water (200 mL) . The reaction mixture was extracted with DCM (50 mL*3) , filtered and concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (10: 1) to provide 13.5 g (59.5%) of white solid product. Chemical Formula: calculated for (M+H
+) C
14H
14BrFN
2O
2: 341.02, Found: 340.7.
Step 3: 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
Phenylmethanamine (4.7 g) and NaHCO
3 (3.7 g) were added to a solution of ethyl 2- (2-bromoethyl) -5- (4-fluorophenyl) pyrazole-3-carboxylate (13.5 g) and potassium iodide (13 g) in acetonitrile (200 mL) at room temperature. The resulting mixture was stirred at 90 ℃ for 16 h. The reaction mixture was cooled to room temperature and concentrated under pressure, diluted with water (100 mL) . The reaction mixture was extracted with DCM (30 mL*3) , filtered and concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (3: 1) to provide 8.9 g (70.0%) of white solid product. Chemical Formula: calculated for (M+H
+) C
19H
16FN
3O: 322.13, Found: 321.8.
Step 4: 5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
LAH (2.1 g) was added to a solution of 2- (4-fluorophenyl) -5- (1-methylphenyl) -6H, 7H-pyrazolo [1, 5-a] pyrazin-4-one (8.9 g) in THF (100 mL) at 0℃. The resulting mixture was stirred at 25 ℃overnight. The reaction mixture was quenched with ice-cold water, diluted with water (100 mL) . The reaction mixture was extracted with DCM (30 mL*3) , filtered and concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (4: 1) to provide 4.3 g (50.3%) of white solid product. Chemical Formula: calculated for (M+H
+) C
19H
18FN
3: 308.15, Found: 307.8.
Step 5: 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
NBS (1270 mg , 7.14 mmol) was added to a stirred solution of 2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazine (2000 mg, 6.49 mmol) in acetonitrile (50 mL) with ice-cooling. The mixture was stirred for 1 h, diluted with water (100 mL) . The reaction mixture was extracted with EA (50 mL*3) , filtered and concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (4: 1) to provide 1.3 g (51.7%) of white solid product. Chemical Formula: calculated for (M+H
+) C
19H
17BrFN
3: 386.06, Found: 385.7.
Step 6: 5-benzyl-2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
Pd (dppf) Cl
2 (377mg) , pyridin-4-ylboranediol (476mg) , K
3PO
4 (1.6g) was added to a solution of 3-bromo-2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazine (1g) in DMF (30 mL) , the mixture was allowed to react at 80 ℃ under N
2 for 16 h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and was eluted with MeOH/DCM (20: 1) to provide 0.55 g (55.3%) of white solid product. Chemical Formula: calculated for (M+H
+) Chemical Formula: C
24H
21FN
4: 385.18, Found: 384.8.
Step 7: 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
Ammonium formate (454 mg) , Pd/C (140 mg) was added to a solution of 4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridine (140mg) in MeOH (20 mL) , the mixture was heated to 50 ℃ for 3 h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and was eluted with MeOH/DCM (20: 1) to provide 60 mg (56.6%) of white solid product. Chemical Formula: calculated for (M+H
+) Chemical Formula: C
17H
15FN
4: 295.13, Found: 294.9.
Step 8: 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
Acetyl acetate was added to a solution of 4- [2- (4-fluorophenyl) -4H, 5H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridine in THF, the mixture was stirred at room temperature (rt) for 1 h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with MeOH/DCM (20: 1) to provide 30 mg (33%) of white solid product. Chemical Formula: calculated for (M+H
+) Chemical Formula: C
19H
17FN
4O: 337.14, Found: 336.8.
1H NMR (400 MHz, CDCl
3) δ 8.60 (dd, J = 15.4, 5.2 Hz, 2H) , 7.42 –7.36 (m, 2H) , 7.14 (dd, J = 12.9, 5.4 Hz, 2H) , 7.04 (t, J = 8.7 Hz, 1H) , 4.91 (s, 1H) , 4.77 (s, 1H) , 4.35 (dt, J = 28.1, 5.5 Hz, 2H) , 4.19 (t, J = 5.5 Hz, 1H) , 4.04 (t, J = 5.5 Hz, 1H) , 2.28 (s, 3H) .
Example 6. Preparation of Compound 1-4
FIG. 6 illustrates the synthetic scheme of compound 1-4. As shown in FIG. 6, the specific synthesis steps are as follows:
Step 1: 2- (4-fluorophenyl) -2, 3a, 4, 5, 6, 7-hexahydro-3H-indazol-3-one
Ethyl 2-oxocyclohexane-1-carboxylate (10.3911 g, 0.0610 mol) and DIEA (14.319 g, 0.111 mol) were added to a solution of (4-fluorophenyl) hydrazine (7 g, 0.0555 mol) in EtOH (100 mL) . The reaction mixture was stirred at 100 ℃ for 16 h. The reaction was completed and examined with LCMS. The mixture was concentrated to provide the crude product. The mixture was quenched with H
2O (50 mL) , filtered and concentrated to provide 2- (4-fluorophenyl) -2, 3a, 4, 5, 6, 7-hexahydro-3H-indazol-3- one (9.5 g, 62.7%yield) as a yellow solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
13H
13FN
2O 232.1, m/z found 233.1 [M+H]
+.
Step 2: 3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-2H-indazole
POBr
3 (11.0682 g, 0.0387 mol) was added to a solution of 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-3aH-indazol-3-one (3 g, 0.0129 mol) in ACN (30 mL) . The reaction mixture was stirred at 90 ℃ for 16 h. The reaction was completed and examined with LCMS. Na
2CO
3 was used to adjust the pH of the mixture (60%SMA and 30%product) to be 7-8. The mixture was extracted with EA (30 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over sodium sulfate, filtered and concentrated to provide the crude product. The residue was purified by combi-flash with PE/EA (5: 1) to provide 3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-2H-indazole (0.6 g, 13.2%yield) as a yellow oil product, which was determined by LCMS, MS (ESI) : mass calculated for C
13H
12BrFN
2 294.0, m/z found 294.9 [M+H]
+.
Step 3: 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-2H-indazole
Pyridin-4-ylboranediol (62.6882 mg, 0.51 mmol) , K
3PO
4 (216.2400 mg, 1.02 mmol) , and Pd (dppf) Cl
2 (24.8540 mg, 0.034 mmol) were added to a solution of 3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydroindazole (100 mg, 0.34 mmol) in DMF (11 mL) . The reaction mixture was stirred at 100 ℃ for 5 h. The reaction was completed and examined with LCMS. The reaction was quenched with H
2O (30 mL) . The mixture was concentrated. The mixture was then extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to provide the crude product. The residue was purified by combi-flash with PE/EA (1: 1) to provide 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-2H-indazole (24 mg, 24.1%yield) as a white solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
18H
16FN
3 293.1, m/z found 293.9 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.56 (dd, J = 4.4, 1.6 Hz, 2H) , 7.29-7.21 (m, 2H) , 7.15 (dd, J = 4.4, 1.6 Hz, 1H) , 2.68 (t, J = 6.0 Hz, 1H) , 2.59 (t, J = 6.0 Hz, 1H) , 1.82 (d, J = 5.6 Hz, 1H) , 1.74 (d, J = 5.6 Hz, 1H) .
Example 7. Preparation of Compound 2-16
FIG. 7 illustrates the synthetic scheme of compound 2-16. As shown in FIG. 7, the specific synthesis steps are as follows:
Step 1: 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazole
Cyclohexane-1, 2-dione (2.7079 g, 0.02415 mol) and NH
4OAc (6.1985 g, 0.0805 mol) were added to a solution of 4-fluorobenzaldehyde (2 g, 0.0161 mol) in EtOH (30 mL) . The reaction mixture was stirred at 80 ℃ for 2 h. The reaction was completed and examined with LCMS. The mixture was concentrated to provide the crude product, The residue was purified by combi-flash with PE/EA (0: 1) to provide 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazole (3.4 g, 92.6%yield) as a brown solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
13H
13FN
2 216.1, m/z found 217.1 [M+H]
+.
Step 2: 2- (4-fluorophenyl) -1- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazole
4-iodopyridine (568.783 mg, 2.7746 mmol) , K
2CO
3 (574.342 mg, 4.1619 mmol) , and CuI (26.3587 mg, 0.13873 mmol) were added to a solution of 2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydro-1H-1, 3-benzodiazole (300 mg, 1.3873 mmol) in NMP (4 mL) under microwave. The reaction mixture was stirred at 220 ℃ for 2.5 hours. The reaction was completed and examined with LCMS. The reaction was quenched with water (20 mL) slowly, the mixture was extracted with EA (30 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over sodium sulfate, filtered and concentrated, The residue was purified by combi-flash with PE/EA (1: 1) to provide 2- (4-fluorophenyl) -1- (pyridin-4-yl) -4, 5, 6, 7-tetrahydro-1H-benzo [d] imidazole (5 mg, 1.20%yield) as a white solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
18H
16FN
3 293.1, m/z found 293.9 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 8.71 (dd, J = 4.5, 1.6 Hz, 2H) , 7.37-7.32 (m, 2H) , 7.11 (dd, J = 4.5, 1.6 Hz, 2H) , 7.01-6.95 (m, 2H) , 2.76 (t, J = 5.8 Hz, 2H) , 2.48 (t, J = 5.8 Hz, 2H) , 1.93-1.85 (m, 4H) .
Example 8. Preparation of Compounds 3-1, 3-2, 3-4 and 3-5
FIG. 8 illustrates the synthetic scheme of compounds 3-1, 3-2, 3-4 and 3-5. As shown in FIG. 8, the specific synthesis steps are as follows:
Step 1: (E) -3- (4-fluorophenyl) -2- (pyridin-4-yl) acrylonitrile
4-fluorobenzaldehyde (3.1462 g, 0.0253 mol) and K
2CO
3 (1.3993 g, 0.0101 mol) were added to a solution of 2- (pyridin-4-yl) acetonitrile (2 g, 0.0169 mol) in MeOH (30 mL) . The reaction mixture was stirred at 80 ℃ for 4 h. The reaction was completed and examined with LCMS. The mixture was concentrated to provide the crude product. Then water was added, the reaction mixture was filtered and the filter cake was concentrated to provide (E) -3- (4-fluorophenyl) -2- (pyridin-4-yl) acrylonitrile (1.8 g, 40.2%yield) as a brown solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
14H
9FN
2 224.1, m/z found 225.0 [M+H]
+.
Step 2: methyl 3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate
DBU (1322.4000 mg, 8.7 mmol) was added to a mixture of (2E) -3- (4-fluorophenyl) -2- (pyridin-4-yl) prop-2-enenitrile (1300 mg, 5.80 mmol) and methyl 2-isocyanoacetate (574.7140 mg, 5.8 mmol) in THF (210 mL) at room temperature. The mixture was stirred at 75 ℃ for 16 h. The reaction mixture was completed and examined by LCMS, and then the mixture was concentrated. The reaction was quenched with water (20 mL) . The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-flash with PE/EA (0: 1) to provide methyl 3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate (0.35 g, 0.02%yield) as a brown solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
17H
13FN
2O
2 296.1, m/z found 296.9 [M+H]
+.
Step 3: methyl 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate
DABCO (11.3120 mg, 0.101 mmol) and DMF (0.5 mL) were added to a solution of methyl 3- (4-fluorophenyl) -4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate (300 mg, 1.01 mol) in DMC (10 mL) . The resulting mixture was heated to 90℃ and stirred at that temperature for 16 h. LCMS (ENB190609-146-R1) showed that the reaction was completed. The reaction was quenched with water (20 mL) slowly, the mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over sodium sulfate, filtered and concentrated to provide methyl 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylate (120 mg, 36.8%yield) as a brown solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
18H
15FN
2O
2 310.1, m/z found 311.0 [M+H]
+.
Step 4: 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid
KOH (53.7600 mg, 0.96 mmol) was added to a solution of methyl 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) pyrrole-2-carboxylate (100 mg, 0.32 mmol) in MeOH/H2O=1: 1 (6 mL) at 25℃. The mixture was stirred at 80 ℃ for 15 hrs. LCMS showed that the reaction was completed. 4 N HCl was used to adjust the pH of the mixture to 7-8. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over sodium sulfate, filtered and concentrated to provide 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxylic acid (60 mg, 60.1%yield) as a brown solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
17H
13FN
2O
2 296.1, m/z found 297.0 [M+H]
+.
Step 5: 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide
NH
4Cl (31.8 mg, 0.6 mmol) , DIEA (77.4 mg, 0.6 mmol) , and HATU (91.2 mg, 0.24 mmol) were added to a solution of 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) pyrrole-2-carboxylic acid (60 mg, 0.2 mmol) in DMF (10 mL) at 25℃. The mixture was stirred at 25 ℃ for 2 hrs. LCMS showed the reaction was completed. The reaction was quenched with water (20 mL) , the mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over sodium sulfate, filtered and concentrated to provide 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carboxamide (70 mg, 118.5%yield) as a brown solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
17H
14FN
3O 295.1, m/z found 296.0 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 8.44 (s, 2H) , 7.32 (dd, J = 8.7, 5.4 Hz, 2H) , 7.17 (t, J = 8.6 Hz, 2H) , 7.12 (s, 1H) , 7.00 (d, J = 11.8 Hz, 2H) , 5.17 (s, 2H) , 4.06 (s, 3H) .
Step 6: 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile
POCl
3 (93.2688 mg, 0.6096 mmol) and TEA (61.5696 mg, 0.6096 mmol) were added to a solution of 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) pyrrole-2-carboxamide (60 mg, 0.02 mmol) in THF (10 mL) at 25℃. The mixture was stirred at 25℃ for 2 hrs. LCMS showed the reaction was completed. The reaction was quenched with water (20 mL) , the mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (30 mL) , dried over sodium sulfate, filtered and concentrated. The residue was purified by combi-flash with PE/EA (0: 1) to provide 3- (4-fluorophenyl) -1-methyl-4- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile (7 mg, 11.9%yield) as a brown solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
17H
12FN
3 277.1, m/z found 278.0 [M+H]
+.
1H NMR (400 MHz, CDCl
3) δ 8.49 (d, J = 5.3 Hz, 2H) , 7.32-7.29 (m, 2H) , 7.13-7.08 (m, 3H) , 7.07-7.05 (m, 2H) , 3.91 (s, 3H) .
Example 9. Preparation of Compound 1-10
FIG. 9 illustrates the synthetic scheme of compound 1-10. As shown in FIG. 9, the specific synthesis steps are as follows:
Step 1: 1-azido-4-Fluorobenzene
4-fluoroaniline (5 g, 45 mmol) was dissolved in a 3 M HCl aqueous solution (50 mL) at 0 ℃. NaNO
2 (3.72 g, 54 mmol) was slowly added and the resulting solution was stirred at the same temperature for 0.5 h. Then NaN
3 (4.38 g, 67.5 mmol) dissolved in water (20 mL) was added portion-wise and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was extracted with MTBE (50 mL*2) and the combined organic layers were dried over Na
2SO
4, filtered off and the solvent was evaporated in vacuo to provide the crude product.
Step 2: 4- ( (trimethylsilyl) ethynyl) pyridine
TEA (9.9 mg, 98 mmol) , PPh
3 (77 mg, 0.2 mmol) and PdCl
2 (PPh
3)
2 (344 mg, 0.4 mmol) were added to a solution of 4-iodopyridine (2 g, 9.8 mmol) in THF (30 mL) . This mixture was evacuated and backfilled with N
2 for several times to remove oxygen from the solution. The reaction mixture was stirred at 25 ℃ for 1 h. CuI (56 mg, 0.2 mmol) and ethynyltrimethylsilane (1.44 g, 14.7 mmol) were added. The reaction mixture was stirred at 25 ℃ for 15 h. Water (50 mL) was added. The residue was extracted with EA (30 mL*3) . The reaction mixture was concentrated to provide the crude product. Chemical Formula: calculated for (M+H
+) C
10H
14NSi, Molecular Weight: 176.31, Found: 176.0.
1H NMR (400 MHz, CDCl
3) δ 8.57 (d, J = 5.6 Hz, 2H) , 7.31 (dd, J = 4.5, 1.6 Hz, 2H) , 0.27 (s, 9H) .
Step 3: 4- (1- (4-fluorophenyl) -1H-1, 2, 3-triazol-5-yl) pyridine
4- ( (trimethylsilyl) ethynyl) pyridine (639 mg, 3.65 mmol) and t-BuOK (409 mg, 3.65 mmol) were added to a solution of 1-azido-4-fluorobenzene (500 mg, 3.65 mmol) in DMF (20 mL) . The reaction mixture was stirred at 25 ℃ for 15 h. Water (20 mL) was added. The residue was extracted with EA (2*20 mL) . The crude was dried over sodium sulphate and dried under a stream of nitrogen in the Radleys blowdown apparatus to provide the crude product. The reaction mixture was concentrated under pressure. The crude product was added to a silica gel column and was eluted with CH
2Cl
2/MeOH (15: 1) . The residue was purified via Genal-Prep-HPLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
13H
10FN
4, Molecular Weight: 240.24, Found: 240.9.
1H NMR (400 MHz, MeOD) δ 8.58 (dd, J = 4.7, 1.4 Hz, 2H) , 8.23 (s, 1H) , 7.57-7.45 (m, 2H) , 7.42-7.26 (m, 4H) .
Example 10. Preparation of Compound 3-7
FIG. 10 illustrates the synthetic scheme of compound 3-7. As shown in FIG. 10, the specific synthesis steps are as follows:
Step 1: methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate
Methyl 2-isocyanoacetate (6.18 g, 62.4 mmol) and Ag2CO3 (1.15 g, 4.2 mmol) were added to a solution of 1-ethynyl-4-fluorobenzene (5 g, 42 mmol) in NMP (20 mL) . The mixture was stirred at 80 ℃ for 1 h under nitrogen atmosphere. The mixture was extracted with EtOAc. The solvents were evaporated in vacuo and crude material was added to a silica gel column, was eluted with PE/EA (20: 1) . Chemical Formula: calculated for (M+H+) C12H10FNO2: 219.22, Found: 219.9.
Step 2: methyl 3- (4-fluorophenyl) -1-methyl-1H-pyrrole-2-carboxylate
The solution of NaH (0.66 g, 27.4 mmol) in DMF (5 mL) was cooled to 0 ℃ in a dry ice-water bath. Methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate (3 g, 13.7 mmol) in DMF (10 mL) were added. The mixture was stirred at 0 ℃ for 1 h, then, ICH3 (2.9 g, 20.5 mmol) was added. The reaction mixture was stirred at 25 ℃ for 1 h. 5 mL water was added, and the mixture was extracted with EtOAc. The solvents were evaporated in vacuo and the crude material was added to a silica gel column and was eluted with PE/EA (20: 1) . Chemical Formula: calculated for (M+H+) C13H12FNO2: 233.24, Found: 233.9.
Step 3: methyl 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylate
ICl (8.4 g, 5.1 mmol) in CCl4 was added to a solution of methyl 3- (4-fluorophenyl) -1-methyl-1H-pyrrole-2-carboxylate (1 g, 4.3 mmol) in CCl4 (5 mL) . The mixture was stirred at 0 ℃ for 15 min. The solvents were evaporated in vacuo and the crude material was added to a silica gel column and was eluted with PE/EA (20: 1) . Chemical Formula: calculated for (M+H+) C13H11FINO2: 359.14, Found: 359.6.
Step 4: 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylic acid
NaOH (0.22 g, 5.5 mmol) was added to a solution of methyl 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylate (0.4 g, 1.1 mmol) in MeOH/H2O (6 mL) . The mixture was stirred at 60 ℃ for 5 h. The reaction was adjusted to pH 5-6 with HCl (6 mol/L) and was extracted with EtOAc. The solvents were evaporated in vacuo to provide the crude product. Chemical Formula: calculated for (M+H+) C12H9FINO2: 345.11, Found: 345.7.
Step 5: 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxamide
HATU (502 mg, 1.32 mmol) , DIEA (506 mg, 3.3 mmol) and NH4Cl (177 mg, 3.3 mmol) were added to a solution of 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxylic acid (380 mg, 1.1 mmol) in DMF (10 mL) . The mixture was stirred at room temperature for 1 h. 5 mL water was added, and the mixture was extracted with EtOAc. The solvents were evaporated in vacuo to provide the crude product. Chemical Formula: calculated for (M+H+) C12H10FIN2O: 344.13, Found: 344.7.
Step 6: 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carbonitrile
POCl3 (468 mg, 3.05 mmol) and Et3N (309 mg, 3.05 mmol) were added to a solution of 3-(4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carboxamide (350 mg, 1.02 mmol) in THF (5 mL) . The mixture was stirred at room temperature for 1 h. The solvents evaporated in vacuo and the crude material was added to a silica gel column and was eluted with PE/EA (20: 1) . Chemical Formula: calculated for (M+H+) C12H8FIN2: 326.11, Found: 326.6.
Step 7: 3- (4-fluorophenyl) -1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile
A solution of 3- (4-fluorophenyl) -4-iodo-1-methyl-1H-pyrrole-2-carbonitrile (50 mg, 0.15 mmol) in THF (3 mL) was stirred at -78 ℃ under nitrogen atmosphere, then, 2.4 M n-BuLi (0.19 mL) was added, the reaction mixture was stirred at -78 ℃ for 1 h. Then, 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (86 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated solution of ammonium chloride and washed for several times with diethyl ether. The solvents were evaporated in vacuo and the crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H+) C18H20BFN2O2: 326.18, Found: 326.8.
Step 8: 3- (4-fluorophenyl) -1-methyl-4- (5-oxo-5, 7-dihydrofuro [3, 4-b] pyridin-4-yl) -1H-pyrrole-2-carbonitrile
4-bromofuro [3, 4-b] pyridin-5 (7H) -one (38 mg, 0.18 mmol) , Na2CO3 (38 mg, 0.36 mmol) and Pd (dppf) Cl2 (13 mg, 0.018 mmol) were added to a solution of 3- (4-fluorophenyl) -1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (60 mg, 0.018mmol) in toluene/H2O (5.5 mL) . The mixture was stirred at 100 ℃ for 16 h under nitrogen atmosphere. The solvents were evaporated in vacuo and the crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H+) C19H12FN3O2: 333.32, Found: 333.7. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.3 Hz, 1H) , 7.69 (s, 1H) , 7.35 –7.22 (m, 2H) , 7.10 (t, J = 8.6 Hz, 2H) , 6.88 (d, J = 5.3 Hz, 1H) , 5.33 (s, 2H) , 3.93 (s, 3H) .
Example 11. Preparation of Compound 2-27
FIG. 11 illustrates the synthetic scheme of compound 2-27. As shown in FIG. 11, the specific synthesis steps are as follows:
Step 1: 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) propan-1-one
Et
3N was added to a solution of 4- [2- (4-fluorophenyl) -4H, 5H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] -2-methylpyridine in DCM. Then propanoyl chloride was added, the mixture was stirred at room temperature for 2 h. The solvents were evaporated in vacuo and crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
20H
19FN
4O: 350.40, Found: 350.9.
1H NMR (400 MHz, CDCl
3) δ 8.59 (d, J=10.7 Hz, 2H) , 7.46-7.35 (m, 2H) , 7.11 (s, 2H) , 7.07-6.96 (m, 2H) , 4.90 (s, 1H) , 4.76 (s, 1H) , 4.37 (s, 1H) , 4.26 (d, J = 43.4 Hz, 2H) , 4.04 (s, 1H) , 2.65-2.20 (m, 2H) , 1.36-1.06 (m, 3H) .
Example 12. Preparation of Compound 2-28
FIG. 12 illustrates the synthetic scheme of compound 2-28. As shown in FIG. 12, the specific synthesis steps are as follows:
Step 1: 1- (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) -2-methylpropan-1-one
Et
3N was added to a solution of 4- [2- (4-fluorophenyl) -4H, 5H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] -2-methylpyridine in DCM. Then 2-methylpropanoyl chloride was added, the mixture was stirred at room temperature for 2 h. The solvents were evaporated in vacuo and crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
21H
22FN
4O: 364.42, Found: 364.8.
1H NMR (400 MHz, CDCl
3) δ 8.58 (s, 2H) , 7.42-7.38 (m, 2H) , 7.12 (d, J=3.7 Hz, 2H) , 7.08-7.00 (m, 2H) , 4.85 (d, J=37.0 Hz, 2H) , 4.24 (dd, J=80.9, 32.3 Hz, 2H) , 1.96 (s, 1H) , 1.39-1.04 (m, 2H) .
Example 13. Preparation of Compounds 2-29 and 2-31
FIG. 13 illustrates the synthetic scheme of compounds 2-29 and 2-31. As shown in FIG. 13, the specific synthesis steps are as follows:
Step 1: ethyl 3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
2-ethoxy-2-oxoethanediazonium was added to a solution of 1-ethynyl-4-fluorobenzene in toluene (300 mL) at room temperature and the resulting mixture was stirred at 130 ℃ for 3 h. The mixture was cooled to room temperature. The reaction mixture was concentrated under pressure. The crude material was added to a flash chromatography and was eluted with PE/EA (3: 1) . Chemical Formula: calculated for (M+H
+) C
12H
11FN
2O
2: 234.23, Found: 234.9.
Step 2: ethyl 1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
1, 2-dibromoethaneand was added to a solution of ethyl 3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate and potassium carbonate in acetonitrile (200 mL) at room temperature, the resulting mixture was stirred at 90 ℃ for 4 h. The mixture was cooled to room temperature. The reaction mixture was concentrated under pressure. The crude material was added to a flash chromatography and was eluted with PE/EA (10: 1) . Chemical Formula: calculated for (M+H
+) C
14H
14BrFN
2O
2: 341.18, Found: 342.02.
Step 3: 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
Phenylmethanamine and NaHCO
3 were added to a solution of ethyl 1- (2-bromoethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate and potassium iodide in acetonitrile (200 mL) at room temperature, the resulting mixture was stirred at 90 ℃ for 16 h. The mixture was cooled to room temperature. The reaction mixture was concentrated under pressure. The crude material was added to a flash chromatography and was eluted with PE/EA (3: 1) . Chemical Formula: calculated for (M+H
+) C
19H
16FN
3O: 324.36, Found: 321.9.
Step 4: 5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
LAH was added to a solution of 5-benzyl-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one in THF (100 mL) at 0℃, and the resulting mixture was stirred at 25 ℃ overnight. The reaction mixture was quenched with ice-cold water. The mixture was filtered, and the filtrate was extracted with DCM. The solvents were evaporated in vacuo and crude material was added to a flash chromatography and was eluted with PE/EA (4: 1) . Chemical Formula: calculated for (M+H
+) C
19H
18FN
3: 307.37, Found: 307.9.
Step 5: 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
NBS was added to a stirred solution of 5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine in acetonitrile with ice-cooling. The mixture was stirred for 2 h. The solvents were evaporated in vacuo and crude material was added to a flash chromatography and was eluted with PE/EA (4: 1) . Chemical Formula: calculated for (M+H
+) C
19H
17BrFN
3: 386.27, Found: 387.7.
Step 6: 5-benzyl-2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
Pd (dppf) Cl
2, pyridin-4-ylboranediol, K
3PO
4 was added to a solution of 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine in DMF, the mixture was allowed to react under N
2 at 80 ℃ for 3 h. The mixture was extracted with DCM. The solvents were evaporated in vacuo and crude material was added to a flash chromatography and was eluted with PE/EA (1: 1) . Chemical Formula: calculated for (M+H
+) C
25H
23FN
4: 398.49, Found: 398.9.
Step 7: 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
Ammonium formate (454 mg) , Pd/c (140 mg) was added to a solution of 5-benzyl-2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (140 mg) in MeOH (20 mL) , the mixture was heated to 50 ℃ for 3 h. The solvents were evaporated in vacuo and crude material was added to a flash chromatography and was eluted with DCM/MeOH (20: 1) . Chemical Formula: calculated for (M+H
+) C
18H
17FN
4: 308.36, Found: 308.9.
Step 8: 1- (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
Et
3N was added to a solution of 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine in DCM. Then acetyl chloride was added, the mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo and crude material was added to a flash chromatography and was eluted with DCM/MeOH (20: 1) . Chemical Formula: calculated for (M+H
+) C
20H
19FN
4O: 350.40, Found: 350.9.
1H NMR (400 MHz, CDCl
3) δ 8.47 (dd, J = 20.0, 5.2 Hz, 1H) , 7.47-7.36 (m, 2H) , 7.02 (t, J = 8.7 Hz, 2H) , 6.93 (dd, J = 26.4, 6.0 Hz, 2H) , 4.87 (s, 1H) , 4.74 (s, 1H) , 4.37 (t, J = 5.4 Hz, 1H) , 4.30 (t, J = 5.4 Hz, 1H) , 4.18 (t, J = 5.3 Hz, 1H) , 4.02 (t, J = 5.4 Hz, 1H) , 2.55 (s, 3H) , 2.22 (d, J = 37.2 Hz, 3H) .
Step 9: 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine-3-yl) -2-methylpyridine-1-oxide
1- [2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4H, 6H, 7H-pyrazolo was dissolved in DCM and cooled to 0℃, m-Chloroperoxybenzoic acid was added, and the reaction mixture was stirred for 1 h at room temperature. The mixture was washed with saturated aqueous Na
2CO
3, dried over Na
2SO
4, filtered, and concentrated to provide the desired product. Chemical Formula: calculated for (M+H
+) C
20H
19FN
4O
2: 366.40, Found: 366.8.
1H NMR (400 MHz, CDCl
3) δ 8.28 (dd, J = 13.4, 6.6 Hz, 1H) , 7.47-7.33 (m, 2H) , 7.08-6.94 (m, 4H) , 4.88 (s, 1H) , 4.74 (s, 1H) , 4.37 (t, J = 5.4 Hz, 1H) , 4.30 (d, J =5.8 Hz, 1H) , 4.19 (d, J = 5.4 Hz, 1H) , 4.03 (t, J = 5.4 Hz, 1H) , 2.54 (s, 3H) , 2.24 (d, J = 32.6 Hz, 3H) .
Example 14. Preparation of Compound 2-30
FIG. 14 illustrates the synthetic scheme of compound 2-30. As shown in FIG. 14, the specific synthesis steps are as follows:
Step 1: methyl 1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
1-bromo-2-chloroethane (5.5213 g, 0.0385 mol) and K
2CO
3 (3.1878 g, 0.0231 mol) were added to a solution of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (1.8 g, 0.0077 mol) in acetone (20 mL) . The reaction mixture was stirred at 70℃ for 4h. The reaction was completed and examined with LCMS. The mixture was concentrated, then H
2O was added, filtered and the filter cake was concentrated. Chemical Formula: calculated for (M+H
+) C
13H
13ClFN
2O
2, Molecular Weight: 283.70, Found: 283.0.
Step 2: (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol
LAH (0.2160 g, 0.0054 mol) was added to a solution of methyl 1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (1.6 g, 0.0054 mol) in tetrahydrofuran (30 mL) at 0 ℃, the reaction mixture was stirred at 0-25℃ for 2 h. The reaction was completed and examined with LCMS. The reaction was quenched with H
2O (50 mL) . The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to provide the crude product. Chemical Formula: calculated for (M+H
+) C
12H
13ClFN
2O, Molecular Weight: 255.69, Found: 255.0.
Step 3: 2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
NaH (84.72 mg, 3.53 mmol) was added to a solution of (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol (900 mg, 3.53 mmol) in DMF (10 mL) at 0℃ and the reaction mixture was stirred at 0-25 ℃ for 2 h. The reaction was completed and examined with LCMS. The reaction was quenched with H
2O (50 mL) , the mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to provide the crude product. Chemical Formula: calculated for (M+H
+) C
12H
11FN
2O, Molecular Weight: 219.23, Found: 219.0.
Step 4: 3-bromo-2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
NBS (284.8 mg, 1.6 mmol) was added to a solution of 2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine (350 mg, 1.6 mmol) in DCM (10 mL) , the reaction mixture was stirred at 25 ℃ for 16 h. The reaction was completed and examined with LCMS. The reaction was quenched with H
2O (50 mL) , The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to provide the crude product. Chemical Formula: calculated for (M+H
+) C
12H
11BrFN
2O, Molecular Weight: 298.13, Found: 298.9.
Step 5: 2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
Pyridin-4-ylboranediol (184.3770 mg, 1.5 mmol) , K
3PO
4 (106 mg, 0.5 mmol) , X-phos (47.7000 mg, 0.1 mmol) , and Pd
2 (dba)
3 (45.8 mg, 0.05 mmol) were added to a solution of 3-bromo-2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine (150 mg, 0.50 mmol) in 1, 4-Dioxane (10 mL) . The reaction mixture was stirred at 90℃ for 16 h. The reaction was completed and examined with LCMS, then filtered and concentrated.
1H NMR (400 MHz, DMSO) δ 8.50 (dd, J = 4.5, 1.6 Hz, 2H) , 7.43-7.36 (m, 2H) , 7.25-7.17 (m, 2H) , 7.10 (dd, J = 4.5, 1.6 Hz, 2H) , 4.92 (s, 2H) , 4.22 (t, J = 5.0 Hz, 2H) , 4.14 (t, J = 5.1 Hz, 2H) Chemical Formula: calculated for (M+H
+) C
17H
15FN
3O, Molecular Weight: 296.32, Found: 296.0.
Example 15. Preparation of Compound 2-33
FIG. 15 illustrates the synthetic scheme of compound 2-33. As shown in FIG. 15, the specific synthesis steps are as follows:
Step 1: (2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone
1-methylpiperidine-4-carboxylic acid in oxalic dichloride was heated to 70 ℃ for 1 h, then the solvent was removed in vacuum, Et
3N, 4- [2- (4-fluorophenyl) -4H, 5H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridine was added, the mixture was stirred at room temperature for 1 h. The solvents were evaporated in vacuo and crude material was purified by PTLC, to obtain the product. Chemical Formula: calculated for (M+H
+) C
24H
26FN
5O: 419.21, Found: 419.8.
1H NMR (400 MHz, CDCl
3) δ8.57 (s, 2H) , 7.47-7.36 (m, 2H) , 7.18 -6.94 (m, 4H) , 4.83 (d, J = 43.8 Hz, 2H) , 4.37 (s, 2H) , 4.13 (d, J = 45.8 Hz, 2H) , 3.10 -2.91 (m, 2H) , 2.37 (s, 2H) , 1.96 (s, 2H) , 1.66 (s, 4H) .
Example 16. Preparation of Compound 2-34
FIG. 16 illustrates the synthetic scheme of compound 2-34. As shown in FIG. 16, the specific synthesis steps are as follows:
Step 1: N-methyl-1H-imidazole-1-carboxamide
CDI (500 mg, 3.08 mmol) and methenamine (95.6 mg, 3.08 mmol) were dissolved in DMF (1 mL) and acetonitrile (3 mL) . The solution was stirred at room temperature for 2 h before being concentrated under an air stream to a thick oil. Flash chromatography (4%MeOH/CH
2Cl
2) provide the product.
Step 2: 2- (4-fluorophenyl) -N-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazine-5 (4H) -carboxamide
N-methyl-1H-imidazole-1-carboxamide (8.7 mg, 0.07 mol) and TEA (7.78 mg, 0.077 mol) were added to a solution of 2- (4-fluorophenyl) -3- (pyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (20 mg, 0.07 mol) in DCM (2 mL) . The reaction mixture was stirred at 25 ℃ for 2 h. The mixture was concentrated, then was purified by prep-TLC and prep-HPLC to provide the product. Chemical Formula: calculated for (M+H
+) C
19H
19FN
5O, Molecular Weight: 351.39, Found: 351.8.
1H NMR (400 MHz, CDCl
3) δ 8.57 (s, 2H) , 7.40 (dd, J = 8.6, 5.4 Hz, 2H) , 7.22 (s, 2H) , 7.05 (t, J = 8.7 Hz, 2H) , 4.85 (s, 1H) , 4.71 (s, 2H) , 4.34 (t, J = 5.3 Hz, 2H) , 4.01 (t, J = 5.3 Hz, 2H) , 2.88 (s, 3H) .
Example 17. Preparation of Compound 2-32
FIG. 17 illustrates the synthetic scheme of compound 2-32. As shown in FIG. 17, the specific synthesis steps are as follows:
Step 1: (4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) methyl acetate
A solution of 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methylpyridine-1-oxide (30 mg) in Ac
2O (2 mL) was stirred at 100 ℃ for 1 h. The mixture was concentrated, and purified by prep-HPLC to provide the product. Chemical Formula: calculated for (M+H
+) C
22H
22FN
4O
3, Molecular Weight: 408.43, Found: 408.8.
1H NMR (400 MHz, CDCl
3) δ 8.59 (dd, J = 9.9, 5.1 Hz, 1H) , 7.40 (dd, J = 7.9, 5.8 Hz, 2H) , 7.15 (s, 1H) , 7.06 (dd, J = 12.0, 5.4 Hz, 3H) , 5.22 (d, J = 3.5 Hz, 2H) , 4.91 (s, 1H) , 4.78 (s, 1H) , 4.38 (t, J = 5.3 Hz, 1H) , 4.31 (d, J = 5.6 Hz, 1H) , 4.20 (d, J = 5.5 Hz, 1H) , 4.07-4.00 (m, 1H) , 2.24 (d, J = 32.1 Hz, 3H) , 2.10 (d, J = 3.5 Hz, 3H) .
Example 18. Preparation of Compound 2-36
FIG. 18 illustrates the synthetic scheme of compound 2-36. As shown in FIG. 18, the specific synthesis steps are as follows:
Step 1: 5-benzyl-2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
SM2 (110 mg, 0.78 mmol) , Cs
2CO
3 (508 mg, 1.56 mmol) and Pd (dppf) Cl
2 (38 mg, 0.052 mmol) were added to a solution of 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (200 mg, 0.52 mmol) in dioxane (5 mL) and water (0.5 mL) . The reaction mixture was stirred at 100 ℃ for 3 h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) Chemical Formula: C
24H
21F
2N
4, Molecular Weight: 402.45, Found: 402.8.
Step 2: 2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
HCOONH
4 (156 mg, 2.48mmol) and Pd/C (10 mg) were added to a solution of 5-benzyl-2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (100 mg, 0.248 mmol) in (5 mL) . The reaction mixture was stirred at 50 ℃ for 5 h. The solution was filtered, and the filtrate was collected. The reaction mixture was concentrated under pressure. The product was confirmed by (consistent with) LCMS. Chemical Formula: calculated for (M+H
+) Chemical Formula: C
17H
15F
2N
4, Molecular Weight: 312.32, Found: 312.8.
Step 3: 1- (2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
Ac
2O (45.8 mg, 0.448 mmol) was added to a solution of 2- (4-fluorophenyl) -3- (3-fluoropyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (70 mg, 0.224 mmol) in THF (5 mL) . The reaction mixture was stirred at 25 ℃ for 15 h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with CH
2Cl
2/MeOH (10: 1) . The residue was purified via Prep-TLC (CH
2Cl
2/MeOH) = (6: 1) to provide the product. The residue was purified via Chiral-Prep-HPLC to provide the product. The residue was purified via Genal-Prep-HPLC to provide the product.
1H NMR (400 MHz, MeOD) δ 8.54 (d, J = 68.1 Hz, 2H) , 7.49-7.26 (m, 3H) , 7.08 (t, J = 8.8 Hz, 2H) , 4.81 (d, J = 14.3 Hz, 2H) , 4.34 (dt, J = 36.5, 5.5 Hz, 2H) , 4.15 (dt, J = 11.0, 5.5 Hz, 2H) , 2.22 (d, J = 35.9 Hz, 3H) . Chemical Formula: calculated for (M+H
+) Chemical Formula: C
19H
17F
2N
4O, Molecular Weight: 354.36, Found: 354.9.
Example 19. Preparation of Compound 1-5
FIG. 19 illustrates the synthetic scheme of compound 1-5. As shown in FIG. 19, the specific synthesis steps are as follows:
Step 1: 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine
Pyridin-4-ylboranediol (71.907 mg, 0.585 mmol) , K3PO4 (165.36 mg, 0.78 mmol) , and Pd (dppf) Cl2 (28.509 mg, 0.039 mmol) were added to a solution of 5-bromo-1- (4-fluorophenyl) -3-methylpyrazole (100 mg, 0.39 mmol) in DMF (11 mL) . The reaction mixture was stirred at 100 ℃ for 5 h. The reaction was completed and examined with LCMS. The reaction was quenched with H
2O (30 mL) , the mixture was then concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to provide the crude product. The residue was purified by combi-flash with PE/EA (1: 1) to 4- (1- (4-fluorophenyl) -3-methyl-1H-pyrazol-5-yl) pyridine (60 mg, 509.5%yield) as a white solid product, which was determined by LCMS, MS (ESI) : mass calculated for C
15H
12FN
3 253.1, m/z found 254.1 [M+H]
+.
1H NMR (400 MHz, DMSO) δ 8.54 (dd, J = 4.6, 1.4 Hz, 2H) , 7.31 (t, J = 7.1 Hz, 4H) , 7.18 (dd, J = 4.6, 1.4 Hz, 2H) , 6.69 (s, 1H) , 2.29 (s, 3H) .
Example 20. Preparation of Compound 1-13
FIG. 20 illustrates the synthetic scheme of compound 1-13. As shown in FIG. 20, the specific synthesis steps are as follows:
Step 1: 1- (4-fluorophenyl) pyrrole-2-carbonitrile
[ (chlorosulfonyl) imino] methanone (2897 mg, 20.47 mmol) was added slowly to a solution of 1- (4-fluorophenyl) pyrrole (3000 mg, 18.6 mmol) in CAN (30 mL) at 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 h. DMF (3 mL) was added dropwise to reaction mixture. The mixture was stirred at the same temperature for 1 h. Water (20 ml) was added. The residue was extracted with MTBE (30 mL*3) . The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (10: 1) . Chemical Formula: calculated for (M+H
+) Chemical Formula: C
11H
8FN
2, Molecular Weight: 186.19, Found: 187.0.
Step 2: 5-bromo-1- (4-fluorophenyl) pyrrole-2-carbonitrile
NBS (48 mg, 0.27 mmol) was added to a solution of 1- (4-fluorophenyl) pyrrole-2-carbonitrile (50 mg, 0.27 mmol) in THF (3 mL) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under pressure. The residue was purified via Prep-TLC (PE/EtOAc) = (5: 1) to provide the product.
Step 3: 1- (4-fluorophenyl) -5- (pyridin-4-yl) -1H-pyrrole-2-carbonitrile
Pyridin-4-ylboranediol (138 mg, 1.125 mmol) , Pd (dppf) Cl2 (55 mg, 0.075 mmol) and K
3PO
4 (318 mg, 1.5 mmol) were added to a solution of 5-bromo-1- (4-fluorophenyl) pyrrole-2-carbonitrile (200 mg, 0.75 mmol) in DMF (10 mL) and water (1 mL) . The reaction mixture was stirred at 100 ℃ for 15 h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (3: 2) to provide the product. Chemical Formula: calculated for (M+H
+) Chemical Formula: C
16H
11FN
3, Molecular Weight: 263.28, Found: 263.9
1H NMR (400 MHz, MeOD) δ 8.51 (dd, J = 4.7, 1.6 Hz, 2H) , 8.01 (d, J = 1.5 Hz, 1H) , 7.71 (dd, J = 4.9, 1.4 Hz, 2H) , 7.68 –7.62 (m, 3H) , 7.37 (t, J = 8.6 Hz, 2H) .
Example 21. Preparation of Compound 2-38
As shown in FIG. 21, the specific synthesis steps are as follows:
Step 1: ethyl 3- (4-fluorophenyl) -1- (oxiran-2-ylmethyl) -1H-pyrazole-5-carboxylate
To a mixture of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (2.34 g, 10 mmol) in DMF (30 mL) was added 2- (chloromethyl) oxirane (9.26 g, 100mmol) , Cs
2CO
3 (4.89 g, 15 mmol) . The reaction was stirred at 25 ℃ for 16 h, LCMS showed desired MS was detected as main peak. The mixture was extracted with EA (50 mL*2) and H
2O (50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to give a white solid (1.96 g, yield: 67.5%) . Chemical Formula: calculated for (M+H
+) C
15H
15FN
2O
3: 290.11, Found: 291.1.
1H NMR (400 MHz, DMSO) δ 7.94 –7.90 (m, 2H) , 7.41 (s, 1H) , 7.26 (t, J = 8.9 Hz, 2H) , 4.87 (dd, J = 14.5, 3.6 Hz, 1H) , 4.61 (dd, J = 14.5, 5.5 Hz, 1H) , 4.34 (q, J = 7.1 Hz, 2H) , 3.42 –3.38 (m, 1H) , 2.80 –2.77 (m, 1H) , 2.52 -2.51 (m, 1H) , 1.34 (t, J = 7.1 Hz, 3H) .
Step 2: 1- (3- (4-fluorophenyl) -5- (hydroxymethyl) -1H-pyrazol-1-yl) propan-2-ol
To a mixture of ethyl 5- (4-fluorophenyl) -2- (oxiran-2-ylmethyl) pyrazole-3-carboxylate (1.45 g, 5.0 mmol) in THF (20 mL) was added Lithium aluminum hydride (380 mg, 10.0 mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 4 h, LCMS showed desired MS was detected as main peak. The reaction was quenched by ice, the mixture was extracted with EA (50 mL*2) and H
2O (50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated to give a white solid (1.29 g, purity: 90%, yield: 92%) . Chemical Formula: calculated for (M+H
+) C
13H
15FN
2O
2: 250.11, Found: 251.0.
1H NMR (400 MHz, DMSO) δ 7.82 -7.77 (m, 2H) , 7.21 (t, J = 8.9 Hz, 2H) , 6.59 (s, 1H) , 5.29 (t, J = 5.6 Hz, 1H) , 5.00 (d, J = 4.7 Hz, 1H) , 4.56 (dd, J = 11.1, 6.3 Hz, 2H) , 4.07 –4.01 (m, 3H) , 1.10 (d, J = 5.9 Hz, 3H) .
Step 3: 2- (4-fluorophenyl) -6-methyl-6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
To a mixture of 1- [3- (4-fluorophenyl) -5- (hydroxymethyl) pyrazol-1-yl] propan-2-ol (1.0 g, 4.0 mmol) in Toluene (20 mL) was added sulfuric acid (1.96 g, 20 mmol) . The reaction was stirred at 110 ℃for 4 h. The mixture was concentrated to remove organic, diluted with H
2O (20 mL) , treated by 1M NaOH to pH~7, then extracted with EA (50 mL*2) and H
2O (50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) to give a white solid (305 mg, yield: 32%) . Chemical Formula: calculated for (M+H
+) C
13H
13FN
2O: 232.10, Found: 233.1.
1H NMR (400 MHz, DMSO) δ 7.82 –7.78 (m, 2H) , 7.22 (t, J = 8.9 Hz, 2H) , 6.50 (s, 1H) , 4.94 (d, J = 15.0 Hz, 1H) , 4.75 (d, J = 15.1 Hz, 1H) , 4.22 (dd, J = 12.4, 3.1 Hz, 1H) , 4.08 -4.01 (m, 1H) , 3.76 (dd, J = 12.1, 10.7 Hz, 1H) , 1.31 (d, J = 6.2 Hz, 3H) .
Step 4: 3-bromo-2- (4-fluorophenyl) -6-methyl-6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
To a mixture of 2- (4-fluorophenyl) -6-methyl-4H, 6H, 7H-pyrazolo [3, 2-c] [1, 4] oxazine (296 mg, 1.27 mmol) in DCM (5 mL) was added NBS (340 mg, 1.905 mmol) stirred at RT for 16 h. LCMS showed desired MS was detected as main peak. The mixture was extracted with DCM (50 mL*2) and H
2O (50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to give a white solid (340 mg, yield: 86%) . Chemical Formula: calculated for (M+H
+) C
13H
12BrFN
2O: 310.01, Found: 310.9.
1H NMR (400 MHz, DMSO) δ 7.87 –7.81 (m, 2H) , 7.34 –7.28 (m, 2H) , 4.85 (d, J = 15.2 Hz, 1H) , 4.72 (d, J = 15.2 Hz, 1H) , 4.23 (dd, J = 12.4, 3.0 Hz, 1H) , 4.12 -4.04 (m, 1H) , 3.80 (dd, J = 12.2, 10.6 Hz, 1H) , 1.32 (d, J = 6.2 Hz, 3H) .
Step 5: 2- (4-fluorophenyl) -6-methyl-3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
To a solution of 3-bromo-2- (4-fluorophenyl) -6-methyl-4H, 6H, 7H-pyrazolo [3, 2-c] [1, 4] oxazine (155 mg, 0.55 mmol) in dioxane/H2O (20 mL/4 mL) was added pyridin-4-ylboranediol (185 mg, 1.5 mmol) , Cs
2CO
3 (245 mg, 0.75 mmol) and Pd (dppd) Cl
2 (82 mg, 0.1 mmol) , and the mixture was stirred at 100 ℃ under dry N
2 for 4 h. The mixture was concentrated to remove organic, diluted with H
2O (20 mL) , then extracted with EA (50 mL*2) and H
2O (50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) to give a crude product, then purified by SFC (chiralpak-OJ, CO2-MEOH (DEA) to give Compound 2-38 (crude) and Compound 2-39 (27.2 mg, HPLC: 99.47%) . Compound 2-38 was purified by HPLC (Gemini-C18 150 x 21.2 mm, 5um, ACN –H
2O 0.1%FA, gradient 10%~ 40%) to give Compound 2-38 (44.8 mg, HPLC: 100%) . Chemical Formula: calculated for (M+H
+) C
18H
16FN
3O: 309.13, Found: 310.1.
Compound 2-38:
1H NMR (400 MHz, DMSO) δ 8.50 (d, J = 5.3 Hz, 2H) , 7.41 –7.36 (m, 2H) , 7.23 –7.18 (m, 2H) , 7.10 (d, J = 6.0 Hz, 2H) , 4.93 (t, J = 19.5 Hz, 2H) , 4.30 (dd, J = 12.6, 3.1 Hz, 1H) , 4.16 -4.08 (m, 1H) , 3.88 –3.81 (m, 1H) , 1.34 (d, J = 6.2 Hz, 3H) .
Example 22. Preparation of Compound 2-37
As shown in FIG. 22, the specific synthesis steps as follows:
Step 1: ethyl (R) -1- (1- ( (tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (2)
PPh
3 (3360 mg, 12.81 mmol) and DIAD (5180 mg, 25.62 mmol) in THF (50 mL) , (R) -1- (Boc-amino) -2-propanol (1795 mg, 10.25 mmol) was added to a solution of 1- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) ethan-1-one (2000 mg, 8.54 mmol) . The reaction mixture was stirred at 25℃ for 15 h. Saturated NH
4Cl aqueous (50 mL) was added. The residue was extracted with EA (30mL*2) . The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (4: 1) to give product.
Chemical Formula: calculated for (M+H
+) : C
20H
26FN
3O
4, Molecular Weight: 391.44, Found: 391.8
Step 2: ethyl (R) -1- (1- ( (tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (3)
TFA (1747 mg, 15.32 mmol) was added to a solution of ethyl (R) -1- (1- ( (tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (3000 mg, 7.66 mmol) in DCM (30 mL) . The reaction mixture was stirred at 25℃ for 15 h. The reaction mixture was concentrated under pressure to give product.
Chemical Formula: calculated for (M+H
+) : C
15H
18FN
3O
2, Molecular Weight: 291.33, Found: 291.8
Step 3: (R) -2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (4)
TEA (1390 mg, 13.74 mmol) was added to a solution of ethyl (R) -1- (1- ( (tert-butoxycarbonyl) amino) propan-2-yl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (2000 mg, 6.87 mmol) in MeOH (5 mL) . The reaction mixture was stirred at 50℃ for 5 h. The reaction mixture was concentrated under pressure to give product.
Chemical Formula: calculated for (M+H
+) : C
13H
12FN
3O, Molecular Weight: 245.26, Found: 245.7
Step 4: (R) -3-bromo-2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (5)
NBS (878 mg, 4.935 mmol) was added to a solution of (R) -2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (1000 mg, 3.29 mmol) in THF (20 mL) . The reaction mixture was stirred at 50℃ for 20 h. The reaction mixture was concentrated under pressure to give product.
Chemical Formula: calculated for (M+H
+) : C
13H
11BrFN
3O, Molecular Weight: 324.15, Found: 324.7
Step 5: (R) -2- (4-fluorophenyl) -7-methyl-3- (pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one
To a solution of (R) -3-bromo-2- (4-fluorophenyl) -7-methyl-6, 7-dihydropyrazolo [1, 5-a] pyrazin-4 (5H) -one (1000 mg, 3.09 mmol) in Dimethoxyethane (20 mL) and water (3 mL) , was added pyridin-4-ylboronic acid (570 mg, 4.63 mmol) , Pd (PPh
3)
4 (357 mg, 0.309 mmol) and Na
2CO
3 (667 mg, 6.18 mmol) . The reaction mixture was stirred at 100℃ for 5 h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with CH
2Cl
2/MeOH (10: 1) to give product.
Chemical Formula: calculated for (M+H
+) : C
18H
15FN
4O, Molecular Weight: 322.34, Found: 322.8
Example 23. Preparation of Compounds 2-39
As shown in FIG. 23, the specific synthesis steps are similar to Example 21.
Compound 2-39:
1H NMR (400 MHz, DMSO) δ 8.50 (dd, J = 4.5, 1.6 Hz, 2H) , 7.41 –7.36 (m, 2H) , 7.21 (t, J = 8.9 Hz, 2H) , 7.10 (dd, J = 4.5, 1.6 Hz, 2H) , 4.95 (d, J = 23.8 Hz, 2H) , 4.30 (dd, J = 12.5, 3.1 Hz, 1H) , 4.14 –4.09 (m, 1H) , 3.87 –3.82 (m, 1H) , 1.35 (d, J = 6.2 Hz, 3H) .
Example 24. Preparation of Compound 2-40
As shown in FIG. 24, the specific synthesis steps are as follows:
Step 1: ethyl 1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate
To a mixture of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (2.34 g, 10 mmol) in DMF (20 mL) was added 1-bromo-3-chloropropane (2.37 g, 15 mmol) , Cs
2CO
3 (4.89 g, 15mmol) . The reaction was stirred at 25 ℃ for 16 h, LCMS showed desired MS was detected as main peak. The mixture was extracted with EA (50 mL*2) and H
2O (50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to give a white solid (1.9 g, yield: 58%) . Chemical Formula: calculated for (M+H
+) C
15H
16ClFN
2O
2: 310.09, Found: 311.1.
1H NMR (400 MHz, DMSO) δ 7.94 –7.89 (m, 2H) , 7.38 (s, 1H) , 7.29 -7.23 (m, 2H) , 4.67 (t, J = 6.9 Hz, 2H) , 4.34 (q, J = 7.1 Hz, 2H) , 3.67 (t, J =6.3 Hz, 2H) , 2.32 -2.24 (m, 2H) , 1.34 (t, J = 7.1 Hz, 3H) .
Step 2: (1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol and 3- (3- (4-fluorophenyl) -5- (hydroxymethyl) -1H-pyrazol-1-yl) propan-1-ol
To a mixture of ethyl 1- (3-chloropropyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (1.24 g, 4.0 mmol) in THF (20 mL) was added Lithium aluminum hydride (304 mg, 8.0 mmol) at 0 ℃. The reaction was stirred at 0 ℃ for 4 h, LCMS showed desired MS was detected as main peak. The reaction was quenched by ice, the mixture was extracted with EA (50 mL*2) and H
2O (50 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated to give two white solids (compound 3, 730 mg) and (compound 3A, 80 mg) . Compound 3: Chemical Formula: calculated for (M+H
+) C
13H
14ClFN
2O: 268.08, Found: 269.1.
1H NMR (400 MHz, DMSO) δ 7.82 –7.78 (m, 2H) , 7.24 –7.19 (m, 2H) , 6.62 (s, 1H) , 5.50 -5.15 (m, 1H) , 4.54 (s, 2H) , 4.25 (t, J =6.9 Hz, 2H) , 3.69 (t, J = 6.5 Hz, 2H) , 2.27 (p, J = 6.6 Hz, 2H) . Compound 3A: Chemical Formula: calculated for (M+H
+) C
13H
15FN
2O
2: 250.11, Found: 251.1.
1H NMR (400 MHz, DMSO) δ 7.79 (dd, J = 8.9, 5.6 Hz, 2H) , 7.21 (t, J = 8.9 Hz, 2H) , 6.58 (s, 1H) , 5.35 (t, J = 5.5 Hz, 1H) , 4.61 (t, J = 5.1 Hz, 1H) , 4.53 (d, J = 5.5 Hz, 2H) , 4.16 (t, J = 7.1 Hz, 2H) , 3.45 -3.39 (m, 2H) , 1.98 -1.91 (m, 2H) .
Step 3: 2- (4-fluorophenyl) -7, 8-dihydro-4H, 6H-pyrazolo [5, 1-c] [1, 4] oxazepine
To a mixture of 3- [3- (4-fluorophenyl) -5- (hydroxymethyl) pyrazol-1-yl] propan-1-ol (80 mg, 0.31 mmol) in Toluene (10 mL) was added sulfuric acid (157 mg, 1.59 mmol) . The reaction was stirred at 110 ℃ for 4 h. The mixture was concentrated to remove organic, diluted with H
2O (20 mL) , treated by 1M NaOH to pH~7, then extracted with EA (30 mL*2) and H
2O (30 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) to give a white solid (20 mg, yield: 27%) . Chemical Formula: calculated for (M+H
+) C
13H
13FN
2O: 232.10, Found: 233.1.
1H NMR (400 MHz, DMSO) δ 7.79 –7.75 (m, 2H) , 7.21 (t, J = 8.9 Hz, 2H) , 6.63 (s, 1H) , 4.63 (s, 2H) , 4.46 –4.42 (m, 2H) , 3.98 –3.95 (m, 2H) , 1.89 –1.84 (m, 2H) .
Step 4: 3-bromo-2- (4-fluorophenyl) -7, 8-dihydro-4H, 6H-pyrazolo [5, 1-c] [1, 4] oxazepine
To a mixture of 2- (4-fluorophenyl) -4H, 6H, 7H, 8H-pyrazolo [3, 2-c] [1, 4] oxazepane (20 mg, 0.09 mmol) in DCM (5 mL) was added NBS (25 mg, 0.135 mmol) stirred at room temperature for 16 h. LCMS showed desired MS was detected as main peak. The mixture was extracted with DCM (30 mL*2) and H
2O (30 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, then purified by column chromatography (PE/EA = 2/1) to give a white solid (16 mg, yield: 56%) . Chemical Formula: calculated for (M+H
+) C
13H
12BrFN
2O: 310.01, Found: 311.0.
1H NMR (400 MHz, DMSO) δ 7.84 –7.79 (m, 2H) , 7.33 –7.27 (m, 2H) , 4.68 (s, 2H) , 4.53 –4.49 (m, 2H) , 4.02 –3.98 (m, 2H) , 1.94 -1.87 (m, 2H) .
Step 5: 2- (4-fluorophenyl) -3- (pyridin-4-yl) -7, 8-dihydro-4H, 6H-pyrazolo [5, 1-c] [1, 4] oxazepine
To a solution of 3-bromo-2- (4-fluorophenyl) -7, 8-dihydro-4H, 6H-pyrazolo [5, 1-c] [1, 4] oxazepine (16 mg, 0.05 mmol) in dioxane/H
2O (5 mL/1 mL) was added pyridin-4-ylboranediol (19 mg, 0.15 mmol) , Cs
2CO
3 (25 mg, 0.075 mmol) and Pd (dppd) Cl
2 (9 mg, 0.01 mmol) , and the mixture was stirred at 100 ℃ under dry N
2 for 4 h. The mixture was concentrated to remove organic solvent, diluted with H
2O (20 mL) , then extracted with EA (30 mL × 2) and H
2O (30 mL) . The organic layer was washed with brine (50 mL) , dried over anhydrous Na
2SO
4, filtered and concentrated, purified by column chromatography (DCM/MeOH = 30/1) to give a crude product, then purified by HPLC (Gemini-C18 150 x 21.2 mm, 5um, ACN –H
2O 0.1%FA, gradient 10%~ 40%) to give a white solid (3.2 mg, yield: 20%, HPLC: 99.72%) . Chemical Formula: calculated for (M+H
+) C
18H
16FN
3O: 309.13, Found: 310.1.
1H NMR (400 MHz, DMSO) δ 8.52 (s, 2H) , 7.39 –7.34 (m, 2H) , 7.22 (d, J = 4.7 Hz, 2H) , 7.08 (t, J = 8.8 Hz, 2H) , 4.71 (s, 2H) , 4.61 –4.58 (m, 2H) , 4.13 –4.10 (m, 2H) , 2.08 -2.02 (m, 2H) .
Example 25. Preparation of Compound 3-11
As shown in FIG. 25, the specific synthesis steps are as follows:
Step 1: 3- (4-fluorophenyl) -1-methyl-4- (1H-pyrazolo [3, 4-b] pyridin-4-yl) -1H-pyrrole-2-carbonitrile
4-bromo-1H-pyrazolo [3, 4-b] pyridine (46 mg, 0.23 mmol) , 2 M Na
2CO
3 aqueous solutions (0.5 mL) and Pd (dppf) Cl
2 (22 mg, 0.03 mmol) were added to a solution of 3- (4-fluorophenyl) -1- methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (50 mg, 0.15 mmol) in EtOH/toluene=8: 2 (5 mL) . The mixture was stirred at 100 ℃ for 1 h under nitrogen atmosphere on microwave. The reaction mixture was concentrated under pressure. The residue was purified via Prep-TLC PE/EA (1: 10) and give the product. Chemical Formula: calculated for (M+H
+) C
18H
12FN
5: 317.33, Found: 317.8.
1H NMR (400 MHz, CDCl
3) δ 12.43 (s, 1H) , 8.49 (d, J = 4.9 Hz, 1H) , 7.76 (s, 1H) , 7.31 (dd, J = 6.0, 2.8 Hz, 2H) , 7.25 (s, 1H) , 7.04 (t, J = 8.7 Hz, 2H) , 6.87 (d, J = 4.9 Hz, 1H) , 3.97 (s, 3H) .
Example 26. Preparation of Compound 2-41
As shown in FIG. 26, the specific synthesis steps are as follows:
Step 1: ethyl 1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazole-5-carboxylate (2)
To a solution of ethyl 5- (4-fluorophenyl) -2H-pyrazole-3-carboxylate (1.8 g, 0.0077 mol) in acetone (20 mL) was added 1-bromo-2-chloroethane (5.5213 g, 0.0385 mol) and K
2CO
3 (3.1878 g, 0.0231 mol) . The reaction mixture was stirred at 70 ℃ for 4 h. The mixture was complete was detected by LCMS. The mixture was concentrated, then was added H
2O, filtered and filter cake was concentrated. Chemical Formula: calculated for (M+H
+) C
13H
12ClFN
2O
2: 282.1, Found: 283.0
Step 2: (1- (2-chloroethyl) -3- (4-fluorophenyl) -1H-pyrazol-5-yl) methanol (3)
To a solution of ethyl 2- (2-chloroethyl) -5- (4-fluorophenyl) pyrazole-3-carboxylate (1.6 g, 0.0054 mol) in tetrahydrofuran (30 mL) was added LAH (0.2160 g, 0.0054 mol) at 0 ℃. The reaction mixture was stirred at 0-25 ℃ for 2 h. The reaction was complete was detected by LCMS. The reaction was quenched by H
2O (50 mL) , The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) C
12H
12ClFN
2O: 254.1, Found: 255.0
Step 3: 2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine (4)
To a solution of [2- (2-chloroethyl) -5- (4-fluorophenyl) pyrazol-3-yl] methanol (900 mg, 3.53 mmol) in DMF (10 mL) was added NaH (84.72 mg, 3.53 mmol) at 0 ℃ and the reaction mixture was stirred at 0-25 ℃ for 2 h. The reaction was complete was detected by lcms. The reaction was quenched by H
2O (50 mL) , The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) C
12H
11FN
2O: 218.1, Found: 219.0
Step 4: 3-bromo-2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine (5)
To a solution of 2- (4-fluorophenyl) -4H, 6H, 7H-pyrazolo [3, 2-c] [1, 4] oxazine (350 mg, 1.6 mmol) in DCM (10 mL) was added NBS (284.8 mg, 1.6 mmol) . The reaction mixture was stirred at 25 ℃ for 16 h. The reaction was complete detected by lcms. The reaction was quenched by H
2O (50 mL) . The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) C
12H
10BrFN
2O: 290.0, Found: 296.9
Step 5: 2- (4-fluorophenyl) -3- (pyridin-4-yl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazine
To a solution of 2- (4-fluorophenyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H, 6H, 7H-pyrazolo [3, 2-c] [1, 4] oxazine (50 mg, 0.15 mmol) in 1, 2-Dimethoxyethane (5 mL) was added 4-bromopyridazine (47.70 mg, 0.3 mmol) , Na
2CO
3 (47.70 mg, 0.4499 mmol) and Pd (dtbpf) Cl
2 (9.76 mg, 0.015 mmol) . The reaction mixture was stirred at 90 ℃ for 16 h. The reaction was complete detected by LCMS. The mixture was filtered and concentrated to give the product. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . The residue was purified via Genal-Prep-HPLC and give the product.
1H NMR (400 MHz, DMSO) δ 9.24 (dd, J = 5.3, 1.2 Hz, 1H) , 9.05 (dd, J = 2.3, 1.2 Hz, 1H) , 7.56 (dd, J = 5.3, 2.4 Hz, 1H) , 7.46 (dd, J = 15.2, 8.7 Hz, 1H) , 7.39 (dd, J = 8.8, 5.5 Hz, 2H) , 7.23 (t, J = 8.9 Hz, 2H) , 5.82 (d, J = 15.2 Hz, 1H) , 5.70 (s, 1H) , 5.07 (d, J = 8.7 Hz, 1H) , 4.53 (d, J = 5.5 Hz, 2H) .
Example 27. Preparation of Compound 3-12
As shown in FIG. 27, the specific synthesis steps are as follows:
Step 1: 3- (4-fluorophenyl) -1-methyl-4- (1H-pyrrolo [2, 3-b] pyridin-4-yl) -1H-pyrrole-2-carbonitrile
4-bromo-1H-pyrrolo [2, 3-b] pyridine (46 mg, 0.23 mmol) , 2 M Na
2CO
3 aqueous solutions (0.5 mL) and Pd (dppf) Cl
2 (22 mg, 0.03 mmol) were added to a solution of 3- (4-fluorophenyl) -1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (50 mg, 0.15 mmol) in EtOH/toluene=8: 2 (5 mL) . The mixture was stirred at 100 ℃ for 1 h under nitrogen atmosphere on microwave. The reaction mixture was concentrated under pressure. The residue was purified via Prep- TLC PE/EA (1: 10) and give the product. Chemical Formula: calculated for (M+H
+) C
19H
13FN
4: 316.34, Found: 316.8.
1H NMR (400 MHz, CDCl
3) δ 9.66 (s, 1H) , 7.32 –7.29 (m, 2H) , 7.27 (d, J =2.0 Hz, 2H) , 7.21 (s, 1H) , 7.01 (t, J = 8.7 Hz, 2H) , 6.81 (s, 1H) , 6.31 (s, 1H) , 3.95 (s, 3H) .
Example 28. Preparation of Compound 2-42
As shown in FIG. 28, the specific synthesis steps are as follows:
Step 1: 4- (2- (4-fluorophenyl) -6, 7-dihydro-4H-pyrazolo [5, 1-c] [1, 4] oxazin-3-yl) pyridin-2-amine
To a solution of 3-bromo-2- (4-fluorophenyl) -4H, 6H, 7H-pyrazolo [3, 2-c] [1, 4] oxazine (500 mg, 1.68 mmol) in EtOH/PhMe/H
2O=8: 4: 1 (13 mL) was added 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (739.46 mg, 3.36 mmol) , Na
2CO
3 (534.24 mg, 5.04 mmol) and Pd (dppf) Cl
2 (245.62 mg, 0.336 mmol) . The reaction mixture was stirred at 100 ℃ for 1 h. The reaction was complete detected by LCMS. The mixture was filtered and concentrated to give the product. The crude material was added to a silica gel column and was eluted with EtOAc.
1H NMR (301 MHz, DMSO) δ 7.81 (dd, J = 4.8, 1.2 Hz, 1H) , 7.45 –7.38 (m, 2H) , 7.22 –7.15 (m, 2H) , 6.21 –6.17 (m, 2H) , 5.87 (s, 2H) , 4.81 (s, 2H) , 4.17 (d, J = 4.8 Hz, 2H) , 4.13 (d, J = 4.8 Hz, 2H) .
Example 29. Preparation of Compound 2-43
As shown in FIG. 29, the specific synthesis steps are as follows:
Step 1: 4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
4- (3, 3, 4, 4-tetramethylcyclopentyl) pyridin-2-amine (102 mg, 0.46 mmol) , 2 M Na
2CO
3 aqueous solutions (0.5 mL) and Pd (dppf) Cl
2 (45 mg, 0.06 mmol) were added to a solution of 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (120 mg, 0.31 mmol) in EtOH/toluene=8: 2 (5 mL) . The mixture was stirred at 100 ℃ for 1 h under nitrogen atmosphere on microwave. The reaction mixture was concentrated under pressure. The residue was purified via Prep-TLC PE/EA (1: 4) and give the product. Chemical Formula: calculated for (M+H
+) C
24H
22FN
5: 399.47, Found: 399.8.
Step 2: 4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
HCOONH
4 (157 mg, 2.5 mmol) and Pd/C (200 mg) were added to a solution of 4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine (100 mg, 0.25 mmol) in MeOH (10 mL) . The mixture was stirred at 60 ℃ for 2 h. The solution was filtered, filtrate was collected and the solution was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
17H
16FN
5: 309.35, Found: 309.8.
Step 3: 1- (3- (2-aminopyridin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
AcOAc (29 mg, 0.29 mmol) and Et
3N (88 mg, 0.87 mmol) were added to a solution of 4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine (90 mg, 0.29 mmol) in DCM (10 mL) . The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under pressure. The residue was purified via Prep-TLC DCM/MeOH (20: 1) and give the product. Chemical Formula: calculated for (M+H
+) C
19H
18FN
5O: 351.39, Found: 351.8.
1H NMR (400 MHz, CDCl
3) δ 7.71 (d, J = 16.3 Hz, 1H) , 7.39 (dd, J = 8.4, 5.0 Hz, 2H) , 7.04 (dd, J = 20.6, 12.0 Hz, 2H) , 6.59 (d, J = 10.3 Hz, 1H) , 6.39 (d, J = 5.6 Hz, 1H) , 4.85 (d, J = 39.9 Hz, 2H) , 4.34 (dd, J = 20.7, 15.4 Hz, 2H) , 4.23 –3.95 (m, 2H) , 2.37 –2.14 (m, 3H) .
Example 30. Preparation of Compound 3-13
As shown in FIG. 30, the specific synthesis steps are as follows:
Step 1: 3- (4-fluorophenyl) -4- (3H-imidazo [4, 5-b] pyridin-7-yl) -1-methyl-1H-pyrrole-2-carbonitrile
7-bromo-3H-imidazo [4, 5-b] pyridine (137 mg, 0.69 mmol) , 2 M Na
2CO
3 aqueous solutions (0.5 mL) and Pd (dppf) Cl
2 (67 mg, 0.092 mmol) were added to a solution of 3- (4-fluorophenyl) -1-methyl-4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrole-2-carbonitrile (150 mg, 0.46 mmol) in EtOH/toluene=8: 2 (5 mL) . The mixture was stirred at 100 ℃ for 1 h under nitrogen atmosphere on microwave. The reaction mixture was concentrated under pressure. The residue was purified via Prep-TLC PE/EA (1: 1) and give the product. Chemical Formula: calculated for (M+H
+) C
18H
12FN
5: 317.33, Found: 317.8.
1H NMR (400 MHz, CDCl
3) δ 8.19 (s, 1H) , 7.93 (d, J = 8.4 Hz, 1H) , 7.32 (td, J = 5.6, 2.1 Hz, 3H) , 7.04 (dd, J = 12.0, 5.3 Hz, 2H) , 6.98 (d, J = 8.4 Hz, 1H) , 3.90 (s, 3H) .
Example 31. Preparation of Compound 2-44
As shown in FIG. 31, the specific synthesis steps are as follows:
Step1: 1- (2- (4-fluorophenyl) -3- (2-methylpyrimidin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
Pd (dppf) Cl
2 (28.5 mg, 0.039 mmol) , 4-bromo-2-methylpyrimidine (101.2 mg, 0.585 mmol) , Cs
2CO
3 (381 mg, 1.17 mmol) was added to a solution of 1- (2- (4-fluorophenyl) -3- (4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one (150 mg, 0.39 mmol) in dioxane/H
2O (20: 4 mL) . The mixture was allowed to react at 90 ℃ under N
2 for 16 h. The reaction mixture was cooled to room temperture and concentrated under pressure. The crude material was added to a silica gel column and was eluted with MeOH/DCM (25: 1) to give product as yellow solid (36 mg, yield: 25.7%) . Chemical Formula: calculated for (M+H
+) Chemical Formula: C
19H
18FN
5O: 351.15, Found: 352.
1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 5.4 Hz, 1H) , 7.52 –7.40 (m, 2H) , 7.12 (q, J = 8.7 Hz, 2H) , 6.77 (dd, J = 14.4, 5.3 Hz, 1H) , 5.17 (d, J = 8.5 Hz, 2H) , 4.42 –4.23 (m, 2H) , 4.16 (t, J = 5.4 Hz, 1H) , 4.01 (t, J = 5.4 Hz, 1H) , 2.74 (d, J = 4.6 Hz, 3H) , 2.28 (d, J = 11.0 Hz, 3H) .
Example 32. Preparation of Compound 2-45
As shown in FIG. 32, the specific synthesis steps are as follows:
Step1: 1- (3- (2-ethylpyridin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
Pd (dppf) Cl
2 (41.7 mg, 0.057 mmol) , 4-bromo-2-ethylpyridine (159 mg, 0.855 mmol) , Cs
2CO
3 (557 mg, 1.71 mmol) was added to a solution of 1- [2- (4-fluorophenyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-5-yl] ethanone (220 mg, 0.57 mmol) in dioxane/H
2O (20: 4 mL) . The mixture was allowed to react at 90 ℃ under N
2 for 16 h. The reaction mixture was cooled to room temperture and concentrated under pressure. The crude material was added to a silica gel column and was eluted with MeOH/DCM (25: 1) to give product as yellow solid (15.5 mg, yield: 7.4%) . Chemical Formula: calculated for (M+H
+) Chemical Formula: C
21H
21FN
4O: 364.17, Found: 365.
1H NMR (400 MHz, CDCl
3) δ 8.50 (dd, J = 17.6, 4.7 Hz, 1H) , 7.39 (dd, J = 8.6, 5.5 Hz, 2H) , 7.01 (t, J = 8.7 Hz, 2H) , 6.93 (s, 2H) , 4.81 (d, J = 51.7 Hz, 2H) , 4.32 (dt, J = 27.2, 5.5 Hz, 2H) , 4.09 (dt, J = 61.0, 5.5 Hz, 2H) , 2.79 (q, J = 7.5 Hz, 2H) , 2.21 (d, J = 36.5 Hz, 3H) , 1.25 (t, J = 7.6 Hz, 3H) .
Example 33. Preparation of Compound 2-46
As shown in FIG. 33, the specific synthesis steps are as follows:
Step 1: 1- (3- (6-aminopyrimidin-4-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
Pd (dppf) Cl
2 (28.5 mg, 0.039 mmol) , 4-bromo-2-isopropylpyridine (117 mg, 0.585 mmol) , Cs
2CO
3 (381 mg, 1.17 mmol) was added to a solution of 1- [2- (4-fluorophenyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-5-yl] ethanone (150 mg, 0.39 mmol) in dioxane/H
2O (20: 4 mL) , the mixture was allowed to react at 90 ℃ under N
2 for 16 h. The reaction mixture was cooled to room temperture and concentrated under pressure. The crude material was added to a silica gel column and was eluted with MeOH/DCM (25: 1) to give product as yellow solid (52 mg, yield: 35%) . Chemical Formula: calculated for (M+H
+) Chemical Formula: C
22H
23FN
4O: 378.19, Found: 379.
1H NMR (400 MHz, CDCl
3) δ 8.53 (dd, J = 15.1, 5.0 Hz, 1H) , 7.39 (dd, J = 8.2, 5.7 Hz, 2H) , 7.06 –6.91 (m, 4H) , 4.82 (d, J = 51.0 Hz, 2H) , 4.32 (dt, J = 27.0, 5.5 Hz, 2H) , 4.09 (dt, J = 60.3, 5.5 Hz, 2H) , 3.03 (dt, J = 13.8, 6.9 Hz, 1H) , 2.21 (d, J = 35.0 Hz, 3H) , 1.23 (d, J = 6.9 Hz, 6H) .
Example 34. Preparation of Compound 2-47
As shown in FIG. 34, the specific synthesis steps are as follows:
Step 1: 3- (4-fluorophenyl) -1H-pyrazol-5-ol
To a mixture of methyl 3- (4-fluorophenyl) -3-oxopropanoate (20 g, 101.9 mmol) in EtOH (250 mL) was added hydrogen diazene (6.3 g, 203.8 mmol) at 25 ℃. The reaction was stirred at 60 ℃ for 3 h. LCMS showed desired MS was detected as main peak. The mixture was concentrated and purified by column chromatography (PE/EA = 6/1) to give a purple solid (17.2 g, yield: 98%) . Chemical Formula: calculated for (M+H
+) C
9H
7FN
2O: 178.05, Found: 179
Step 2: 6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazole
To a mixture of 3- (4-fluorophenyl) -1H-pyrazol-5-ol (1200 mg, 6.74 mmol) in ACN (50 mL) was added 1, 2-dibromoethane (2500 mg, 13.48 mmol) and K
2CO
3 (3728 mg, 27 mmol) at 25 ℃, The reaction was stirred at 80 ℃ for 3 h. LCMS showed desired MS was detected as main peak. The reaction mixture was cooled to room temperature and concentrated under pressure. diluted with water (50 mL) . Extration with DCM (50 mL*3) , filtured and concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (10: 1) to give product as a pink solid (3700 mg, yield: 80.6%) . Chemical Formula: calculated for (M+H
+) C
11H
9FN
2O: 204.07, Found: 205
Step 3: 7-bromo-6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazole
To a stirred solution of 6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazole (3600 mg, 17.63 mmol) in acetonitrile (100 mL) was added NBS (1883 mg, 10.57 mmol) with ice-cooling. The mixture was stirred at 25 ℃ for 1 h. LCMS showed desired MS was detected as main peak. The reaction mixture was concentrated under pressure and diluted with water (50 mL) . Extration with EA (50 mL*3) , filtured and concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (4: 1) to give product as a yellow solid (1080 mg, yield: 19.48%) . Chemical Formula: calculated for (M+H
+) C
11H
8BrFN
2O: 283.18, Found: 284
Step 4: 4- (6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazol-7-yl) pyridin-2-amine
Pd (dppf) Cl
2 (38.78 mg, 0.053 mmol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (134.2 mg, 0.61 mmol) , Cs
2CO
3 (518 mg, 1.59 mmol) was added to a solution of 7-bromo-6- (4-fluorophenyl) -2, 3-dihydropyrazolo [5, 1-b] oxazole (150 mg, 0.53 mmol) in dioxane/H
2O (15: 3 mL) , the mixture was allowed to react at 90 ℃ under N
2 for 16 h. The reaction mixture was cooled to room temperature and concentrated under pressure. The crude material was added to a silica gel column and was eluted with MeOH/DCM (25: 1) to give product as yellow solid (14.9 mg, yield: 9.3%) . Chemical Formula: calculated for (M+H
+) Chemical Formula: C
16H
13FN
4O: 296.11, Found: 297.
1H NMR (400 MHz, CDCl
3) δ 7.70 (d, J = 6.0 Hz, 1H) , 7.51 –7.43 (m, 2H) , 7.11 (t, J = 8.7 Hz, 2H) , 6.58 (d, J = 6.0 Hz, 1H) , 6.46 (s, 1H) , 5.71 (s, 2H) , 5.26 –5.19 (m, 2H) , 4.46 –4.40 (m, 2H) .
Example 35. Preparation of Compound 2-48
As shown in FIG. 35, the specific synthesis steps are as follows:
Step 1: (2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) (1-methylpiperidin-4-yl) methanone
methylpiperidine-4-carboxylic acid (41.8 mg, 0.29 mmol) , T
3P (155 mg, 0.49 mmol) and DIPEA (150.9 mg, 1.17 mmol) were added to a solution of 2- (4-fluorophenyl) -3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (60 mg, 0.19 mmol) in DCM (5 mL) . The mixture was stirred at 25 ℃ for 3 h. The reaction mixture was concentrated under pressure. The residue was purified via Prep-TLC DCM/MeOH (5: 1) and give the product. Chemical Formula: calculated for (M+H
+) C
25H
28FN
5O: 433.53, Found: 433.8.
1H NMR (400 MHz, CDCl
3) δ 8.48 (d, J = 25.6 Hz, 1H) , 8.34 (s, 1H) , 7.37 (s, 2H) , 7.12 –6.84 (m, 3H) , 4.79 (d, J = 43.8 Hz, 2H) , 4.33 (d, J = 28.8 Hz, 2H) , 4.11 (d, J = 48.7 Hz, 2H) , 3.30 (s, 2H) , 3.03 (s, 2H) , 2.66 (d, J = 20.2 Hz, 4H) , 2.54 (s, 3H) , 2.40 –1.92 (m, 4H) .
Example 36. Preparation of Compound 2-49
As shown in FIG. 36, the specific synthesis steps are as follows:
Step 1: 2- (4-fluorophenyl) -5-methyl-3- (2-methylpyridin-4-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine
To a solution of 4- [2- (4-fluorophenyl) -4H, 5H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] -2-methylpyridine (50 mg, 0.16 mmol) in HCOOH (3 mL) was added HCHO (24 mg, 0.8 mmol) . The reaction mixture was stirred at 70 ℃ for 2 h. The reaction was not complete detected by LCMS. The reaction mixture was concentrated under pressure. The mixture was adjusted to pH= 8 with Na
2CO
3. The organic phase was washed with water (5 mL) . The residue was extracted with EA (5mL*3) . Solvent was dried over sodium sulphate and dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure. The residue was purified via Genal-Prep-HPLC and give the product.
1H NMR (400 MHz, CDCl
3) δ 8.42 (d, J = 5.2 Hz, 1H) , 7.42 –7.36 (m, 2H) , 7.05 –6.97 (m, 2H) , 6.94 (s, 1H) , 6.90 (d, J = 4.8 Hz, 1H) , 4.30 (t, J = 5.6 Hz, 2H) , 3.67 (s, 2H) , 3.01 –2.94 (m, 2H) , 2.54 (d, J = 4.0 Hz, 6H) .
Example 37. Preparation of Compound 3-14
As shown in FIG. 37, the specific synthesis steps are as follows:
Step 1: methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate
To a solution of 1-ethynyl-4-fluorobenzene (3000 mg, 24.97 mmol) in NMP (50 mL) , was added methyl 2-isocyanoacetate (3711.3410 mg, 37.455 mmol) , Ag
2CO
3 (2756.6880 mg, 9.988 mmol) , the reaction mixture was stirred at 80℃ for 1 h. The reaction was complete detected by lcms. The reaction was quenched by H
2O (50 mL) , The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the crude product. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) C
12H
10FNO
2: 219.1, Found: 220.0
Step 2: methyl 3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate
To a solution of methyl 3- (4-fluorophenyl) -1H-pyrrole-2-carboxylate [800 mg, 3.65 mmol] in CCl
4 [10 mL] , then was added acetyl chloride [592.6030 mg, 3.65 mmol] at 0℃, The reaction mixture was stirred at 0℃ for 15 mins. The reaction was complete detected by lcms. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) C
12H
9FINO
2: 345.0, Found: 345.9
Step 3: methyl 1- (2- ( (tert-butoxycarbonyl) amino) ethyl) -3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate
To a solution of methyl 3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate [400 mg, 1.16 mmol] in DMF [10 mL] , then was added tert-butyl N- (2-chloroethyl) carbamate [416.776 mg, 2.32 mmol] , K
2CO
3 [480.24 mg, 3.48 mmol] , The reaction mixture was stirred at 100℃ for 16h. The reaction was complete detected by lcms. The reaction was quenched by H
2O (50 mL) , The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the product. Chemical Formula: calculated for (M+Na
+) C
19H
22FIN
2O
4: 488.1, Found: 510.9
Step 4: methyl 1- (2-aminoethyl) -3- (4-fluorophenyl) -4-iodo-1H-pyrrole-2-carboxylate
To a solution of methyl 1- (2- { [ (tert-butoxy) carbonyl] amino} ethyl) -3- (4-fluorophenyl) -4-iodopyrrole-2-carboxylate [500 mg, 1.0240 mmol] in DCM [3 mL] , then was added HCl-dioxane [3 mL] , The reaction mixture was stirred at 25℃ for 2h. The reaction was complete detected by lcms. The reaction mixture was concentrated under pressure. The mixture was adjusted to PH= 8 with Na
2CO
3. The residue was extracted with EA (x5mL) . Solvent was dried over sodium sulphateand dried under a stream of nitrogen in the Radleys blowdown apparatus to give the crude product. The solution was filtered , filtrate was collected. The reaction mixture was concentrated under pressure . Chemical Formula: calculated for (M+H
+) C
14H
14FIN
2O
2: 388.0, Found: 388.9
Step 5: 8- (4-fluorophenyl) -7-iodo-3, 4-dihydropyrrolo [1, 2-a] pyrazin-1 (2H) -one
To a solution of methyl 1- (2-aminoethyl) -3- (4-fluorophenyl) -4-iodopyrrole-2-carboxylate [300 mg, 0.77 mmol] in MeOH [5 mL] , then was added K
2CO
3 [159.39 mg] , The reaction mixture was stirred at 50℃ for 2h. The reaction was complete detected by lcms. The reaction was quenched by H
2O (50 mL) , The mixture was concentrated. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the product. calculated for (M+H
+) C
13H
10FIN
2O: 356.0, Found: 356.8
Step 6: 8- (4-fluorophenyl) -7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 4-dihydropyrrolo [1, 2-a] pyrazin-1 (2H) -one
To a solution of 8- (4-fluorophenyl) -7-iodo-2H, 3H, 4H-pyrrolo [1, 2-a] pyrazin-1-one [120 mg, 0.34 mmol] in 1, 4-Dioxane [5 mL] , then was added 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane [129.5089 mg, 0.51 mmol] , KAcO [99.9600 mg, 1.02 mmol] , Pd (dppf) Cl
2 [49.7080 mg] , The reaction mixture was stirred at 100℃ for 16h. The reaction was complete detected by lcms. The mixture was extracted with EA (50 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the product. calculated for (M+H
+) C
19H
22BFN
2O
3: 356.2, Found: 357.0
Step 7: 4- (8- (4-fluorophenyl) -1-oxo-1, 2, 3, 4-tetrahydropyrrolo [1, 2-a] pyrazin-7-yl) furo [3, 4-b] pyridin-5 (7H) -one
To a solution of 8- (4-fluorophenyl) -7- (4, 4, 5-trimethyl-1, 3, 2-dioxaborolan-2-yl) -2H, 3H, 4H-pyrrolo [1, 2-a] pyrazin-1-one [50 mg, 0.14 mmol] in 1, 4-Dioxane [5 mL] , then was added 4-bromo-7H-furo [3, 4-b] pyridin-5-one [44.94 mg, 0.2100 mmol] , Na
2CO
3 [44.52 mg, 0.42 mmol] , Pd (dppf) Cl
2 [20.47 mg, 0.0280 mmol] , The reaction mixture was stirred at 100℃ for 16h. The reaction was complete detected by lcms. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure. The residue was purified via Genal-Prep-HPLC and give the product.
1H NMR (400 MHz, CDCl
3) δ 8.39 (d, J = 5.2 Hz, 1H) , 8.00 (s, 1H) , 7.69 (s, 1H) , 7.52 (s, 1H) , 7.01 (dd, J = 10.0, 6.8 Hz, 2H) , 6.72 (d, J = 5.2 Hz, 1H) , 5.82 (s, 1H) , 5.28 (s, 1H) , 4.37 –4.23 (m, 2H) , 3.76 (s, 2H) .
Example 38. Preparation of Compound 2-50
As shown in FIG. 38, the specific synthesis steps are as follows:
Step 1: 1- (4-fluorophenyl) -6-hydroxyhexane-1, 3-dione
To a mixture of NaH (60%, 0.56 g, 14.4 mmol) in dry diethyl ether (15 mL) at 0 ℃ under argon, ethanol (2 mL) was added followed by dihydrofuran-2 (3H) -one (0.62 g, 7.2 mmol) . Then a solution of 1- (4-fluorophenyl) ethan-1-one (1 g, 7.2 mmol) in diethyl ether (5 mL) was added slowly at 0 ℃. And the resulting suspension was allowed to warm slowly to room temperature. The reaction mixture was stirred 72 h at 25 ℃. The reaction mixture was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
12H
13FO
3: 224.23, Found: 224.8.
Step 2: 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propan-1-ol
To a solution of 1- (4-fluorophenyl) -6-hydroxyhexane-1, 3-dione (500 mg, 2.23 mmol) in EtOH (20 mL) , hydrazine hydrate (wt 80%, 178 mg, 4.46 mmol) were added. The mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
12H
13FN
2O: 220.25, Found: 220.8.
Step 3: 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propyl methanesulfonate
To a solution of 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propan-1-ol (500 mg, 2.27 mmol) in DCM (20 mL) at 0 ℃, methanesulfonyl chloride (0.264 mL, 3.4 mmol) and DIPEA (880 mg, 6.8 mmol) were added. The mixture was stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
13H
15FN
2O
3S: 298.33, Found: 298.8.
Step 4: 2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazole
To a solution of 3- (3- (4-fluorophenyl) -1H-pyrazol-5-yl) propyl methanesulfonate (300 mg, 1.0 mmol) in DMF (15 mL) at 0 ℃, NaI (15.08 mg, 0.1 mmol) and NaH (29 mg, 1.2 mmol) were added. The mixture was added at 0 ℃ for 0.5 h and then stirred at 25 ℃ for 1 h. The reaction mixture was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
12H
11FN
2: 202.23, Found: 202.8.
Step 5: 3-bromo-2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazole
To a solution of 2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazole (200 mg, 0.99 mmol) in CH
3CN (15 mL) , NBS (264 mg, 1.48 mmol) was added. The mixture was stirred at 25 ℃for 2 h. The reaction mixture was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
12H
10BrFN
2: 281.13, Found: 280.8.
Step 6: 4- (2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazol-3-yl) pyridin-2-amine
To a solution of 3-bromo-2- (4-fluorophenyl) -5, 6-dihydro-4H-pyrrolo [1, 2-b] pyrazole (250 mg, 0.89 mmol) in EtOH/toluene=8: 2 (15 mL) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridin-2-amine (294 mg, 1.3 mmol) , 2M Na
2CO
3 aqueous solutions (1.5 mL) and Pd (dppf) Cl
2 (130 mg, 0.18 mmol) were added. The mixture was stirred at 100 ℃ for 1 h under nitrogen atmosphere on microwave. The reaction mixture was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
17H
15FN
4: 294.33, Found: 294.8.
1H NMR (400 MHz, CDCl
3) δ 8.45 (s, 2H) , 7.65 –7.50 (m, 1H) , 7.48 –7.35 (m, 2H) , 7.07 (ddd, J = 8.7, 5.3, 1.9 Hz, 2H) , 6.61 –6.36 (m, 2H) , 4.25 (t, J = 7.1 Hz, 2H) , 3.09 (t, J = 7.1 Hz, 2H) , 2.80 –2.64 (m, 2H) .
Example 39. Preparation of Compound 2-51
As shown in FIG. 39, the specific synthesis steps are as follows:
Step 1: 4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
4- (3, 3, 4, 4-tetramethylcyclopentyl) pyridin-2-amine (102 mg, 0.46 mmol) , 2 M Na
2CO
3 aqueous solutions (0.5 mL) and Pd (dppf) Cl
2 (45 mg, 0.06 mmol) were added to a solution of 5-benzyl-3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (120 mg, 0.31 mmol) in EtOH/toluene=8: 2 (5 mL) . The mixture was stirred at 100 ℃ for 1 h under nitrogen atmosphere on microwave. The reaction mixture was concentrated under pressure. The residue was purified via Prep- TLC PE/EA (1: 4) and give the product. Chemical Formula: calculated for (M+H
+) C
24H
22FN
5: 399.47, Found: 399.8.
Step 2: 4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
HCOONH
4 (157 mg, 2.5 mmol) and Pd/C (200 mg) were added to a solution of 4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine (100 mg, 0.25 mmol) in MeOH (10 mL) . The mixture was stirred at 60 ℃ for 2 h. The solution was filtered, filtrate was collected and the solution was concentrated under pressure. Chemical Formula: calculated for (M+H
+) C
17H
16FN
5: 309.35, Found: 309.8.
Example 40. Preparation of Compound 2-52
As shown in FIG. 40, the specific synthesis steps are as follows:
Step 1: tert-butyl (4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate
To a solution of 4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridin-2-amine (2000 mg, 4.99 mmol) in DCM (20 mL) , (Boc)
2O (1631.7300 mg, 7.485 mmol) , DIPEA (1287.4200 mg, 9.98 mmol) , DMAP (121.7560 mg, 0.9980 mmol) was added. The reaction mixture was stirred at 25 ℃ for 2 h. The reaction was complete detected by lcms. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) C
29H
30FN
5O
2: 499.2, Found: 500.1
Step 2: tert-butyl (4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate
To a solution of tert-butyl (4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate (1200 mg, 2.39 mmol) in EA (10 mL) , Pd/C (800 mg) and AcOH (0.5 mL) was added. The reaction mixture was stirred at 25 ℃ under H
2 for 2 h. The reaction was complete detected by lcms. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure. The organic phase was washed with 2M sodium carbonate solution (5 mL) . The residue was extracted with EA (10 mL*3) . The combined organic layers were washed with brine (10 mL) , dried over sodium sulfate, filtered and concentrated to give the product. Chemical Formula: calculated for (M+H
+) C
22H
24FN
5O
2: 409.2, Found: 410.1
Step 3: tert-butyl (4- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate
To a solution of tert-butyl (4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate (230 mg, 0.5603 mmol) in THF (5 mL) , formaldehyde (84.05 mg, 2.8015 mmol) was added. The reaction mixture was stirred at 70 ℃ for 16 h. Sodium triacetoxyborohydride (142.54 mg, 0.6723 mmol) was added. The reaction mixture was stirred at 25 ℃ for 2 h. The reaction was complete detected by lcms. The reaction mixture was concentrated under pressure. The organic phase was washed with water (5 mL) . The residue was extracted with EA (5 mL*3) . The combined organic layers were washed with brine (10 mL) , dried over sodium sulfate, filtered and concentrated to give the product. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) . Chemical Formula: calculated for (M+H
+) C
23H
26FN
5O
2: 423.2, Found: 424.0
Step 4: 4- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-amine
To a solution of tert-butyl (4- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) carbamate (200 mg, 0.47 mmol) in DCM (4 mL) , then HCl-dioxane (4 mL) was added. The reaction mixture was stirred at 25 ℃ for 2 h. The reaction was complete detected by lcms. The reaction mixture was concentrated under pressure. The organic phase was washed with 2M sodium carbonate solution (5 mL) . The residue was extracted with EA (5 mL*3) . The combined organic layers were washed with brine (10 mL) , dried over sodium sulfate, filtered and concentrated to give the product. The residue was purified via Genal-Prep-HPLC and give the product.
1H NMR (400 MHz, DMSO) δ 7.83 (d, J = 5.2 Hz, 1H) , 7.46 –7.37 (m, 2H) , 7.21 –7.14 (m, 2H) , 6.21 (dd, J = 7.4, 2.0 Hz, 2H) , 5.90 (s, 2H) , 4.16 (t, J = 5.4 Hz, 2H) , 3.57 (s, 2H) , 2.90 (t, J = 5.5 Hz, 2H) , 2.41 (s, 3H) .
Example 41. Preparation of Compound 2-53
As shown in FIG. 41, the specific synthesis steps are as follows:
Step 1: 1- (2- (4-fluorophenyl) -3- (1H-pyrrolo [2, 3-b] pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
To a solution of 1- [2- (4-fluorophenyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-5-yl] ethanone (1000 mg, 2.5958 mmol) in 1, 4-Dioxane/H
2O=10: 1 (30 mL) , 4-bromo-1H-pyrrolo [2, 3 -b] pyridine (767.18 mg, 3.8937 mmol) , Na
2CO
3 (825.46 mg, 7.7874 mmol) , Pd (dppf) Cl
2 (379.51 mg, 0.5191 mmol) was added. The reaction mixture was stirred at 100 ℃ for 16 h. The reaction was complete detected by lcms. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with DCM/MeOH (10: 1) . Chemical Formula: calculated for (M+H
+) C
21H
18FN
5O: 375.1, Found: 376.0
Step 2: 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -3, 3-dibromo-1, 3-dihydro-2H-pyrrolo [2, 3-b] pyridin-2-one
To a solution of 1- (2- (4-fluorophenyl) -3- (1H-pyrrolo [2, 3-b] pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one (500 mg, 1.3319 mmol) in t-BuOH (10 mL) , Py-HBr
3 (1704.83 mg, 5.3276 mmol) was added in small portions over 6 h at room temperature. The reaction mixture was concentrated under pressure. The organic phase was washed with water (5 mL) . The residue was extracted with EA (5 mL*3) . The combined organic layers were washed with brine (50 mL) , dried over sodium sulfate, filtered and concentrated to give the product. Chemical Formula: calculated for (M+H
+) C
21H
16Br
2FN
5O
2: 547.0, Found: 547.5
Step 3: 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -1, 3-dihydro-2H-pyrrolo [2, 3-b] pyridin-2-one
To a solution of 4- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -3, 3-dibromo-1, 3-dihydro-2H-pyrrolo [2, 3-b] pyridin-2-one (220 mg, 0.4006 mmol) in EA (5 mL) , Pd/C (100 mg) was added. The reaction mixture was stirred at 25 ℃ under H
2 for 5 h. The reaction was complete detected by lcms. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure. The residue was purified via Genal-Prep-HPLC and give the product.
1H NMR (400 MHz, MeOD) δ 8.09 (dd, J = 50.2, 26.5 Hz, 2H) , 7.45 –7.34 (m, 2H) , 7.09 (t, J = 8.8 Hz, 2H) , 7.02 (dd, J = 14.8, 5.2 Hz, 1H) , 4.78 (d, J = 12.4 Hz, 2H) , 4.31 (dt, J = 36.0, 5.6 Hz, 2H) , 4.12 (dt, J = 11.0, 5.6 Hz, 2H) , 2.86 (s, 2H) , 2.19 (d, J = 39.6 Hz, 3H) .
Example 42. Preparation of Compound 2-54
As shown in FIG. 42, the specific synthesis steps are as follows:
Step 1: (4-bromopyridin-2-yl) acetic acid
To a solution of 4-bromo-2-methylpyridine (4.0 g, 0.0233 mol) in THF (30 mL) was added dimethyl carbonate (2.52 g, 0.0279 mol) and LDA (13.8 mL) at -78℃. The mixture was stirred for 1 h at -78 ℃ and stirred for 5 h at rt. LCMS showed the reaction was completed. The reaction was quenched with saturated aqueous solution of NH
4Cl and washed with water, extracted with EA. Dried over Na
2SO
4. The crude product was purified by silica gel column (PE : EtOAc = 4: 1) to give the product. Chemical Formula: C
8H
8BrNO
2. calculated for (M+H
+)
: 230.06, Found: 231.1
Step 2: methyl 2- {4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridin-2-yl} acetate
To a solution of methyl 2- (4-bromopyridin-2-yl) acetate (150 mg, 0.652 mmol) in DMF (5 mL) was added 2- (4-fluorophenyl) -5- (1-methylphenyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazine (566.37 mg, 1.304 mmol) , Pd (dppf) Cl
2 (53.2 mg, 0.0652 mmol) and K
2CO
3 (180.23 mg, 1.304 mmol) at rt. The mixture was stirred for 3 h at 90℃ under N
2. LCMS showed the reaction was completed. The solution was washed with brine and extracted with EA. Dried over Na
2SO
4. The crude product was purified by silica gel column (PE : EtOAc = 10: 1) to give the product. Chemical Formula: C
27H
25FN
4O
2. calculated for (M+H
+)
: 456.52, Found: 457.1.
Step 3: methyl 2- (4- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) acetate
To a solution of methyl 2- {4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridin-2-yl} acetate (300 mg, 0.6557 mmol) in MeOH (10 mL) was added Pd/C (150mg) . The mixture was stirred for 6 h at rt. The reaction was filtered, and the filtrate was concentrated in vacuo. The residue was purified via Genal-Prep-HPLC and give the product. Chemical Formula: C
21H
21FN
4O
2. calculated for (M+H
+) : 380.42, Found: 381.1.
1H NMR (400 MHz, DMSO) δ 8.41 (d, J = 4.0 Hz, 1H) , 7.41 –7.34 (m, 2H) , 7.18 (t, J = 8.9 Hz, 2H) , 7.12 -7.09 (m, 1H) , 7.02 (dd, J = 5.1, 1.5 Hz, 1H) , 4.19 (t, J = 4.0 Hz, 2H) , 3.80 (s, 2H) , 3.65 (s, 2H) , 3.60 (s, 3H) , 2.92 (t, J = 5.4 Hz, 2H) , 2.41 (s, 3H) .
Example 43. Preparation of Compound 2-55
As shown in FIG. 43, the specific synthesis steps are as follows:
Step 1: 1- (4-bromopyridin-2-yl) propan-2-one
To a solution of 4-bromo-2-methylpyridine (3 g, 17.4 mmol) in THF (30 mL) , LDA (13 mL, 26 mmol, 2N) was added. The reaction mixture was stirred at -78 ℃ for 1 h. N-methoxy-N-methylacetamide (2.69 g, 26 mmol) was added. The reaction mixture was stirred at 25 ℃ for 15 h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (10: 1) to give product. Chemical Formula: calculated for (M+H
+) C
8H
8BrNO: 214.06, Found: 214.0.
Step 2: 1- (4- (5-benzyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) propan-2-one
To a solution of 2- (4-fluorophenyl) -5- (1-methylphenyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazine (6 g, 13.9 mmol) in dioxane (30 mL) and water (5 mL) , 1- (4-bromopyridin-2-yl) propan-2-one (2 g, 9.3 mmol) , potassium carbonate (2.57 g, 18.6 mmol) and tetrakis (triphenylphosphine) palladium (1 g, 0.9 mmol) was added. The reaction mixture was stirred at 100 ℃ for 18 h. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with PE/EtOAc (1: 1) to give product. Chemical Formula: calculated for (M+H
+) C
27H
25FN
4O: 440.52, Found: 441.1.
Step 3: 1- (4- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) pyridin-2-yl) propan-2-ol
To a solution of 1- {4- [2- (4-fluorophenyl) -5- (1-methylphenyl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridin-2-yl} propan-2-one (1200 mg) in MeOH (30 mL) , Pd/C (100 mg) was added. The reaction mixture was stirred at 25 ℃ for 15 h. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure to give product. Chemical Formula: calculated for (M+H
+) C
20H
21FN
4O: 352.41, Found: 353.8.
Step 4: 1- (2- (4-fluorophenyl) -3- (2- (2-hydroxypropyl) pyridin-4-yl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
To a solution of 1- {4- [2- (4-fluorophenyl) -4H, 5H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-3-yl] pyridin-2-yl} propan-2-ol (300 mg, 0.85 mmol) and NaHCO
3 (143 mg, 1.7 mmol) in THF (10 mL) and water (10 mL) , acetyl acetate (174 mg, 1.7 mmol) was added at 0 ℃. The reaction mixture was stirred at 25 ℃ for 5 h. The residue was extracted with THF (10 mL*2) . The reaction mixture was concentrated under pressure. The residue was purified via Genal-Prep-HPLC and give the product.
1H NMR (400 MHz, MeOD) δ 8.40 (d, J = 5.3 Hz, 1H) , 8.32 (s, 1H) , 7.41 (dd, J = 8.7, 5.4 Hz, 2H) , 7.18 –7.00 (m, 4H) , 4.30 (dt, J = 34.8, 5.2 Hz, 2H) , 4.10 (ddd, J = 20.0, 12.4, 5.7 Hz, 3H) , 2.82 (qd, J = 13.3, 6.5 Hz, 2H) , 2.21 (d, J = 35.0 Hz, 3H) , 1.21 –1.11 (m, 3H) .
Example 44. Preparation of Compound 2-56
As shown in FIG. 44, the specific synthesis steps are as follows:
Step 1: 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2, 3-dihydrofuro [3, 2-b] pyridine
To a solution of 3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (100 mg, 0.34 mmol) in Dioxane (5mL) and Water (0.5ml) 、7- (3, 3, 4, 4-tetramethylborolan-1-yl) -2, 3-dihydrofuro [3, 2-b] pyridine (85.11 mg, 0.35mmol) 、Pd (dppf) Cl2 (10mg, 10%w/w) ) and K
3PO
4 (144.34mg, 0.68 mmol) were added in . The mixture was stirred at 90℃ under N2 atmosphere for 4h. The reaction mixture was diluted with water, and the water phase was extracted with EA twice time, the organic phase was combined and concentrated under pressure. The residue was purified via Prep-TLC and give the product as off-white solid (77.92mg, 68.6%)
Chemical Formula: calculated for (M+H
+) : C
19H
17FN
4O: 336.37, Found: 337.
Step 2: 1- (3- (2, 3-dihydrofuro [3, 2-b] pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
To a solution of 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2, 3-dihydrofuro [3, 2-b] pyridine (35mg, 0.10 mmol) in DCM (65mL) , TEA (20.24 mg, 0.20mmol) was added in and then acetyl chloride (8.64mg, 0.11mmol) was dropped in at 0 ℃. The mixture was stirred at 25℃ for 2h. The reaction mixture was diluted with water, and the water phase was extracted with DCM twice time, the organic phase was combined and concentrated under pressure. The residue was purified via Genal-Prep-HPLC and give the product as white solid (30.95mg, 78.6%)
Chemical Formula: calculated for (M+H
+) : C
21H
19FN
4O
2, 378.41, Found: 339.
Example 45. Preparation of Compound 2-57
As shown in FIG. 45, the specific synthesis steps are as follows:
Step1: 1- (3- (2, 3-dihydrofuro [3, 2-b] pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
To a stirred mixture of 7-bromo-2, 3-dihydrofuro [3, 2-b] pyridine (68 mg, 0.34 mmol, 1.0 equiv) and 2- (4-fluorophenyl) -5-methyl-3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (121 mg, 0.34 mmol, 1.0 equiv) in toluene (15 mL) were added Cs
2CO
3 (230 mg, 0.69 mmol, 2.0 equiv) and Pd (dppf) Cl
2 CH
2Cl
2 (28 mg, 0.034 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 100 ℃ under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1: 2) to afford 1- (3- (2, 3-dihydrofuro [3, 2-b] pyridin-7-yl) -2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one (36 mg, 28%) as a light brown solid.
Example 46. Preparation of Compound 2-58
As shown in FIG. 46, the specific synthesis steps are as follows:
Step 1: 1- (3-bromo-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one
To a solution of 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine (150mg, 0.51mmol) in DCM (10 mL) , TEA (103.21mg, 1.02mmol) was added in and then acetyl chloride (40.04mg, 0.51mmol) was dropped in at 0 ℃. The mixture was stirred at 25℃ for 2h. The reaction mixture was diluted with water, and the water phase was extracted with DCM twice time, the organic phase was combined and concentrated under pressure. The residue was purified via Prep-TLC and give the product as off-white solid (147.14mg, 85.9%)
Chemical Formula: calculated for (M+H
+) C
14H
13BrFN
3O: 338.18, Found: 339.
Step 2: 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine
To a solution of 1- (3-bromo-2- (4-fluorophenyl) -6, 7-dihydropyrazolo [1, 5-a] pyrazin-5 (4H) -yl) ethan-1-one (35mg, 0.10 mmol) in Dioxane (3mL) and Water (0.5ml) 、2-methyl-7- (3, 3, 4, 4-tetramethylborolan-1-yl) -2, 3-dihydroisoxazolo [4, 5-b] pyridine (28.40 mg, 0.11mmol) 、Pd (dppf) Cl2 (3.5mg, 10%w/w) ) and K
3PO
4 (42.45mg, 0.20 mmol) were added in . The mixture was stirred at 90℃ under N2 atmosphere for 4h. The reaction mixture was diluted with water, and the water phase was extracted with EA twice time, the organic phase was combined and concentrated under pressure. The residue was purified via Genal-Prep-HPLC and give the product as white solid (15.27mg, 37.5%)
Chemical Formula: calculated for (M+H
+) C
21H
20FN
5O
2: 393.42, Found: 394.
Example 47. Preparation of Compound 2-59
As shown in FIG. 47, the specific synthesis steps are as follows:
Step 1: 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine
To a solution of 3-bromo-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (100mg, 0.34mmol) in Dioxane (5mL) and Water (0.5ml) 、2-methyl-7- (3, 3, 4, 4-tetramethylborolan-1-yl) -2, 3-dihydroisoxazolo [4, 5-b] pyridine (87.78 mg, 0.34mmol) 、Pd (dppf) Cl
2 (10mg, 10%w/w) ) and K
3PO
4 (144.34mg, 0.68 mmol) were added in . The mixture was stirred at 85℃ under N2 atmosphere for 6h. The reaction mixture was diluted with water, and the water phase was extracted with EA twice time, the organic phase was combined and concentrated under pressure. The residue was purified via Prep-TLC and give the product as gray solid (85.31mg, 71.9%)
Chemical Formula: calculated for (M+H
+) C
19H
18FN
5O: 351.39 , Found: 352.
Step 2: 7- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine
To a solution of 7- (2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) -2-methyl-2, 3-dihydroisoxazolo [4, 5-b] pyridine (50mg, 0.14 mmol) in THF (65mL) , paraformaldehyde (4.50 mg, 0.15mmol) was added in and the mixture was stirred at 25 ℃ for 30min. Then sodium cyanoborohydride (17.60mg, 0.28mmol) was added in at 0 ℃. The mixture was stirred at 25℃ for 2h. The reaction was quenched with water, and was extracted with EA twice time, the organic phase was combined and concentrated under pressure. The residue was purified via Genal-Prep-HPLC and give the product as white solid (24.91mg, 47.9%)
Chemical Formula: calculated for (M+H
+) C
20H
20FN
5O: 365.41, Found: 366.
Example 48. Preparation of Compound 2-60
As shown in FIG. 48, the specific synthesis steps are as follows:
Step 1: 7- (2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) furo [3, 2-b] pyridin-2 (3H) -one
To a solution of 3-bromo-2- (4-fluorophenyl) -5-methyl-4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazine (30 mg, 0.10 mmol) in Dioxane (3mL) and Water (0.3ml) 、7- (3, 3, 4, 4-tetramethylborolan-1-yl) furo [3, 2-b] pyridin-2 (3H) -one (28.29 mg, 0.11 mmol) 、Pd (dppf) Cl
2(3mg, 10%w/w) and K
3PO
4 (42.45mg, 0.20 mmol) were added in . The mixture was stirred at 90℃under N
2 atmosphere for 4h. The reaction mixture was diluted with water, and the water phase was extracted with EA twice time, the organic phase was combined and concentrated under pressure. The residue was purified via Prep-TLC and give the product as yellow solid (16.14mg, 45.8%)
Chemical Formula: calculated for (M+H+) C
20H
17FN
4O
2: 364.38, Found: 365.
Example 49. Preparation of Compound 2-61
As shown in FIG. 49, the specific synthesis steps are as follows:
Step 1: 7- (5-acetyl-2- (4-fluorophenyl) -4, 5, 6, 7-tetrahydropyrazolo [1, 5-a] pyrazin-3-yl) furo [3, 2-b] pyridin-2 (3H) -one
To a solution of 1- [2- (4-fluorophenyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -4H, 6H, 7H-pyrazolo [1, 5-a] pyrazin-5-yl] ethanone (100 mg, 0.259 mmol) in 1, 4-Dioxane/H
2O=10: 1 (30 mL) , 7-bromofuro [3, 2-b] pyridin-2 (3H) -one (83.23 mg, 0.389 mmol) , Na
2CO
3 (82.546 mg, 0.778 mmol) , Pd (dppf) Cl
2 (37.951 mg, 0.0519 mmol) was added. The reaction mixture was stirred at 100 ℃for 16 h. The reaction was complete detected by lcms. The solution was filtered, filtrate was collected. The reaction mixture was concentrated under pressure. The crude material was added to a silica gel column and was eluted with DCM/MeOH (10: 1) . Chemical Formula: calculated for (M+H
+) C
21H
17FN
4O
3: 392.3, Found: 393.0
Example 50. Biological activity
The CK1δ kinase assay was performed with a buffer (40 μL, pH 7.5) containing 50 mM Tris, 10 mM MgCl
2, 1 mM dithiothreitol, 100 μg/mL BSA with 10 μM ATP, 2nM wild type CK1δ, and 42 μM peptide substrate PLSRTLpSVASLPGL (Flotow et al., 1990) in the presence of 1 μL of a CK1δinhibitor (e.g., a compound of the present application) or 4%DMSO (e.g., as control) . The reaction mixture was incubated for 85 min at 25 ℃; detection was carried out as described for the Kinase-Glo Assay (Promega) . Luminescent output was measured on the Perkin Elmer Envision plate reader (PerkinElmer, Waltham, MA) .
Bmal1-dLuc or Per2-dLuc U2OS cells were suspended in the culture medium (DMEM supplemented with 10%fetal bovine serum, 0.29 mg/mL L-glutamine, 100 units/mL penicillin, and 100 mg/mL streptomycin) and plated onto 96-well white solid-bottom plates at 200 μL (10, 000 cells) per well. After 2 days, 100 μL of the explant medium (DMEM supplemented with 2%B27, 10 mM HEPES, 0.38 mg/mL sodium bicarbonate, 0.29 mg/mL L-glutamine, 100 units/mL penicillin, 100 mg/mL streptomycin, 0.1 mg/mL gentamicin, and 1 mM luciferin, pH 7.2) was dispensed to each well, followed by the application of 1 μL of a compound of the present application (dissolved in DMSO; final concentration was 0.7%in DMSO) . The plate was covered with an optically clear film and set to microplate reader (Infinite M200, Tecan) . The luminescence was recorded every 1 h for 3-4 days. The period parameter was obtained from the luminescence rhythm by curve fitting program CellulaRhythm or MultiCycle (Actimetrics) , both of which generated similar results.
The CK1δ inhibition results (IC50) are summarized in table 5.
Table 5
Number | Compound | CK1δ (IC50, nM) |
1. | 2-8 | * |
2. | 2-5 | 499.1 |
3. | 2-6 | 253.8 |
4. | 2-7 | 613.9 |
5. | 2-13 | 67.32 |
6. | 2-14 | 61.47 |
7. | 3-8 | 212 |
8. | 2-12 | 74.93 |
9. | 3-4 | 480 |
10. | 3-5 | 7712 |
11. | 3-1 | 180 |
12. | 3-2 | 11098 |
13. | 2-16 | 408 |
14. | 1-2 | 93 |
15. | 1-4 | 9778 |
16. | 1-10 | 214.8 |
17. | 3-7 | 132 |
18. | 2-27 | 81.29 |
19. | 2-28 | 367.9 |
20. | 2-29 | 176.9 |
21. | 2-30 | 163.3 |
22. | 2-33 | 278.9 |
Number | Compound | CK1δ (IC50, nM) |
23. | 2-31 | * |
24. | 1-3 | * |
25. | 2-37 | 1841 |
26. | 2-38 | 369.8 |
27. | 2-39 | 273.4 |
28. | 2-40 | 685.8 |
29. | 3-11 | 168.1 |
30. | 2-41 | 10000 |
31. | 3-12 | 10000 |
32. | 2-42 | 319.7 |
33. | 2-43 | 355.2 |
34. | 3-13 | 2199 |
35. | 2-44 | 962.8 |
36. | 2-45 | 3107 |
37. | 2-46 | 16961 |
38. | 2-47 | 800.1 |
39. | 2-48 | 495.8 |
40. | 2-49 | 106 |
41. | 3-14 | 319.5 |
42. | 2-50 | 131.1 |
43. | 2-51 | 722.8 |
44. | 2-52 | 39.7 |
Number | Compound | CK1δ (IC50, nM) |
45. | 2-53 | 10000 |
46. | 2-54 | 10000 |
47. | 2-55 | 10000 |
48. | 2-56 | 10000 |
49. | 2-57 | 10000 |
50. | 2-58 | 10000 |
51. | 2-59 | 10000 |
52. | 2-60 | 10000 |
53. | 2-61 | 10000 |
The “*” in Table 5 indicates that the value exceeds the measurement range, for example, the value is >100000.
The CK1δ inhibition results (EC50) are summarized in table 6.
Table 6
Number | Compound | CK1δ (EC50, nM) |
1. | 2-1 | 7.9 |
2. | 1-2 | 19.3 |
3. | 2-12 | * |
4. | 1-4 | 15.4 |
5. | 2-5 | 20.2 |
6. | 2-6 | 14.8 |
7. | 1-5 | 11.8 |
8. | 3-8 | 11.2 |
Number | Compound | CK1δ (EC50, nM) |
9. | 2-16 | 17.4 |
10. | 2-7 | * |
11. | 2-13 | 10.8 |
12. | 2-14 | 9.4 |
13. | 2-8 | * |
14. | 3-4 | * |
15. | 3-5 | * |
16. | 3-1 | * |
17. | 3-2 | * |
18. | 1-10 | * |
19. | 3-7 | 7.5 |
20. | 2-27 | 12 |
21. | 2-28 | 9.7 |
22. | 2-29 | 5.3 |
23. | 2-30 | 4.5 |
24. | 2-33 | 5.5 |
25. | 2-31 | * |
26. | 2-34 | 17.9 |
27. | 2-32 | 7.4 |
28. | 2-36 | 12.8 |
29. | 1-3 | * |
30. | 2-38 | 5.6 |
Number | Compound | CK1δ (EC50, nM) |
31. | 2-39 | 3.14 |
32. | 2-40 | 6.8 |
33. | 3-11 | 2.2 |
34. | 2-42 | 1.9 |
35. | 2-43 | 2.5 |
36. | 2-44 | 5.2 |
37. | 2-47 | 3.3 |
38. | 2-48 | 8.1 |
39. | 2-49 | 9 |
40. | 3-14 | 5 |
41. | 2-50 | 0.7 |
42. | 2-51 | 2.5 |
43. | 2-52 | 4.5 |
The “*” in Table 6 indicates that the value exceeds the measurement range, for example, the value is >30.
Example 51. Assay of Drug Transport
Preparation of Caco-2 Cells
50 μL and 25 mL of cell culture medium were added to each well of the Transwell insert and reservoir, respectively. And then the HTS transwell plates were incubated at 37 ℃, 5%CO
2 for 1 hour before cell seeding.
Caco-2 cells were diluted to 6.86х10
5 cells/mL with culture medium and 50 μL of cell suspension were dispensed into the filter well of the 96-well HTS Transwell plate. Cells were cultivated for 14-18 days in a cell culture incubator at 37 ℃, 5%CO
2, 95%relative humidity. Cell culture medium was replaced every other day, beginning no later than 24 hours after initial plating.
Preparation of Stock Solutions
10 mM stock solutions of test compounds were prepared in DMSO. The stock solutions of positive controls were prepared in DMSO at the concentration of 10 mM. Digoxin and propranolol were used as control compounds in this assay.
Assessment of Cell Monolayer Integrity
Medium was removed from the reservoir and each Transwell insert and replaced with prewarmed fresh culture medium.
Transepithelial electrical resistance (TEER) across the monolayer was measured using Millicell Epithelial Volt-Ohm measuring system (Millipore, USA) .
The Plate was returned to the incubator once the measurement was done.
The TEER value was calculated according to the following equation:
TEER measurement (ohms) *Area of membrane (cm
2) = TEER value (ohm·cm
2)
TEER value should be greater than 230 ohm·cm
2, which indicates the well-qualified Caco-2 monolayer.
Assay Procedures
The Caco-2 plate was removed from the incubator and washed twice with pre-warmed HBSS (10 mM HEPES, pH 7.4) , and then incubated at 37 ℃ for 30 minutes.
The stock solutions of control compounds and test compounds were diluted in DMSO to get 1 mM solutions and then diluted with HBSS (10 mM HEPES, pH 7.4) get 5 μM working solutions. The final concentration of DMSO in the incubation system was 0.5%.
To determine the rate of drug transport in the apical to basolateral direction. 125 μL of 5 μM working solution of control compound and test compounds were added to the Transwell insert (apical compartment) , and transfer 50 μL sample (D0 sample) immediately from the apical compartment to a new 96-well plate. Fill the wells in the receiver plate (basolateral compartment) with 235 μL of HBSS (10 mM HEPES, pH 7.4) .
To determine the rate of drug transport in the basolateral to apical direction. 285 μL of 5 μM working solution of control compound and test compounds were to the receiver plate wells (basolateral compartment) , and transfer 50 μL sample (D0 sample) immediately from the basolateral compartment to a new 96-well plate. Fill the wells in the Transwell insert (apical compartment) with 75 μL of HBSS (10 mM HEPES, pH 7.4) . The assay was performed in duplicate.
The plates were incubated at 37 ℃ for 2 hours.
At the end of the incubation, 50 μL samples from donor sides (apical compartment for Ap→Bl flux, and basolateral compartment for Bl→Ap) and receiver sides (basolateral compartment for Ap→Bl flux, and apical compartment for Bl→Ap) were transferred to wells of a new 96-well plate, followed by the addition of 4 volume of cold methanol containing appropriate internal standards (IS) . Samples were Vortexed for 5 minutes and then centrifuged at 3, 220 g for 40 minutes. An aliquot of 100 μL of the supernatant was mixed with an appropriate volume of ultra-pure water before LC-MS/MS analysis.
To determine the Lucifer Yellow leakage after 2-hour transport period, stock solution of Lucifer yellow was prepared in water and diluted with HBSS (10 mM HEPES, pH 7.4) to reach the final concentration of 100 μM. 100 μL of the Lucifer yellow solution was added to each Transwell insert (apical compartment) , followed by filling the wells in the receiver plate (basolateral compartment) with 300 μL of HBSS (10 mM HEPES, pH 7.4) . The plates were Incubated at 37 ℃ for 30 mins. 80 μL samples were removed directly from the apical and basolateral wells (using the basolateral access holes) and transferred to wells of new 96 wells plates. The Lucifer Yellow fluorescence (to monitor monolayer integrity) signal was measured in a fluorescence plate reader at 485 nM excitation and 530 nM emission.
Data Analysis
The apparent permeability coefficient (P
app) , in units of centimeter per second, can be calculated for Caco-2 drug transport assays using the following equation:
P
app = (V
A× [drug]
acceptor) / (Area×Time× [drug]
initial, donor)
Where V
A is the volume (in mL) in the acceptor well, Area is the surface area of the membrane (0.143 cm
2 for Transwell-96 Well Permeable Supports) , and time is the total transport time in seconds.
The efflux ratio will be determined using the following equation:
Efflux Ratio=P
app (B-A) /P
app (A-B)
Where P
app (B-A) indicates the apparent permeability coefficient in basolateral to apical direction, and P
app (A-B) indicates the apparent permeability coefficient in apical to basolateral direction.
The recovery can be determined using the following equation:
Recovery%= (V
A× [drug]
acceptor+V
D× [drug]
donor) / (V
D× [drug]
initial, donor)
Where V
A is the volume (in mL) in the acceptor well (0.235 mL for Ap→Bl flux, and 0.075 mL for Bl→Ap) , V
D is the volume (in mL) in the donor well (0.075 mL for Ap→Bl flux, and 0.235 mL for Bl→Ap)
The leakage of Lucifer Yellow, in unit of percentage (%) , can be calculated using the following equation:
%LY leakage = 100× [LY]
acceptor/ ( [LY]
donor+ [LY]
acceptor)
LY leakage of <1%is acceptable to indicate the well-qualified Caco-2 monolayer.
The P
app (B-A) , P
app (A-B) and Efflux ratio are summarized in Table 7.
Table 7
Compound | P app (A-B) (10 -6, cm/s) | P app (B-A) (10 -6, cm/s) | Efflux Ratio |
Digoxin | 0.30 | 16.98 | 56.52 |
Propranolol | 26.55 | 13.63 | 0.51 |
2-43 | 8.5 | 30.8 | 3.6 |
2-50 | 19.25 | 17.32 | 0.9 |
2-52 | 22.76 | 23.87 | 1.05 |
Example 52. Assay of Intrinsic Clearance
1. The master solution was prepared according to Table 8.
Table 8
Reagent | Stock Concentration | Volume | Final Concentration |
Phosphate buffer | 200 mM | 200 μL | 100 mM |
Ultra-pure H 2O | - | 106 μL | - |
MgCl 2 solution | 50 mM | 40 |
5 mM |
2. Three separated experiments were performed as follows. a) With NADPH: 10 μL of 20 mg/mL liver microsomes and 40 μL of 10 mM NADPH were added to the incubations. The final concentrations of microsomes and NADPH were 0.5 mg/mL and 1 mM, respectively. b) Without NADPH: 10 μL of 20 mg/mL liver microsomes and 40 μL of ultra-pure H
2O were added to the incubations. The final concentration of microsomes was 0.5 mg/mL. c) Heat-inactivated microsomes without NADPH: 10 μL of 20 mg/mL heat-inactivated liver microsomes and 40 μL of ultra-pure H
2O were added to the incubations. The final concentration of microsomes was 0.5 mg/mL.
3. The reaction was started with the addition of 4 μL of 200 μM test compound solution or control compound solution at the final concentration of 2 μM and carried out at 37 ℃.
4. Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45 and 60 min. The reaction was stopped by the addition of 4 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 2 μM ketoprofen) . Samples were centrifuged at 3, 220 g for 40 minutes. Aliquot of 100 μL of the supernatant was mixed with 100 μL of ultra-pure H
2O and then used for LC-MS/MS analysis.
5. Data Analysis
All calculations were carried out using Microsoft Excel.
Peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs.incubation time curve.
The in vitro half-life (in vitro t
1/2) was determined from the slope value:
in vitro t
1/2 = - (0.693/k)
Conversion of the in vitro t
1/2 (min) into the in vitro intrinsic clearance (in vitro CL
int, in μL/min/mg protein) was done using the following equation (mean of duplicate determinations) :
in vitro CL
int = (0.693 *volume of incubation (μl) ) / (in vitro t
1/2 *amount of proteins (mg) )
Conversion of the in vitro t
1/2 (min) into the scale-up unbound intrinsic clearance (Scale-up CL
int, in mL/min/kg) was done using the following equation (mean of duplicate determinations) :
The Scaling Factors for Intrinsic Clearance Prediction in Liver Microsomes are summarized in Table 9.
Table 9
a. Iwatsubo et al, Davies and Morris, 1993, 10 (7) pp 1093-1095.
b. Barter et al, 2007, Curr Drug Metab, 8 (1) , pp 33-45; Iwatsubo et al, 1997, JPET, 283 pp 462-469.
The Papp (B-A) , Papp (A-B) and Efflux ratio are summarized in Table 10.
Table 10
While preferred embodiments of the present application have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the present application are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the present application described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the present application and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Claims (43)
- A method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt thereof:wherein Ar l is an aryl group that is optionally substituted by one or more R 1 substituents, and each R 1 is independently selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, perfluorohydrocarbyloxy, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, sulfonyl or sulfoxido, wherein the substituent on the sulfur atom is hydrocarbyl, sulfonylamide,wherein the substituents on the sulfonamido nitrogen atom are hydrido or hydrocarbyl, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroaryl-hydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino, N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,wherein the substituent (s) on the aminohydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,amino, and a N-monosubstituted or N, N-disubstituted amino group,wherein the substituent (s) on the amino nitrogen are selected from the group consisting of hydrido, hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, hydrocarboyl, arylsulfonyl, and hydrocarbylsulfonyl or wherein the amino nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group;wherein X 1, X 2 and X 3 are each independently C or N;R 7 is absent or -CN;wherein R 2 is -NH 2, -CN or Z,wherein Z is independently selected from the group consisting of: hydrido, hydrocarbyl, halogen, carboxy, cyano, azido, hydrocarbylsulfonyl, carbonyloxyhydrocarbyl, carbonylamido, and -X-Y,wherein -X is -O, -Sor -NQ,-Y is hydrido, hydrocarbyl or hydrocarbylaryl,Q is hydrido, hydrocarbyl, hydroxylhydrocarbyl, 2-, 3-, or 4-pyridylhydrocarbyl, or arylhydrocarbyl,wherein R 3 is a halogen or -CN,wherein ring A is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring A is optionally substituted with a R 4 substituent, and R 4 is =O;wherein R 5 is independently selected from the group consisting of: -COO-C 1-C 6 alkyl, -CO-R 10 and R 52,wherein R 10 is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said R 10 is optionally substituted with a R 8 substituent, said R 8 substituent is C 1-C 6 alkyl,wherein R 52 is independently selected from the group consisting of an azido, hydrido, hydrocarbyl, amido, halohydrocarbyl, perhalohydrocarbyl, hydrocarbyloxycarbonyl, N-piperazinylcarbonyl, aminocarbonyl, piperazinyl and an aryl group that is substituted by one or more substituents, said one or more substituents being selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonyl-hydrocarbyl, heterocyclooxy, hydroxycarbonyl-hydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarby-amino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonyl-hydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyl-oxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclo-hydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroaryl-sulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclo-hydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,wherein the substituent (s) on the aminohydrocarbyl nitrogen are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group,wherein R 6 is C 1-C 6 alkyl or R 61,wherein R 61 is independently selected from the group consisting of: an azido, hydrido, hydrocarbyl, amido, hydrocarbylamino, halohydrocarbyl, perhalohydrocarbyl and an aryl substituent that is optionally substituted by one or more substituents selected from the group consisting of a halogen, hydrocarbyl, hydrocarbyloxy, nitro, cyano, perfluorohydrocarbyl, trifluoromethylhydrocarbyl, hydroxy, mercapto, hydroxycarbonyl, aryloxy, arylthio, arylamino, arylhydrocarbyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroarylhydrocarbyl, hydrocarbyloxycarbonylhydrocarbyl, heterocyclooxy, hydroxycarbonylhydrocarbyl, heterocyclothio, heterocycloamino, cyclohydrocarbyloxy, cyclohydrocarbylthio, cyclohydrocarbylamino, heteroarylhydrocarbyloxy, heteroarylhydrocarbylthio, heteroarylhydrocarbylamino, arylhydrocarbyloxy, arylhydrocarbylthio, arylhydrocarbylamino, heterocyclic, heteroaryl, hydroxycarbonylhydrocarbyloxy, alkoxycarbonylalkoxy, hydrocarbyloyl, arylcarbonyl, arylhydrocarbyloyl, hydrocarboyloxy, arylhydrocarboyloxy, hydroxyhydrocarbyl, hydroxyhydrocarbyloxy, hydrocarbylthio, hydrocarbyloxyhydrocarbylthio, hydrocarbyloxycarbonyl, hydroxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbyl, hydrocarbylhydroxycarbonylhydrocarbylthio, hydrocarbyloxycarbonylhydrocarbyloxy, hydrocarbyloxycarbonylhydrocarbylthio, amino, hydrocarbylcarbonylamino, arylcarbonylamino, cyclohydrocarbylcarbonylamino, heterocyclohydrocarbylcarbonylamino, arylhydrocarbylcarbonylamino, heteroarylcarbonylamino, heteroarylhydrocarbylcarbonylamino, heterocyclohydrocarbyloxy, hydrocarbylsulfonylamino, arylsulfonylamino, arylhydrocarbylsulfonylamino, heteroarylsulfonylamino, heteroarylhydrocarbylsulfonylamino, cyclohydrocarbylsulfonylamino, heterocyclohydrocarbylsulfonylamino and N-monosubstituted or N, N-disubstituted aminohydrocarbyl group,wherein the substituent (s) on the amino-hydrocarbyl nitrogen atom are selected from the group consisting of hydrocarbyl, aryl, arylhydrocarbyl, cyclohydrocarbyl, arylhydrocarbyloxycarbonyl, hydrocarbyloxycarbonyl, and hydrocarboyl, or wherein the aminohydrocarbyl nitrogen and two substituents attached thereto form a 5-to 8-membered heterocyclic or heteroaryl ring group, andwherein ring B is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring B is optionally substituted with a R 9 substituent, and said R 9 is PMB, wherein, PMB represents group
- The method according to claim 1, wherein R 1 is F.
- The method according to any one of claims 1-2, wherein the compound of Formula I comprises one of said R 1 substituent.
- The method according to any one of claims 1-3, wherein R 3 is F or -CN.
- The method according to any one of claims 1-5, wherein R 5 is -COO-CH 2CH 3 or -CO-R 10.
- The method according to claim 7, wherein R 8 is -CH 3.
- The method according to any one of claims 1-8, wherein R 6 is -CH 3.
- The method according to any one of claims 1-11, wherein X 1 is C, X 2 is C, X 3 is N, R 7 is absent, A is and B iswherein R 2 is Z, Z is -NR 23R 24,R 23 is hydrido, or C 1-C 6 hydrocarbyl, R 24 is independently selected from a group consisting of hydrido, lower hydrocarbyl, aryl lower hydrocarbyl, hydroxyl lower hydrocarbyl, and 2 -pyridyl lower hydrocarbyl, 3 -pyridyl lower hydrocarbyl and 4-pyridyl lower hydrocarbyl;Ar 1 is an aryl group that is substituted by a halogen or halo group, lower hydrocarbyl, or hydrocarbyloxy group;R 6 is R 61, R 61 is hydrido, or C 1-C 6 hydrocarbyl; andR 5 is R 52, R 52 is hydrido, or lower hydrocarbyl.
- The method according to any one of claims 1-12, wherein X 1 is C, X 2 is C, X 3 is N, R 7 is absent, A is and B iswherein R 2 is Z, Z is -OR 25,R 25 is hydrido, C 1-C 6 hydrocarbyl, or aryl lower hydrocarbyl;Ar 1 is an aryl group that is independently substituted with a halogen, lower hydrocarbyl, or hydrocarbyloxy group;R 6 is R 61, R 61 is C 1-C 6 hydrocarbyl; andR 5 is R 52, R 52 is hydrido.
- The method according to any one of claims 1-13, wherein X 1 is C, X 2 is C, X 3 is N, R 7 is absent, A is and B iswherein R 2 is -CN;Ar 1 is an aryl group that is substituted by a halogen, lower hydrocarbyl or a hydrocarbyloxy group;R 6 is R 61, R 61 is lower hydrocarbyl; andR 5 is R 52, R 52 is hydrido or lower hydrocarbyl.
- A method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula II, or a pharmaceutically acceptable salt thereof:wherein R 1 is a halogen,n is 0, 1 or 2,X 1, X 2, X 3, X 4, X 5 and X 6 are each independently C or N,R 2 is absent, or =O,R 3 is absent or -CN,wherein R 4 is a halogen,wherein R 5 is selected from the group consisting of: -NH 2, C 1-C 6 alkyl, C 1-C 6 alkyl-NH-C 1-C 6 alkyl, C 1-C 6 alkyl-OH and C 1-C 6 alkyl-O-CO-C 1-C 6 alkyl,wherein ring A is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring A is optionally substituted with a R 6 substituent, the R 6 is =O,B is a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said B is optionally substituted with one or more R 7 substituents, andwherein each R 7 is independently selected from the group consisting of: CO-C 1-C 6 alkyl, Bn, =O, C 1-C 6 alkyl, CO-NH-C 1-C 6 alkyl, CO-C 1-C 6 alkyl-CN, R 8, R 8-C 1-C 6 alkyl, and CO-R 8-C 1-C 6 alkyl, wherein R 8 is a 4-to 7-membered cycloalkyl or heterocycloalkyl or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-.
- The method according to claim 15, wherein R 1 is F.
- The method according to any one of claims 15-16, wherein n is 1.
- The method according to any one of claims 15-16, wherein n is 2.
- The method according to any one of claims 15-18, wherein R 4 is F.
- The method according to any one of claims 15-19, wherein R 5 is selected from the group consisting of: -NH 2, -CH 3, -CH 2-NH-CH 3, -CH 2-OH and -CH 2-O-CO-CH 3.
- The method according to any one of claims 15-22, wherein the number of R 7 is 1 or 2.
- A method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula III, or a pharmaceutically acceptable salt thereof:wherein R 1 is a halogen,n is 0, 1, or 2,X 1 and X 2 are each independently C or N,wherein R 2 is C 1-C 6 alkyl,ring A is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring C is optionally substituted with a R 3 substituent, R 3 is =O,wherein R 4 is -CN, -COO-C 1-C 6 alkyl, or amido group,R 5 is C 1-C 6 alkyl, andring C is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said ring C is optionally substituted with a R 6 substituent, R 6 is =O.
- The method according to claim 26, wherein R 1 is F.
- The method according to any one of claims 26-27, wherein n is 1.
- The method according to any one of claims 26-28, wherein R 2 is -CH 3.
- The method according to any one of claims 26-30, wherein R 4 is -CN, -CO-NH 2, or -COO-CH 3.
- The method according to any one of claims 26-31, wherein R 5 is -CH 3.
- A method for inhibiting CK1 delta or CK1 epsilon activity, comprising administering an effective amount of the compound of Formula IV, or a pharmaceutically acceptable salt thereof:wherein R 1 is a halogen,n is 0, 1 or 2,R 2 is a 4-to 7-membered cycloalkyl or heterocycloalky or a 5-to 6-membered heteroaryl, wherein up to 2 carbon atoms are replaced with a heteroatom selected from =N-and -O-, and said R 2 is optionally substituted with a R 3 substituent, and R 3 is =O.
- The method according to claim 35, wherein R 1 is F.
- The method according to any one of claims 35-36, wherein n is 1.
- The method according to any one of claims 1-39, wherein the method is an in vitro method, an ex vivo method, or an in vivo method.
- A method for treating a neurological and/or psychiatric disease or disorder in a mammal, which comprises administering to the mammal a therapeutically effective amount of a compound as defined in any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.
- The method according to claim 41, wherein said disease or disorder is a mood disorder, a sleep disorder or a circadian disorder.
- The method according to claim 42, wherein the mood disorder is selected from the group consisting of a depressive disorder and a bipolar disorder.
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