CN116761798A - Indazoles as kinase inhibitors - Google Patents

Indazoles as kinase inhibitors Download PDF

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Publication number
CN116761798A
CN116761798A CN202180092014.9A CN202180092014A CN116761798A CN 116761798 A CN116761798 A CN 116761798A CN 202180092014 A CN202180092014 A CN 202180092014A CN 116761798 A CN116761798 A CN 116761798A
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Prior art keywords
compound
ring
optionally substituted
alkyl
formula
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罗伯特·L·胡德金斯
丹尼尔·C·班森
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Terra Biosciences
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Terra Biosciences
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Priority claimed from PCT/US2021/065679 external-priority patent/WO2022147246A1/en
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Abstract

Disclosed herein are compounds and methods for treating diseases and/or conditions associated with FGFR inhibition.

Description

Indazoles as kinase inhibitors
Cross Reference to Related Applications
The present application claims the benefit of U.S. provisional patent application No. 63/132,031, filed on 12/30/2020, and U.S. provisional patent application No. 63/216,879, filed on 6/2021. Each of these applications is incorporated herein by reference in its entirety.
Technical Field
The present disclosure relates to indazoles useful in the treatment of cancer, pharmaceutical compositions comprising one or more such indazoles, and methods of treating cancer using such indazoles.
Background
Kinase inhibitors have been used to block kinase activity, thereby treating cancer (e.g., by inhibiting the mitotic process). These kinase inhibitors are typically small molecules that target kinases to block the development, growth, or spread of cancer.
However, despite the known variety of kinase inhibitors, there remains a need for selective inhibitors for the treatment of diseases such as hyperproliferative diseases, which offer one or more advantages over existing compounds. These advantages include: enhancing activity and/or efficacy; a beneficial kinase selectivity profile according to the respective therapeutic needs; improving side effect characteristics, such as reducing undesired side effects, reducing the intensity of side effects or reducing (cellular) toxicity; improving targeting of mutant receptors in diseased cells; improving physicochemical properties such as solubility/stability in water, body fluids and/or pharmaceutical formulations; improving pharmacokinetic properties, e.g., achieving reduced or simpler dosing regimens; easier drug substance production, for example by a shorter synthetic route or easier purification.
Disclosure of Invention
The compounds disclosed herein provide potent and selective small molecule kinase inhibitors.
In some aspects, the disclosure relates to compounds of formula (I)
Or a pharmaceutically acceptable salt thereof,
wherein n=1, 2 or 3;
m=0, 1, 2 or 3;
each R 1 Independently H, CN or optionally substituted C 1 -C 6 An alkyl group;
each R 2 Independently H, CN or optionally substituted C 1 -C 6 An alkyl group;
or two R's attached to the same carbon atom 1 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to different carbon atoms 1 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or two R's attached to different carbon atoms 2 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
Or R is 1 Radicals and R 2 The groups are connected to form a 6-9 membered bridged bicyclic ring;
a=n or CH;
Z＝S(O) 2 ；S(O)；O、NR 3 or CR (CR) 4 R 4’ ；
R 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b ；
Or R is 3 And R is R 1 Or R is 2 Together forming an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R a is H or C 1 -C 6 An alkyl group;
R b is H or C 1 -C 6 An alkyl group;
or R is a And R is b Together with the N atom to which they are both attached form an optionally substituted 3A membered to 7 membered heterocycloalkyl ring;
R c is optionally substituted C 1 -C 6 Alkyl, or cycloalkyl;
R 4 is H, -F or optionally substituted C 1 -C 6 An alkyl group;
R 4’ is H, -F, -OH, -CN, -NH 2 、-NH(C 1 -C 3 Alkyl), -N (C) 1 -C 3 Alkyl group 2 、-N(C 1 -C 3 Alkyl) -SO 2 (C 1 -C 3 Alkyl), -C 1 -C 6 Haloalkyl, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 An alkoxy group;
or R is 4 And R is 4’ Together with the C atom to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-to 7-membered cycloalkyl ring;
or R is 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an oxo group;
or R is 4’ And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-to 7-membered cycloalkyl ring;
y is a 5-or 6-membered heteroaryl ring, or a 6-membered aryl ring;
Q 5 、Q 6 、Q 7 、Q 8 and Q 9 Each independently is N or CR 5 Wherein Q is 5 、Q 6 、Q 7 、Q 8 And Q 9 One or two of which are N and the remainder are CR 5 ；
R 5 Is H, halogen, C 1 -C 3 An alkyl group; c (C) 1 -C 3 Alkoxy, or cycloalkyl;
x= O, S or NR, wherein R is H or C 1 -C 3 An alkyl group;
R 6 is C 1 -C 6 An alkyl group;
R 7 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy radicalA group, or-cycloalkyl; and
R 8 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl.
In some embodiments, the compounds of formula (I) are those wherein
n=1, 2 or 3;
m=1, 2 or 3;
each R 1 Independently is H; or optionally substituted C 1 -C 6 An alkyl group;
each R 2 Independently is H; or optionally substituted C 1 -C 6 An alkyl group;
or two R's attached to the same carbon atom 1 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to different carbon atoms 1 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or two R's attached to different carbon atoms 2 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or R is 1 Radicals and R 2 The groups are connected to form a 6-9 membered bridged bicyclic ring;
a=n or CH;
Z＝S(O) 2 ；S(O)；O、NR 3 or CR (CR) 4 R 4’ ；
R 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b ；
R a Is H or C 1 -C 6 An alkyl group;
R b is H or C 1 -C 6 An alkyl group;
or R is a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R c is optionally substituted C 1 -C 6 Alkyl, or cycloalkyl;
R 4 is H or optionally substituted C 1 -C 6 An alkyl group;
R 4’ is H, -OH or optionally substituted C 1 -C 6 An alkyl group;
or R is 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
y is a 5-or 6-membered heteroaryl ring;
Q 5 、Q 6 、Q 7 、Q 8 and Q 9 Each independently is N or CR 5 Wherein Q is 5 、Q 6 、Q 7 、Q 8 And Q 9 One or two of which are N and the remainder are CR 5 ；
R 5 Is H, halogen, C 1 -C 3 An alkyl group; c (C) 1 -C 3 Alkoxy, or cycloalkyl;
x= O, S or NR, wherein R is H or C 1 -C 3 An alkyl group;
R 6 is C 1 -C 6 An alkyl group;
R 7 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl; and
R 8 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy radicalA group, or-cycloalkyl.
Stereoisomers of the compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof are also described. Methods of using the compounds of formula (I), and pharmaceutical compositions comprising the compounds of formula (I) are described.
Detailed Description
The disclosure may be more fully understood by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, for the sake of brevity, the various features of the disclosed compositions and methods described in the context of a single aspect may also be provided separately or in any subcombination.
The term "optionally substituted" or "substituted" as used herein to describe substituents as defined herein means that the substituent may be, but is not necessarily, substituted with one or more of the following: halogen (namely-F, -Cl, -Br, -I), cyano, -OH, -C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, 3-7 membered heterocycloalkyl, -C 3 -C 6 Spirocycloalkyl, 3-7 membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Haloalkyl (e.g., -CF) 3 ；-CHF 2 、-CH 2 CF 3 Etc. -C) 1 -C 6 Alkoxy, -C 1 -C 6 Haloalkoxy (e.g. -OCF) 3 ；-OCHF 2 、-OCH 2 CF 3 Etc., C 1 -C 6 Alkylthio (e.g., -SCH) 3 ；-SCH 2 CH 3 Etc., C 1 -C 6 Alkylamino (e.g., -CH) 2 NH 2 、-CH 2 CH 2 NH 2 Etc. -NH 2 、-NH(C 1 -C 6 Alkyl), -N (C) 1 -C- 6 Alkyl group 2 、-NH(C 1 -C 6 Alkoxy), -C (O) NHC 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 、-COOH、-C 1 -C 6 Alkyl COOH、-C 3 -C 6 Cycloalkyl COOH, -C (O) NH 2 、-C 1 -C 6 Alkyl CONH 2 、-C 3 -C 6 Cycloalkyl CONH 2 、-C 1 -C 6 Alkyl CONHC 1 -C 6 Alkyl, -C 1 -C 6 Alkyl CON (C) 1 -C 6 Alkyl group 2 、-C(O)C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -NHCO (C) 1 -C 6 Alkyl), -N (C) 1 -C 6 Alkyl) C (O) (C 1 -C 6 Alkyl), -S (O) C 1 -C 6 Alkyl, -S (O) 2 C 1 -C 6 Alkyl, oxo (i.e., =o), 6-12 membered aryl, or 5-to 12-membered heteroaryl groups. In other embodiments, "optionally substituted" or "substituted" means that the substituent may, but need not, be substituted with-C (O) (C 1 -C 6 Haloalkyl) -NHSO 2 (C 1 -C 6 Alkyl), -N (C) 1 -C 6 Alkyl) SO 2 (C 1 -C 6 Alkyl) or-P (O) (C 1 -C 6 Alkyl group 2 (e.g., -P (O) (CH) 3 ) 2 ) One or more substitutions in (a). In some embodiments, each of the above optional substituents is itself optionally substituted with one or two of these groups.
When a range of carbon atoms is used herein, e.g., C 1 -C 6 All ranges are contemplated, as well as individual numbers of carbon atoms. For example, "C 1 -C 3 "include C 1 -C 3 、C 1 -C 2 、C 2 -C 3 、C 1 、C 2 And C 3 . Thus, for example, "C 1 To C 4 Alkyl "groups refer to all alkyl groups having 1 to 4 carbons (e.g., 1, 2, 3, or 4), i.e., CH 3 -、CH 3 CH 2 -、CH 3 CH 2 CH 2 -、(CH 3 ) 2 CH-、CH 3 CH 2 CH 2 CH 2 -、CH 3 CH 2 CH(CH 3 ) -and (CH) 3 ) 3 C-。“C 1 To C 6 An alkyl "group refers to all alkyl groups having 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6).
As used herein, the term "alkyl" refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, isopropyl, sec-butyl, tert-butyl, and the like. Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and the like. An alkyl group may have from 1 to 30 carbon atoms (whenever present herein, a numerical range (e.g., "1 to 30") means each integer within the given range; e.g., "1 to 30 carbon atoms" means an alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, although the present definition also includes the term "alkyl" where no numerical range is specified). The "alkyl" group may also be a medium size alkyl group having 1 to 12 carbon atoms. The "alkyl" group may also be a lower alkyl group having 1 to 6 carbon atoms. The alkyl group may be substituted or unsubstituted. Merely by way of example, "C 1 -C 5 Alkyl "means having one to five carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl (branched and straight), and the like. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl. In several embodiments, "Me" is methyl (e.g., CH 3 )。
As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. The alkenyl group may be unsubstituted or substituted.
As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched hydrocarbon chain. Alkynyl groups may be unsubstituted or substituted.
As used herein, "cycloalkyl" refers to a fully saturated (no double bondOr triple bonds) a mono-or polycyclic hydrocarbon ring system. When composed of two or more rings, the rings may be connected together in a fused manner. Cycloalkyl groups may contain 3 to 12 carbon atoms. For example, C 3 -C 6 Cycloalkyl groups represent three to six carbon atoms in the ring, i.e. the ring is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Cycloalkyl groups may be unsubstituted or substituted.
As used herein, the term "spirocycloalkyl ring" refers to a cycloalkyl ring sharing one carbon atom with another cyclic ring. For example, a 3-7 membered spirocycloalkyl ring means that there are 3, 4, 5, 6 or 7 carbon atoms in the cycloalkyl ring sharing one carbon atom with another cyclic ring. By way of example, shown below are exemplary 3-7 membered spirocycloalkyl groups attached to the piperidine ring:
as used herein, "aryl" refers to a carbocyclic (all-carbon) single or multiple ring aromatic ring system (including fused ring systems in which two carbocycles share a common chemical bond) that has a completely delocalized pi electron system in all rings. The number of carbon atoms in the aryl group can vary. For example, the aryl group may be C 6 -C 14 Aryl group, C 6 -C 10 Aryl groups or C 6 An aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. The aryl group may be substituted or unsubstituted.
As used herein, "heteroaryl" refers to a mono-or polycyclic aromatic ring system (ring system having a fully delocalized pi-electron system) containing one or more heteroatoms (i.e., elements other than carbon, including but not limited to nitrogen, oxygen, and sulfur). The number of atoms in the ring of the heteroaryl group can vary. For example, heteroaryl groups may have 4 to 14 atoms in the ring, 5 to 10 atoms in the ring, or 5 to 6 atoms in the ring. Furthermore, the term "heteroaryl" includes fused ring systems in which two rings (e.g., at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings) share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2, 3-oxadiazole, 1,2, 4-oxadiazole, thiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings may also include bridging nitrogen atoms. Such as, but not limited to: pyrazolo [1,5-a ] pyridine, imidazo [1,2-a ] pyridine, pyrazolo [1,5-a ] pyrimidine. Heteroaryl groups may be substituted or unsubstituted.
As used herein, "heterocycloalkyl" refers to ternary, quaternary, pentanary, hexabasic, heptabasic, octabasic, nonabasic, decabasic, up to 18 basic monocyclic, bicyclic, and tricyclic ring systems, wherein carbon atoms and 1 to 5 heteroatoms constitute the ring system. Heterocycloalkyl groups may optionally contain one or more unsaturated bonds, however, in such a position that a completely delocalized pi-electron system is not always present in all rings. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. Heterocycloalkyl groups can further contain one or more carbonyl or thiocarbonyl functional groups such that the definition includes oxo and thio systems such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates. When composed of two or more rings, the rings may be connected together in a fused manner. In addition, any nitrogen in the heterocycloalkyl group can be quaternized. The heterocycloalkyl group can be unsubstituted or substituted. Examples of such "heterocycloalkyl" include, but are not limited to, 1, 3-dioxin, 1, 3-dioxane, 1, 4-dioxane, 1, 2-dioxane, 1, 3-dioxolane, 1, 4-dioxolane, 1, 3-oxathiacyclohexane, 1, 4-oxathiacyclohexane, 1, 3-dithiocyclohexane, 1, 3-dithiane, 1, 4-oxacyclohexane, tetrahydro-1, 4-thiazine, 2H-1, 2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydropyrimidine, thiobarbituric acid, and the like trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidone, thiazoline, thiazolidine, morpholine, ethylene oxide, piperidine N-oxide, piperidine, piperazine, pyrrolidine, pyrrolidone (pyrrosidone), 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiomorpholine sulfoxide, thiomorpholine sulfone and benzo-fused analogues thereof (e.g., benzoimidazolone, tetrahydroquinoline, 3, 4-methylenedioxyphenyl).
As used herein, the term "spiroheterocycloalkyl ring" refers to a heterocycloalkyl ring that shares one carbon atom with another ring. For example, a 3-7 membered spiroheterocycloalkyl ring means that there are 3, 4, 5, 6 or 7 atoms in the heterocycloalkyl ring, and only one carbon atom in the heterocycloalkyl ring is also a member of the other ring. By way of example, shown below are exemplary 3-7 membered spiroheterocycloalkyl groups attached to the piperidine ring:
as used herein, the term "bridged bicyclic" refers to a ring system comprising two linked cycloalkyl or heterocycloalkyl rings sharing at least three atoms. For example, a 6-9 membered bridged bicyclic ring means that there are 6, 7, 8 or 9 atoms in the bridged bicyclic ring. By way of example, the following shows an exemplary 6-9 membered bridged bicyclic ring:
the term "amino" as used herein refers to-NH 2 A group.
As used herein, the term "hydroxy" refers to an-OH group.
As used herein, the term "halogen atom" or "halogen" refers to fluorine, chlorine, bromine and iodine.
The term "pharmaceutically acceptable salt" refers to a salt of a compound to which no drug is administeredThe organisms used cause significant irritation and do not eliminate the biological activity and properties of the compounds. In several embodiments, the salt is an acid addition salt of a compound. Pharmaceutically acceptable salts may be obtained by reacting the compounds with mineral acids such as hydrohalic acids (e.g., hydrochloric or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutically acceptable salts can also be obtained by reacting the compounds with organic acids (e.g., aliphatic or aromatic carboxylic or sulfonic acids such as formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acids). Pharmaceutically acceptable salts can also be obtained by: reacting the compound with a base to form a salt, e.g., an ammonium salt, an alkali metal salt (e.g., sodium or potassium salt), an alkaline earth metal salt (e.g., calcium or magnesium salt), a salt of an organic base (e.g., dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, C 1 -C 7 Alkylamines, cyclohexylamine, triethanolamine, ethylenediamine), and salts with amino acids (e.g., arginine and lysine).
Other pharmaceutically acceptable salts include trifluoroacetate salts.
It will be appreciated that in any of the compounds described herein having one or more chiral centers, each center may independently have an R-configuration or an S-configuration or mixtures thereof, if absolute stereochemistry is not explicitly indicated. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. Furthermore, it is understood that in any of the compounds described herein having one or more double bonds, geometric isomers are produced that may be defined as E or Z, each double bond may independently be E or Z, mixtures thereof. It is to be understood that in any of the compounds described herein having one or more chiral centers, all possible diastereomers are also contemplated. It is to be understood that in any of the compounds described herein, all tautomers are contemplated. It should also be understood that in any of the compounds described herein, all isotopes of the atoms included are contemplated. For example, any example of hydrogen may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium), or other isotopes; any example of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any example of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any example of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; any example of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.
As used herein, the term "kinase inhibitor" means any compound, molecule, or composition that inhibits or reduces kinase activity. Inhibition may be achieved, for example, by blocking phosphorylation of kinases (e.g., competing with the phosphorylating entity Adenosine Triphosphate (ATP), by binding to sites other than the active site, by affecting their activity through conformational changes, or by depriving kinases of their chaperone systems that rely on to maintain cell stability, resulting in their ubiquitination and degradation.
As used herein, "subject," "host," "patient," and "individual" are used interchangeably and shall be given their ordinary meaning and shall also refer to organisms having FGFR proteins. This includes mammals, such as humans, non-human primates, ungulates, canines, felines, equines, mice, rats, and the like. The term "mammal" includes both human and non-human mammals.
The term "sample" or "biological sample" shall be given its ordinary meaning and also covers various sample types obtained from an organism as well as being useful in imaging, diagnosis, prognosis or monitoring assays. The term encompasses liquid samples of blood and other biological origin, solid tissue samples, such as biopsy specimens or tissue cultures or cells derived therefrom and their progeny. The term encompasses samples that have been treated in any way after acquisition, for example by treatment with reagents, solubilization or enrichment of certain components. The term encompasses clinical samples and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.
The terms "treatment", "treatment" and the like shall be given their ordinary meanings and shall also be included herein to generally refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof, and/or may be therapeutic in terms of partially or completely stabilizing or curing a disease and/or adverse reactions attributable to the disease. As used herein, "treatment" shall have its ordinary meaning and shall also encompass any treatment of a disease in a mammal (particularly a human) and include: (a) Preventing the occurrence of a disease or condition in a subject who may be susceptible to the disease or condition but has not yet been diagnosed as having the disease or condition; (b) inhibiting disease symptoms, e.g., arresting their development; and/or (c) alleviating symptoms of the disease, e.g., causing regression of the disease or symptoms.
The terms "cancer," "neoplasm," and "tumor" are used interchangeably herein and shall be given their ordinary meaning and shall also refer to cells that exhibit relatively spontaneous growth such that they exhibit an abnormal growth phenotype characterized by a significant loss of control of cell proliferation. In general, target cells for detection or treatment in the present application include precursor cells, precancerous cells (e.g., benign cells), malignant cells, premetastatic cells, metastatic cells, and non-metastatic cells. As used herein, "FGFR-associated cancers" refer to those cancers that involve an increase in mutant FGFR kinase activity (e.g., sustained activation of FGFR).
The term "control" shall be given its ordinary meaning and shall also include a sample or standard for comparison with a sample being examined, processed, characterized, analyzed, etc. In several embodiments, the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In several embodiments, the control is a historical control or standard reference value or range of values. In several embodiments, the control is a comparison to a wild-type FGFR arrangement or protocol.
With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural depending upon the context and/or application. Various singular/plural permutations may be explicitly set forth herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims shall not be construed as limiting the scope.
In some aspects, the disclosure relates to compounds of formula (I)
Or a pharmaceutically acceptable salt thereof.
In some aspects, n in the compound of formula (I) is 1, 2, or 3.
In some embodiments, n is 1. In other embodiments, n is 2. In other embodiments, n is 3.
In other aspects, m in the compound of formula (I) is 0, 1, 2, or 3. In some aspects, m in the compound of formula (I) is 0 or 1. In some aspects, m in the compound of formula (I) is 0, 1, or 2. In some aspects, m in the compound of formula (I) is 1 or 2. In some aspects, m in the compound of formula (I) is 2 or 3.
In other aspects, m in the compound of formula (I) is 1, 2, or 3.
In some embodiments, m is 1. In other embodiments, m is 2. In other embodiments, m is 3.
In some embodiments, m is 0.
In some aspects, each R in the compound of formula (I) 1 Independently H, CN or optionally substituted C 1 -C 6 An alkyl group.
In some aspects, each R in the compound of formula (I) 1 Independently H or optionally substituted C 1 -C 6 An alkyl group.
In some embodiments, at least one R in the compound of formula (I) 1 Is H. In other embodiments, each R in the compound of formula (I) 1 Is H.
In some embodimentsR in the compound of formula (I) 1 Is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments, R in the compound of formula (I) 1 Is unsubstituted C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments, R in the compound of formula (I) 1 is-CH 3 。
In some embodiments of the compounds of formula (I), one or more R 1 Is H and one or more R 1 Is optionally substituted C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I), one or more R 1 Is substituted C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I), one or more R 1 Is substituted C 1 -C 6 Alkyl radicals, e.g. -CH 2 OH、-CH 2 N(CH 3 ) 2 or-CH 2 -CN、-CH 2 SO 2 CH 3 or-CH 2 N(CH 3 )SO 2 CH 3 。
In some aspects, each R in the compound of formula (I) 2 Independently H, CN or optionally taken Substituted C 1 -C 6 An alkyl group.
In some aspects, each R in the compound of formula (I) 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
In some embodiments, at least one R in the compound of formula (I) 2 Is H. In other embodiments, each R in the compound of formula (I) 2 Is H.
In some embodiments, R in the compound of formula (I) 2 Is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments, R in the compound of formula (I) 2 Is unsubstituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments, R in the compound of formula (I) 2 is-CH 3 。
In some embodiments of the compounds of formula (I), one or more R 2 Is H and one or more R 2 Is optionally substituted C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I), one or more R 2 Is substituted C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I), one or more R 1 Is substituted C 1 -C 6 Alkyl radicals, e.g. -CH 2 OH、-CH 2 N(CH 3 ) 2 or-CH 2 -CN、-CH 2 SO 2 CH 3 or-CH 2 N(CH 3 )SO 2 CH 3 。
In some aspects of the compounds of formula (I), two R's attached to the same carbon atom 1 Groups, together with the carbon atoms to which they are both attached, form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
In some aspects of the compounds of formula (I), two R's attached to the same carbon atom 1 The groups, together with the carbon atoms to which they are both attached, form an optionally substituted 3-7 membered spirocycloalkyl ring. In some embodiments, two R's are used 1 The 3-7 membered spirocycloalkyl ring formed by the groups is an optionally substituted 3 membered spirocycloalkyl ring, an optionally substituted 4 membered spirocycloalkyl ring, an optionally substituted 5 membered spirocycloalkyl ring, an optionally substituted 6 membered spirocycloalkyl ring, an optionally substituted 7 membered spirocycloalkyl ring, an optionally substituted spirocyclopropyl ring, an optionally substituted spirocyclobutyl ring, an optionally substituted spirocyclopentyl ring, an optionally substituted spirocyclohexyl ring or an optionally substituted spiroheptyl ring.
In some embodiments, two R's are used 1 The ring formed by the groups is a spiro cyclopropyl ring.
In some embodiments, two R's are used 1 The 3 ring formed by the groups is a spirocyclobutyl ring.
In some embodiments, two R's are used 1 The ring formed by the groups is a spirocyclopentyl ring.
In some embodiments, two R's are used 1 The ring formed by the groups is a spirocyclohexyl ring.
In some embodiments, two R's are used 1 The ring formed by the groups is a spiro heptyl ring.
In other aspects of the compounds of formula (I), two R's attached to the same carbon atom 1 The radicals together with the carbon atoms to which they are both attached form an optional groupSubstituted 3-7 membered spiroheterocycloalkyl ring. In some embodiments, two R's are used 1 The 3-7 membered spiroheterocycloalkyl ring formed by the groups is an optionally substituted 3-membered spiroheterocycloalkyl ring, an optionally substituted 4-membered spiroheterocycloalkyl ring, an optionally substituted 5-membered spiroheterocycloalkyl ring, an optionally substituted 6-membered spiroheterocycloalkyl ring, an optionally substituted 7-membered spiroheterocycloalkyl ring, an optionally substituted spiroaziridinyl ring, an optionally substituted spiroazetidinyl ring, an optionally substituted spiropyrrolidinyl ring, an optionally substituted spiropiperidinyl ring, an optionally substituted spiroazepanyl ring, an optionally substituted spirocyclic oxiranyl ring, an optionally substituted spirooxetanyl ring, an optionally substituted spirotetrahydrofuranyl ring, an optionally substituted spirotetrahydropyranyl ring, an optionally substituted spirooxaheptyl ring, or the like.
In some aspects of the compounds of formula (I), two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o).
In some aspects of the compounds of formula (I), two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
In some aspects of the compounds of formula (I), two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring. In some embodiments, two R's are used 2 The 3-7 membered spirocycloalkyl ring formed by the groups is an optionally substituted 3 membered spirocycloalkyl ring, an optionally substituted 4 membered spirocycloalkyl ring, an optionally substituted 5 membered spirocycloalkyl ring, an optionally substituted 6 membered spirocycloalkyl ring, an optionally substituted 7 membered spirocycloalkyl ring, an optionally substituted spirocyclopropyl ring, an optionally substituted spirocyclobutyl ring, an optionally substituted spirocyclopentyl ring, an optionally substituted spirocyclohexyl ring or an optionally substituted spiroheptyl ring.
In some embodiments, two R's are used 2 The ring formed by the groups is a spiro cyclopropyl ring.
In some embodiments, two R's are used 2 The ring formed by the groups is a spirocyclobutyl ring.
In some embodiments, two R's are used 2 The ring formed by the groups is a spirocyclopentyl ring.
In some embodiments, two R's are used 2 The ring formed by the groups is a spirocyclohexyl ring.
In some embodiments, two R's are used 2 The spirocycloalkyl ring formed by the groups is a spiroheptyl ring.
In other aspects of the compounds of formula (I), two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spiroheterocycloalkyl ring. In some embodiments, two R's are used 2 The 3-7 membered spiroheterocycloalkyl ring formed by the groups is an optionally substituted 3-membered spiroheterocycloalkyl ring, an optionally substituted 4-membered spiroheterocycloalkyl ring, an optionally substituted 5-membered spiroheterocycloalkyl ring, an optionally substituted 6-membered spiroheterocycloalkyl ring, an optionally substituted 7-membered spiroheterocycloalkyl ring, an optionally substituted spiroaziridinyl ring, an optionally substituted spiroazetidinyl ring, an optionally substituted spiropyrrolidinyl ring, an optionally substituted spiropiperidinyl ring, an optionally substituted spiroazepanyl ring, an optionally substituted spirocyclic oxiranyl ring, an optionally substituted spirooxetanyl ring, an optionally substituted spirotetrahydrofuranyl ring, an optionally substituted spirotetrahydropyranyl ring, an optionally substituted spirooxaheptyl ring, or the like.
In some aspects of the compounds of formula (I), two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o).
In some aspects of the compounds of formula (I), two R's attached to different carbon atoms 1 The groups together with the carbon atoms to which they are attached form an optionally substituted 3-7 membered cycloalkyl ring, e.g., an optionally substituted 3-7 membered cycloalkyl ring, an optionally substituted 3-6 membered cycloalkyl ring, an optionally substituted 3-5 membered cycloalkyl ring, an optionally substituted 3-4 membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropyl ring, an optionally substituted cyclobutyl ring, an optionally substituted cyclopentyl ring, an optionally substitutedA cyclohexyl ring or an optionally substituted cycloheptyl ring.
In some aspects of the compounds of formula (I), two R's attached to different carbon atoms 2 The groups together with the carbon atoms to which they are attached form an optionally substituted 3-7 membered cycloalkyl ring, e.g., an optionally substituted 3-7 membered cycloalkyl ring, an optionally substituted 3-6 membered cycloalkyl ring, an optionally substituted 3-5 membered cycloalkyl ring, an optionally substituted 3-4 membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropyl ring, an optionally substituted cyclobutyl ring, an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, or an optionally substituted cycloheptyl ring.
In some aspects of the compounds of formula (I), R 1 Radicals and R 2 The groups are joined to form a 6-9 membered bridged bicyclic ring, e.g., a 6-9 membered bridged bicyclic ring, a 6-8 membered bridged bicyclic ring, a 6-7 membered bridged bicyclic ring, a 6-membered bridged bicyclic ring, a 7-membered bridged bicyclic ring, an 8-membered bridged bicyclic ring, a 9-membered bridged bicyclic ring.
In some aspects, a in the compound of formula (I) is N or CH.
In some embodiments of the compounds of formula (I), a is N.
In some embodiments of the compounds of formula (I), a is CH.
In some aspects of the disclosure, Z in the compounds of formula (I) is S (O) 2 ；S(O)；O、NR 3 Or CR (CR) 4 R 4’ 。
In some embodiments of the compounds of formula (I), Z is S (O) 2 。
In some embodiments of the compounds of formula (I), Z is S (O).
In some embodiments of the compounds of formula (I), Z is O.
In some embodiments of the compounds of formula (I), Z is NR 3 。
In some embodiments of the compounds of formula (I), Z is CR 4 R 4’ 。
In the present disclosureIn some aspects, R in a compound of formula (I) 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b The method comprises the steps of carrying out a first treatment on the surface of the Or R is 3 And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
In some aspects of the disclosure, R in the compounds of formula (I) 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b 。
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 Is H.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 Is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 Is a 3-5 membered cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, etc. In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 Is a 3-5 membered substituted cycloalkyl group, for example, substituted cyclopropyl, cyclobutyl, cyclopentyl, etc.
In some embodiments, R 3 Is cyclobutyl. In some embodiments, R 3 Is a substituted cyclobutyl.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 Is a 3-5 membered heterocycloalkyl. In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 Is a 3-5 membered substituted heterocycloalkyl.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 is-C (O) NR a R b 。
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 is-C (O) OR c 。
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 is-C (O) R c 。
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 is-S (O) 2 R c 。
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 is-S (O) 2 NR a R b 。
In some aspects of the invention, R in the compounds of formula (I) a Is H or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) a Is H.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) a Is C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some aspects of the invention, R in the compounds of formula (I) b Is H or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) b Is H.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) b Is C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some aspects of the disclosure, R a And R is b Together with the N atoms to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring, for example, an optionally substituted 3-to 7-membered heterocycloalkyl ring, an optionally substituted 3-to 6-membered heterocycloalkyl ring, an optionally substituted 3-to 5-membered heterocycloalkyl ring, an optionally substituted 3-to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 7-membered heterocycloalkyl ring, an optionally substituted aziridinyl ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, or an optionally substituted azepanyl ring.
In some aspects of the disclosure, R in the compounds of formula (I) c Is optionally substituted C 1 -C 6 Alkyl or cycloalkyl.
In some embodiments of the compounds of formula (I), R c Is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments, R c Is methyl.
In some embodiments, R c Is (dimethylamino) methyl, i.e. -CH 2 N(CH 3 ) 2 。
In some embodiments, R c Is ethyl.
In some embodiments, R c Is (dimethylamino) ethyl, i.e. -CH 2 CH 2 N(CH 3 ) 2 。
In other embodiments of the compounds of formula (I), R c Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
In some embodiments of the compounds of formula (I), R in the compounds of formula (I) 3 And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered heterocycloalkyl ring, e.g., aziridine, azetidine, pyrrolidine, pyrazine, imidazoline, and the like. Thus, in some embodiments of the compounds of formula (I), the substructuresIs, for example,
in some aspects of the disclosure, R in the compounds of formula (I) 4 Is H, -F or optionally substituted C 1 -C 6 An alkyl group.
In some aspects of the disclosure, R in the compounds of formula (I) 4 Is H or optionally substituted C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I), R 4 Is H.
In some embodiments of the compounds of formula (I), R 4 Is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (I), R 4 Is unsubstituted C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like. In some embodiments of the compounds of formula (I), R 4 Is methyl (i.e. -CH) 3 .)。
In some embodiments of the compounds of formula (I), R 4 Is substituted C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I), R 4 is-CH 2 OH。
In some embodiments of the compounds of formula (I), R 4 is-F.
In some aspects of the disclosure, R in the compounds of formula (I) 4’ Is H, -F, -OH, -CN, -NH 2 、-NH(C 1 -C 3 Alkyl), -N (C) 1 -C 3 Alkyl group 2 、-N(C 1 -C 3 Alkyl) -SO 2 (C 1 -C 3 Alkyl), -C 1 -C 6 Haloalkyl, optionally substituted C 1 -C 6 Alkyl, optionally substituted C 1 -C 6 An alkoxy group; or R4 and R 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-membered ringA to 7 membered cycloalkyl ring; or R4 and R 4’ Together with the carbon atoms to which they are both attached, form an oxo group; or R is 4’ And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-to 7-membered cycloalkyl ring.
In some aspects of the disclosure, R in the compounds of formula (I) 4’ Is H, -OH or optionally substituted C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I), R 4’ Is H.
In some embodiments of the compounds of formula (I), R 4’ is-F.
In some embodiments of the compounds of formula (I), R 4’ is-OH.
In some embodiments of the compounds of formula (I), R 4’ is-CN.
In some embodiments of the compounds of formula (I), R 4’ is-NH 2 。
In some embodiments of the compounds of formula (I), R 4’ is-NH (C) 1 -C 3 Alkyl), e.g., -NH (C) 1 Alkyl), -NH (C) 2 Alkyl), -NH (C) 3 Alkyl), -NH (CH) 3 )、-NH-CH(CH 3 ) 2 Etc. In some embodiments of the compounds of formula (I), R 4’ is-NH (CH) 3 ). In some embodiments of the compounds of formula (I), R 4’ is-NH-CH (CH) 3 ) 2 。
In some embodiments of the compounds of formula (I), R 4’ is-N (C) 1 -C 3 Alkyl group 2 For example, -N (C) 1 Alkyl group 2 、-N(C 2 Alkyl group 2 、-N(C 3 Alkyl group 2 、-N(C 1 Alkyl) (C) 2 Alkyl), -N (CH) 3 ) 2 Etc. In some embodiments of the compounds of formula (I), R 4’ is-N (CH) 3 ) 2 。
In some embodiments of the compounds of formula (I), R 4’ is-N (C) 1 -C 3 Alkyl) -SO 2 (C 1 -C 3 Alkyl), e.g., -N (C) 1 Alkyl) -SO 2 (C 1 -C 3 Alkyl), -N (C) 2 Alkyl) -SO 2 (C 1 -C 3 Alkyl), -N (C) 3 Alkyl) -SO 2 (C 1 -C 3 Alkyl), -N (C) 1 -C 3 Alkyl) -SO 2 (C 1 Alkyl), -N (C) 1 -C 3 Alkyl) -SO 2 (C 2 Alkyl), -N (C) 1 -C 3 Alkyl) -SO 2 (C 3 Alkyl), -NH-SO 2 (CH 3 )、-N(CH 3 )-SO 2 (CH 3 ) Etc. In some embodiments of the compounds of formula (I), R 4’ is-N (CH) 3 )-SO 2 (CH 3 )。
In some embodiments of the compounds of formula (I), R 4’ is-C 1 -C 6 Haloalkyl radicals, e.g. -C 1 Haloalkyl, -C 2 Haloalkyl, -C 3 Haloalkyl, -C 4 Haloalkyl, -C 5 Haloalkyl, -C 6 Haloalkyl, -CF 3 、-CH 2 CF 3 、-CHF 2 、-CH 2 CHF 2 Etc.
In some embodiments of the compounds of formula (I), R 4’ Is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (I), R 4’ Is unsubstituted C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like. In some embodiments of the compounds of formula (I), R 4’ Is methyl (i.e. -CH) 3 .)。
In some embodiments of the compounds of formula (I), R 4’ Is substituted C 1 -C 6 Alkyl radicals, e.g. -CH 2 OH、-CH 2 N(CH 3 ) 2 、-C(CH 3 ) 2 -OH、-CH 2 -CN、-CH 2 SO 2 CH 3 or-CH 2 N(CH 3 )SO 2 CH 3 。
In some embodiments of the compounds of formula (I), R 4’ Is optionally substituted C 1 -C 6 Alkoxy groups, e.g. optionally substituted C 1 -C 6 Alkoxy, C 1 -C 5 Alkoxy, C 1 -C 4 Alkoxy, C 1 -C 3 Alkoxy, C 1 -C 2 Alkoxy, C 1 Alkoxy, C 2 Alkoxy, C 3 Alkoxy, C 4 Alkoxy, C 5 Alkoxy, C 6 Alkoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and the like.
In some embodiments of the compounds of formula (I), R 4’ Unsubstituted C 1 -C 6 Alkoxy groups, e.g. C 1 -C 6 Alkoxy, C 1 -C 5 Alkoxy, C 1 -C 4 Alkoxy, C 1 -C 3 Alkoxy, C 1 -C 2 Alkoxy, C 1 Alkoxy, C 2 Alkoxy, C 3 Alkoxy, C 4 Alkoxy, C 5 Alkoxy, C 6 Alkoxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and the like. Some of the compounds of formula (I)In embodiments, R 4’ is-OCH 3 。
In some aspects of the disclosure, R in the compounds of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-to 7-membered cycloalkyl ring, e.g., an optionally substituted 3-to 7-membered heterocycloalkyl ring, an optionally substituted 3-to 6-membered heterocycloalkyl ring, an optionally substituted 3-to 5-membered heterocycloalkyl ring, an optionally substituted 3-to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 7-membered heterocycloalkyl ring, an optionally substituted aziridine ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring, an optionally substituted azepanyl ring, an optionally substituted oxetanyl ring, an optionally substituted tetrahydrofuranyl ring, an optionally substituted tetrahydrothiophene 1, 1-dioxide or an optionally substituted tetrahydro-2H-thiopyran 1, 1-dioxide, or an optionally substituted 3-to 7-membered cycloalkyl ring, an optionally substituted 3-to 6-membered heterocycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted cycloalkyl ring.
In some aspects of the disclosure, R in the compounds of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring, e.g., an optionally substituted 3-to 7-membered heterocycloalkyl ring, an optionally substituted 3-to 6-membered heterocycloalkyl ring, an optionally substituted 3-to 5-membered heterocycloalkyl ring, an optionally substituted 3-to 4-membered heterocycloalkyl ring, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, an optionally substituted 3-to 5-membered heterocycloalkyl ring,An optionally substituted 7 membered heterocycloalkyl ring, an optionally substituted aziridinyl ring, an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, an optionally substituted piperidinyl ring or an optionally substituted azepanyl ring.
In embodiments of the present disclosure, R in the compounds of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 3-to 7-membered cycloalkyl ring, for example, an optionally substituted 3-to 7-membered cycloalkyl ring, an optionally substituted 3-to 6-membered cycloalkyl ring, an optionally substituted 3-to 5-membered cycloalkyl ring, an optionally substituted 3-to 4-membered cycloalkyl ring, an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted 7-membered cycloalkyl ring, an optionally substituted cyclopropyl ring, an optionally substituted cyclobutyl ring, an optionally substituted cyclopentyl ring, an optionally substituted cyclohexyl ring, or an optionally substituted cycloheptyl ring.
In some embodiments, R in the compound of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 4-membered cycloalkyl ring or an optionally substituted 5-membered cycloalkyl ring.
In some embodiments, R in the compound of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted cyclobutyl ring or an optionally cyclopentyl ring.
In some embodiments, R in the compound of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached form a hydroxy-substituted cyclopentyl ring, for example,
in other embodiments, R in the compound of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached, form a methoxy-substituted cyclobutyl ring, e.g.,
in some embodiments of formula (I), R 4’ And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-to 7-membered cycloalkyl ring.
In some embodiments of formula (I), R 4’ And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
In other embodiments of formula (I), R 4’ And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered cycloalkyl ring, e.g., an optionally substituted 3-membered cycloalkyl ring, an optionally substituted 4-membered cycloalkyl ring, an optionally substituted 5-membered cycloalkyl ring, an optionally substituted 6-membered cycloalkyl ring, an optionally substituted fused 7-membered cycloalkyl ring, a cyclopropyl ring, and the like.
In some embodiments, wherein R 4’ And R is R 1 Or R is 2 Together form an optionally substituted cyclopropyl ring, and thus, in some embodiments of the compounds of formula (I), the substructureIs, for example,/->
In some aspects of the disclosure, R in the compounds of formula (I) 4 And R is 4’ Together with the carbon atoms to which they are both attached form oxo groups, i.e
In some aspects of the invention, Y in the compounds of formula (I) is a 5-or 6-membered heteroaryl ring or a 6-membered aryl ring.
In some aspects of the disclosure, Y in the compounds of formula (I) is a 5-or 6-membered heteroaryl ring. In some aspects of the disclosure, Y in the compounds of formula (I) is a substituted 5-or 6-membered heteroaryl ring.
In some embodiments, Y in the compound of formula (I) is a 5-membered heteroaryl ring, e.g., furan, pyrrole, thiophene, isoxazole, oxazole, pyrazole, imidazole, isothiazole, thiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,2, 5-thiadiazole, 1,3, 4-thiadiazole, 1,2,3, 5-thiadiazole, 1,3, 4-oxadiazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, 1,2,3, 5-oxatriazole, 2H-1,2, 3-triazole, 1H-1,2, 4-triazole, 1H-1,2, 3-triazole, 4H-1,2, 4-triazole, 2H-tetrazole, 1H-tetrazole, and the like.
In some embodiments, Y in the compound of formula (I) is a substituted 5-membered heteroaryl ring, e.g., substituted furan, pyrrole, thiophene, isoxazole, oxazole, pyrazole, imidazole, isothiazole, thiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,2, 5-thiadiazole, 1,3, 4-thiadiazole, 1,2,3, 5-thiadiazole, 1,3, 4-oxadiazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, 1,2,3, 5-oxadiazole, 2H-1,2, 3-triazole, 1H-1,2, 4-triazole, 1H-1,2, 3-triazole, 4H-1,2, 4-triazole, 2H-tetrazole, 1H-tetrazole, and the like.
In some embodiments, Y in the compound of formula (I) is a 6 membered heteroaryl ring, e.g., pyridine, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, 1,3, 5-triazine, 1,2,3, 4-tetrazine, 1,2,3, 5-tetrazine, 1,2,4, 5-tetrazine, and the like. In some embodiments, Y in the compound of formula (I) is a substituted 6 membered heteroaryl ring, e.g., substituted pyridine, pyridazine, pyrimidine, pyrazine, 1,2, 3-triazine, 1,2, 4-triazine, 1,3, 5-triazine, 1,2,3, 4-tetrazine, 1,2,3, 5-tetrazine, 1,2,4, 5-tetrazine, and the like.
In some embodiments of the compounds of formula (I), Y is a 6 membered aryl ring. In some embodiments, Y is a substituted 6 membered aryl ring. In some embodiments, Y is a phenyl ring. In some embodiments, Y is a substituted phenyl ring.
In some embodiments, Y is
In some aspects of the disclosure, Q in the compounds of formula (I) 5 、Q 6 、Q 7 、Q 8 And Q 9 Each independently is N or CR 5 Wherein Q is 5 、Q 6 、Q 7 、Q 8 And Q 9 One or two of which are N and the others are each independently CR 5 。
In some embodiments, Q 5 、Q 6 、Q 7 、Q 8 Or Q 9 One of them is N and the others are each independently CR 5 。
In some embodiments, Q 5 Is N and Q 6 、Q 7 、Q 8 And Q 9 Each independently is CR 5 。
In some embodiments, Q 6 Is N and Q 5 、Q 7 、Q 8 And Q 9 Each independently is CR 5 。
In some embodiments, Q 7 Is N and Q 5 、Q 6 、Q 8 And Q 9 Each independently is CR 5 。
In some embodiments, Q 8 Is N and Q 5 、Q 6 、Q 7 And Q 9 Each independently is CR 5 。
In some embodiments, Q 9 Is N and Q 5 、Q 6 、Q 7 And Q 8 Each independently is CR 5 。
In other embodiments, Q 5 、Q 6 、Q 7 、Q 8 Or Q 9 Two of which are N and the others are each independently CR 5 。
In some embodiments, Q 5 And Q 6 Is N and Q 7 、Q 8 And Q 9 Each independently is CR 5 。
In some embodiments, Q 5 And Q 7 Is N and Q 6 、Q 8 And Q 9 Each independently is CR 5 。
In some embodiments, Q 5 And Q 8 Is N and Q 6 、Q 7 And Q 9 Each independently is CR 5 。
In some implementationsIn embodiments, Q 5 And Q 9 Is N and Q 6 、Q 7 And Q 8 Each independently is CR 5 。
In some embodiments, Q 6 And Q 7 Is N and Q 5 、Q 8 And Q 9 Each independently is CR 5 。
In some embodiments, Q 6 And Q 8 Is N and Q 5 、Q 7 And Q 9 Each independently is CR 5 。
In some embodiments, Q 6 And Q 9 Is N and Q 5 、Q 7 And Q 8 Each independently is CR 5 。
In some embodiments, Q 7 And Q 8 Is N and Q 5 、Q 6 And Q 9 Each independently is CR 5 。
In some embodiments, Q 7 And Q 9 Is N and Q 5 、Q 6 And Q 8 Each independently is CR 5 。
In some embodiments, Q 8 And Q 9 Is N and Q 5 、Q 6 And Q 7 Each independently is CR 5 。
In some aspects of the disclosure, each R in the compounds of formula (I) 5 Independently H, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy or cycloalkyl. In some aspects of the disclosure, each R in the compounds of formula (I) 5 Independently H, halogen, substituted C 1 -C 3 Alkyl, substituted C 1 -C 3 Alkoxy or substituted cycloalkyl.
In some embodiments of the compounds of formula (I), R 5 Is H.
In some embodiments of the compounds of formula (I), R 5 Halogen, for example, -F, -Cl, -Br or-I.
In some embodiments, at least one R 5 is-Cl.
In some embodiments of the compounds of formula (I), R 5 Is C 1 -C 3 Alkyl radicals, e.g. C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, -CH 3 、-CH 2 CH 3 -propyl, etc.
In some embodiments, R 5 is-CH 3 。
In some embodiments of the compounds of formula (I), R 5 Is C 1 -C 3 Alkoxy groups, e.g. C 1 -C 3 Alkoxy, C 1 -C 2 Alkoxy, C 1 Alkoxy, C 2 Alkoxy, C 3 Alkoxy, -OCH 3 、-OCH 2 CH 3 -propoxy, and the like. In some embodiments, R 5 is-OCH 3 。
In some embodiments of the compounds of formula (I), R 5 Cycloalkyl, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
In some embodiments of the compounds of formula (I), two R 5 Is halogen, and the rest R 5 Is H.
In other embodiments of the compounds of formula (I), two R 5 is-Cl, and the rest of R 5 Is H.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 And Q 8 Each independently is CR 5 Wherein R is 5 Is H; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 、Q 8 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 And Q 8 Each independently is CR 5 Wherein R is 5 Is H; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-F; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is CR (CR) 5 Wherein R is 5 Is C 1 -C 3 An alkyl group; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is CR (CR) 5 Wherein R is 5 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogenA hormone; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is N; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is N; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is C 1 -C 3 An alkyl group; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is N; and Q is 7 Is N.
In some embodiments of the compounds of formula (I), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-CH 3 ；Q 6 Is CR (CR) 5 Wherein R is 5 Is H and Q 8 Is N; and Q is 7 Is N.
In some aspects of the disclosure, X in the compounds of formula (I) is O, S or NR, wherein R is H or C 1 -C 3 An alkyl group.
In some embodiments of the compounds of formula (I), X is O.
In some embodiments of the compounds of formula (I), X is S.
In some embodiments of the compounds of formula (I), X is NR, wherein R is H or C 1 -C 3 An alkyl group.
In some embodiments of the compounds of formula (I), X is NR, wherein R is H, i.e., X is NH.
In some embodiments of the compounds of formula (I), X is NR, wherein R is C 1 -C 3 Alkyl radicals, i.e. -N (C) 1 -C 3 Alkyl) -, e.g., -N (C) 1 -C 3 Alkyl) -, N (C) 1 -C 2 Alkyl) -, N (C) 1 Alkyl) -, N (C) 2 Alkyl) -, N (C) 3 Alkyl) -, N (CH) 3 )-、-N(CH 2 CH 3 )-、-N(CH 2 CH 2 CH 3 ) -and the like.
In some aspects of the disclosure, R in the compounds of formula (I) 6 Is C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of the present disclosure, R 6 is-CH 3 。
In some aspects, R in the compound of formula (I) 7 Is H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or-cycloalkyl.
In some embodiments, R in the compound of formula (I) 7 Is H.
In some embodiments, R in the compound of formula (I) 7 Halogen, for example, -F, -Cl, -Br or-I.
In some embodiments, R in the compound of formula (I) 7 is-F.
In other embodiments, R in the compound of formula (I) 7 is-Cl.
In some embodiments, R in the compound of formula (I) 7 is-C 1 -C 6 Alkyl groups, such as substituted or unsubstituted: c (C) 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like. In some embodiments, R 7 is-CH 3 。
In some embodiments, R in the compound of formula (I) 7 is-C 1 -C 6 Alkoxy radicals, e.g. -C 1 -C 6 Alkoxy, -C 1 -C 5 Alkoxy, -C 1 -C 4 Alkoxy, -C 1 -C 3 Alkoxy, -C 1 -C 2 Alkoxy, -C 1 Alkoxy, -C 2 Alkoxy, -C 3 Alkoxy, -C 4 Alkoxy, -C 5 Alkoxy, -C 6 Alkoxy, -OCH 3 、-OCH 2 CH 3 -propoxy, and the like. In some embodiments, R 7 is-OCH 3 。
In some embodiments, R in the compound of formula (I) 7 Is-cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
In some aspects, R 8 Is H, halogen, -C 1 -C 6 Alkyl, -C 1 -C 6 Alkoxy or-cycloalkyl.
In some embodiments, R in the compound of formula (I) 8 Is H.
In some embodiments, R in the compound of formula (I) 8 Halogen, for example, -F, -Cl, -Br or-I.
In some embodiments, R in the compound of formula (I) 8 is-C 1 -C 6 Alkyl groups, for example, substituted or unsubstituted: c (C) 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like. In some embodiments, R 8 is-CH 3 。
In some embodiments, R in the compound of formula (I) 8 is-C 1 -C 6 Alkoxy radicals, e.g.，-C 1 -C 6 Alkoxy, -C 1 -C 5 Alkoxy, -C 1 -C 4 Alkoxy, -C 1 -C 3 Alkoxy, -C 1 -C 2 Alkoxy, -C 1 Alkoxy, -C 2 Alkoxy, -C 3 Alkoxy, -C 4 Alkoxy, -C 5 Alkoxy, -C 6 Alkoxy, -OCH 3 、-OCH 2 CH 3 -propoxy, and the like. In some embodiments, R 8 is-OCH 3 。
In some embodiments, R in the compound of formula (I) 8 Is-cycloalkyl, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.
In some embodiments of the compounds of formula (I), R 7 is-F and R 8 Is H.
In some embodiments of the compounds of formula (I), R 7 is-Cl and R 8 Is H.
In some embodiments of the compounds of formula (I), R 7 is-CH 3 And R is 8 Is H.
In some embodiments of the compounds of formula (I), R 7 is-OCH 3 And R is 8 Is H.
In some embodiments of the compounds of formula (I), R 7 is-H and R 8 is-F.
In some embodiments of the compounds of formula (I), R 7 is-H and R 8 is-Cl.
In some embodiments of the compounds of formula (I), R 7 is-H and R 8 is-CH 3 。
In some embodiments of the compounds of formula (I), R 7 is-H and R 8 Is OCH 3 。
In some aspects of the disclosure, the compound of formula (I) is a compound of formula (IA):
wherein Q is 1 、Q 2 、Q 3 、Q 4 One or two of which are each N and the others are each independently CR 5a Wherein each R is 5a Independently H, halogen, -CN, -C 1 -C 3 Alkyl, -C 1 -C 3 Haloalkyl, -C 1 -C 3 Alkoxy, -SO 2 C 1 -C 3 Alkyl, -CH 2 -OH、-CH 2 -N(C 1 -C 3 Alkyl group 2 or-CH 2 -NH(C 1 -C 3 Alkyl), and the other variables are as described for formula (I).
In some aspects of the disclosure, the compound of formula (I) is a compound of formula (IA), wherein R 5a Can be-P (O) (C) 1 -C 6 Alkyl group 2 For example, -P (O) (CH 3 ) 2 。
In some aspects of the disclosure, the compound of formula (I) is a compound of formula (IA), wherein each R 5a Independently H, halogen, -CN or C 1 -C 3 An alkyl group.
In some embodiments, Q 1 、Q 2 、Q 3 、Q 4 One of them is N and the others are each independently CR 5a 。
In some embodiments, Q 1 Is N and Q 2 、Q 3 And Q 4 Each independently is CR 5a 。
In some embodiments, Q 2 Is N and Q 1 、Q 3 And Q 4 Each independently is CR 5a 。
In some embodiments, Q 3 Is N and Q 1 、Q 2 And Q 4 Each independently is CR 5a 。
In some embodiments, Q 4 Is N and Q 1 、Q 2 And Q 3 Each independently is CR 5a 。
In other embodiments, Q 1 、Q 2 、Q 3 、Q 4 Two of which are N, whichThe remainder being each independently CR 5a 。
In some embodiments, Q 1 And Q 2 Is N and Q 3 And Q 4 Each independently is CR 5a 。
In some embodiments, Q 1 And Q 3 Is N and Q 2 And Q 4 Each independently is CR 5a 。
In some embodiments, Q 1 And Q 4 Is N and Q 2 And Q 3 Each independently is CR 5a 。
In some embodiments, Q 2 And Q 3 Is N and Q 1 And Q 4 Each independently is CR 5a 。
In some embodiments, Q 2 And Q 4 Is N and Q 1 And Q 3 Each independently is CR 5a 。
In some embodiments, Q 3 And Q 4 Is N and Q 1 And Q 2 Each independently is CR 5a 。
In some aspects of the compounds of formula (IA), each R 5a Independently H, halogen, -CN or C 1 -C 3 An alkyl group.
In other aspects of the compounds of formula (IA), each R 5a Is H, halogen, -CN, C 1 -C 3 Alkyl, -C 1 -C 3 Haloalkyl, -C 1 -C 3 Alkoxy, -SO 2 C 1 -C 3 Alkyl, -CH 2 -N(C 1 -C 3 Alkyl group 2 or-CH 2 -NH(C 1 -C 3 Alkyl).
In some embodiments of the compounds of formula (IA), R 5a Is H.
In some embodiments of the compounds of formula (IA), R 5a Halogen, i.e., -F, -Cl, -Br or-I.
In some embodiments of the compounds of formula (IA), at least one R 5a is-F.
Compounds of formula (IA)In some embodiments of the compounds, R 5a is-CN.
In some embodiments of the compounds of formula (IA), R 5a Is C 1 -C 3 Alkyl radicals, e.g. C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, -CH 3 、-CH 2 CH 3 -propyl, etc. In some embodiments, R 5a is-CH 3 。
In some embodiments of the compounds of formula (IA), R 5a Is C 1 -C 3 Haloalkyl radicals, e.g. C 1 -C 3 Haloalkyl, C 1 -C 2 Haloalkyl, C 1 Haloalkyl, C 2 Haloalkyl, C 3 Haloalkyl, -CF 3 、-CH 2 CF 3 Etc. In some embodiments, R 5a is-CF 3 。
In some embodiments of the compounds of formula (IA), R 5a is-C 1 -C 3 Alkoxy radicals, e.g. -C 3 Alkoxy, -C 2 Alkoxy or-C 1 Alkoxy, -OCH 2 CH 3 、-OCH 3 Etc. In some embodiments, R 5a is-OCH 3 。
In some embodiments of the compounds of formula (IA), R 5a is-SO 2 C 1 -C 3 Alkyl radicals, e.g. -SO 2 C 1 Alkyl, -SO 2 C 2 Alkyl, -SO 2 C 3 Alkyl, -SO 2 CH 2 CH 3 、-SO 2 CH 3 Etc. In some embodiments, R 5a is-SO 2 CH 3 。
In some embodiments of the compounds of formula (IA), R 5a is-CH 2 -N(C 1 -C 3 Alkyl group 2 For example, -CH 2 -N(C 3 Alkyl group 2 、-CH 2 -N(C 2 Alkyl group 2 、-CH 2 -N(C 1 Alkyl group 2 、-CH 2 -N(C 3 Alkyl group)(C 1 Alkyl), -CH 2 -N(C 2 Alkyl) (C) 1 Alkyl), -CH 2 -N(C 3 Alkyl) (C) 2 Alkyl), -CH 2 -N(CH 3 ) 2 Etc. In some embodiments, R 5a is-CH 2 -N(CH 3 ) 2 。
In some embodiments of the compounds of formula (IA), R 5a is-CH 2 -NH(C 1 -C 3 Alkyl), e.g., -CH 2 -NH(C 3 Alkyl), -CH 2 -NH(C 2 Alkyl), -CH 2 -NH(C 1 Alkyl), -CH 2 -NH(CH 3 ) Etc. In some embodiments, R 5a is-CH 2 -NH(CH 3 )。
In some embodiments of the compounds of formula (IA), X is O.
In some aspects of the present disclosure, the compound of formula (IA) is a compound of formula (IA-1):
wherein the variables have values represented by formulas (I) and (IA) above.
In some embodiments of the compounds of formula (IA-1), R 6 is-CH 3 。
In some embodiments of the compounds of formula (IA-1), Q 3 Is CR (CR) 5a 。
In some embodiments of the compounds of formula (IA-1), at least one R 5a Is halogen. In some embodiments of the compounds of formula (IA-1), at least one R 5a is-F.
In some aspects of the present disclosure, the compound of formula (IA) is a compound of formula (IA-2):
wherein the variables have values represented by formulas (I) and (IA) above.
In some aspects of the compounds of formula (IA-2), n is 2 and m is 2.
In some aspects of the compounds of formula (IA-2), n is 1 and m is 1.
In some aspects of the compounds of formula (IA-2), n is 1 and m is 2.
In some aspects of the compounds of formula (IA-2), n is 3 and m is 2.
In some aspects of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-3):
wherein the variable has a value represented by the above formula (IA-2).
In some embodiments of the compounds of formula (IA-3), each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (IA-3), each R 1 And each R 2 Is H.
In some embodiments of the compounds of formula (IA-3), each R 1 And each R 2 Independently optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (IA-3), at least one R 1 Is H, and at least one R 2 Is optionally substituted C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (IA-3), at least one R 1 Is optionally substituted C 1 -C 6 Alkyl, and at least one R 2 Is H.
In some embodiments of the compounds of formula (IA-3), each R 1 Is H, and one R 2 Is optionally substituted C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (IA-3), one R 1 Is optionally substituted C 1 -C 6 Alkyl, and each R 2 Is H.
In some embodiments of the compounds of formula (IA-3), each R 1 Is H, and two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-7 membered spirocycloalkyl ring, for example, a 3-membered spirocycloalkyl ring, a 4-membered spirocycloalkyl ring, a 5-membered spirocycloalkyl ring, a 6-membered spirocycloalkyl ring, a 7-membered spirocycloalkyl ring, a spiropropyl ring, a spirobutyl ring, a spiropentyl ring, a spirohexyl ring or a spiroheptyl ring.
In some embodiments of the compounds of formula (IA-3), each R 1 Is H, and two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-membered spirocycloalkyl ring, e.g., a spirocyclopropyl ring.
In some embodiments of the compounds of formula (IA-3), one R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H. In such embodiments, the 6-9 membered bridged bicyclic ring is a 6 membered bridged bicyclic ring, a 7 membered bridged bicyclic ring, an 8 membered bridged bicyclic ring, or a 9 membered bridged bicyclic ring. In some embodiments, the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
In some embodiments of the compounds of formula (IA-3), each R 1 Is H, and two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o).
In some aspects of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-4):
wherein the variable has a value represented by the above formula (IA-2).
In some embodiments of the compounds of formula (IA-4), two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o).
In some aspects of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-5):
wherein the variable has a value represented by the above formula (IA-2).
In some embodiments of the compounds of formula (IA-5), each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (IA-5), each R 1 And each R 2 Is H.
In some embodiments of the compounds of formula (IA-5), each R 1 And two R2 groups attached to the same carbon atom together with the carbon atom to which they are both attached form a 3-7 membered spirocycloalkyl ring, for example, a 3-membered spirocycloalkyl ring, a 4-membered spirocycloalkyl ring, a 5-membered spirocycloalkyl ring, a 6-membered spirocycloalkyl ring, a 7-membered spirocycloalkyl ring, a spirocyclopropyl ring, a spirocyclobutyl ring, a spirocyclopentyl ring, a spirocyclohexyl ring, or a spiroheptyl ring.
In some embodiments of the compounds of formula (IA-5), the 3-7 membered spirocycloalkyl ring is a 3 membered spirocycloalkyl ring.
In some embodiments of the compounds of formula (IA-5), one R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H. In such embodiments, the 6-9 membered bridged bicyclic ring is a 6 membered bridged bicyclic ring, a 7 membered bridged bicyclic ring, an 8 membered bridged bicyclic ring, or a 9 membered bridged bicyclic ring. In some embodiments, the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
In some aspects of the disclosure, the compound of formula (I) is a compound of formula (IA-8):
wherein R is 9 is-C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C (O) C 1 -C 6 Haloalkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 Alkyl and other variables have values as shown in formula (I) above.
In some embodiments of the compounds of formula (IA-8), R 9 is-CH 2 CF 3 、-CH 2 CHF 2 、-C(O)CF 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、-SO 2 CH 2 CH 3 、-SO 2 CH(CH 3 ) 2 、-CH 3 、-CH(CH 3 ) 2 、-C(O)N(CH 3 ) 2 or-SO 2 CH 3 。
In some embodiments of the compounds of formula (IA-8), R 7 And R is 8 Each is H.
In some embodiments of the compounds of formula (IA-8), each R 1 And each R 2 Is H.
In some embodiments of the compounds of formula (IA-8), Q 1 、Q 2 、Q 3 、Q 4 In (a) and (b)One is N and the others are each independently CR 5a 。
In some embodiments of the compounds of formula (IA-8), Q 4 Is N and Q 1 、Q 2 、Q 3 Each independently is CR 5a 。
In other embodiments of the compounds of formula (IA-8), Q 1 、Q 2 、Q 3 、Q 4 Two of which are N and the others are each independently CR 5a 。
In other embodiments of the compounds of formula (IA-8), Q 2 And Q 4 Is N and Q 1 And Q 3 Each independently is CR 5a 。
In some embodiments of the compounds of formula (IA-8), Q 5 、Q 6 、Q 7 、Q 8 Or Q 9 One of them is N and the others are each independently CR 5 。
In some embodiments of the compounds of formula (IA-8), Q 7 Is N and Q 5 、Q 6 、Q 8 And Q 9 Each independently is CR 5 。
In some embodiments of the compounds of formula (IA-8), Q 5 、Q 6 、Q 7 、Q 8 Or Q 9 Two of which are N and the others are each independently CR 5 。
In some embodiments, Q 6 And Q 7 Is N and Q 5 、Q 8 And Q 9 Each independently is CR 5 。
In some aspects of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-6):
wherein the variable has a value represented by the above formula (IA-2).
In some embodiments of the compounds of formula (IA-6), two R's attached to the same carbon atom 1 Radicals and the carbon atomsTogether represent a carbonyl group (c=o).
In some embodiments of the compounds of formula (IA-6), two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
In some embodiments of the compounds of formula (IA-6), two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spiroheterocycloalkyl ring, e.g., an optionally substituted 3-membered spiroheterocycloalkyl ring, an optionally substituted 4-membered spiroheterocycloalkyl ring, an optionally substituted 5-membered spiroheterocycloalkyl ring, an optionally substituted 6-membered spiroheterocycloalkyl ring, an optionally substituted 7-membered spiroheterocycloalkyl ring, an optionally substituted spiroaziridinyl ring, an optionally substituted spiroazetidinyl ring, an optionally substituted spiropyrrolidinyl ring, an optionally substituted spiropiperidinyl ring, an optionally substituted spiroazepanyl ring, an optionally substituted spirooxiranyl ring, an optionally substituted spirooxetanyl ring, an optionally substituted spirotetrahydrofuran ring, an optionally substituted spirotetrahydropyran ring, an optionally substituted spirooxetanyl ring, and the like.
In some embodiments of the compounds of formula (IA-6), the optionally substituted 3-7 membered spiroheterocycloalkyl ring is an optionally substituted spiroazetidinyl ring (spiroazetidinyl), an optionally substituted spiropyrrolidinyl ring, or an optionally substituted spiropiperidinyl ring.
In some embodiments of the compounds of formula (IA-6), the optionally substituted 3-7 membered spiroheterocycloalkyl ring is a spiroazetidine ring, a spiropyrrolidinyl ring, a spiropiperidinyl ring, an N-methyl spiropiperidinyl ring, or an N- (methylsulfonyl) spiropiperidinyl ring.
In some aspects of the present disclosure, the compound of formula (IA-2) is a compound of formula (IA-7):
wherein the variable has a value represented by the above formula (IA-2).
In formula (IA-7)In some embodiments of the compounds, each R 1 Is H.
In some embodiments of the compounds of formula (IA-7), two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o).
In some embodiments of the compounds of formula (IA-7), each R 2 Is H.
In some embodiments of the compounds of formula (IA-7), two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o).
In some aspects of the disclosure, compounds of formula (IA) (and subclasses IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7) are wherein Q 2 Those compounds that are N. In other aspects of the disclosure, compounds of formula (IA) (and subclasses IA-8) are wherein Q 2 Those compounds that are N.
In some aspects of the disclosure, compounds of formula (IA) (and subclasses IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7) are wherein Q 4 Those compounds that are N. In other aspects of the disclosure, compounds of formula (IA) (and subclasses IA-8) are wherein Q 4 Those compounds that are N.
In some aspects of the disclosure, the compound of formula (IA) is wherein Q 2 And Q 4 Those compounds each of which is N.
In some aspects of the disclosure, the compound of formula (IA) is wherein Q 4 Is CR (CR) 5a Those of (3).
In some embodiments, wherein Q 4 Is CR (CR) 5a ，CR 5a Is H.
In which Q is 4 Is CR (CR) 5a In some embodiments of CR 5a Is halogen.
In which Q is 4 Is CR (CR) 5a In some embodiments of CR 5a is-F.
In some embodiments of the compounds of formula (IA), Q 2 Is N and Q 4 Is CR (CR) 5a Wherein CR is 5a is-F.
In some aspects of the disclosure, the compound of formula (I) is a compound of formula (IB):
wherein the variables have values shown in formula (I) above.
In some aspects of the present disclosure, the compound of formula (IB) is a compound of formula (IB-1):
wherein the variables have values shown in formula (I) above.
In some aspects of the present disclosure, the compound of formula (IB-1) is a compound of formula (IB-2):
wherein the variables have values shown in formula (I) above.
In some embodiments of the compounds of formulas (IB), (IB-1) and (IB-2), n=2 and m=2.
In other embodiments of the compounds of formulas (IB), (IB-1) and (IB-2), n=1 and m=1.
In some embodiments of the compounds of formulas (IB), (IB-1) and (IB-2), n=1 and m=2.
In other embodiments of the compounds of formulas (IB), (IB-1) and (IB-2), n=3 and m=2.
In some embodiments of the compounds of formulas (IB), (IB-1) and (IB-2), each R 1 Is H, and each R 2 Is H.
In some aspects, a in the compound of formula (I) is N or CH.
In some embodiments of the compounds of formula (I), a is N.
In some embodiments of the compounds of formula (I), a is CH.
In some aspects, Z in the compound of formula (I) is S (O) 2 ；S(O)；O；NR 3 The method comprises the steps of carrying out a first treatment on the surface of the Or CR (CR) 4 R 4’ 。
In some embodiments of the compounds of formula (I), Z is S (O) 2 。
In some embodiments of the compounds of formula (I), Z is S (O).
In some embodiments of the compounds of formula (I), Z is O.
In some embodiments of the compounds of formula (I), Z is NR 3 。
In which Z is NR 3 In some embodiments of the compounds of formula (I), R 3 Is H.
In which Z is NR 3 In other embodiments of the compounds of formula (I), R 3 is-C (O) NR a R b 。
In which Z is NR 3 In other embodiments of the compounds of formula (I), R 3 is-S (O) 2 NR a R b 。
Wherein R is 3 is-C (O) NR a R b or-S (O) 2 NR a R b In some embodiments of the compounds of formula (I), R a Is H and R b Is H.
In some embodiments of the compounds of formula (I), R 3 is-C (O) NH 2 。
Wherein R is 3 is-C (O) NR a R b or-S (O) 2 NR a R b In some embodiments of the compounds of formula (I), R a Is H and R b Is C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
Wherein R is 3 is-C (O) NR a R b or-S (O) 2 NR a R b In some embodiments of the compounds of formula (I), R a Is C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like; and R is b Is C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (I), R 3 is-C (O) N (CH) 3 ) 2 。
Wherein R is 3 is-C (O) NR a R b or-S (O) 2 NR a R b In some embodiments of the compounds of formula (I), R a And R is b The N atoms to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring, for example, an optionally substituted 3-membered heterocycloalkyl, an optionally substituted 4-membered heterocycloalkyl, an optionally substituted 5-membered heterocycloalkyl, an optionally substituted 6-membered heterocycloalkyl, or an optionally substituted 7-membered heterocycloalkyl.
In some embodiments of the compounds of formula (I), the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted piperidinyl, optionally substituted piperazinyl, or optionally substituted morpholinyl ring.
In some embodiments of the compounds of formula (I), the optionally substituted 3-to 7-membered heterocycloalkyl ring is a 4-methylpiperazin-1-yl or morpholinyl ring.
Wherein R is 3 is-C (O) NR a R b In some embodiments of the compounds of formula (I), R 3 Is that
Wherein R is 3 is-S (O) 2 NR a R b In some embodiments of the compounds of formula (I), R 3 Is that
In which Z is NR 3 In some embodiments of the compounds of formula (I), R 3 is-C (O) OR c 。
In which Z is NR 3 In some embodiments of the compounds of formula (I), R 3 is-C (O) R c 。
In which Z is NR 3 In some embodiments of the compounds of formula (I), R 3 is-S (O) 2 R c 。
In which Z is NR 3 And R is 3 is-C (O) OR c 、-C(O)R c or-S (O) 2 R c In some embodiments of the compounds of formula (I), R c Is optionally substituted C 1 -C 6 Alkyl or 3-7 membered cycloalkyl.
In some embodiments of the compounds of formula (I), R c Is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl,N-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (I), R c Is methyl, i.e. -CH 3 。
In some embodiments of the compounds of formula (I), R c Is (C) 1 -C 6 Alkyl group 2 N-methyl, i.e. -CH 2 N(C 1 -C 6 Alkyl group 2 。
In some embodiments of the compounds of formula (I), R c Is (dimethylamino) methyl, i.e. -CH 2 N(CH 3 ) 2 。
In some embodiments of the compounds of formula (I), R c Is ethyl.
In some embodiments of the compounds of formula (I), R c Is (C) 1 -C 6 Alkyl group 2 N-ethyl, i.e. -CH 2 CH 2 N(C 1 -C 6 Alkyl group 2 。
In some embodiments of the compounds of formula (I), R c Is (dimethylamino) ethyl, i.e. -CH 2 CH 2 N(CH 3 ) 2 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) OCH 3 、-C(O)CH 3 or-S (O) 2 CH 3 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) OCH 3 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) CH 3 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) CH 2 N(CH 3 ) 2 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) CH 2 CH 2 N(CH 3 ) 2 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-S (O) 2 CH 3 。
In other embodiments of the compounds of formula (I), R c is-CH 2 CH 3 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) OCH 2 CH 3 、-C(O)CH 2 CH 3 or-S (O) 2 CH 2 CH 3 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) OCH 2 CH 3 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-C (O) CH 2 CH 3 。
In some embodiments of the compounds of formula (I), wherein Z is NR 3 And R is 3 is-S (O) 2 CH 2 CH 3 。
In some embodiments of the compounds of formula (I), R c Is a 3-7 membered cycloalkyl group, for example, a 3-membered cycloalkyl group, a 4-membered cycloalkyl group, a 5-membered cycloalkyl group, a 6-membered cycloalkyl group or a 7-membered cycloalkyl group.
In some embodiments of the compounds of formula (I), wherein Z is NR 3 ，R 3 Is optionally substituted C 1 -C 6 Alkyl radicals, e.g. C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In which Z is NR 3 And R is 3 Is optionally substituted C 1 -C 6 In some embodiments of compounds of formula (I) of alkyl, C 1 -C 6 Alkyl is-CH 3 。
In which Z is NR 3 And R is 3 Is optionally substituted C 1 -C 6 In some embodiments of compounds of formula (I) of alkyl, C 1 -C 6 Alkyl is-CH 2 CH 3 。
In which Z is NR 3 And R is 3 Is optionally substituted C 1 -C 6 In other embodiments of compounds of formula (I) of alkyl, C 1 -C 6 Alkyl is-CH (CH) 3 ) 2 。
In which Z is NR 3 And R is 3 Is optionally substituted C 1 -C 6 In other embodiments of compounds of formula (I) of alkyl, optionally substituted C 1 -C 6 Alkyl is 2-hydroxyethyl, i.e. -CH 2 CH 2 OH。
In which Z is NR 3 And R is 3 Is optionally substituted C 1 -C 6 In other embodiments of compounds of formula (I) of alkyl, optionally substituted C 1 -C 6 Alkyl is-CH 2 C(CH 3 ) 2 OH。
In which Z is NR 3 In some embodiments of the compounds of formula (I), R 3 Is a 3-5 membered cycloalkyl group, for example, a 3-membered cycloalkyl group, a 4-membered cycloalkyl group or a 5-membered cycloalkyl group.
In which Z is NR 3 And R is 3 In some embodiments of compounds of formula (I) that are 3-5 membered cycloalkyl groups, the 3-5 membered cycloalkyl group is cyclobutyl.
In which Z is NR 3 In some embodiments of the compounds of formula (I), R 3 Is a 3-5 membered heterocycloalkyl group, for example, a 3-membered heterocycloalkyl group, a 4-membered heterocycloalkyl group or a 5-membered heterocycloalkyl group.
In which Z is NR 3 And R is 3 In some embodiments of compounds of formula (I) that are 3-5 membered heterocycloalkyl, 3-5 membered heterocycloalkyl is oxetanyl,
in some embodiments of the compounds of formula (I), Z is CR 4 R 4’ 。
Wherein Z is CR 4 R 4’ In some embodiments of the compounds of formula (I), R 4 And R is 4’ Each is H.
Wherein Z is CR 4 R 4’ In some embodiments of the compounds of formula (I), R 4 And R is 4’ Each is optionally substituted C 1 -C 6 Alkyl groups, e.g. optionally substituted C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, pentyl, hexyl, and the like.
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ ，R 4 Is H and R 4’ Is OH.
Wherein Z is CR 4 R 4’ In some embodiments of the compounds of formula (I), R 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring, for example, an optionally substituted 3-membered heterocycloalkyl ring, an optionally substituted 4-membered heterocycloalkyl ring, an optionally substituted 5-membered heterocycloalkyl ring, an optionally substituted 6-membered heterocycloalkyl ring, or an optionally substituted 7-membered heterocycloalkyl ring.
In some embodiments of the compounds of formula (I), the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 4-membered heterocycloalkyl ring.
In some embodiments of the compounds of formula (I), the optionally substituted 4-membered heterocycloalkyl ring is an azetidinyl ring.
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Carbon attached to both of themTogether, the atoms form an optionally substituted azetidinyl ring, which is unsubstituted, i.e
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached form an optionally substituted azetidinyl ring, which is
In other embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted azetidinyl ring, which may be N-substituted.
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached form an N-substituted azetidinyl ring, the N-substituent being-C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C (O) C 1 -C 6 Haloalkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached form an N-substituted azetidinyl ring, the N-substituent being-C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I)In the scheme, the N-substituent is-CH 3 、-CH(CH 3 ) 2 、-C(O)N(CH 3 ) 2 or-SO 2 CH 3 I.e.,
in other embodiments of the compounds of formula (I), the N-substituent is-CH 2 CF 3 、-CH 2 CHF 2 、-C(O)CF 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 or-SO 2 CH 2 CH 3 For example, the first and second substrates may be coated, for example,
in some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached form an N-substituted azetidinyl ring, which is
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached form an N-substituted azetidinyl ring, the N-substituent being-C (O) OCH 2 CH 3 、-SO 2 CH(CH 3 ) 2 or-SO 2 CH 2 CH 3 。
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached form an N-substituted azetidinyl ring, which is
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted thietane 1, 1-dioxide ring.
In some embodiments of the compounds of formula (I), Z is:
wherein Z is CR 4 R 4’ In some embodiments of the compounds of formula (I), R 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 4-membered heterocycloalkyl ring, which is an optionally substituted oxetane ring, e.g.,
in some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring, which is an optionally substituted 5-membered heterocycloalkyl ring.
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 5-membered heterocycloalkyl ring, which optionally substituted 5-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2, 5-dione ring, an N-substituted pyrrolo-2, 5-dione ring, an unsubstituted imidazolidinyl-2-one ring, an N-substituted imidazolidinyl-2-one ring, a tetrahydrofuranyl ring or a tetrahydrothiophene-1, 1-dioxide ring 。
In some embodiments of the compounds of formula (I), the N-substituent is-C 1 -C 6 Alkyl radicals, e.g. -CH 3 。
In some embodiments, the N-substituent is-C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
In some embodiments, the N-substituent is-C (O) OC 1 -C 6 Alkyl radicals, e.g. -C (O) OCH 3 、-C(O)OCH 2 CH 3 、-C(O)OCH(CH 3 ) 2 or-SO 2 C 1 -C 6 Alkyl radicals, e.g. -SO 2 CH 3 。
In some embodiments of the compounds of formula (I), Z is
In other embodiments of the compounds of formula (I), Z is
In some embodiments of the compounds of formula (I), wherein Z is CR 4 R 4’ And R is 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring, which is an optionally substituted 6-membered heterocycloalkyl ring.
In some embodiments of the compounds of formula (I), the optionally substituted 6-membered heterocycloalkyl ring is an unsubstituted piperazin-2-one ring or an N-substituted piperazin-2-one ring.
In some embodiments of the compounds of formula (I), the N-substituent is-CH 3 。
In some embodiments of the compounds of formula (I), Z is
In other embodiments of the compounds of formula (I), the optionally substituted 6-membered heterocycloalkyl ring is a substituted or unsubstituted piperidine ring, or a tetrahydro-2H-thiopyran 1, 1-dioxide ring.
In some embodiments of the compounds of formula (I), the piperidine ring is N-substituted with: -C (O) OC 1 -C 6 Alkyl radicals, e.g. -C (O) OCH 3 、-C(O)OCH 2 CH 3 、-C(O)OCH(CH 3 ) 2 、-C 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl or-SO 2 C 1 -C 6 Alkyl radicals, e.g. -SO 2 CH 3 、-SO 2 CH 2 CH 3 。
In some embodiments of the compounds of formula (I), the piperidine ring is N-substituted with: -C (O) OC 1 -C 6 Alkyl radicals, e.g. -C (O) OCH 3 、-C(O)OCH 2 CH 3 、-C(O)OCH(CH 3 ) 2 ,-C 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl or-SO 2 C 1 -C 6 Alkyl radicals, e.g. -SO 2 CH 3 。
In some embodiments of the compounds of formula (I), Z is
In some embodiments of other compounds of formula (I), Z is
A compound of formula (II)
In some aspects, the disclosure relates to compounds of formula (II)
Or a pharmaceutically acceptable salt thereof,
wherein n=1, 2 or 3; m=1, 2 or 3;
each R 1 Is independently H; or optionally substituted C 1 -C 6 An alkyl group;
each R 2 Independently is H; or optionally substituted C 1 -C 6 An alkyl group;
or two R's attached to the same carbon atom 1 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
Or two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to different carbon atoms 1 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or two R's attached to different carbon atoms 2 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or R is 1 Radicals and R 2 The groups are connected to form a 6-9 membered bridged bicyclic ring;
a=n or CH;
Z＝S(O) 2 ；S(O)；O、NR 3 or CR (CR) 4 R 4’ ；
R 3 Is H; optionally substituted-C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b ；
R a Is H or C 1 -C 6 An alkyl group;
R b is H or C 1 -C 6 An alkyl group;
or R is a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R c is optionally substituted C 1 -C 6 Alkyl or cycloalkyl;
R 4 is H or optionally substituted C 1 -C 6 An alkyl group;
R 4’ is H, -OH or optionally substituted C 1 -C 6 An alkyl group;
or R is 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
y is a 5-or 6-membered heteroaryl ring;
Q 5 、Q 6 、Q 7 、Q 8 and Q 9 Each independently is CR 5 ；
R 5 Is H, halogen, C 1 -C 3 An alkyl group; c (C) 1 -C 3 Alkoxy, or cycloalkyl;
x= O, S or NR, wherein R is H or C 1 -C 3 An alkyl group; and
R 6 is C 1 -C 6 An alkyl group.
In some aspects of the disclosure, the compound of formula (II) is a compound of formula (IIA):
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Wherein Q is 1 、Q 2 、Q 3 、Q 4 One or two of them are N and the others are CR 5a Wherein each CR is 5a Independently H, halogen or C 1 -C 3 Alkyl, and the other variables are as shown in formula (II).
In some aspects, the compound of formula (II) is a compound of formula (IIB):
wherein the variables have values represented by formula (II) above.
In some embodiments of the compounds of formula (II), Q 6 And Q 8 Each independently is CR 5 Wherein each R is 5 Is halogen, and Q 5 、Q 7 And Q 9 Each independently is CR 5 Wherein each R is 5 Is H.
In some embodiments of the compounds of formula (II), Q 6 And Q 8 Each independently is CR 5 Wherein each R is 5 is-F and Q 5 、Q 7 And Q 9 Each independently is CR 5 Wherein each R is 5 Is H.
In some embodiments of the compounds of formula (II), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen, and Q 6 、Q 7 And Q 8 Each independently is CR 5 Wherein R is 5 Is H.
In some embodiments of the compounds of formula (II), Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl, and Q 6 、Q 7 And Q 8 Each independently is CR 5 Wherein each R is 5 Is H.
In some aspects, the disclosure relates to the following compounds, or pharmaceutically acceptable salts thereof:
in other aspects, the disclosure relates to the following compounds, or pharmaceutically acceptable salts thereof:
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In other aspects, the disclosure relates to the following compounds, or pharmaceutically acceptable salts thereof:
in some aspects, the disclosure relates to compounds shown in the following examples, or pharmaceutically acceptable salts thereof.
References herein to formula (I) or formula (II) or subclasses thereof are intended to encompass certain formulas and any subclasses of those formulas disclosed herein. For example, references to formula (I) also encompass subclasses of formulas IA, IA-1, IA-2, IA-3, IA-4, IA-5, IA-6, IA-7, IB-1 and IB-2. References to formula (I) also encompass subclasses of formula IA-8.
The present disclosure also contemplates stereoisomers of the compounds of formula (I) or formula (II). Accordingly, the present disclosure encompasses all stereoisomers and stereoisomers, including all enantiomers and diastereomers, or mixtures thereof, of any compound disclosed or claimed herein.
Pharmaceutically acceptable salts and solvates of the compounds of formula (I) or formula (II) are also within the scope of the present disclosure.
It is appreciated that certain features of the invention, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, each individual embodiment is contemplated as being combinable with any other embodiment, unless explicitly incompatible or explicitly excluded, and such combination is contemplated as another embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. Although embodiments may be described as part of a series of steps or as part of a more general structure, each of the steps may itself be considered a separate embodiment, in combination with the others.
Pharmaceutical compositions and methods of administration
The subject pharmaceutical compositions are generally formulated to provide a therapeutically effective amount of a compound of the present disclosure as an active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, or derivative thereof. In some embodiments, the pharmaceutical compositions contain a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), permeation enhancers, solubilizers, and adjuvants.
The subject pharmaceutical compositions may be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. If desired, one or more compounds of the invention and other agents may be mixed into a formulation, or the two components may be formulated into separate formulations for their use alone or in combination.
In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (w/v) or (w/v) of any two of the above numbers (w/v).
In some embodiments of the present invention, in some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9.75%, 8.50%, 8.25%, 8.8%, 8.75%, 7.50%, 7.25%, 7.75%, 6.50%, 6.25% >. 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% (or the numbers (w/v) within the range of any two of the above).
In some embodiments, the concentration of one or more compounds of the invention is within the following range: about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w/w, w/v or v/v.
In some embodiments, the concentration of one or more compounds of the invention is within the following range: about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v.
In some embodiments of the present invention, in some embodiments, the amount of one or more compounds of the present invention is equal to or less than 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g, or 0.0001g (or a number within a range defined by any two of the above).
In some embodiments of the present invention, in some embodiments, the amount of one or more compounds of the present invention is greater than 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g (or numbers within the range defined by any two of the foregoing).
In some embodiments, the amount of one or more compounds of the present invention is in the range of 0.0001-10g, 0.0005-9g, 0.001-8g, 0.005-7g, 0.01-6g, 0.05-5g, 0.1-4g, 0.5-4g, or 1-3 g.
In some embodiments, the compounds according to the invention are effective over a broad dosage range. For example, in adult treatment, dosages of 0.01 to 1000mg, 0.5 to 100mg, 1 to 50mg, and 5 to 40mg per day are examples of dosages that can be used. Exemplary dosages are 10 to 30mg per day. The precise dosage will depend on the route of administration, the form of administration of the compound, the subject to be treated, the weight of the subject to be treated, and the preference and experience of the attending physician.
Unless otherwise indicated, the amounts of the compounds described herein are shown on a free base basis. That is, the amount represents the amount of the compound administered, excluding, for example, solvents (e.g., in solvates) or counterions (e.g., in pharmaceutically acceptable salts).
Non-limiting exemplary pharmaceutical compositions and methods of preparing the same are described below.
Pharmaceutical compositions for oral administration.
In some embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a compound of the present invention and a pharmaceutical excipient suitable for oral administration.
In some embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) pharmaceutical excipients suitable for oral administration. In some embodiments, the composition further comprises: (iv) an effective amount of a third agent.
In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete dosage forms, for example capsules, cachets or tablets, or as liquid or aerosol sprays, each containing a predetermined amount of the active ingredient, such as a powder or granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms may be prepared by any pharmaceutical method, but all methods include the step of associating the active ingredient with a carrier that constitutes one or more essential ingredients. Generally, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired appearance. For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with excipients such as, but not limited to, binding agents, lubricants, inert diluents and/or surfactants or dispersants. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
The invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, as water may promote the degradation of some compounds. For example, water (e.g., 5%) may be added in the pharmaceutical field as a means of simulating long-term storage to determine characteristics (e.g., shelf life or stability of the formulation over time). The anhydrous pharmaceutical compositions and dosage forms of the present invention may be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. The pharmaceutical compositions and dosage forms of the present invention containing lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacture, packaging and/or storage is contemplated. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous nature. Thus, anhydrous compositions can be packaged using materials known to prevent exposure to water so that they can be included in a suitable prescription kit. Examples of suitable packages include, but are not limited to, sealed foils, plastics, and the like, unit dose containers, blister packs, and strip packs.
The active ingredients may be combined with the pharmaceutical carrier in intimate admixture according to conventional pharmaceutical compounding techniques. The carrier may take a variety of forms depending on the form of formulation desired for administration. In preparing the compositions for oral dosage forms, in the case of oral liquid preparations (e.g., suspensions, solutions and elixirs) or aerosols, any of the usual pharmaceutical media may be employed as a carrier, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; or in the case of oral solid formulations, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents may be used, in some embodiments lactose is not employed. Suitable carriers include, for example, powders, capsules and tablets, as well as solid oral formulations. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques.
Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural and synthetic gums (e.g., acacia), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, carboxymethylcellulose sodium), polyvinylpyrrolidone, methylcellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.
Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextran, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.
Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may produce tablets that may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and thus the rate and extent of release of the active ingredient from the dosage form may be altered. Thus, a sufficient amount of disintegrant may be used to form the dosage forms of the compounds disclosed herein, neither too little nor too much to adversely alter the release of the active ingredient. The amount of disintegrant used can vary depending on the type of formulation and mode of administration, and can be readily discerned by one of ordinary skill in the art. About 0.5 to about 15 weight percent of the disintegrant, or about 1 to about 5 weight percent of the disintegrant, may be used in the pharmaceutical composition. Disintegrants that may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, potassium polcalide, sodium starch glycolate, potato or tapioca starch, other starches, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.
Lubricants useful in forming the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower seed oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, a solidified synthetic silica aerosol, or mixtures thereof. The lubricant may optionally be added in an amount of less than about 1 weight percent of the pharmaceutical composition.
When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavouring agents, colouring matter or dyes and, if desired, emulsifying agents and/or suspending agents together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.
The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material (e.g., glyceryl monostearate or glyceryl distearate) may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).
Surfactants useful in forming the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants, a mixture of lipophilic surfactants, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.
Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of about 10 or less than about 10. The empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or more hydrophobic and have greater solubility in oil, while surfactants with higher HLB values are more hydrophilic and have greater solubility in aqueous solutions.
Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic or zwitterionic compounds for which the HLB measurement is generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value of about 10 or less. However, the HLB value of surfactants is only a rough guideline and is commonly used to achieve formulation of industrial, pharmaceutical and cosmetic emulsions.
The hydrophilic surfactant may be ionic or nonionic. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidate; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glyceride derivatives of amino acids, oligopeptides and polypeptides; lecithin and hydrogenated lecithin; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate; a fatty acid salt; docusate sodium; acyl lactylates; monoacetyltartaric acid esters and diacetyltartaric acid esters of mono-and diglycerides; succinyl monoglycerides and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.
In the above group, the ionic surfactant includes, for example: lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; alkyl sulfate; a fatty acid salt; docusate sodium; an acyl compound; monoacetyltartaric acid esters and diacetyltartaric acid esters of mono-and diglycerides; succinyl monoglycerides and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.
The ionic surfactant may be in the following ionized form: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, fatty acid lactate, stearoyl-2-lactate, stearoyl lactate, succinylated monoglyceride, mono/diglyceride of mono/diacetyl tartaric acid, citric acid esters of mono/diglyceride, choline sarcosine, caprate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, tertiary acetyl sulfate, docusate, lauroyl carnitine, palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.
Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; alkyl maltosides; alkyl thioglucosides; lauryl polyethylene glycol glyceride; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ether; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenol; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid ester; polyglycerin fatty acid esters; polyoxyalkylene sorbitol fatty acid esters, such as polyethylene glycol sorbitol fatty acid esters; hydrophilic transesterification products of polyols with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; polyoxyethylene sterols, derivatives and analogs thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitol fatty acid esters, and hydrophilic transesterification products of polyols with at least one member of the group consisting of triglycerides, vegetable oils and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol or saccharides.
Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 trioleate, PEG-32 dioleate, PEG-20 laurate, PEG-30 laurate, PEG-20 stearate, PEG-20 oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/glyceryl caprylate, PEG-8 caprate/glyceryl caprylate, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, PEG-30 soybean sterol, PEG-20 trioleate, PEG-40 sorbitol oleate, PEG-80 sorbitol laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglycerol-10 oleate, tween 40, tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.
Suitable lipophilic surfactants include, by way of example only: a fatty alcohol; a glycerol fatty acid ester; acetylated glycerin fatty acid ester; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitol fatty acid ester; polyethylene glycol sorbitol fatty acid ester; sterols and sterol derivatives; polyoxyethylene sterols and sterol derivatives; polyethylene glycol alkyl ether; a sugar ester; a sugar ether; lactic acid derivatives of mono-and diglycerides; a hydrophobic transesterification product of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Preferred lipophilic surfactants in this group include glycerol fatty acid esters, propylene glycol fatty acid esters and mixtures thereof, or hydrophobic transesterification products of polyols with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils and triglycerides.
In one embodiment, the composition may include a solubilizing agent to ensure good solubilization and/or dissolution of the compounds of the present invention and to minimize precipitation of the compounds of the present invention. This is particularly important for compositions that are not intended for oral use, such as compositions for injection. Solubilizing agents may also be added to increase the solubility of the hydrophilic drug and/or other components (e.g., surfactants), or to maintain the composition as a stable or homogeneous solution or dispersion.
Examples of suitable solubilizing agents include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, carbitol (transcutol), dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycogenol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, epsilon-caprolactam, N-alkylpyrrolidone, N-hydroxyalkyl pyrrolidone, N-alkylpiperidone, N-alkyl caprolactam, dimethylacetamide, polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyltriethyl citrate, acetyltributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsilon-caprolactone and its isomers, delta-valerolactone and its isomers, beta-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, monocaprylic acid, diethylene glycol monoethyl ether, and water.
Mixtures of solubilizing agents may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl octanoate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethyl pyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrin, ethanol, polyethylene glycol 200-100, glycogenol, carbitol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizing agents include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycogen and propylene glycol.
The amount of the solubilizing agent that can be included is not particularly limited. The amount of a given solubilizing agent can be limited to a biologically acceptable amount, which can be readily determined by one of skill in the art. In some cases, it may be advantageous to include an amount of solubilizing agent that far exceeds the biologically acceptable amount, e.g., to maximize the concentration of the drug, using conventional techniques to remove excess solubilizing agent, e.g., distillation or evaporation, prior to providing the composition to the subject. Thus, if present, the weight ratio of the solubilizing agent may be 10 wt%, 25 wt%, 50 wt%, 100 wt%, or up to about 200 wt%, based on the combined weight of the drugs, and other excipients. If desired, very small amounts of solubilizers, for example 5%, 2%, 1% or even less, can also be used. Typically, the solubilizing agent may be present in an amount of from about 1% to about 100% by weight, more typically from about 5% to about 25% by weight.
The composition may further comprise one or more pharmaceutically acceptable additives and adjuvants. Such additives and adjuvants include, but are not limited to, antiblocking agents, defoamers, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers, tonicity agents, flavoring agents, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants and mixtures thereof.
Furthermore, an acid or base may be incorporated into the composition to facilitate processing, enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic calcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, TRIS (hydroxymethyl) aminomethane (TRIS), and the like. Also suitable bases are salts of pharmaceutically acceptable acids such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzene sulfonic acid, propionic acid, p-toluene sulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluene sulfonic acid, uric acid, and the like. Salts of polybasic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation may be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.
Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.
Pharmaceutical compositions for injection.
In some embodiments, the present invention provides pharmaceutical compositions for injection comprising a compound of the present invention and a pharmaceutical excipient suitable for injection. The components and amounts of the agents in the composition are as described herein.
Forms in which the novel compositions of the invention may be incorporated for administration by injection include aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.
Aqueous solutions in saline are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like).
Sterile injectable solutions are prepared by incorporating the compounds of the invention in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
Pharmaceutical compositions for topical (e.g., transdermal) delivery.
In some embodiments, the present invention provides a pharmaceutical composition for transdermal delivery comprising a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.
The compositions of the present invention may be formulated as solid, semi-solid or liquid forms of formulation suitable for topical or surface application, such as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO) -based solutions. Generally, carriers with higher densities can provide areas with prolonged exposure to the active ingredient. Conversely, a solution formulation may expose the active ingredient more directly to the selected area.
The pharmaceutical compositions may also contain suitable solid or gel phase carriers or adjuvants, which are compounds that effect an increase in the penetration of the therapeutic molecule or aid in the delivery of the therapeutic molecule across the skin's stratum corneum penetration barrier. Many of these penetration enhancing molecules are known to those trained in the art of surface formulations.
Examples of such carriers and adjuvants include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers (e.g., polyethylene glycol).
Another exemplary formulation for use in the methods of the invention employs a transdermal delivery device ("patch"). Such transdermal patches may be used for continuous or discontinuous infusion of the compounds of the present invention in controlled amounts, with or without another agent.
The construction and use of transdermal patches for delivering pharmaceutical agents is well known in the art. See, for example, U.S. Pat. nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be configured for continuous, pulsatile, or on-demand delivery of agents.
Pharmaceutical compositions for inhalation.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by the oral or nasal respiratory route to achieve local or systemic effects. The composition in the preferred pharmaceutically acceptable solvent may be nebulized by use of inert gases. The aerosolized solution may be inhaled directly from the aerosolizing device, or the aerosolizing device may be attached to a mask tent or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.
Other pharmaceutical compositions.
The pharmaceutical compositions may also be prepared from the compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural or intraspinal administration. The preparation of such pharmaceutical compositions is well known in the art. See, for example, anderson, philip o; knoben, james e; troutman, william G, editions, manual of clinical drug data (Handbook of Clinical Drug Data), tenth edition, mcGraw-Hill,2002; pratt and Taylor, editors, principle of drug action (Principles of Drug Action), third edition, churchill Livingston, new York,1990; katzung, editorial, basic and clinical pharmacology (Basic and Clinical Pharmacology), ninth edition, mcGraw Hill,20037ybg; goodman and Gilman, editors, pharmacological foundation of therapeutics (The Pharmacological Basis of Therapeutics), tenth edition, mcGraw Hill,2001; ramington pharmaceutical science (Remingtons Pharmaceutical Sciences), 20 th edition, lippincott Williams & wilkins, 2000; martindale, university of Pharmacopeia (The Extra Pharmacopoeia), thirty-second edition (The Pharmaceutical Press, london, 1999); all of which are incorporated herein by reference in their entirety.
Administration of the compounds or pharmaceutical compositions of the invention may be accomplished by any method capable of delivering the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal, or infusion), topical administration (e.g., transdermal administration), rectal administration, local delivery through a catheter or stent, or by inhalation. The compounds may also be administered intra-fat or intra-sheath.
The amount of compound administered will depend on the severity of the subject, disorder or condition being treated, the rate of administration, the disposition of the compound, and the discretion of the prescribing physician. However, an effective dose is in the range of about 0.001 to about 100mg/kg body weight/day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70kg person this corresponds to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day. In some cases, dosage levels below the lower limit of the above range may not only be sufficient, but in other cases larger doses may be employed without causing any detrimental side effects, for example by dividing such large doses into several small doses for administration throughout the day.
In some embodiments, the compounds of the invention are administered in a single dose.
Typically, such administration will be by injection (e.g., intravenous injection) to rapidly introduce the agent. However, other approaches may be used as appropriate. Single doses of the compounds of the invention may also be used to treat acute conditions.
In some embodiments, the compounds of the invention are administered in multiple doses. The administration may be about once, twice, three times, four times, five times, six times or more than six times per day. Administration may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment, the compound of the invention and the other agent are administered together from about once per day to about 6 times per day. In another embodiment, the administration of the compounds and agents of the present invention lasts less than about 7 days. In yet another embodiment, administration lasts more than about 6 days, 10 days, 14 days, 28 days, two months, six months, or one year. In some cases, continuous administration may be achieved and maintained as long as necessary.
The administration of the compounds of the present invention may be continued as long as necessary. In some embodiments, the compounds of the invention are administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the compounds of the invention are administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the compounds of the invention are administered chronically on a continuous basis, e.g., for the treatment of chronic effects.
An effective amount of a compound of the present invention may be administered in single or multiple doses by any acceptable mode of administration of agents having similar utility, including rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical administration, or as an inhalant.
The compositions of the present invention may also be delivered by dipping or coating means (e.g., stents), for example, or cylindrical polymers inserted into the artery. Such methods of administration may, for example, help prevent or ameliorate restenosis following surgery (e.g., balloon angioplasty). Without being bound by theory, the compounds of the present invention may slow or inhibit migration and proliferation of smooth muscle cells in the arterial wall that cause restenosis. The compounds of the invention may be administered, for example, by local delivery from a strut of a stent, from a stent graft, from a graft, or from a stent cover or sheath. In some embodiments, the compounds of the present invention are mixed with a matrix. Such a matrix may be a polymer matrix and may be used to bind the compound to the scaffold. Suitable polymer matrices for such use include, for example, lactone-based polyesters or copolyesters such as polylactides, polycaprolactone glycolides, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxanes, poly (ethylene-vinyl acetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methacrylate, polyvinylpyrrolidone), fluorinated polymers (e.g., polytetrafluoroethylene), and cellulose esters. Suitable matrices may be non-degradable or may degrade over time to release one or more compounds. The compounds of the present invention may be applied to the surface of the stent by various methods, such as dip/spin coating, spray coating, dip coating and/or brush coating. The compound may be applied to the solvent and the solvent may be allowed to evaporate, thereby forming a compound layer on the scaffold. Alternatively, the compound may be located in the body of the stent or graft, for example in a microchannel or micropore. Upon implantation, the compound diffuses out of the body of the stent to contact the arterial wall. Such scaffolds may be prepared by immersing scaffolds produced to contain such micropores or microchannels in a solution of a compound of the invention in a suitable solvent, and then evaporating the solvent. Excess drug on the stent surface can be removed by an additional brief solvent wash. In other embodiments, the compounds of the invention may be covalently linked to a stent or graft. Covalent linkers that degrade in vivo can be used, resulting in the release of the compounds of the invention. Any biostable linkage may be used for this purpose, such as an ester, amide or anhydride linkage. The compounds of the invention may also be administered intravascularly from a balloon used during angioplasty. Extravascular administration of compounds may also be performed to reduce restenosis by pericardial or by adventitial application of the formulations of the present invention.
For example, a variety of stent devices that may be used as described are disclosed in the following references, all of which are incorporated herein by reference: U.S. patent No. 5451233; U.S. patent No. 5040548; U.S. patent No. 5061273; U.S. patent No. 5496346; U.S. patent No. 5292331; U.S. patent No. 5674278; U.S. patent No. 3657744; U.S. patent No. 4739762; U.S. patent No. 5195984; U.S. patent No. 5292331; U.S. patent No. 5674278; U.S. patent No. 5879382; U.S. patent No. 6344053.
The compounds of the invention may be administered in dosages. It is known in the art that individualization of the dosing regimen is necessary for optimal treatment due to inter-subject variability in the pharmacokinetics of the compounds. Dosages of the compounds of the present invention can be determined by routine experimentation in light of the present disclosure.
When a compound of the invention is administered in a composition comprising one or more agents, and the half-life of the agent is shorter than the half-life of the compound of the invention, the unit dosage forms of the agent and the compound of the invention can be adjusted accordingly.
The subject pharmaceutical compositions may be, for example, in a form suitable for oral administration, such as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions, for parenteral injection, such as sterile solutions, suspensions or emulsions, for topical administration, such as ointments or creams, or for rectal administration, such as suppositories. The pharmaceutical composition may be in unit dosage form suitable for single administration of precise dosages. The pharmaceutical compositions will comprise conventional pharmaceutical carriers or excipients and, as active ingredient, a compound according to the invention. In addition, it may include other pharmaceutical agents or agents, carriers, adjuvants, and the like.
Exemplary forms of parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions (e.g., aqueous propylene glycol or dextrose). Such dosage forms may be suitably buffered if desired.
Application method
FGFR receptors (FGFR 1, FGFR2, FGFR3 and FGFR 4) share several common structural features, including three extracellular immunoglobulin-like (Ig) domains, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain that is divided by a kinase insertion domain, followed by a cytoplasmic c-terminal tail (Johnson et al, cancer research progression (adv. Cancer res.) 60:1-40,1993; and Wilkie et al, contemporary biology (curr. Biol.) 5:500-507,1995). In FGFR1, the kinase insertion domain spans positions 582 to 595 of the αa1 isoform of FGFR 1. In FGFR2, the kinase insertion domain spans positions 585 to 598 of the FGFR2 Ille isoform. In FGFR3, the kinase insertion domain spans positions 576 to 589 of the FGFR3 Ille isoform. In FGFR4, the kinase insertion domain spans positions 571 to 584 of FGFR4 isoform 1. The c-terminal tail of FGFR begins at the end of the tyrosine kinase domain and extends to the c-terminus of the protein. Several isoforms of each FGFR have been identified, which are the result of alternative splicing of their mRNA (Johnson et al, molecular cell biology (mol. Cell. Biol.) 11:4627-4634,1995; and Chellaiah et al, J. Biol. Chem.) 269:11620-11627,1994).
Some receptor variants resulting from this alternative splicing have different ligand binding specificities and affinities (Zimmer et al, journal of biochemistry (J. Biol. Chem.) 268:7899-7903,1993; cheon et al, proc. Natl. Acad. Sci. U.S.A.) 91:989-993,1994; and Miki et al, proc. Natl. Acad. Sci. U.S.A.) 89:246-250,1992. The protein sequence of FGFR proteins and nucleic acids encoding FGFR proteins are known in the art. FGFR signaling regulates key biological processes including cell proliferation, survival, migration, and differentiation. FGFR genes, FGFR proteins, or deregulation of their expression or activity or level are associated with many types of cancer. For example, deregulation of FGFR can occur through a variety of mechanisms, such as FGFR gene overexpression, FGFR gene amplification, activating mutations (e.g., point mutations or truncations), and chromosomal rearrangements that result in FGFR fusion proteins. Deregulation of FGFR genes, FGFR proteins, or expression or activity or levels thereof can lead (or partially lead) to the development of a variety of different FGFR-associated cancers.
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Note: deletion of FGFR3 isoform Ille residues 795-808 also deleted the stop codon, lengthening the protein by 99 amino acids (ATGPQQCEGSLAAHPAAGAQPLPGMRLSADGETATQSFGLCVCVCVCVCVCTSACACVRAHLASRCRGTLGVPAAVQRSPDWCCSTEGPLFWGDPVQNVSGPTRWDPVGQGAGPDMARPLPLHHGTSQGALGPSHTQS); ge et al, J Cancer research journal (Am J Cancer Res.) 7 (7): 1540-1553,2017.PMID: 2874403; jiao et al, nat Genet, 45 (12): 1470-1473,2013.Doi:10.1038/ng.2813; jusakul et al, cancer discovery (Cancer discover.) 7 (10): 1116-1135,2017.Doi:10.1158/2159-8290.CD-17-0368; guyard et al, respiratory research (Respir Res.), 18 (1): 120,2018.doi:10.1186/s12931-017-0605-y; paik et al, clinical Cancer research (Clin Cancer Res.), 23 (18): 5366-5373,2017.Doi:10.1158/1078-0432.CCR-17-0645; roy et al, modern pathology (Mod Patho/.), 30 (8): 1133-1143,2017.doi:10.1038/modPathol.2017.33; chakrabarty et al, J.England J Cancer (Br J Cancer), 117 (1): 136-143,2017.doi:10.1038/bjc.2017.148; hoang et al, science of transformation medicine (Sci Transl Med.), 5 (197): 197ra102.doi:10.1126/scitranslmed.3006200; kim et al, annual oncology (Ann Oeal.), 28 (6): 1250-1259.Doi:10.1093/annonc/mdx098, each of which is incorporated herein by reference.
Compounds of the present disclosure have been found to inhibit FGFR1, FGFR2, FGFR3 and/or FGFR4 and are therefore considered useful for the treatment of diseases and conditions treatable with FGFR1, FGFR2, FGFR3 and/or FGFR4 inhibitors. For example, the compounds of the present disclosure are useful for treating FGFR-related diseases and disorders, e.g., proliferative disorders (e.g., cancer), including hematological cancers and solid tumors, as well as angiogenesis-related disorders. The compounds of the present disclosure are also useful for treating disorders caused by autosomal dominant mutations in FGFR (e.g., FGFR 3), including, for example, developmental disorders. Developmental disorders to be treated with the compounds of the present disclosure include achondroplasia (Ach) and related dysplasia of cartilage including achondroplasia (Hch), severe achroplasia with delayed development and acanthosis nigricans (sadddan) and lethal dysplasia (TD).
Non-limiting examples of FGFR-related diseases and conditions include acanthosis nigricans, achondroplasia, apert syndrome, beare-Stevenson syndrome (BSS), bucky fingers, high stature and hearing loss syndrome (CATSHL) syndrome, cleft labialis and cleft palate, congenital heart disease (e.g., associated with the genitalia), craniofacial preservation, crouzon syndrome, abnormal finger deformity, craniofacial lipomatosis, hartsfield syndrome, cartilage dysplasia, hypogonadism (e.g., hypogonadism 2 with or without olfaction, kallman syndrome), ichthyosis vulgaris and/or atopic dermatitis, jackson-Weiss syndrome, lethal lung acinar dysplasia, small eye disease, muenke coronary premature closure, osteoarthropathy, pfeier's syndrome, seborrheic keratosis, and joint failure of the cranium, and joint with the leading to a lethal joint (e.g., type I or type I) or joint failure and craniofacial dysplasia (also known as anterior joint failure) and osteomalacia.
Non-limiting examples of FGFR 1-related diseases and conditions include congenital heart disease (e.g., associated with the genitalia), craniocerebral premature closure, craniofacial lipomatosis, hartsfield syndrome, hypogonadism (e.g., hypogonadism 2 with or without olfactory loss, kallman syndrome), ichthyosis vulgaris and/or atopic dermatitis, jackson-Weiss syndrome, osteochondrodysplasia, pfeiffer syndrome, trigonomic head deformity 1 (also known as ectopic craniocerebral premature closure), and tumor-induced osteomalacia.
Non-limiting examples of FGFR 2-related diseases and conditions include Apert syndrome, beare-Stevenson syndrome (BSS), crouzon syndrome, metaindication, jackson-Weiss syndrome, lethal lung acinar dysplasia, pfeiffer syndrome, and complications. Non-limiting examples of FGFR 3-related diseases and conditions include acanthosis nigricans, achondroplasia, flexor fingers, high-grade and hearing loss syndrome (CATSHL) syndrome, cleft lip and cleft palate, craniosynostosis, dysplasia of the cartilage, small eye deformity, muenke coronary craniosynostosis, seborrheic keratosis, and lethal dysplasia (e.g., type I or type II). See also UniParc entry UPI00000534B8; uniParc entry UPI000000lCOF; uni Pare entry UPI000002A99A; uniParc entry UPI000012A72A; yong-Xing et al, human molecular genetics (hum. Mol. Genet.) 9 (13): 2001-2008,2000; eeva-Maria Laitinen et al, PLoS One 7 (6): e39450,2012; hart et al Oncogene 19 (29): 3309-3320,2000; shiang et al, cells (Cell) 76:335-342,1994; rosseau et al, nature 371:252-254,1994; tavormina et al, nature genet., 9:321-328,1995; bellus et al, nature genet.) 10:357-359,1995; muenke et al, nature genet.) 8:269-274,1994; rutland et al, nature genet.) 9:173-176,1995; rearon et al, nature genet.) 8:98-103,1994; wilkie et al, nature genet.) 9:165-172,1995; jabs et al, nature genet.) 8:275-279,1994; japanese patent No. JP05868992B2; ye et al, plastic and reconstructive surgery (plasmid. Reconstre. Surg.), 137 (3): 952-61,2016; U.S. patent No. 9447098B2; bellus et al, journal of medical genetics (Am. J. Med. Genet.) 85 (1): 53-65,1999; PCT patent application publication No. WO2016139227Al; australian patent application publication No. AU2014362227Al; chinese patent number CN102741256B; ohishi et al, journal of medical genetics A (am. J. Med. Genet. A.), doi 10.1002/ajmg. A.37992,2016; nagahara et al, clinical pediatric endocrinology (clin. Pediattr. Endocrinol.), 25 (3): 103-106,2016; hibberd et al, journal of medical genetics A (am. J. Med. Genet. A.), doi 10.1002/ajmg. A.37862,2016; dias et al, experimental and molecular pathology (exp.mol. Pathol.), 101 (1): 116-23,2016; lin et al, molecular medicine report (mol. Med. Rep.), 14 (3): 1941-6,2016; barnett et al, human mutation (hum. Mutat.), 37 (9): 955-63,2016; krstevska-Konstantinova et al, medical record (Med. Arch.), 70 (2): 148-50,2016; kuentz et al, journal of skin diseases in the united kingdom (br.j. Dermotol.), doi 10.1111/bjd.14681,2016; ron et al, journal of case report in the united states (am.j.case rep.), 15;17:254-8,2016; fernandes et al, journal of medical genetics A (am. J. Med. Genet. A.), 170 (6): 1532-7,2016; lindy et al, journal of medical genetics A (am. J. Med. Genet. A.), 170 (6): 1573-9,2016; bennett et al, journal of human genetics (am. J. Hum. Genet.), 98 (3): 579-87,2016; lchiyama et al, journal of the European dermatology (J.Eur. Acad. Dermatol. Venereal.), 30 (3): 442-5,2016; zhao et al, J.Clin.Exp.Med., international journal of clinical and laboratory medicine (Int., J.Clin., med.), 8 (10): 19241-9,2015; hasegawa et al, journal of medical genetics, a.c. (am. J. Med. Genet. A.), 170A (5): 1370-2,2016; legeai-Malet, endocrine progression (endocr. Dev.), 30:98-105,2016; takagi, journal of medical genetics A (am. J. Med. Genet. A.), 167A (ll): 2851-4,2015; goncalves, fertility and infertility (fertil. Steril.), 104 (5): 1261-7.El,2015; miller et al, journal of clinical oncology (Journal of Clinical Oncology), 34:Supp. Journal 15, pp. Ii93. Abstract number: e22500,2016 annual meeting of clinical oncology in the united states (2016 Annual Meeting of the American Society of Clinical Oncology), chicago, IL; sarabipore et al, J.Mol.Biol.), 428 (20): 3903-3910,2016; escobar et al, journal of medical genetics A (am. J. Med. Genet. A.), 170 (7): 1908-11,2016; mazen et al, sex progression (Sex Dev.), 10 (1): 16-22,2016; taylan et al, J.allergy & clinical immunology (J Allergy Clin lmmunol), 136 (2): 507-9,2015.Doi:10.1016/j.jaci.2015.02.010; kant et al, european journal of endocrinology (EuroJourn Endocrinol), 172 (6): 763-770,2015.Doi:10.1530/EJE-14-0945; gonzalez-Del Angel et al, journal of medical genetics A (am. J. Med. Genet. A.), 176 (1): 161-166,2018.Doi:10.1002/ajmg. A.38526; lei and Deng, J.International Biol Sci 13 (9): 1163:1171,2017.doi:10.7150/ijbs.20792; lajeune et al, european journal of genetics (Eur J Hum Genet), 14 (3): 289-298,2006.Doi:10.1038/sj. Ejhg.5201558; karadimas et al, prenatal diagnosis (Prenat diagnostic), 26 (3): 258-261,2006.Doi:10.1002/pd.1392; lbrahimi et al, human molecular genetics (Hum Mo/Genet) 13 (19): 2313-2324,2004.Doi:10.1093/hmg/ddh235; trarbach et al, journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab.), 91 (10): 4006-4012,2006.Doi:10.1210/jc.2005-2793; dode et al, nature Genet, 33 (4): 463-465,2003.Doi:10.1038/ng1122, each of which is incorporated herein by reference.
The term "angiogenesis-related disorder" refers to a disease characterized in part by an increase in the number or size of blood vessels in a subject's or patient's tissue as compared to similar tissue of a subject not having the disease. Non-limiting examples of angiogenesis-related disorders include: cancers (e.g., any of the exemplary cancers described herein, such as prostate cancer, lung cancer, breast cancer, bladder cancer, kidney cancer, colon cancer, stomach cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, sarcoma, and lymphoma), exudative macular degeneration, proliferative diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, iridocytosis, corneal neovascularization, ciliary inflammation, sickle cell retinopathy, and pterygium).
The compounds of the present disclosure inhibit wild-type FGFR1, FGFR2, FGFR3, and/or FGFR4. In other aspects, compounds of the disclosure inhibit mutated FGFR1, FGFR2, FGFR3, and/or FGFR4. In other aspects, compounds of the disclosure inhibit FGFR1, FGFR2, FGFR3, and/or FGFR4, including FGFR kinase inhibitor mutations.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-related cancer) is a hematologic cancer. In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-related cancer) is a solid tumor.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-associated cancer) is lung cancer (e.g., small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, large cell carcinoma, mesothelioma, lung neuroendocrine carcinoma, smoking-associated lung cancer), prostate cancer, colorectal cancer (e.g., rectal adenocarcinoma), endometrial cancer (e.g., endometrioid endometrial cancer, endometrial adenocarcinoma), breast cancer (e.g., hormone receptor positive breast cancer, triple negative breast cancer, breast neuroendocrine carcinoma), skin cancer (e.g., melanoma, skin squamous cell carcinoma, basal cell carcinoma, large squamous cell carcinoma), gall bladder cancer, liposarcoma (e.g., dedifferentiated liposarcoma, myxoid liposarcoma), pheochromocytoma, myoepithelial cancer, urothelial cancer, seminoma, gastric cancer, head and neck cancer (e.g., head and neck (squamous) cancer, head and neck adenoid carcinoma), brain cancer (e.g., glioma, neuroblastoma, glioblastoma, hairy cell astrocytoma, rosette forming glioma, embryogenic dysplastic neuroepithelial tumor, anaplastic astrocytoma, medulloblastoma, ganglioglioma, oligodendroglioma), malignant peripheral schwannoma, sarcoma (e.g., soft tissue sarcoma (e.g., leiomyosarcoma), osteosarcoma), esophageal cancer (e.g., esophageal adenocarcinoma), lymphoma, bladder cancer (e.g., bladder urothelial (transitional cell) carcinoma), cervical cancer (e.g., cervical squamous cell carcinoma, cervical adenocarcinoma), fallopian tube cancer (e.g., fallopian tube cancer), ovarian cancer (e.g., ovarian serous carcinoma, ovarian mucous carcinoma), cholangiocarcinoma, adenoid cystic carcinoma, pancreatic cancer (e.g., exocrine pancreatic carcinoma, ductal adenocarcinoma of the pancreas, intraepithelial neoplasia), salivary gland cancer (e.g., polymorphous salivary gland adenocarcinoma, salivary gland adenoid cystic carcinoma), oral cancer (e.g., oral squamous cell carcinoma), uterine cancer, gastric or gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor, myeloma (e.g., multiple myeloma), lymphoepithelial tumor, anal cancer (e.g., anal squamous cell carcinoma), prostate cancer (e.g., prostate adenocarcinoma), renal cell carcinoma, thymus carcinoma, gastroesophageal junction adenocarcinoma, testicular cancer, rhabdomyosarcoma (e.g., rhabdomyosarcoma, embryonal rhabdomyosarcoma), kidney papillary carcinoma, liver cancer (e.g., hepatocellular carcinoma, intrahepatic cholangiocarcinoma), carcinoid, myeloproliferative diseases (also known as myeloproliferative neoplasms (MPN); for example, 8pll myeloproliferative syndrome (EMS, also known as stem cell leukemia/lymphoma), acute Myelogenous Leukemia (AML), chronic Myelogenous Leukemia (CML)), lymphomas (e.g., T cell lymphoma, T lymphoblastic lymphoma, acute Lymphoblastic Leukemia (ALL), B cell lymphoma), myeloid and lymphoid tumors, chronic neutrophilic leukemia, phospho-urinary mesenchymal tumor, thyroid cancer (e.g., undifferentiated thyroid cancer) or cholangiocarcinoma.
In some embodiments of any of the methods or uses described herein, the cancer (e.g., FGFR-related cancer) is selected from the group consisting of: acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), juvenile cancer, adrenocortical carcinoma, anal carcinoma, appendiceal carcinoma, astrocytoma, atypical teratoma-like/rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, burkitt's lymphoma, carcinoid, unidentified primary carcinoma, cardiac tumor, cervical cancer, childhood cancer, chordoma, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative tumor, localized neoplasm, colon cancer, colorectal cancer, craniopharyngeal tumor, cutaneous T-cell lymphoma, cutaneous angiosarcoma, cholangiocarcinoma, ductal carcinoma in situ, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma Ewing sarcoma, extracranial germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, bone fibrous cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic disease, glioma, hairy cell tumor, hairy cell leukemia, head and neck cancer, breast tumor, head and neck tumor, CNS tumor, primary CNS tumor, heart cancer, hepatocellular carcinoma, histiocytosis, hodgkin's lymphoma, hypopharynx cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kaposi's sarcoma, renal cancer, langerhans' cell cytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant bone fibrous cell tumor, bone cancer, melanoma, merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer, midline carcinoma, oral cancer, multiple endocrine tumor syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, neoplasm by site, neoplasm, myelogenous leukemia, multiple myeloma, myeloproliferative neoplasm, nasal and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer, lung neoplasm, respiratory tract tumor, bronchial carcinoma, bronchogenic neoplasm, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma; paranasal and nasal cancers, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma, pleural pneumoblastoma, pregnancy-associated breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, colon tumor, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, sarcoma, sezary syndrome, skin cancer, spitz tumor, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer, gastric cancer, T cell lymphoma, testicular cancer, throat cancer, thymoma and thymus cancer, thyroid cancer, renal pelvis and ureter transitional cell carcinoma, unknown primary cancer, urinary tract cancer, uterine sarcoma, vaginal cancer, vulval cancer and Wilms tumors.
In some embodiments, the hematologic cancer (e.g., a hematologic cancer that is associated with FGFR) is selected from the group consisting of: leukemias, lymphomas (non-hodgkin lymphomas), hodgkin's disease (also known as hodgkin's lymphoma), and myelomas, such as Acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), acute Promyelocytic Leukemia (APL), chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myelomonocytic leukemia (CMML), chronic Neutrophilic Leukemia (CNL), acute Undifferentiated Leukemia (AUL), anaplastic Large Cell Lymphoma (ALCL), prolymphocytic leukemia (PML), juvenile myelomonocytic leukemia (JMML), adult T cell ALL, AML with three-line myelodysplasia (AML/TMDS), mixed-line leukemia (MLL), myelodysplastic syndrome (MDS), myeloproliferative disease (MPD), and Multiple Myeloma (MM).
Other examples of hematological cancers include myeloproliferative diseases (MPD), such as Polycythemia Vera (PV), primary thrombocytopenia (ET), and idiopathic primary myelofibrosis (IMF/IPF/PMF). In some embodiments, the hematologic cancer (e.g., a hematologic cancer of FGFR-related cancer) is AML or CMML. In some embodiments, the cancer (e.g., FGFR-related cancer) is a solid tumor. Examples of solid tumors (e.g., solid tumors of FGFR-related cancers) include, for example, lung cancer (e.g., lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer), bladder cancer, colorectal cancer, brain cancer, testicular cancer, cholangiocarcinoma, cervical cancer, prostate cancer, and seminomas. See, e.g., turner and Grose, nature review for cancer (Nat. Rev. Cancer), 10 (2): 116-129,2010.
In some embodiments, the cancer is selected from the group consisting of: bladder cancer, brain cancer, breast cancer, bile duct cancer, head and neck cancer, lung cancer, multiple myeloma, rhabdomyosarcoma, urinary tract cancer, and uterine cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.
In some embodiments, the FGFR 1-related cancer is selected from the group consisting of lung cancer, breast cancer, and brain cancer.
In some embodiments, the cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer.
In some embodiments, the FGFR 2-related cancer is selected from the group consisting of breast cancer, uterine cancer, cholangiocarcinoma, and lung cancer. In some embodiments, the cancer is selected from the group consisting of lung cancer, bladder cancer, urinary tract cancer, multiple myeloma, and head and neck cancer.
In some embodiments, the FGFR 3-related cancer is selected from the group consisting of lung cancer, bladder cancer, urinary tract cancer, multiple myeloma, and head and neck cancer.
In some embodiments, the cancer is selected from the group consisting of lung cancer, rhabdomyosarcoma, and breast cancer.
In some embodiments, the FGFR 4-associated cancer is selected from the group consisting of lung cancer, rhabdomyosarcoma, and breast cancer.
In some aspects, compounds of the disclosure can be used to treat cancers associated with the expansion or overexpression of FGFR1, e.g., breast cancer (cancer) or carcinoma (carpinoma) (e.g., hormone receptor positive breast cancer, ductal carcinoma (breast)), pancreatic ductal carcinoma adenocarcinoma, pancreatic exocrine carcinoma, smoking-related lung cancer, small cell lung cancer, lung adenocarcinoma, non-small cell lung cancer, squamous cell lung cancer or carcinoma, prostate cancer or carcinoma, ovarian cancer, fallopian tube cancer, bladder cancer, rhabdomyosarcoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), esophageal cancer (e.g., esophageal squamous cell carcinoma), sarcoma (e.g., osteosarcoma), hepatocellular carcinoma, renal cell carcinoma, colorectal cancer (e.g., colorectal adenocarcinoma), prostate cancer, salivary gland tumor, glioblastoma multiforme, bladder cancer, urothelial carcinoma, unknown primary carcinoma, squamous non-lung tumor, gastric cancer, gastroesophageal junction carcinoma, adenoid cystic carcinoma, squamous cell carcinoma, oral squamous cell carcinoma, cholangiocarcinoma, leiomyosal sarcoma, melanoma, neuroendocrine carcinoma, squamous cell carcinoma, uterine sarcoma.
In some aspects, compounds of the disclosure may be used to treat cancers associated with FGFR2 expansion, e.g., gastric cancer, gastroesophageal junction adenocarcinoma, breast cancer (e.g., triple negative breast cancer), colon cancer, colorectal cancer (e.g., colorectal adenocarcinoma), urothelial cancer, bladder adenocarcinoma, unidentified primary cancer, cholangiocarcinoma, endometrial adenocarcinoma, esophageal adenocarcinoma, gallbladder carcinoma, ovarian cancer, fallopian tube carcinoma, exocrine pancreatic carcinoma, sarcoma, squamous cell carcinoma.
In some aspects, the compounds of the present disclosure are useful for treating cancers associated with FGFR2 overexpression, e.g., mucoid fatty cancer, rectal cancer, renal cell carcinoma, breast cancer.
In some aspects, the compounds of the present disclosure are useful for treating cancers associated with upregulation of FGFR3 activity, e.g., colorectal cancer, hepatocellular carcinoma, pancreatic exocrine cancer. In some aspects, the compounds of the present disclosure are useful for treating cancers associated with overexpression of FGFR3 activity, e.g., multiple myeloma, thyroid cancer. In some aspects, the compounds of the present disclosure are useful for treating cancers associated with expansion of FGFR3 activity, e.g., bladder and salivary gland-like cystic cancers, urothelial cancers, breast cancers, carcinoids, unidentified primary cancers, colorectal cancers (e.g., colorectal adenocarcinoma), gall bladder cancers, stomach cancers, gastroesophageal junction adenocarcinomas, gliomas, mesotheliomas, non-small cell lung cancers, ovarian cancers, fallopian tube cancers, exocrine pancreatic cancers.
In some aspects, the compounds of the present disclosure are useful for treating cancers associated with FGFR4 amplification, e.g., rhabdomyosarcoma, prostate cancer or cancer, breast cancer, urothelial cancer, carcinoid, unidentified primary cancer, esophageal adenocarcinoma, head and neck cancer, hepatocellular carcinoma, non-small cell lung cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, renal cell carcinoma.
In some aspects, the compounds of the present disclosure are useful for treating cancers associated with upregulation of FGFR4 activity, e.g., colorectal cancer, hepatocellular carcinoma, adrenal cancer, breast cancer.
In some aspects, the compounds of the present disclosure are useful for treating cancers associated with over-expression of FGFR4 activity, e.g., pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma.
In some aspects, the compounds of the present disclosure are more selective for one FGFR than another. As used herein, a compound "selective" for a first target over a second target means that the compound has greater activity against the first target than the second target. The fold selectivity may be calculated by any method known in the art. For example, fold selectivity can be calculated by dividing the IC50 value (or Kd value) of a compound for a second target (e.g., FGFR l) by the IC50 value of the same compound for a first target (e.g., FGFR2 or FGFR 3). The IC50 value may be determined by any method known in the art. In some embodiments, the compound is first determined to have an activity of less than 500nM on the first target. In some embodiments, the compound is first determined to have an activity of less than 500nM on the second target.
For example, in some aspects, the compounds of the present disclosure are more selective for FGFR3 than for FGFR 1. In some aspects, the compound is at least 3-fold more selective for FGFR3 than for FGFR 1. In some aspects, the compound is 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000-fold more selective for FGFR3 than FGFR 1.
In some aspects, the compounds of the disclosure are more selective for FGFR2 than for FGFR 1. In some aspects, the compound is at least 3-fold more selective for FGFR2 than for FGFR 1. In some aspects, the compound is 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 75, 100, 200, 500, or 1000-fold more selective for FGFR2 than FGFR 1.
In some aspects, compounds of the disclosure are selective for a first FGFR family member (e.g., FGFR2 or FGFR 3) over a second FGFR family member (e.g., FGFR1 or FGFR 4). In some aspects, the compounds of the disclosure are at least 3-fold more selective for a first FGFR family member than for a second FGFR family member. In some aspects, the compound is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000-fold more selective for the first FGFR family member than the second FGFR family member.
In some aspects, the compounds of the present disclosure are more selective for FGFR kinase than for another kinase other than FGFR kinase. For example, the compounds of the present disclosure are at least 3-fold more selective for FGFR kinase than for another kinase that is not an FGFR kinase. In some aspects, the compounds of the present disclosure are at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 200, 300, 400, 500, 600, 700, 800, 900, or at least 1000-fold more selective for FGFR kinases than for non-FGFR kinases. Kinases other than FGFR kinases include, for example, KDR kinase and Aurora B kinase.
In some embodiments, the compounds of the present disclosure exhibit brain and/or Central Nervous System (CNS) penetration. Such compounds are capable of crossing the blood brain barrier and inhibiting FGFR kinases in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treating a subject with cancer (e.g., FGFR-related cancer, e.g., FGFR-related brain cancer or CNS cancer) can include administering (e.g., orally administering) a compound to the subject. In some such embodiments, the compounds provided herein can be used to treat a primary brain tumor or a metastatic brain tumor. For example, FGFR-associated primary brain tumors or metastatic brain tumors.
In some embodiments, the compounds of the present disclosure exhibit one or more of high GI absorption, low clearance, and low likelihood of drug-drug interactions.
In some aspects, the compounds of the present disclosure can be used to treat a subject diagnosed with (or identified as having) an FGFR-related disease or disorder (e.g., FGFR-related cancer), comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure. Also provided herein are methods of treating a subject identified or diagnosed as having an FGFR-related disease or disorder (e.g., an FGFR-related cancer) comprising administering to the subject a therapeutically effective amount of a compound of the disclosure. In some embodiments, a subject having an FGFR-related disease or disorder (e.g., an FGFR-related cancer) has been identified or diagnosed by using a test or assay approved by a regulatory body, e.g., FDA approved, for identifying an FGFR gene, an FGFR kinase, or any expression or activity or level imbalance thereof in the subject or a biopsy sample from the subject, or by performing any of the non-limiting assay examples described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the FGFR-related disease or disorder is FGFR-related cancer. For example, the FGFR-associated cancer can be a cancer comprising one or more FGFR inhibitor resistance mutations.
Also provided are methods for treating a disease or disorder in a subject in need thereof, the method comprising: (a) detecting a FGFR-associated disease or disorder in a subject; (b) Administering to a subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or an immunotherapy). In some embodiments, the subject has been previously treated with the first FGFR inhibitor or has been previously treated with another treatment. In some embodiments, the subject is determined to have an FGFR-associated disease or disorder by using a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying an FGFR gene, an FGFR kinase, or any expression or activity or level imbalance thereof in the subject or a biopsy sample from the subject, or by performing any of the non-limiting assay examples described herein. In some embodiments, the test or assay is provided as a kit.
Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting FGFR-associated cancer in a subject; (b) Administering to a subject a therapeutically effective amount of a compound of the present disclosure. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or an immunotherapy). In some embodiments, the subject has previously received a first FGFR inhibitor treatment or has previously received another anti-cancer treatment, e.g., at least partially resecting a tumor or radiation therapy. In some embodiments, the subject is determined to have FGFR-associated cancer by using a regulatory agency-approved, e.g., FDA-approved, test or assay for identifying a FGFR gene, FGFR kinase, or any expression or activity or level imbalance thereof in the subject or a biopsy sample from the subject, or by performing any of the non-limiting assay examples described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is FGFR-associated cancer. For example, the FGFR-associated cancer can be a cancer comprising one or more FGFR inhibitor resistance mutations. In some embodiments, the cancer is FGFR-associated cancer. For example, the FGFR-associated cancer can be a cancer comprising one or more FGFR activating mutations.
Also provided are methods for treating a subject, comprising assaying a sample obtained from the subject to determine whether the subject has a deregulation of an FGFR gene, an FGFR kinase, or any expression or activity or level thereof, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or solvate thereof, to the subject determined to have a deregulation of an FGFR gene, an FGFR kinase, or any expression or activity or level thereof. Some embodiments of these methods further comprise administering to the subject an additional therapy or therapeutic agent (e.g., a second FGFR inhibitor, a second compound of the disclosure, or an immunotherapy). In some embodiments of these methods, the subject has been previously treated with the first FGFR inhibitor or has been previously treated with another anti-cancer treatment, e.g., at least partially resecting the tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a FGFR-related disease or disorder (e.g., FGFR-related cancer), a subject exhibiting one or more symptoms of a FGFR-related disease or disorder (e.g., FGFR-related cancer), or a subject at elevated risk of developing a FGFR-related disease or disorder (e.g., FGFR-related cancer). In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is a regulatory agency approved assay, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy. Additional non-limiting assays useful in these methods are described herein. Additional assays are also known in the art. In some embodiments, the FGFR gene, FGFR kinase, or any expression or activity or level deregulation thereof comprises one or more FGFR inhibitor resistance mutations.
Also provided herein is a method of selecting a treatment for a subject, wherein the method comprises the steps of: assaying a sample obtained from the subject to determine whether the subject has a deregulation of the FGFR gene, FGFR kinase, or any expression or activity or level thereof (e.g., one or more FGFR inhibitor resistance mutations), and identifying or diagnosing that the subject has a deregulation of the FGFR gene, FGFR kinase, or any expression or activity or level thereof, such as having an FGFR-associated cancer. Some embodiments further comprise administering the selected treatment to a subject identified or diagnosed as having FGFR-associated cancer. For example, in some embodiments, the selected treatment may comprise administering a therapeutically effective amount of a compound of the present disclosure to a subject identified or diagnosed as having FGFR-associated cancer. In some embodiments, the assay is an in vitro assay. For example, the assay utilizes next generation sequencing, immunohistochemistry, or split FISH analysis. In some embodiments, the assay is regulatory agency approved, e.g., an FDA approved kit. In some embodiments, the assay is a liquid biopsy.
Also provided herein are methods of treating FGFR-associated cancer in a subject comprising (a) administering one or more doses (e.g., two or more, three or more, four or more, five or more, or ten or more doses) of a first FGFR kinase inhibitor to a subject identified or diagnosed as having an FGFR-associated cancer (e.g., any of the types of FGFR-associated cancer described herein) (e.g., identified or diagnosed as having an FGFR-associated cancer using any of the exemplary methods described herein or known in the art); (b) After step (a), determining the level of circulating tumor DNA in a biological sample obtained from the subject (e.g., a biological sample comprising blood, serum, or plasma); (c) A subject identified as having the same or elevated levels of circulating tumor DNA as compared to a reference level of circulating tumor DNA (e.g., any reference level of circulating tumor DNA described herein) is administered a therapeutically effective amount of a second FGFR inhibitor or a compound of the disclosure as monotherapy or in combination with additional therapies or therapeutic agents. In some examples of these methods, the reference level of circulating tumor DNA is the level of circulating tumor DNA in a biological sample obtained from the subject prior to step (a). Some embodiments of these methods further comprise determining the level of circulating tumor DNA in the biological sample obtained from the subject prior to step (a). In some examples of these methods, the reference level of circulating tumor DNA is a threshold level of circulating tumor DNA (e.g., the average level of circulating tumor DNA in a population of subjects having similar FGFR-associated cancer and having similar staged FGFR-associated cancer, but receiving no treatment or placebo, or having not received treatment). In some examples of these methods, the first FGFR inhibitor is: ARQ-087, ASP5878, AZD4547, B-701, BAY1179470, BAY1187982, BGJ398, brivanib (brivanib), debio 1347, doritinib (dovitinib), E7090, erdasatinib (erdafitinib), FPA144, HMPL-453, INCB054828, lenvartinib, derittinib (lucitanib), LY3076226, MAX-40279, nidaminib, orantinib, petatinib, panatinib (ponatinib), PRN1371, luo Jiati ni (rogatainib), softinib (sulfatinib), TAS-120 or RLY-4008.
The compounds of the present disclosure may also be administered with additional therapies or therapeutic agents. In some aspects, the additional therapies or therapeutic agents include one or more of radiation therapy, chemotherapy (e.g., any of the exemplary chemotherapeutic agents described herein or known in the art), checkpoint inhibitors (e.g., any of the exemplary checkpoint inhibitors described herein or known in the art), surgery (e.g., at least partially resecting a tumor), and one or more other kinase inhibitors (e.g., any of the kinase inhibitors described herein or known in the art).
The compounds of the present disclosure may also be used as adjuvants for cancer treatment, i.e., they may be used in combination with one or more additional therapies or therapeutic agents, such as chemotherapeutic agents that act through the same or different mechanisms of action. In some embodiments, the compounds of the present disclosure may be used prior to administration of an additional therapeutic agent or additional therapy. For example, one or more doses of a compound of the present disclosure may be administered to a subject in need thereof for a period of time, followed by at least partial tumor resection. In some embodiments, treatment with one or more doses of a compound of the present disclosure reduces the size of the tumor (e.g., tumor burden) prior to at least partial resection of the tumor. In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, e.g., a first FGFR inhibitor or a multi-kinase inhibitor, immunotherapy, radiation therapy, or a platinum-based drug (e.g., cisplatin)). In some embodiments, the subject has a cancer (e.g., a locally advanced or metastatic tumor) refractory or intolerant to prior therapies (e.g., administration of a chemotherapeutic agent, e.g., a first FGFR inhibitor or a multi-kinase inhibitor, immunotherapy, radiation therapy, or platinum-based drugs (e.g., cisplatin)).
In some embodiments of any of the methods described herein, the compounds of the present disclosure are administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic agents (e.g., chemotherapeutic agents). Non-limiting examples of additional therapeutic agents include: other FGFR targeted therapeutics (i.e., first or second FGFR kinase inhibitors), other kinase inhibitors (e.g., receptor tyrosine kinase targeted therapeutics (e.g., trk inhibitors or EGFR inhibitors)), signal transduction pathway inhibitors, checkpoint inhibitors, apoptosis pathway modulators (e.g., obatacrax); cytotoxic chemotherapy, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy and radiotherapy.
Also provided herein are methods of treating a disease or disorder comprising administering to a subject in need thereof a pharmaceutical combination for treating the disease or disorder comprising (a) a compound of the present disclosure, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier, for simultaneous, separate or sequential use in treating the disease or disorder, wherein the amounts of the compound of the present disclosure and the additional therapeutic agent together are effective to treat the disease or disorder. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered simultaneously as separate doses. In some embodiments, the compound of the present disclosure and the additional therapeutic agent are administered sequentially in any order as separate doses, in jointly therapeutically effective amounts, e.g., in daily or intermittent doses. In some embodiments, the compounds of the present disclosure and the additional therapeutic agent are administered simultaneously as a combined dose. In some embodiments, the disease or disorder is a FGFR-related disease or disorder. In some embodiments, the subject has been administered one or more doses of a compound of the present disclosure prior to administration of the pharmaceutical composition.
In some embodiments, the treatment period is at least 7 days (e.g., at least or about 8 days, at least or about 9 days, at least or about 10 days, at least or about 11 days, at least or about 12 days, at least or about 13 days, at least or about 14 days, at least or about 15 days, at least or about 16 days, at least or about 17 days, at least or about 18 days, at least or about 19 days, at least or about 20 days, at least or about 21 days, at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, or at least or about 30 days).
In some embodiments, the treatment period is at least 21 days (e.g., at least or about 22 days, at least or about 23 days, at least or about 24 days, at least or about 25 days, at least or about 26 days, at least or about 27 days, at least or about 28 days, at least or about 29 days, at least or about 30 days, at least or about 31 days, at least or about 32 days, at least or about 33 days, at least or about 34 days, at least or about 35 days, at least or about 36 days, at least or about 37 days, at least or about 38 days, at least or about 39 days, or at least or about 40 days).
Also provided herein are pharmaceutical compositions containing a compound of the present disclosure as an active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical application. In preparing the compositions provided herein, the active ingredient is typically admixed with, diluted with or otherwise enclosed in a carrier such as in the form of a capsule, sachet, paper or other container. When an adjuvant is used as a diluent, it may be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the composition may be in the form of: tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders. In some embodiments, the composition is formulated for oral administration. In some embodiments, the composition is formulated as a tablet or capsule.
Compositions comprising compounds of the present disclosure may be formulated in unit dosage forms, each dosage containing from about 5 to about 1,000mg (1 g), more typically from about 100mg to about 500mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units for human subjects and other subjects, each unit containing a predetermined amount of active material (i.e., a compound of the present disclosure) to produce the desired therapeutic effect, as well as suitable pharmaceutical excipients.
In some embodiments, the compositions provided herein contain from about 5mg to about 50mg of the active ingredient, i.e., a compound of the present disclosure. Those of ordinary skill in the art will appreciate that this is embodied as containing from about 5mg to about 10mg, from about 10mg to about 15mg, from about 15mg to about 20mg, from about 20mg to about 25mg, from about 25mg to about 30mg, from about 30mg to about 35mg, from about 35mg to about 40mg, from about 40mg to about 45mg, or from about 45mg to about 50mg of the active ingredient. In some embodiments, the compositions provided herein contain from about 50mg to about 500mg of the active ingredient. Those of ordinary skill in the art will understand that this includes containing from about 50mg to about 100mg, from about 100mg to about 150mg, from about 150mg to about 200mg, from about 200mg to about 250mg, from about 250mg to about 300mg, from about 350mg to about 400mg, or from about 450mg to about 500mg of the active ingredient. In some embodiments, the compositions provided herein contain from about 500mg to about 1,000mg of the active ingredient. Those of ordinary skill in the art will understand that this includes an active ingredient containing from about 500mg to about 550mg, from about 550mg to about 600mg, from about 600mg to about 650mg, from about 650mg to about 700mg, from about 700mg to about 750mg, from about 750mg to about 800mg, from about 800mg to about 850mg, from about 850mg to about 900mg, from about 900mg to about 950mg, or from about 950mg to about 1,000 mg.
The active compounds can be effective over a wide dosage range and are generally administered in pharmaceutically effective amounts. However, it will be appreciated that the amount of the compound actually administered will generally be determined by the physician, in light of the relevant circumstances, including the condition to be treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual subject, the severity of the subject's symptoms, and the like.
In some embodiments, the compounds provided herein may be administered in an amount ranging from about 1mg/kg to about 100mg/kg. In some embodiments, the compounds provided herein may be administered in an amount of about 1mg/kg to about 20mg/kg, about 5mg/kg to about 50mg/kg, about 10mg/kg to about 40mg/kg, about 15mg/kg to about 45mg/kg, about 20mg/kg to about 60mg/kg, or about 40mg/kg to about 70 mg/kg. For example, about 5mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 55mg/kg, about 60mg/kg, about 65mg/kg, about 70mg/kg, about 75mg/kg, about 80mg/kg, about 85mg/kg, about 90mg/kg, about 95mg/kg, or about 100mg/kg. In some embodiments, such administration may be once daily or twice daily (BID) administration.
Examples
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It should be understood that the scope of the present invention is not limited by the following examples and scope of preparation.
In several embodiments, where a single enantiomer is provided, the enantiomer may be isolated by conventional methods (chiral chromatography, preparation of diastereomeric salts, chiral derivatization, crystallization, enzymatic reaction, etc.). In several embodiments, the chiral intermediate compounds are purified to produce enantiomerically pure (or substantially enantiomerically pure, enantiomerically enriched, etc.) intermediates.
Example 1.4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -1, 4-thiazine 1, 1-dioxide
Step 1.5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole. A mixture of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (1.0 g,2.90mmol,1.0 eq.) of [ (1S) -1- (3, 5-dichloro-4-pyridinyl) ethyl ] methanesulfonate (780 mg,2.90mmol,1.0 eq.) and cesium carbonate (1.41 g,14.45mmol,1.5 eq.) in N, N-dimethylformamide (20 mL) was heated at 130℃for 16h. Volatiles were removed under reduced pressure and the residue was suspended in saturated ammonium chloride (50 mL). The solution was extracted with ethyl acetate (3X 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified on a Buchi automatic chromatography system (Sorbech 40g silica gel column) eluting with a 0 to 30% ethyl acetate gradient in heptane to give a white solid (1.01 g,88% yield). Analysis: LCMS: M/z=517.2 (m+h).
Step 2.3- (6-chloro-3-pyridinyl) -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1-tetrahydropyran-2-yl-indazole. To a solution of 5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (1.32 g,2.55mmol,1.0 eq.), 2-chloro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (780 mg,3.31mmol,1.3 eq.), [1,1' bis (diphenylphosphine) ferrocene ] dichloropalladium (II) (190 mg,0.255mmol,0.1 eq.) and potassium carbonate (700 mg,5.1mmol,2.0 eq.) in 1, 4-dioxane (20 mL) and water (1 mL) was purged with nitrogen for 15 minutes. After heating at 90 ℃ for 16h, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was suspended in saturated sodium bicarbonate (20 mL) and extracted with ethyl acetate (3X 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (Sorbech 25g silica gel column) eluting with a 0 to 50% ethyl acetate gradient in heptane to give a white solid (870 mg,68% yield). Analysis: LCMS: M/z=503.1 (m+h).
Step 3.4- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyridin-2-yl) thiomorpholin 1, 1-dioxide. To a solution of the product from step 2 (280 mg,0.56mmol,1.0 eq), (150 mg,1.12mmol,2.0 eq), xantphos (64 mg,0.11mmol,0.2 eq), tris (dibenzylideneacetone) dipalladium (0) (51 mg,0.06mmol,0.1 eq) and cesium carbonate (264 mg,1.1mmol,2.0 eq) in N, N-dimethylformamide (10 mL) was sparged nitrogen for 15 minutes. After heating at 95 ℃ for 16 hours, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (Sorbech 40g column), eluting with a 0 to 100% ethyl acetate gradient in heptane, to give a brown solid (290 mg,89% yield). Analysis: LCMS: M/z=601.2 (m+h).
Step 4.4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ]]-1H-indazol-3-yl]-2-pyridyl group]-1, 4-thiazinan 1, 1-dioxide. A solution of the step 3 product (290 mg,0.47mmol,1.0 eq.) in 1, 4-dioxane (2.0 mL) and water (0.5 mL) was treated with 4M HCl in 1, 4-dioxane (0.95 mL,3.79mmol,8.0 eq.) and heated in a CEM microwave reactor at 100deg.C for 1 hour. Volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL) followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 80% acetonitrile in water, to give a white solid (29 mg,12% yield). Analysis: LCMS: M/z= 518.1 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.04(s,1H),8.60(s,2H),8.59(d,J＝2.1Hz,1H),7.93(dd,J＝2.4,8.9Hz,1H),7.47(d,J＝9.0Hz,1H),7.20-7.15(m,2H),7.10(dd,J＝2.3,9.0Hz,1H),6.10(q,J＝6.7Hz,1H),4.18-4.11(m,4H),3.20-3.15(m,4H),1.76(d,J＝6.6Hz,3H)。
EXAMPLE 2 (R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (6- (piperazin-1-yl) pyridin-3-yl) -1H-indazole dihydrochloride
Step 1.4- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester. To a solution of 5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (3.1 g,5.99mmol,1 eq.) and 4- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyridinyl ] piperazine-1-carboxylic acid tert-butyl ester (3.03 g,7.78mmol,1.3 eq.) in a 20:1 mixture of 1, 4-dioxane and water (50 mL) was purged with nitrogen for 10 minutes. Potassium carbonate (1.65 g,11.98mmol,2.0 eq.) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium (II) dichloride (0.44 g,0.6mmol,0.1 eq.) were added and the reaction mixture was purged with nitrogen for another 5 minutes. The reaction was heated at 90℃for 16 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure. The residue was diluted with water (100 mL) and dichloromethane (100 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was pre-adsorbed onto silica gel (5 g) and purified on an intel automated chromatography system (Sorbtech 120g silica gel column) eluting with a 0 to 30% ethyl acetate gradient in heptane to give a white solid (2.19 g,56% yield). Analysis: LCMS, M/z=653 (m+h).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (6- (piperazin-1-yl) pyridin-3-yl) -1H-indazole dihydrochloride. A solution of the step 1 product (70.0 mg,0.11mmol,1.0 eq.) in 1, 4-dioxane (1.0 mL) was treated with 4M HCl in dioxane (0.27 mL,1.1mmol,10.0 eq.) overnight at room temperature. Volatiles were removed under reduced pressure. The residue was triturated with a 1 to 3 mixture of dichloromethane and methanol (2.8 mL) to give a white solid (23.0 mg,40% yield). Analysis: LCMS: M/z= 469.2 (free base m+h). 1 H NMR(400MHz,DMSO-d6)δ9.47(br s,2H),8.59(s,2H),8.50(d,J＝2.1Hz,1H),8.13(dd,J＝2.0,9.0Hz,1H),7.50(d,J＝9.0Hz,1H),7.29(d,J＝9.2Hz,1H),7.18(d,J＝1.8Hz,1H),7.11(dd,J＝2.2,9.0Hz,1H),6.12(q,J＝6.6Hz,1H),3.97-3.93(m,4H),3.27(br s,4H),1.76(d,J＝6.6Hz,3H)。
EXAMPLE 3 [4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] piperazin-1-yl ] -morpholinomethione
(4- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyridin-2-yl) piperazin-1-yl) (morpholino) methanone. Triethylamine (28.0 uL,0.204mmol,1.1 eq.) and morpholine-4-carbonyl chloride (30.5 mg,0.204mmol,1.1 eq.) were added to a solution of example 2 (102.6 mg,0.185mmol,1 eq.) in anhydrous THF (3 mL at room temperature). After stirring for 1 hour, the reaction was diluted with saturated brine (20 mL) and dichloromethane (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a yellow solid (90 mg,73% yield). Analysis: LCMS: M/z=666 (m+h).
(R) - (4- (5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) pyridin-2-yl) piperazin-1-yl) (morpholinyl) methanone. Example 3 step 1 (90 mg,0.135mmol,1 eq.) in 1, 4-dioxane (4.0 mL) and water (1 mL) was treated with 4M HCl in 1, 4-dioxane (0.27 mL,1.08mmol,8.0 eq.) and heated in a CEM microwave reactor at 60 ℃ for 20 minutes. 4M HCl in 1, 4-dioxane (0.27 mL,1.08mmol,8.0 eq.) was added and the reaction was heated in a CEM microwave reactor at 60℃for an additional 20 minutes. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in methanol (20 mL), treated with MP-carbonate resin (3.2 mmol/g,1 g), stirred for 30 min, filtered and concentrated under reduced pressure. The residue was pre-adsorbed onto Celite (1 g) and purified on an intel automated chromatographic system (RediSep Rf Gold HP C, 15.5g column), eluting with a 0 to 100% acetonitrile gradient in water. The product-containing fractions were collected and lyophilized to give a white solid (36.9 mg,47% yield). Analysis: LCMS: M/z=582.2 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.01(br s,1H),8.60(s,2H),8.56(d,J＝2.2Hz,1H),7.89(dd,J＝2.4,8.9Hz,1H),7.47(d,J＝9.0Hz,1H),7.16(d,J＝2.1Hz,1H),7.09(dd,J＝2.3,9.0Hz,1H),6.98(d,J＝8.8Hz,1H),6.10(q,J＝6.6Hz,1H),3.63-3.57(m,8H),3.33-3.30(m,4H),3.22-3.18(m,4H),1.76(d,J＝6.6Hz,3H)。
examples 4-9 were synthesized using the procedure of example 3.
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EXAMPLE 10.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- (5-fluoro-6-piperazin-1-yl-3-pyridinyl) -1H-indazole
Using the procedure of example 1, synthesis of example using 2-chloro-3-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine and BOC-piperazine gave a white solid. Analysis: LCMS: M/z= 487.0 (m+h); 1 H NMR(400MHz,CDCl 3 )δ8.50(s,1H),8.44(s,2H),7.66(dd,J＝1.7,14.1Hz,1H),7.38(d,J＝8.9Hz,1H),7.19(d,J＝2.0Hz,1H),7.15(dd,J＝2.2,9.0Hz,1H),6.06(q,J＝6.6Hz,1H),3.61-3.53(m,4H),3.12-3.01(m,4H),1.83(d,J＝6.7Hz,3H)。
EXAMPLE 11.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- (2-piperazin-1-ylpyrimidin-5-yl) -1H-indazole
Using 4- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidin-2-yl]Tert-butyl piperazine-1-carboxylate and the procedure of example 2 example 11 was synthesized to give an off-white solid (150 mg,64% yield). Analysis: LCMS: M/z=470.1 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.11(br s,1H),8.75(s,2H),8.57(s,2H),7.47(d,J＝8.9Hz,1H),7.24(d,J＝2.0Hz,1H),7.09(dd,J＝2.2,9.0Hz,1H),6.14(q,J＝6.6Hz,1H),3.82-3.67(m,4H),2.87-2.68(m,4H),1.75(d,J＝6.7Hz,3H)。
example 12.4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] piperazine-1-carboxamide
(R) -4- (5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) pyridin-2-yl) piperazine-1-carboxamide. (trimethylsilyl) isocyanate (66. Mu.L, 0.49mmol,1.1 eq.) and triethylamine (68. Mu.L, 0.49 mmo) were reacted at room temperaturel,1.1 eq.) was added sequentially to a solution of example 2 (208 mg,0.45mmol,1 eq.) in anhydrous THF (5 mL). After stirring for 20 hours, volatiles were removed under reduced pressure and the crude product was pre-adsorbed onto Celite (0.5 g) and then purified on an intel automated chromatographic system (RediSep Rf Gold HP C, 15.5g column), eluting with a gradient of 0 to 100% acetonitrile in water. The product-containing fractions were collected and lyophilized to give a white solid (36.0 mg,16% yield). Analysis: LCMS: M/z= 512.2 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.02(br s,1H),8.60(s,2H),8.56(d,J＝2.0Hz,1H),7.87(dd,J＝2.4,8.8Hz,1H),7.46(d,J＝8.9Hz,1H),7.16(d,J＝2.1Hz,1H),7.09(dd,J＝2.3,9.0Hz,1H),7.01(d,J＝8.9Hz,1H),6.14-6.02(m,3H),3.62-3.50(m,5H),3.50-3.39(m,4H),1.76(d,J＝6.6Hz,3H)。
EXAMPLE 13 [4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -3-fluoro-2-pyridinyl ] piperazin-1-yl ] - (4-methylpiperazin-1-yl) methanone
(R) - (4- (5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) -3-fluoropyridin-2-yl) piperazin-1-yl) (4-methylpiperazin-1-yl) methanone. Triethylamine (21.6. Mu.L, 0.156mmol,2.0 eq.) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (17.6 mg,0.089mmol,1.0 eq.) were added sequentially to a solution of example 10 (43 mg,0.089mmol,1 eq.) in anhydrous THF (5 mL) at room temperature. After stirring for 1 hour, triethylamine (21.6. Mu.L, 0.156mmol,2.0 eq.) and 4-methylpiperazine-1-carbonyl chloride hydrochloride (17.6 mg,0.089mmol,1.0 eq.) were additionally added and the reaction was stirred at room temperature for 20 hours. Volatiles were removed under reduced pressure. The crude product was pre-adsorbed onto Celite (0.5 g) and purified on an intel automated chromatographic system (RediSep Rf Gold HP C, 15.5g column), eluting with a 0 to 100% acetonitrile gradient in water. Further purification on an intel automated chromatography system (Sorbtech 25g silica gel column) eluting with a 0 to 15% methanol gradient in dichloromethane afforded a white solid (12.0 mg,22% yield). Analysis: LCMS: M/z=613.2 (m+h); 1 H NMR(400MHz,CDCl 3 )δ10.51(br s,1H),8.50(t,J＝1.5Hz,1H),8.43(s,2H),7.69(dd,J＝1.8,13.9Hz,1H),7.37(dd,J＝0.4,8.9Hz,1H),7.17(d,J＝1.8Hz,1H),7.14(d,J＝9.3Hz,1H),6.05(q,J＝6.7Hz,1H),3.62-3.57(m,4H),3.47-3.42(m,4H),3.40-3.34(m,4H),2.44(br t,J＝4.8Hz,4H),2.33(s,3H),1.82(d,J＝6.7Hz,3H)。
EXAMPLE 14.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [2- (4-methylsulfonylpiperazin-1-yl) pyrimidin-5-yl ] -1H-indazole
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (2- (4- (methylsulfonyl) piperazin-1-yl) pyrimidin-5-yl) -1H-indazole. Methanesulfonyl chloride (25 mg,0.22mmol,1 eq.) in acetonitrile (1 mL) was added dropwise to a solution of example 11 (104 mg,0.22mmol,1 eq.) in pyridine (10 mL) at 0 ℃. After stirring at room temperature for 16 hours, methanesulfonyl chloride (13 mg,0.11mmol,0.5 eq.) in acetonitrile (0.5 mL) was additionally added. After stirring for 70 hours, the reaction was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an intel chip automated chromatography system (RediSep Rf GOLD 100g HP c18 column), eluting with a 0 to 100% acetonitrile gradient in water to give an off-white solid (20 mg,17% yield). Analysis: LCMS: M/z= 548.1 (m+h); 1 H NMR(400MHz,DMSO-d6)δ＝13.12(br s,1H),8.82(s,2H),8.57(s,2H),7.48(d,J＝9.0Hz,1H),7.26(d,J＝2.1Hz,1H),7.11(dd,J＝2.3,9.0Hz,1H),6.15(q,J＝6.7Hz,1H),4.00-3.91(m,4H),3.27-3.22(m,4H),2.92(s,3H),1.76(d,J＝6.6Hz,3H)。
EXAMPLE 15 [4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] pyrimidin-2-yl ] piperazin-1-yl ] - (4-methylpiperazin-1-yl) methanone
4-methylpiperazine-1-carbonyl chloride (44 mg,0.22mmol,1 eq.) was added to example 11 (104 mg, 0)22mmol,1 eq.) in pyridine (10 mL). After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an intel automated chromatography system ((RediSep Rf GOLD 100g HP c18 column), eluting with a 0 to 100% acetonitrile in water to give an off-white solid (30 mg,23% yield). Analysis LCMS: M/z=596.2 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.05(br s,1H),8.79(s,2H),8.57(s,2H),7.48(d,J＝9.2Hz,1H),7.25(d,J＝2.1Hz,1H),7.10(dd,J＝2.3,9.0Hz,1H),6.14(q,J＝6.7Hz,1H),3.88-3.79(m,4H),3.29-3.25(m,4H),3.24-3.17(m,4H),2.31(br t,J＝4.6Hz,4H),2.19(s,3H),1.76(d,J＝6.6Hz,3H)。
EXAMPLE 16.3- [6- (3, 6-diazabicyclo [3.1.1] hept-3-yl) -3-pyridinyl ] -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazole
Step 1.3- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester. To a solution of 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3-iodo-1-tetrahydropyran-2-yl-indazole (170 mg,0.33mmol,1.0 eq), 3- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-pyridinyl ] -3, 6-diazabicyclo [3.1.1] heptane-6-carboxylic acid tert-butyl ester (128 mg,0.40mmol,1.2 eq), [1,1' bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (24 mg,0.04mmol,0.1 eq) and potassium carbonate (91 mg,0.66mmol,2.0 eq) in 1, 4-dioxane (10 mL) and water (1 mL) was purged with nitrogen for 15 minutes, then heated at 90 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (Sorbech 25g silica gel column) eluting with a 0 to 70% ethyl acetate gradient in heptane to give a white solid (80 mg,36% yield). Analysis: LCMS: M/z= 665.1 (m+h).
Step 2.3- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) pyridin-2-yl) -3, 6-diazabicyclo [3.1.1]Heptane. A solution of the step 1 product (80 mg,0.13mmol,1.0 eq.) in 1, 4-dioxane (2.0 mL) and water (0.5 mL) was treated with 4M HCl in 1, 4-dioxane (0.65 mL,2.65mmol,20.0 eq.) and heated in a CEM microwave reactor at 100deg.C for 1 hour. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL) followed by the addition of MP-carbonate resin (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 100% acetonitrile in water. The product-containing fractions were lyophilized to give an off-white solid (8 mg,14% yield). Analysis: LCMS: M/z=481.1 (m+h); 1 h NMR (400 MHz, methanol-d 4) delta 8.55 (dd, j=0.5, 2.3hz, 1H), 8.46 (s, 2H), 7.97 (ddd, j=2.0, 4.5,8.6hz, 2H), 7.48-7.35 (m, 2H), 7.17 (dd, j=2.3, 9.0hz, 1H), 7.11 (d, j=2.1 hz, 1H), 6.87 (d, j=8.4 hz, 1H), 6.12 (q, j=6.6 hz, 1H), 4.52 (br d, j=6.1 hz, 2H), 4.12-3.99 (m, 4H), 3.18-3.06 (m, 1H), 1.97 (d, j=10.3 hz, 1H), 1.82 (d, j=6.7 hz, 3H).
EXAMPLE 17.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [ 5-fluoro-6- (4-methylsulfonyl-piperazin-1-yl) -3-pyridinyl ] -1H-indazole
Step 1.3- (6-chloro-4-fluoropyridin-3-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole. A solution of 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3-iodo-1-tetrahydropyran-2-yl-indazole (0.4 g,0.77mmol,1 eq.) and 2-chloro-4-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) pyridine (0.258 g,1.0mmol,1.3 eq.) in a 20:1 mixture of 1, 4-dioxane and water (10 mL) was purged with nitrogen for 15 minutes. Potassium carbonate (0.28 g,2.0mmol,2.6 eq.) and (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloride (56 mg,0.077mmol,0.01 eq.) were added and the reaction mixture was further purged with nitrogen for 5 minutes. The reaction was heated at 90℃for 16h. After cooling to room temperature, the reaction was concentrated under reduced pressure and diluted with saturated brine (20 mL) and dichloromethane (20 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was pre-adsorbed onto silica gel (1 g) and purified on an intel automated chromatography system (Sorbtech 40g silica gel column) eluting with a 5% to 50% ethyl acetate in heptane gradient to provide a white solid (360 mg,89% yield). Analysis: LCMS: M/z= 521.8 (m+h).
Step 2.4- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyridin-2-yl) piperazine-1-carboxylic acid tert-butyl ester. To a solution of the product of step 1 (360 mg,0.69mmol,1 eq.), BOC-piperazine (193 mg,1.04mmol,1.5 eq.), xantphos (80 mg,0.14mmol,0.2 eq.), tris (dibenzylideneacetone) dipalladium (0) (63 mg,0.07mmol,0.1 eq.) and cesium carbonate (450 mg,1.4mmol,2.0 eq.) in N, N-dimethylformamide (10 mL) was sparged nitrogen for 10 minutes. After heating at 95 ℃ for 16 hours, the reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (Sorbech 25g silica gel column) eluting with a 0 to 15% methanol gradient in dichloromethane to give a brown solid (107 mg,23% yield). Analysis: LCMS: M/z= 653.1 (m+h).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (4-fluoro-6- (piperazin-1-yl) pyridin-3-yl) -1H-indazole. A solution of the step 2 product (90 mg,0.14mmol,1 eq.) in 1, 4-dioxane (2.0 mL) and water (0.2 mL) was treated with 4M HCl in 1, 4-dioxane (0.7 mL,2.68mmol,20 eq.) and heated in a CEM microwave reactor at 100deg.C for 1 hour. Volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL) followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 25g column), eluting with a gradient of 0 to 80% acetonitrile in water, to give an off-white solid (15 mg,20% yield). Analysis: LCMS: M/z= 487.1 (m+h).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (4-fluoro-6- (4- (methylsulfonyl) piperazin-1-yl) pyridin-3-yl) -1H-indazole. Methanesulfonyl chloride (3 μl,0.04mmol,1.5 eq.) was added to a solution of the product of step 3 (15 mg,0.03mmol,1.0 eq.) in pyridine (2.0 mL) at room temperature. After stirring for 16 hours, volatiles were removed under reduced pressure. The residue was first purified on a Buchi automated chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 80% acetonitrile in water, and then again on a Teledyne ACCQPrep automated chromatography system (Waters Atlantis T3 Prep OBD column, 5 μm, 19X 250 mm), eluting with a gradient of 0 to 80% acetonitrile (containing 0.1% formic acid) in water. The product-containing fractions were lyophilized to give (R) -ADE-163 as a white solid (12 mg,70% yield). Analysis: LCMS: M/z=565.1 (m+h); 1 HNMR(400MHz,CD3OD)δ8.47(s,2H),8.36(d,J＝10.8Hz,1H),7.45(d,J＝9.0Hz,1H),7.17(dd,J＝2.4,9.0Hz,1H),6.86(t,J＝2.4Hz,1H),6.78(d,J＝13.7Hz,1H),6.05(q,J＝6.7Hz,1H),3.81-3.76(m,4H),3.38-3.34(m,4H),2.89(s,3H),1.80(d,J＝6.6Hz,3H)。
EXAMPLE 18.3- (6-chloro-3-pyridinyl) -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazole
Using the conditions of example 1, step 4, p 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-3-chloro-1-tetrahydropyran-2-yl-indazole deprotection. Analysis: LCMS: M/z= 421.1 (m+h); 1 HNMR(400MHz,DMSO)δ13.42(br s,1H),8.84)dd,J＝0.6,2.4Hz,1H),8.59(s,2H),8.21(dd,J＝2.6,8.3Hz,1H),7.67(dd,J＝0.6,8.3Hz,1H),7.54(d,J–9.2Hz,1H),7.24d,J＝2.2Hz,1H),7.13(dd,J＝2.2,9Hz,1H),6.14(q,J＝6.6Hz,1H),1.77(d,J＝6.6Hz,3H)。
EXAMPLE 19.4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] pyrimidin-2-yl ] -N, N-dimethyl-piperazine-1-carboxamide
4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-1H-indazol-3-yl]Pyrimidin-2-yl]-N, N-dimethyl-piperazine-1-carboxamide. Triethylamine (65 mg, 0.328 mmol,3 eq.) and N, N-dimethylcarbamoyl chloride (23 mg,0.213mmol,1 eq.) in acetonitrile (1 mL) are added dropwise to a solution of example 11 (100 mg,0.213mmol,1 eq.) in THF (10 mL) at room temperature. After stirring for 16 hours, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (6 mL) and purified on an intel chip automated chromatography system (RediSep Rf GOLD 100g HP c18 column), eluting with a 0 to 100% acetonitrile gradient in water to give an off-white solid (40 mg,35% yield). Analysis: LCMS: M/z= 541.2 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.13(br s,1H),8.79(s,2H),8.57(s,2H),7.47(d,J＝9.0Hz,1H),7.25(d,J＝2.1Hz,1H),7.10(dd,J＝2.2,9.0Hz,1H),6.14(q,J＝6.7Hz,1H),3.87-3.80(m,4H),3.26-3.21(m,4H),2.80(s,6H),1.76(d,J＝6.6Hz,3H)。
EXAMPLE 20.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [6- (6-methylsulfonyl-3, 6-diazabicyclo [3.1.1] hept-3-yl) -3-pyridinyl ] -1H-indazole
5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-3- [6- (6-methylsulfonyl-3, 6-diazabicyclo [ 3.1.1)]Hept-3-yl) -3-pyridinyl]-1H-indazole. Triethylamine (24.8. Mu.L, 0.178mmol,1.2 eq.) and methanesulfonyl chloride (11.5. Mu.L, 0.149mmol,1 eq.) were added sequentially to a solution of example 16 (71 mg,0.149mmol,1 eq.) in anhydrous THF (2 mL) at room temperature. After stirring for 16 hours, methanesulfonyl chloride (2×11.5 μl,0.149mmol,2 eq.) and triethylamine (24.8 μl,0.178mmol,1.2 eq.) were additionally added at 24-hour intervals and stirred for a total of 72 hours. Volatiles were removed under reduced pressure and the crude product was pre-adsorbed onto Celite (0.5 g) and then purified on an intel automated chromatographic system (RediSep Rf Gold HP C, 15.5g column), using 0 to 100 in water % acetonitrile gradient elution. The fractions containing the product were collected and lyophilized to give a white solid. Analysis: LCMS: M/z= 559.1 (m+h); 1 H NMR(400MHz,CDCl3)δ8.71(d,J＝2.3Hz,1H),8.43(s,2H),7.97(dd,J＝2.1,8.7Hz,1H),7.35(d,J＝9.0Hz,1H),7.26(s,1H),7.24(d,J＝2.1Hz,1H),7.13(dd,J＝1.9,9.0Hz,1H),6.64(d,J＝8.8Hz,1H),6.05(q,J＝6.7Hz,1H),4.57(br d,J＝6.2Hz,2H),4.10(br d,J＝11.7Hz,2H),3.88(br d,J＝11.7Hz,2H),3.14-3.08(m,1H),2.95(s,3H),1.82(d,J＝6.6Hz,3H)。
EXAMPLE 21.3- [6- (4, 7-diazaspiro [2.5] oct-7-yl) -3-pyridinyl ] -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazole
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (6-fluoropyridin-3-yl) -1H-indazole. To a solution of 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3-iodo-1-tetrahydropyran-2-yl-indazole (3.0 g,5.80mmol,1.0 eq), 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (1.6 g,6.96mmol,1.2 eq), [1,1' bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (430 mg,0.58mmol,0.1 eq) and potassium carbonate (1.6 g,11.66mmol,2.0 eq) in 1, 4-dioxane (30 mL) and water (3 mL) was purged with nitrogen for 15 minutes and then heated at 100 ℃ for 16 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (Sorbech 40g silica gel column) eluting with a 0 to 60% ethyl acetate gradient in heptane to give a white solid (2.5 g,88% yield). Analysis: LCMS: M/z= 487.1 (m+h).
Step 2.7- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyridin-2-yl) -4, 7-diazaspiro [2.5] octane-4-carboxylic acid tert-butyl ester. A suspension of the product of step 1 (350 mg,0.72mmol,1.0 eq), tert-butyl 4, 7-diazaspiro [2.5] octane-4-carboxylate (310 mg,1.44mmol,2.0 eq) and potassium carbonate (400 mg,2.88mmol,4.0 eq) in DMSO (5.0 mL) was heated in a sealed tube at 120℃for 20 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 100% acetonitrile in water, to give an off-white solid (417 mg,87% yield). Analysis: LCMS: M/z= 679.1 (m+h).
Step 3.3- [6- (4, 7-diazaspiro [2.5]]Oct-7-yl) -3-pyridinyl]-5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-1H-indazole. A solution of the 4M HCl step 2 product (25 mg,0.04mmol,1.0 eq.) in 1, 4-dioxane (0.2 mL,0.75mmol,20.0 eq.) and water (0.4 mL) was used and heated in a microwave oven at 100deg.C for 1 hour. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in 20% methanol in dichloromethane (10 mL) followed by the addition of MP-carbonate (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 80% acetonitrile. The product fractions were lyophilized to give an off-white solid (7.5 mg,20% yield). Analysis: LCMS: M/z= 495.1 (m+h); 1 H NMR(400MHz,CD3OD)δ8.50-8.44(m,3H),7.88(dd,J＝2.4,8.8Hz,1H),7.43(d,J＝9.0Hz,1H),7.16(dd,J＝2.3,9.0Hz,1H),7.11(d,J＝2.0Hz,1H),6.91(d,J＝8.4Hz,1H),6.13(q,J＝6.6Hz,1H),3.66-3.62(m,2H),3.51(s,2H),3.08-3.02(m,2H),1.82(d,J＝6.6Hz,3H),0.72-0.65(m,4H)。
EXAMPLE 22.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [6- (4-methylsulfonyl-4, 7-diazaspiro [2.5] oct-7-yl) -3-pyridinyl ] -1H-indazole
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Methanesulfonyl chloride (21. Mu.L, 0.26mmol,1.5 eq.) was added to example 21 (100 mg,0.17mmol,1.0 asAmount) in pyridine (5.0 mL). After stirring for 16 hours, methanesulfonyl chloride (21. Mu.L, 0.26mmol,1.5 eq.) was additionally added at room temperature along with N, N-diisopropylethylamine (0.1 mL). After stirring for a further 2 hours, volatiles were removed under reduced pressure. The residue was first purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 80% acetonitrile in water, and then again on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 4g column), eluting with a gradient of 0 to 80% acetonitrile in water. The product-containing fractions were lyophilized to give an off-white solid (16.0 mg,16% yield). Analysis: LCMS: M/z= 573.2 (m+h); 1 H NMR(400MHz,CD3OD)δ8.48(s,3H),7.90(dd,J＝2.4,8.9Hz,1H),7.44(d,J＝8.9Hz,1H),7.17(dd,J＝2.3,9.0Hz,1H),7.11(d,J＝1.7Hz,1H),6.93(dd,J＝0.5,8.9Hz,1H),6.13(q,J＝6.6Hz,1H),3.80-3.74(m,4H),3.04(s,3H),1.82(d,J＝6.7Hz,3H),1.29(s,3H),1.23-1.20(m,2H),1.00-0.96(m,2H)。
EXAMPLE 23 (R) -7- (5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) pyridin-2-yl) -N, N-dimethyl-4, 7-diazaspiro [2.5] octane-4-carboxamide
Dimethylformamide (23. Mu.L, 0.26mmol,1.5 eq.) was added to a solution of example 21 (100 mg,0.17mmol,1.0 eq.) in pyridine (5.0 mL) at room temperature. After stirring for 16 hours, dimethylcarbamoyl chloride (23. Mu.L, 0.26mmol,1.5 eq.) was additionally added at room temperature along with N, N-diisopropylethylamine (0.1 mL). After stirring for a further 2 hours, volatiles were removed under reduced pressure. The residue was first purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 80% acetonitrile in water, then again on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 4g column), eluting with a gradient of 0 to 80% acetonitrile in water to give an off-white solid (5 mg,5% yield). Analysis: LCMS: M/z= 566.3 (m+h); 1 H NMR(400MHz,CD3OD)δ8.52(dd,J＝0.6,2.4Hz,1H),8.47(s,2H),7.93(dd,J＝2.4,8.9Hz,1H),7.88(dd,J＝0.4,9.2Hz,1H),7.24(dd,J＝2.4,9.1Hz,1H),7.16(d,J＝2.3Hz,1H),6.92(dd,J＝0.5,8.9Hz,1H),6.16(q,J＝6.6Hz,1H),3.70-3.65(m,2H),3.55(s,2H),3.24(s,6H),3.08-3.01(m,2H),1.83(d,J＝6.7Hz,3H),0.76-0.61(m,4H)。
EXAMPLE 24.7- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -4, 7-diazaspiro [2.5] octane-4-carboxamide
Step 1.4-Nitrophenyl (R) -7- (5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) pyridin-2-yl) -4, 7-diazaspiro [2.5] octane-4-carboxylate. P-nitrophenyl chloroformate (48.8 mg,0.242mmol,1.1 eq.) and triethylamine (150. Mu.L, 1.1mmol,5 eq.) were added sequentially to a solution of example 21 (119 mg,0.22mmol,1 eq.) in anhydrous THF (3 mL) at room temperature. After stirring overnight, the brown solution was diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an intel automated chromatography system (RediSep Rf Gold HP C, 4g column), eluting with a 0 to 100% acetonitrile in water to give a white solid (40 mg,28% yield). Analysis: LCMS: M/z= 660.1 (m+h).
Step 2.7- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ]]-1H-indazol-3-yl]-2-pyridyl group]-4, 7-diazaspiro [2.5]]Octane-4-carboxamide. Concentrated ammonium hydroxide (71. Mu.L, 0.515mmol,10 eq.) was added to a solution of the product of step 1 (34 mg,0.0515mmol,1 eq.) in DMSO (2 mL). The yellow solution was heated at 90 ℃ overnight, cooled to room temperature and diluted with water (5 mL) and ethyl acetate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on an intel automated chromatography system (RediSep Rf Gold HP C, 4g column), eluting with a 0 to 100% acetonitrile in water to give a white solid (40 mg,28% yield). Analysis: LCMS: M/z= 538.2 (m+h). 1 H NMR(400MHz,CDCl3)δ10.12(br s,1H),8.64(d,J＝1.8Hz,1H),8.42(s,2H),7.93(dd,J＝2.3,8.8Hz,1H),7.36(d,J＝9.0Hz,1H),7.21(d,J＝2.2Hz,1H),7.13(dd,J＝2.3,9.0Hz,1H),6.72(d,J＝8.4Hz,1H),6.05(q,J＝6.6Hz,1H),5.08(s,2H),3.85(br s,2H),3.61(s,4H),1.81(d,J＝6.7Hz,3H),1.14-1.05(m,4H)。
EXAMPLE 25.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- (6-fluoro-3-pyridinyl) -1H-indazole
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3-iodo-1H-indazole. 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy was treated with trifluoroacetic acid (3 mL,39.2mmol,20 eq.) at room temperature]A mixture of 3-iodo-1-tetrahydropyran-2-yl-indazole (1.0 g,1.93mmol,1 eq.) in dichloromethane (10 mL) for 24 h. The mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), washed with saturated sodium bicarbonate (100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was dried overnight at room temperature under vacuum to give an orange solid (1.05 g), which was subsequently used. Analysis: LCMS (ESI) M/z=434 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.37(br s,1H),8.60(s,2H),7.46(d,J＝8.9Hz,1H),7.13(dd,J＝2.4,9.0Hz,1H),6.59(d,J＝2.3Hz,1H),6.07(q,J＝6.6Hz,1H),1.75(d,J＝6.6Hz,3H)。
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (6-fluoropyridin-3-yl) -1H-indazole. To a solution of the product of step 1 (1.0 g,2.3mmol,1 eq.) and 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (0.67 g,2.995mmol,1.3 eq.) in a 20 to 1 mixture of 1, 4-dioxane and water (21 mL) was purged with nitrogen for 15 minutes. Potassium carbonate (0.8235 g,5.98mmol,2.6 eq.) and (1, 1' -bis (diphenylphosphino) ferrocene) palladium (II) dichloride (168 mg,0.23mmol,0.01 eq.) were added and the reaction mixture was purged with nitrogen for another 5 minutes. The reaction was heated at 90℃for 2 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). Separating the layers, drying the organic layer over sodium sulfate, filtering and reducing Concentrating under pressure. The residue was adsorbed onto silica gel (2 g) and purified on an intel automated chromatography system (Sorbtech 40g silica gel column) eluting with a 20% to 80% ethyl acetate in heptane gradient to yield a yellow solid (0.42 g,45% yield). Analysis: LCMS (ESI) M/z=403.1 (m+h); 1 HNMR(400MHz,CDCl 3 )δ10.55(br s,1H),8.68(d,J＝2.1Hz,1H),8.43(s,2H),8.24(dt,J＝2.4,8.1Hz,1H),7.39(dd,J＝0.8,8.7Hz,1H),7.20-7.14(m,2H),7.06(dd,J＝2.8,8.4Hz,1H),6.06(q,J＝6.7Hz,1H),1.82(d,J＝6.6Hz,3H)。
EXAMPLE 26.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -1-oxa-8-azaspiro [4.5] decane
Step 1.8- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyridin-2-yl) -1-oxa-8-azaspiro [4.5] decane. A suspension of 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- (6-fluoro-3-pyridinyl) -1-tetrahydropyran-2-yl-indazole (100 mg,0.21mmol,1.0 eq.), 1-oxa-8-azaspiro [4.5] decane (110 mg,0.42mmol,3.0 eq.) and potassium carbonate (145 mg,1.05mmol,5.0 eq.) in 1-methyl-2-pyrrolidone (5 mL) was heated in a sealed tube at 120℃for 16 h. The reaction mixture was cooled to room temperature and taken up under reduced pressure with celite. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 100% acetonitrile in water, to give a white solid (105 mg,84% yield). Analysis: LCMS (ESI) M/z= 608.1 (m+h),
(R) -8- (5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) pyridin-2-yl) -1-oxa-8-azaspiro [4.5]Decane. A solution of the step 1 product (105 mg,0.18mmol,1.0 eq.) in 1, 4-dioxane (2.0 mL) and water (0.1 mL) was treated with 4M HCl in 1, 4-dioxane (0.86 mL,3.45mmol,20.0 eq.) and heated in a microwave oven at 100deg.C for 1 hour. After cooling to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in dichloroTo 20% methanol in methane (10 mL) was then added MP-carbonate resin (1.0 g). After stirring at room temperature for 1 hour, the suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 80% acetonitrile in water. The product-containing fractions were lyophilized to give a white solid (40.1 mg,44% yield). Analysis: LCMS (ESI) M/z=524.2 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.01(br s,1H),8.60(s,2H),8.53(d,J＝2.1Hz,1H),7.83(dd,J＝2.4,8.9Hz,1H),7.46(d,J＝9.0Hz,1H),7.16(d,J＝2.1Hz,1H),7.08(dd,J＝2.3,8.9Hz,1H),6.98(d,J＝8.8Hz,1H),6.10(q,J＝6.7Hz,1H),3.80-3.73(m,4H),3.58–3.51(m,2H),1.94-1.86(m,2H),1.76(d,J＝6.6Hz,3H),1.74-1.68(m,2H),1.61(t,J＝5.6Hz,4H)。
examples 27-34 were synthesized using the procedure of example 26.
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EXAMPLE 41.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -3-fluoro-2-pyridinyl ] -1, 8-diazaspiro [4.5] decan-2-one
This example was synthesized by the method of example 17 using 3- (6-chloro-4-fluoropyridin-3-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole to afford a white solid (49 mg,35% yield). Analysis: LCMS: M/z= 555.2 (m+h); 1H NMR (400 MHz, CDCl 3) δ10.57 (br s, 1H), 8.47 (t, J=1.6 Hz, 1H), 8.44 (s, 2H), 7.64 (dd, J=2.0, 14.1Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.13 (dd, J=2.3, 9.0Hz, 1H), 6.09-5.97 (m, 2H), 4.16 (td, J=3.8, 13.4Hz, 2H), 3.40 (t, J=6.8 Hz, 2H), 3.21 (br t, J=11.7 Hz, 2H), 2.22-2.10 (m, 4H), 1.82 (d, J=6.7 Hz, 3H), 1.66-1.52 (m, 2H).
Example 42.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -3-fluoro-2-pyridinyl ] -1, 8-diazaspiro [4.5] decan-2-one
This example was synthesized by the method of example 17 using 3- (6-chloro-4-fluoropyridin-3-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H) to synthesize-pyran-2-yl) -1H-indazole to give a white solid (45 mg,58% yield). Analysis: LCMS: M/z= 555.2 (m+h); 1H NMR (400 MHz, CDCl 3) δ11.91 (br s, 1H), 8.42 (s, 2H), 8.39 (t, J=1.6 Hz, 1H), 7.80 (s, 1H), 7.57 (dd, J=1.9, 14.0Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.14 (dd, J=2.2, 8.9Hz, 1H), 7.11 (d, J=2.0 Hz, 1H), 6.03 (q, J=6.7 Hz, 1H), 3.84-3.71 (m, 2H), 3.36-3.24 (m, 2H), 2.51 (t, J=8.1 Hz, 2H), 2.05 (t, J=8.1 Hz, 2H), 1.90-1.78 (m, 7H).
EXAMPLE 43.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -3-fluoro-2-pyridinyl ] -1-methyl-1, 8-diazaspiro [4.5] decan-2-one
This example was synthesized by the method of example 17 using 3- (6-chloro-4-fluoropyridin-3-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H) for the synthesis of-pyran-2-yl) -1H-indazole. Analysis: LCMS: M/z= 569.2 (m+h); 1H NMR (400 MHz, DMSO-d 6) delta 13.17 (s, 1H), 8.57 (s, 2H), 8.46 (t, J=1.7 Hz, 1H), 7.78 (dd, J=2.0, 14.4Hz, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 7.11 (dd, J=2.3, 9.0Hz, 1H), 6.13 (q, J=6.6 Hz, 1H), 4.11 (br d, J=13.4 Hz, 2H), 3.12-3.03 (m, 2H), 2.64 (s, 3H), 2.32-2.26 (m, 2H), 2.06-1.97 (m, 4H), 1.76 (d, J=6.6 Hz, 3H), 1.49 (br d, J=12.5 Hz, 2H).
EXAMPLE 44.9- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -3-fluoro-2-pyridinyl ] -1-methyl-1, 4, 9-triazaspiro [5.5] undecan-5-one
This example was synthesized by the method of example 17 using 3- (6-chloro-4-fluoropyridin-3-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H) for the synthesis of-pyran-2-yl) -1H-indazole. Analysis: LCMS: M/z= 584.2 (m+h); 1H NMR (400 MHz, DMSO-d 6) delta 13.16 (br s, 1H), 8.57 (s, 2H), 8.44 (t, J=1.7 Hz, 1H), 7.74 (dd, J=2.0, 14.5Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 7.45 (s, 1H), 7.20 (d, J=2.2 Hz, 1H), 7.10 (dd, J=2.3, 9.0Hz, 1H), 6.14 (q, J=6.6 Hz, 1H), 3.85 (br d, J=12.8 Hz, 2H), 3.38-3.32 (m, 2H), 3.06 (t, J=5.9 Hz, 2H), 2.41 (s, 3H), 2.05-1.91 (m, 4H), 1.76 (d, J=6.7 Hz, 3H).
EXAMPLE 45.3- [6- (2, 6-diazaspiro [3.3] hept-2-yl) -3-pyridinyl ] -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazole
(R) -6- (5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -1H-indazol-3-yl) pyridin-2-yl) -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester. A mixture of example 25 (0.292 g, 0.284 mmol,1 eq.) and tert-butyl 2, 6-diazaspiro [3.3] heptane-2-carboxylate (0.29 g, 1.460 mmol,2 eq.) and potassium carbonate (0.4 g,2.93mmol,4 eq.) in anhydrous N-methylpyrrolidone was heated at 120℃for 16 hours. The reaction mixture was filtered through a syringe filter and the filtrate was pre-adsorbed onto Celite (5 g). The material was purified on an intel automated chromatography system (RediSep Rf Gold HP C, 15.5g column), eluting with a gradient of 0 to 100% acetonitrile in water. Fractions containing the product were collected and lyophilized to give a pale yellow solid (0.3 g,71% yield) for analysis: LCMS (ESI) M/z=581 (m+h).
Step 2.3- [6- (2, 6-diazaspiro [3.3] hept-2-yl) -3-pyridinyl ] -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazole. A solution of the product of step 1 (50 mg,0.086mmol,1 eq.) in anhydrous dichloromethane (2 mL) was treated with trifluoroacetic acid (0.53 mL,6.88mmol,80 eq.) at room temperature for 16 hours. Trifluoroacetic acid (0.23 ml,3.01mmol,35 eq.) was added and stirred for 1 hour. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in methanol (10 mL), treated with MP-carbonate resin (3.2 mmol/g,1 g), stirred for 30 min, filtered and concentrated under reduced pressure. The residue was adsorbed onto Celite (1 g) and purified on an intel automated chromatography system (RediSep Rf Gold HP C, 15.5g column), eluting with a gradient of 0 to 100% acetonitrile in water. The product-containing fractions were collected and lyophilized to give a white solid (30 mg,73% yield). Analysis: LCMS: M/z=481.1 (m+h); 1H NMR (400 MHz, DMSO-d 6) delta 13.00 (br s, 1H), 8.59 (s, 2H), 8.50 (d, J=1.8 Hz, 1H), 7.84 (dd, J=2.3, 8.7Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.08 (dd, J=2.3, 9.0Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 6.10 (q, J=6.6 Hz, 1H), 4.20-3.82 (m, 5H), 3.66 (br s, 4H), 1.76 (d, J=6.6 Hz, 3H).
EXAMPLE 46.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3] hept-6-yl) -3-pyridinyl ] -1H-indazole
(5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3] hept-6-yl) -3[ -pyridinyl ] -1H-indazole. Triethylamine (20.5 uL,0.148mmol,1.2 eq.) and methylsulfonyl chloride (9.5 uL,0.123mmol,1.0 eq.) are added sequentially to a solution of example 45 (59.0 mg,0.123mmol,1 eq.) in dry THF (3 mL.) after stirring for 2 hours, the reaction mixture is concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL.) the organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to Celite (1 g.) the product is purified on an Interhim automatic chromatographic system (RediSep Rf Gold HP C, 15.5g column), eluted with a gradient of 0 to 100% acetonitrile in water and the product is contained in a dry solid fraction (37.45.0 M=35.37.35% H); 1H NMR (400 MHz, DMSO-d 6) delta 13.02 (br s, 1H), 8.59 (s, 2H), 8.52 (dd, J=0.6, 2.2Hz, 1H), 7.87 (dd, J=2.4, 8.6Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.09 (dd, J=2.3, 9.0Hz, 1H), 6.54 (dd, J=0.4, 8.6Hz, 1H), 6.10 (q, J=6.6 Hz, 1H), 4.17 (s, 4H), 4.12 (s, 4H), 3.03 (s, 3H), 1.76 (d, j=6.6 hz, 3H).
Example 47.6- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -N, N-dimethyl-2, 6-diazaspiro [3.3] heptane-2-carboxamide
6- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -N, N-dimethyl-2, 6-diazaspiro [3.3] heptane-2-carboxamide. Triethylamine (24.4. Mu.L, 0.175mmol,1.2 eq.) and dimethylcarbamoyl chloride (14.8. Mu.L, 0.161mmol,1.1 eq.) were added sequentially to a solution of example 45 (70.0 mg,0.146mmol,1 eq.) in anhydrous THF (3 mL) at room temperature. After stirring for 2 hours, dimethylcarbamoyl chloride (4. Mu.L, 0.044mmol,0.3 eq.) and triethylamine (8.1. Mu.L, 0.058mmol,0.4 eq.) were additionally added and the reaction stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and diluted with saturated brine (30 mL) and dichloromethane (30 mL). The layers were separated. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was adsorbed onto Celite (1 g) and purified on an intel automated chromatographic system (RediSep Rf Gold HP C, 15.5g column), eluting with a gradient of 0 to 100% acetonitrile in water. The product-containing fractions were collected and lyophilized to give a white solid (33.0 mg,41% yield). Analysis: LCMS: M/z= 552.2 (m+h); 1H NMR (400 MHz, DMSO-d 6) delta 8.59 (s, 2H), 8.51 (dd, J=0.7, 2.3Hz, 1H), 7.86 (dd, J=2.3, 8.6Hz, 1H), 7.46 (d, J=8.9 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.09 (dd, J=2.3, 9.0Hz, 1H), 6.53 (dd, J=0.6, 8.7Hz, 1H), 6.11 (q, J=6.6 Hz, 1H), 4.14 (s, 4H), 4.10 (s, 4H), 2.77 (s, 6H), 1.76 (d, J=6.6 Hz, 3H), 1.36 (s, 1H).
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EXAMPLE 48.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] pyrimidin-2-yl ] -1, 8-diazaspiro [4.5] decan-2-one
Step 1.3- (2-chloropyrimidin-5-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole. To a mixture of 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3-iodo-1-tetrahydropyran-2-yl-indazole (1.5 g,2.89mmol,1 eq.), 2-chloro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrimidine (284 mg,3.76mmol,1.3 eq.), [1,1' -bis (diphenylphosphine) ferrocene ] -dichloropalladium (II) (211 mg,0.289mmol,0.1 eq.), potassium carbonate (798 mg,5.79mmol,2 eq.) and water (2 mL) in 1, 4-dioxane (24 mL) was purged with nitrogen for 10 minutes. The mixture was stirred vigorously under nitrogen at 90 ℃ overnight. The brown reaction mixture was cooled to room temperature and diluted with water (20 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 10 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was adsorbed onto Celite (10 g) and purified on an intel automated chromatography system (Sorbtech 80g silica gel column) eluting with a 0 to 50% ethyl acetate gradient in heptane to give a white solid (1.17 g,80% yield). Analysis: LCMS: M/z=504.1 (m+h).
Step 2.8- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyrimidin-2-yl) -1, 8-diazaspiro [4.5] decan-2-one. A mixture of the product of step 1 (185 mg, 0.365 mmol,1 eq.) 1, 8-diazaspiro [4.5] decan-2-one (62 mg,0.403mmol,1.1 eq.) and potassium carbonate (76 mg,0.549mmol,1.5 eq.) in anhydrous NMP (3 mL) was heated at 120deg.C overnight. The reaction mixture was cooled to room temperature and diluted with water (10 mL) and ethyl acetate (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give a white solid (290 mg), which was subsequently used. Analysis: LCMS M/z= 622.1 (m+h).
Step 3.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ]]-1H-indazol-3-yl]Pyrimidin-2-yl]-1, 8-diazaspiro [4.5]]Decan-2-one. The product of step 2 (290 mg) was dissolved in a 1 to 1 mixture of trifluoroacetic acid and dichloromethane (2 mL) at room temperature, and the red solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The brown residue was adsorbed onto Celite (1 g) and purified on an intel automated chromatographic system (RediSep Rf GOLD HP C, 15g column), eluting with a 0 to 100% methanol in water gradient, to give a white solid after lyophilization (100 mg,40% two step yield). Analysis: LCMS: M/z= 538.2 (m+h); 1 H NMR(400MHz,CDCl 3 )δ12.24(br s,1H),8.61(s,2H),8.55(s,1H),8.41(s,2H),7.43(dd,J＝0.5,9.0Hz,1H),7.14(dd,J＝2.3,9.0Hz,1H),7.10(d,J＝2.1Hz,1H),6.03(q,J＝6.7Hz,1H),4.44-4.34(m,2H),3.36-3.21(m,2H),2.51(t,J＝8.1Hz,2H),2.02(t,J＝8.1Hz,2H),1.80(d,J＝6.7Hz,3H),1.74-1.69(m,4H)。
Examples 49-58 were synthesized using the procedure of example 26.
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EXAMPLE 59.3- (2-Chloropyrimidin-5-yl) -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazole
Example 48 step 1 product (60 mg,0.12mmol,1 eq.) in dichloromethane (0.6 mL) was treated with trifluoroacetic acid (0.6 mL,7.84mmol,65 eq.) at room temperature overnight. Volatiles were removed under reduced pressure. The residue was dissolved in a 3 to 1 mixture of dichloromethane and methanol (2.4 mL) and used(2.42 g) for 2 hours. The resin was filtered and the filtrate was concentrated directly onto Celite. The residue was purified by Biotage automated chromatography (RediSep HP Gold C, 18 g column), eluting with a 0 to 100% acetonitrile in water gradient to give an off-white solid (17.6 mg,36% yield). Analysis: LCMS: M/z= 422.0 (m+h); 1 H NMR(400MHz,CDCl3)δ10.41(br s,1H),9.11(s,2H),8.45(s,2H),7.45(dd,J＝0.5,9.0Hz,1H),7.21(dd,J＝2.3,9.0Hz,1H),7.15(d,J＝2.1Hz,1H),6.08(q,J＝6.6Hz,1H),1.84(d,J＝6.6Hz,3H)。
EXAMPLE 60.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [2- [4- (oxetan-3-yl) -1, 4-diazepan-1-yl ] pyrimidin-5-yl ] -1H-indazole
5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-3- [2- [4- (oxetan-3-yl) -1, 4-diazepan-1-yl]Pyrimidin-5-yl]-1H-indazole. A mixture of example 59 (135 mg,0.321mmol,1.0 eq), 1- (oxetan-3-yl) -1, 4-diaza (136 mg,0354mmol,1.1 eq.) and potassium carbonate (444 mg,3.22mmol,10 eq.) in N-methylpyrrolidone was heated at 120℃overnight. The brown reaction mixture was cooled to room temperature and diluted with water (5 mL) and ethyl acetate (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3X 5 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The brown oil was adsorbed onto Celite (1 g) and purified on an intel automated chromatographic system (RediSep Rf Gold HP C, 15g column), eluting with a 0 to 100% methanol and water gradient, to give a white solid (100 mg,57% yield). Analysis: LCMS: M/z= 541.2 (m+h); 1 H NMR(400MHz,CDCl3)δ10.11(br s,1H),8.75(s,2H),8.42(s,2H),7.36(dd,J＝0.6,9.0Hz,1H),7.19(d,J＝2.1Hz,1H),7.13(dd,J＝2.3,9.0Hz,1H),6.05(q,J＝6.7Hz,1H),4.69-4.63(m,2H),4.63-4.56(m,2H),4.03-3.98(m,2H),3.95(t,J＝6.4Hz,2H),3.71(quin,J＝6.5Hz,1H),2.65-2.58(m,2H),2.49-2.42(m,2H),2.07-2.00(m,2H),1.82(d,J＝6.6Hz,3H)。
EXAMPLE 61.3- [2- (1, 4-diazepin-1-yl) pyrimidin-5-yl ] -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazole
Step 1.4- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyrimidin-2-yl) -1, 4-diazepane-1-carboxylic acid tert-butyl ester. Potassium carbonate (164.1 mg,1.2mmol,4 eq.) and 1-Boc-hexahydro-1, 4-diazepine (117. Mu.L, 0.6mmol,2 eq.) were added sequentially to 3- (2-chloropyrimidin-5-yl) -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy, purged with nitrogen, at room temperature]A solution of-1-tetrahydropyran-2-yl-indazole (149.8 mg,0.30mmol,1 eq.) in N-methyl-2-pyrrolidone (3.0 mL). The resulting mixture was heated at 120 ℃ overnight. After cooling to room temperature, the reaction was concentrated under reduced pressure. In BiotageAutomatic chromatographic system (Biotage)60 μm 15.5g silica gel column) was purified, eluting with a 0 to 100% ethyl acetate gradient in heptane, to give a yellow solid (178 mg,90% yield). Analysis: LCMS: M/z= 668.2 (m+h).
Step 2.3- [2- (1, 4-diazepin-1-yl) pyrimidin-5-yl]-5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-1H-indazole trifluoroacetate salt. The step 1 product (178.6 mg,0.27mmol,1 eq.) in methylene chloride (2.0 mL) was treated with trifluoroacetic acid (2.0 mL,26.1mmol,96 eq.) at room temperature for 2 hours. The reaction mixture was concentrated directly onto Celite and purified on a Biotage automated chromatography system (RediSep Gold HP C column 50 g), eluting with a gradient of 0 to 100% acetonitrile in water, to give an off-white solid (103 mg,72% yield). Analysis: LCMS: M/z=484.2 (m+h), 1 H NMR(400MHz,CD3OD)δ8.76(s,2H),8.47(s,2H),7.47(dd,J＝0.4,9.1Hz,1H),7.19(dd,J＝2.3,9.0Hz,1H),7.09(d,J＝2.1Hz,1H),6.14(q,J＝6.6Hz,1H),4.56(br s,1H),4.22-4.17(m,2H),4.06(t,J＝6.2Hz,2H),3.49-3.46(m,2H),3.38-3.35(m,2H),2.21(td,J＝5.9,11.5Hz,2H),1.83(d,J＝6.6Hz,3H)。
Example 62.4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] pyrimidin-2-yl ] -1, 4-diazacycloheptane-1-carboxamide
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Step 1.3- (2- (1, 4-diazepan-1-yl) pyrimidin-5-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole: a suspension of 3- (2-chloropyrimidin-5-yl) -5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1-tetrahydropyran-2-yl-indazole (145 mg,0.28mmol,1 eq.) and potassium carbonate (160 mg,1.12mmol,4 eq.) in 1-methyl-2-pyrrolidone (2 mL) was treated with 1, 4-diazacyclohexane dihydrochloride (97 mg,0.57mmol,2 eq.). After heating at 120 ℃ for 16 hours, the reaction mixture was cooled to room temperature and diluted with water (10 mL). The resulting solid was stirred at room temperature for 30 min and filtered to give a light brown solid (86 mg,53% yield), which was subsequently used. Analysis: LCMS (ESI) M/z=568.1 (m+h).
Step 2.4- (5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) pyrimidin-2-yl) -1, 4-diazacyclo-1-carboxamide (209-4): trimethylsilyl isocyanate (23 μl,0.17mmol,1.1 eq.) was added to a solution of the product of step 1 (86 mg,0.15mmol,1 eq.) and triethylamine (24 μl,0.17mmol,1.1 eq.) in THF (2 mL) at room temperature. After 4 hours, volatiles were removed under reduced pressure. The residue was purified on a Buchi automatic chromatography system (Sorbech 24g silica gel column) eluting with a 0 to 80% ethyl acetate gradient in heptane to give a light brown solid (25 mg,27% yield). Analysis: LCMS (ESI) M/z= 611.1 (m+h).
(4- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy)]-1H-indazol-3-yl]Pyrimidin-2-yl]-1, 4-ground nitrogen-1-carboxamide. The product of step 2 (25 mg,0.04mmol,1 eq.) was treated with a 1 to 1 mixture of dichloromethane-trifluoroacetic acid (0.5 mL) at room temperature for 2 hours. Volatiles were removed under reduced pressure. The residue was diluted with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3X 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Buchi automatic chromatography system (RediSep Rf Gold HP C, 50g column), eluting with a gradient of 0 to 80% acetonitrile in water. The product-containing fractions were lyophilized to give a white solid (11 mg,53% yield). Analysis: LCMS (ESI) M/z=527.2 (m+h); 1 H NMR(400MHz,CD3OD)δ8.70-8.67(m,2H),8.48(s,2H),7.45(d,J＝9.0Hz,1H),7.17(dd,J＝2.3,9.0Hz,1H),7.09(d,J＝2.2Hz,1H),6.14(q,J＝6.6Hz,1H),4.55(br s,2H),4.02(t,J＝5.5Hz,2H),3.91(t,J＝6.1Hz,2H),3.69-3.64(m,2H),3.49-3.45(m,2H),2.05-1.99(m,2H),1.82(d,J＝6.6Hz,3H)。
EXAMPLE 63.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -3- [2- (4-methylsulfonyl-1, 4-diazepin-1-yl) pyrimidin-5-yl ] -1H-indazole
Example 61 (76.5 mg,0.16mmol,1 eq.) in THF (1.6 mL) was treated with triethylamine (22.0. Mu.L, 0.63mmol,4 eq.) and methanesulfonyl chloride (12.2. Mu.L, 0.63mmol,4 eq.) for 4 days at 40 ℃. The reaction mixture was concentrated directly onto Celite and then purified on a Biotage automatic chromatography system (RediSep Gold HP C18 g column), eluting with a gradient of 0 to 100% acetonitrile in water to give a white solid (14.8 mg,17% yield). Analysis: LCMS: M/z=562.2 (m+h); 1 H NMR(400MHz,DMSO-d6)δ13.13(s,1H),8.77(s,2H),8.56(s,2H),7.47(d,J＝8.9Hz,1H),7.23(d,J＝1.7Hz,1H),7.09(dd,J＝2.3,9.0Hz,1H),6.14(q,J＝6.7Hz,1H),3.97(t,J＝5.6Hz,2H),3.91(t,J＝6.0Hz,2H),3.50(t,J＝5.5Hz,2H),3.34-3.31(m,2H),2.84(s,3H),1.90(quin,J＝5.7Hz,2H),1.76(d,J＝6.7Hz,3H)。
Examples 64-68 were synthesized using the procedure and method of examples 3-9 using tert-butyl 4- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] piperidine-1-carboxylate or 1-methyl-4- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] piperidine.
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Examples 69-72 were synthesized using the procedure and method of examples 3-9 using tert-butyl 4- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2-pyridinyl ] piperidine-1-carboxylate.
Examples 73-76 were synthesized using the procedure and method of examples 3-9 using 6-oxo-5-oxa-2, 7-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester and 2-oxo-1-oxa-3, 8-diazaspiro [4.5] decane-8-carboxylic acid tert-butyl ester.
EXAMPLE 77.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -3-fluoro-2-pyridinyl ] -2λ6-thia-8-azaspiro [4.5] decane 2, 2-dioxide
Using the methods of examples 17 and 42, 3- (6-chloro-4-fluoropyridin-3-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole and 2λ6-thia-8-azaspiro [4.5]Decane 2, 2-dioxide synthesis this example. LCMS: M/z= 590.2 (m+h); 1 HNMR(400MHz,DMSO-d6)δ＝13.18(br s,1H),8.57(s,2H),8.44(t,J＝1.7Hz,1H),7.76(dd,J＝1.9,14.5Hz,1H),7.49(d,J＝9.0Hz,1H),7.20(d,J＝2.1Hz,1H),7.10(dd,J＝2.3,9.0Hz,1H),6.13(q,J＝6.6Hz,1H),3.77-3.69(m,2H),3.35-3.28(m,4H),3.24(t,J＝7.6Hz,2H),2.10(t,J＝7.6Hz,2H),1.88-1.81(m,2H),1.78-1.70(m,5H)。
EXAMPLE 78.8- [5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -2λ6-thia-8-azaspiro [4.5] decane 2, 2-dioxide
The procedure of examples 17 and 42 was used with 3- (6-chloro-pyridin-3-yl) -5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -1- (tetrahydro-2H-pyran-2-yl) -1H-indazole and 2λ6-thia-8-azaspiro [4.5 ]]Decane 2, 2-dioxide synthesis this example. LCMS: M/z= 572.2 (m+h). 1 H NMR(400MHz,DMSO-d6)δ＝12.97(s,1H),8.60(s,2H),8.54(d,J＝2.2Hz,1H),7.84(dd,J＝2.4,8.9Hz,1H),7.45(d,J＝8.9Hz,1H),7.16(d,J＝1.6Hz,1H),7.09(dd,J＝2.3,9.0Hz,1H),7.00(d,J＝8.9Hz,1H),6.10(q,J＝6.7Hz,1H),3.96-3.87(m,2H),3.40-3.32(m,2H),3.24(t,J＝7.5Hz,2H),3.18(s,2H),2.09(t,J＝7.6Hz,2H),1.81(br d,J＝4.9Hz,2H),1.76(d,J＝6.6Hz,3H),1.65(ddd,J＝3.9,9.6,13.4Hz,2H)。
(R) -1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol and (S) -1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol
(trichloro-4-pyridinyl) ethanol. A500 mL three-necked round bottom flask was charged with 2,3, 5-trichloropyridine-4-carbaldehyde (40 g,0.19 mol) and THF (200 mL). MeMgBr (70 mL,0.21 mol) was added in portions and the mixture was stirred for 1h at-70 ℃. The reaction was quenched with aqueous ammonium chloride, extracted with ethyl acetate (200 mL. Times.3), and concentrated by Na 2 SO 4 Drying and concentrating. The residue was purified by a silica gel column (PE/ea=30/1) to give (33 g) a yellow liquid (33 g, 77%). Analysis: LCMS: M/z=227 (m+h).
Step 2.1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol. The product of step 1 (33 g,0.147 mmol), methylboronic acid (26.3 g,0.429 mmol), K 2 CO 3 (40 g,0.290 mmol) and Pd (PPh) 3 ) 2 Cl 2 (3g) The mixture in dioxane (300 mL) was stirred at 110 ℃ overnight. The resulting mixture was filtered and the filtrate concentrated in vacuo to give the crude product, which was further purified by silica gel column chromatography to give a yellow liquid (15 g, 50%). LCMS: M/z=206.1 (m+h). The product was isolated by preparative HPLC (Chiralpak ID 5X 25cm, hexane/ethanol (80/20), 60mL/min,38 ℃) to give (S) -1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol (5 g) and (R) -1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol R (5 g) as yellow liquids. Peak 1.5 min; (S) -1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol. Analysis: LCMS: M/z=206.1 (m+h). 1 H NMR(400MHz,CDCl 3 ) Delta 8.36 (s, 1H), 5.57 (m, 1H), 2.93 (b, 1H), 2.64 (s, 3H), 1.65 (d, 3H). Peak 2.9 min;(R) -1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol. Analysis: LCMS: M/z=206.1 (m+h). 1 H NMR(400MHz,CDCl 3 )δ8.36(s,1H),5.57(m,1H),2.93(b,1H),2.64(s,3H),1.65(d,3H)。
Using the procedure and method of example 64, tert-butyl 4- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] piperidine-1-carboxylate, (3S) -3- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] pyrrolidine-1-carboxylate (3R) -3- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] pyrrolidine-1-carboxylic acid tert-butyl ester or 3- [4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazol-1-yl ] azetidine-1-carboxylic acid tert-butyl ester and (1R) -1- (3, 5-dichloro-4-pyridinyl) ethanol or (1R) -1- (3, 5-dichloro-2-methyl-4-pyridinyl) ethanol example 79-95 was synthesized.
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Examples 96-140 were synthesized using the procedure described previously.
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Example 144.2- [5- [5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -6λ6-thia-2-azaspiro [3.4] octane 6, 6-dioxide
Step 1.1- (3, 5-dichloropyridazin-4-yl) ethanone. To 3, 5-dichloropyridazine (50.0 g,0.336 mol) in CH 3 To a solution of CN (500 mL) and water (500 mL) was added 2-oxopropionic acid (37.0 g,0.403 mol), K 2 S 2 O 8 (136.0 g,0.504 mol) and AgNO 3 (11.4 g,0.067 mol). The reaction mixture was stirred at 70℃for 6 hours. After completion, the reaction was cooled to room temperature and ACN was removed. The aqueous solution was extracted with EtOAc (3X 500 mL). The combined organic layers were washed with brine (2X 300 mL), and dried over Na 2 SO 4 Drying and concentrating. The residue was purified by flash column chromatography on silica gel (petroleum ether/etoac=4/1) to give 1- (3, 5-dichloropyridazin-4-yl) ethanone as a pale yellow solid (35.0 g, 56%). LCMS M/z=191 (m+1).
Step 2.1- (3, 5-dimethylpyridazin-4-yl) ethanone. To a solution of 1- (3, 5-dichloropyridazin-4-yl) ethanone (35.0 g,0.184 mol) in dioxane (700 mL) and water (35 mL) was added 2,4, 6-trimethyl-1,3,5,2,4,6-trioxytriborane (157 mL,3.5mol/L in THF, 0.552 mol), K 2 CO 3 (63.5 g,0.460 mol) and Pd (dppf) Cl 2 (5.3 g,0.0074 mol). The mixture is put under N 2 Stirring is carried out for 36h at 110℃under an atmosphere. After completion, the reaction was cooled to room temperature and concentrated. The crude product was purified by flash column chromatography on silica gel (DCM/meoh=60/1) to give a brown oil (17.5 g, 63.2%). LCMS M/z-151 (M+1).
Step 3.1- (3, 5-dimethylpyridazin-4-yl) ethanol. To a solution of 1- (3, 5-dimethylpyridazin-4-yl) ethanone (17.5 g,0.12 mol) in THF (180 mL) at 0deg.C was added NaBH 4 (5.06 g,0.132 mol) and then MeOH (18 mL) were added dropwise at the same temperature. The reaction mixture was stirred at 0 ℃ for 2 hours. When the reaction was complete, silica (80 g) was added to the mixture at 0 ℃ and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (DCM/meoh=40/1) to give a light brown solid, yielding the racemic product 1-6 (9.5 g,52.0% yield). The racemate was separated by SFC to give peak 1 (4.0 g,23% yield, S-enantiomer) as a white solid LCMS m/z=153 [ m+1]； 1 H NMR(400MHz,CDCl 3 )δ8.65(s,1H),5.31-5.26(m,1H),3.37(s,1H),2.67(s,3H),2.43(s,3H),1.49(d,J＝6.8Hz,3H),[α]D= 47.092. Peak 2 (4.3 g,24% yield, R-enantiomer) as a white solid. LCMS M/z=153 (m+1); 1 H NMR(400MHz,CDCl 3 )δ8.61(s,1H),5.30-5.25(m,1H),3.71(s,1H),2.68(s,3H),2.41(s,3H),1.48(d,J＝6.8Hz,3H),[α]D＝+44.534。
step 4.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole. At 0℃under N 2 Next, PPh was added to a solution of 3-iodo-1-tetrahydropyran-2-yl-indazol-5-ol (678 mg,1.97 mmol) and (S) -1- (3, 5-dimethylpyridazin-4-yl) ethanol (200 mg,1.31 mmol) in anhydrous THF (5 mL) 3 (517 mg,2.62 mmol). Then, a solution of DIAD (390 mg,1.70mmol,1.3 eq) in THF (2.5 mL) was added dropwise and the resulting mixture was stirred at room temperature for 16h. After completion, the reaction solvent was removed. The residue was purified by flash column chromatography on silica gel (petroleum ether/thf=3/1) to give a white solid (53% yield). LCMS M/z=479 (m+1); 1 H NMR(400MHz,DMSO-d6)δ8.85(s,1H),7.67(d,J＝8.8Hz,1H),7.19(d,J＝9.2Hz,1H),6.46(s,1H),5.86(q,J＝4.0Hz,1H),5.76(t,J＝7.2Hz,1H),3.83-3.81(m,1H),3.70-3.65(m,1H),2.79(s,3H),2.44(s,3H),2.40-2.21(m,1H),1.99-1.88(m,2H),1.68-1.66(m,4H),1.65-1.54(m,2H)。
Step 5.5- [ (1R) -1- (3, 5-dimethyl-4-pyridinyl) ethoxy]-3- (6-fluoro-3-pyridinyl) -1-tetrahydropyran-2-yl-indazole. To 5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (500 mg,1.05mmol,1.0 eq), 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (439 mg,1.57mmol,1.5 eq) in dioxane (5.0 mL) and H 2 K was added to a solution in O (0.5 mL) 2 CO 3 (288 mg,2.09mmol,2.0 eq) and Pd (dppf) Cl 2 (50 mg,0.1 w/w). At N 2 The reaction mixture was stirred at 90℃for 2h under protection. After the reaction was completed, the solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether/etoac=3/7) to give a yellow solid (410 mg, 88%). LCMS M/z=448 (m+1).
Step 6.2- [5- [5- [ (1R) -1- (3, 5-dimethyl-4-pyridinyl) ethoxy ]]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl group]-6λ6-thia-2-azaspiro [3.4 ]]Octane 6, 6-dioxide. To a solution of the product of step 5 (160 mg,0.36mmol,1.0 eq) in DMSO (3.0 mL) was added DIEA (231 mg,1.79mmol,5.0 eq) and 6λ6-thia-2-azaspiro [3.4 ]]Octane 6, 6-Hydrogen dioxide chloride (106 mg,0.54mmol,1.5 eq.). At N 2 The reaction mixture was stirred at 100℃for 16h. After cooling to room temperature, the solution was diluted with EtOAc (30 mL) and washed with brine (2×15 mL). The organic layer was concentrated and the crude product purified by preparative TLC (EtOAc) to give a yellow solid (120 mg, 57%). LCMS M/z=589 (m+1).
Step 7.2- [5- [5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ]]-1H-indazol-3-yl]-2-pyridyl group]-6λ6-thia-2-azaspiro [3.4]]Octane 6, 6-dioxide. To a solution of the product of step 6 (110 mg,0.19mmol,1.0 eq) in DCM (3 mL) was added TFA (0.6 mL). The reaction mixture was stirred at rt for 4h. After completion, the solution was concentrated in vacuo. The residue was diluted with EtOAc (10 mL) and washed with saturated sodium bicarbonate solution (5 mL). The organic layer was concentrated and eluted by preparative HPLC (preparative C18, 5. Mu.M Triart column, 20X 150mm, YMC-Actus; gradient elution with 40% MeCN in water to 60% MeCN in water for 8min, both solvents containing 0.05% NH) 3 ·H 2 O) to give a white solid (58 mg, 62%). LCMS m/z=505 [ m+1 ]]； 1 HNMR(400MHz,DMSO-d6)δ13.00(s,1H),8.83(s,1H),8.51(s,1H),7.86(d,J＝7.6Hz,1H),7.46(d,J＝9.2Hz,1H),7.08-7.03(m,2H),6.54(d,J＝8.0Hz,1H),5.87(q,J＝6.0Hz,1H),4.07-3.97(m,4H),3.50(s,2H),3.28-3.24(m,2H),2.78(s,3H),2.50-2.44(m,2H),2.44(s,3H),1.67(d,J＝6.4Hz,3H)。
EXAMPLE 145.2- [5- [5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -6λ6-thia-2-azaspiro [3.4] octane 6, 6-dioxide
Step 1.5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole. At 0℃under N 2 Next, PPh was added to a solution of (R) -1- (3, 5-dimethylpyridazin-4-yl) ethanol (200 mg,1.31mmol,1.0 eq) and 3-iodo-1-tetrahydropyran-2-ylinazol-5-ol (678 mg,1.97mmol,1.5 eq) in DCM (7.5 mL) 3 (862mg, 3.28mmol,2.5 eq). Then, a solution of DIAD (390 mg,1.97mmol,1.5 eq) in DCM (2.5 mL) was added dropwise and the resulting mixture stirred at rt for 3h. After completion, the reaction mixture was concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/thf=3/1) to give a white solid (56% yield). LCMS M/z=479 (m+1); 1H NMR (400 MHz, DMSO-d 6) delta 8.85 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.19 (dd, J=9.2 Hz,2.4Hz, 1H), 6.47 (s, 1H), 5.86 (q, J=4.0 Hz, 1H), 5.76 (t, J=7.2 Hz, 1H), 3.83-3.81 (m, 1H), 3.70-3.65 (m, 1H), 2.79 (s, 3H), 2.44 (s, 3H), 2.32-2.25 (m, 1H), 1.99-1.87 (m, 2H), 1.68-1.66 (m, 4H), 1.65-1.54 (m, 2H).
Step 2.5- [ (1S) -1- (3, 5-dimethyl-4-pyridinyl) ethoxy]-3- (6-fluoro-3-pyridinyl) -1-tetrahydropyran-2-yl-indazole. To 5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole solution (900 mg,1.88mmol,1.0 eq), 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (545 mg,2.44mmol,1.3 eq) in dioxane (30.0 mL) and H 2 K was added to the solution in O (3 mL) 2 CO 3 (518.6 mg,3.76mmol,2.0 eq) and Pd (dppf) Cl 2 (153 mg,0.19mmol,0.1 eq). At N 2 The reaction mixture was stirred at 90℃for 3 hours under protection. After the reaction was completed, the solid was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether/etoac=1/1) to give the product of example 7c (800 mg, 95.0%)Yield), as a yellow solid. LCMS M/z=448 (m+1).
Step 3:2- [5- [5- [ (1S) -1- (3, 5-dimethyl-4-pyridinyl) ethoxy]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl group]-6λ6-thia-2-azaspiro [3.4 ]]Octane 6, 6-dioxide. To 5- [ (1S) -1- (3, 5-dimethyl-4-pyridinyl) ethoxy]To a solution of (E) -3- (6-fluoro-3-pyridinyl) -1-tetrahydropyran-2-yl-indazole (170 mg,0.38mmol,1.0 eq) in DMSO (5.0 mL) was added DIEA (245 mg,1.90mmol,5.0 eq) and 6λ6-thia-2-azaspiro [3.4 ]]Octane 6, 6-dioxide hydrochloride (90 mg,0.46mmol,1.2 eq). At N 2 The reaction mixture was stirred at 105℃for 16h. After cooling to room temperature, the solution was diluted with EtOAc (30 mL) and washed with brine (2×15 mL). The organic layer was concentrated and the product purified by preparative TLC (EtOAc) to give a yellow solid (170 mg, 76%). LCMS m/z=589 [ m+1 ] ]。
Step 3:2- [5- [5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-1H-indazol-3-yl]-2-pyridyl group]-6λ6-thia-2-azaspiro [3.4 ]]Octane 6, 6-dioxide. To 2- [5- [5- [ (1S) -1- (3, 5-dimethyl-4-pyridinyl) ethoxy ]]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl group]-6λ6-thia-2-azaspiro [3.4 ]]To a solution of octane 6, 6-dioxide (170 mg,0.29mmol,1.0 eq) in DCM (10 mL) was added TFA (2.0 mL). The reaction mixture was stirred at rt for 2h. After completion, the solution was concentrated in vacuo. The crude product was treated with MeOH (5 mL) and NaHCO was added 3 (excess) was added to the solution, which was stirred at r.t. for 20min. DCM (20 mL) was then added, the precipitate filtered off and the filtrate concentrated. The crude product was eluted by preparative HPLC (preparative C18, 5. Mu.M Triart column, 20X 150mm, YMC-acts; 20% MeCN in water to 56% MeCN in water gradient for 8min, where the solvent contained 0.05% NH 3H 2O) to give a white solid (45 mg, 31%). LCMS M/z=505 (m+1); 1 HNMR(400MHz,DMSO-d6)δ13.00(s,1H),8.84(s,1H),8.51(d,J＝1.6Hz,1H),7.86(dd,J＝8.8Hz,2.4Hz,1H),7.46(d,J＝8.8Hz,1H),7.07(dd,J＝9.2Hz,2.4Hz,1H),7.03-7.02(m,1H),6.54(d,J＝8.4Hz,1H),5.88(q,J＝6.4Hz,1H),4.06(d,J＝8.4Hz,2H),3.99(d,J＝8.0Hz,2H),3.50(s,2H),3.26(t,J＝7.2Hz,2H),2.78(s,3H),2.50-2.47(m,2H),2.44(s,3H),1.67(d,J＝6.8Hz,3H)。
examples 141-156 were synthesized using the procedure and intermediates described in example 144 and example 145.
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Examples 157-165 were synthesized using the procedure and intermediates previously described.
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Synthesis of (R) -1- (3, 5-dichloropyridazin-4-yl) ethanol and (S) -1- (3, 5-dichloropyridazin-4-yl) ethanol.
Step 1.1- (3, 5-dichloropyridazin-4-yl) ketene. To 3, 5-dichloropyridazine (25.0 g,168.9 mmol), 2-oxopropionic acid (18.6 g,202.7 mmol) in MeCN (200 mL)/H 2 AgNO was added to the solution in O (200 mL) 3 (5.74 g,33.8 mmol) and K 2 S 2 O 8 (68.4 g,253.4 mmol). The mixture was heated to 70 ℃ and stirred for 8 hours. After completion of the reaction, meCN was removed in vacuo and saturated NaHCO 3 Aqueous solution the resulting aqueous solution was adjusted to ph=7-8. The solution was extracted with ethyl acetate (400 mL. Times.2). The organic layer is treated by Na 2 SO 4 Dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/pe=1:4) to give a pale yellow solid (14.0 g,43% yield). Lcms=191 (m+1).
Step 2 to a solution of 1- (3, 5-dichloropyridazin-4-yl) ethanone (14.0 g,73.3 mmol) in MeOH (30 mL) at-10deg.C was added NaBH 4 (3.06 g,80.6 mmol) and stirred for 10min. After completion of the reaction, the solution was added to DCM (300 mL)/saturated NH 4 Cl (100 mL). The organic layer was separated over Na 2 SO 4 Dried and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (ethyl acetate/pe=1:3) to give the racemate which was separated by chiral-HPLC to give (R) -1- (3, 5-dichloropyridazin-4-yl) ethanol (4.0 g,28.6; [ α ])]D= +8.1) and (S) -1- (3, 5-dichloropyridazin-4-yl) ethanol (3.4 g,24.3%; [ alpha ] ]D= -11.9) as a pale yellow solid. 1H NMR (300 MHz, CDCl 3) δ9.05 (s, 1H), 5.70-5.49 (m, 1H), 2.77 (s, 1H), 1.68 (d, J=6.9 Hz, 3H); lcms=193.1 (m+1).
Example 191.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -6-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3] hept-6-yl) -3-pyridinyl ] -1H-indazole.
(E) -N' - (2-bromo-5-hydroxy-4-methoxybenzylidene) -4-methylbenzenesulfonyl hydrazine. Parluenesulfonyl hydrazide (0.56 g,3.0mmol,1.0 eq) was added to a solution of 2-bromo-5-hydroxy-4-methoxy-benzaldehyde (0.7 g,3.0mmol,1.0 eq) in methanol (7.0 mL) at rt. The resulting mixture was heated at 60℃for 2h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), and then heptane (80 mL) was added to give a pale yellow solid (1.21 g, 100%). LCMS: M/z= 399.0 (m+h).
Step 2.6-methoxy-1-tosyl-1H-indazol-5-ol. Cuprous oxide (0.22 g,1.5mmol,0.5 eq.) was added to a solution of (E) -N' - (2-bromo-5-hydroxy-4-methoxybenzylidene) -4-methylbenzenesulfonyl hydrazide (1.2 g,3.0mmol,1.0 eq.) in isoamyl alcohol (30 mL) at room temperature. After heating at 132 ℃ for 2 hours, the mixture was cooled to room temperature and diluted with water (80 mL). The mixture was extracted with ethyl acetate (4X 50 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated onto silica gel (8.0 g) and purified on a Biotage automated purification system (Biotage) Silica,50g; purification on 0% to 100% ethyl acetate in heptane gave a pale yellow solid (0.66 g,70% yield). LCMS: M/z=319.1 (m+h).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-methoxy-1-tosyl-1H-indazole. (1S) -1- (3, 5-dichloro-4-pyridinyl) ethyl ] methanesulfonate (0.57 g,2.1mmol,1.0 eq.) and cesium carbonate (1.03 g,3.2mmol,1.5 eq.) were added to a solution of 6-methoxy-1-tosyl-1H-indazol-5-ol (0.67 g,2.1mmol,1.0 eq.) in acetonitrile (21 mL) at room temperature. After heating at 90 ℃ overnight, the mixture was cooled to room temperature and concentrated under reduced pressure onto silica gel (6.0 g). The product was purified on a Biotage automated purification system (Sorbtech silica, 40 g) eluting with a 0% to 60% ethyl acetate gradient in heptane to give a white solid (0.71 g,70% yield). LCMS M/z=492.1 (m+h).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-methoxy-1H-indazole. 1M tetrabutylammonium fluoride in THF (7.2 mL,7.2mmol,18.0 eq.) was added to a solution of (R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-methoxy-1-tosyl-1H-indazole (0.20 g,0.4mmol,1.0 eq.) in tetrahydrofuran (4 mL) at room temperature. After heating at 50℃for 4 days, the solvent was removed under reduced pressure. The residue was concentrated onto silica gel (2.0 g) and purified on a Biotage automated purification system (Sorbtech silica, 12 g) eluting with a 0% to 100% ethyl acetate gradient in heptane to give a white solid (74.7 mg, 54%). LCMS M/z= 338.0 (m+h).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3-iodo-6-methoxy-1H-indazole. Potassium hydroxide (27.9 mg,0.50mmol,2.25 eq.) and iodine (84.1 mg,0.33mmol,1.5 eq.) were added to a solution of (R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-methoxy-1H-indazole (74.7 mg,0.22mmol,1.0 eq.) in N, N-dimethylformamide (2.2 mL) at 0deg.C. The resulting mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with ethyl acetate (10 mL) and washed with water (4X 5 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure onto silica gel (1.5 g). The product was purified on a Biotage automated purification system (Sorbtech silica, 12 g) eluting with a 0% to 100% ethyl acetate gradient in heptane to give an off-white solid (80 mg, 77%). LCMS M/z=463.9 (m+h).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-methoxy-3- (6- (methylsulfonyl) -2, 6-diazaspiro [3.3] hept-2-yl) pyridin-3-yl) -1H-indazole. To a mixture of (R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3-iodo-6-methoxy-1H-indazole (80 mg,0.17mmol,1.0 eq), 2-methylsulfonyl-6- [5- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2-pyridinyl ] -2, 6-diazaspiro [3.3] heptane (71.9 mg,0.19mmol,1.1 eq), tetrakis (triphenylphosphine) -palladium (0) (20.0 mg,0.02m,0.1 eq) and potassium carbonate (47.6 mg,0.35mmol,2.0 eq) in 1, 4-dioxane (4.0 mL) and water (0.4 mL) was purged with nitrogen for 10 minutes. After heating at 100deg.C for 10 hours, the reaction was cooled to room temperature, diluted with ethyl acetate (10 mL) and washed with water (4 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure onto silica gel (1 g). The product was purified on a Biotage automated purification system (Sorbtech silica, 4 g), eluting with a 0% to 100% ethyl acetate gradient in heptane, then with a 0% to 10% methanol gradient in ethyl acetate, to give a white solid (31.0 mg,31% yield, 98.1%). LCMS M/z= 589.1 (m+h); 1H NMR (400 mhz, dmso-d 6) δ=12.81 (s, 1H), 8.60 (s, 2H), 8.45 (d, j=1.8 hz, 1H), 7.81 (dd, j=2.3, 8.6hz, 1H), 7.06 (s, 1H), 6.99 (s, 1H), 6.52 (d, j=8.1 hz, 1H), 5.99-5.93 (m, 1H), 4.16 (s, 4H), 4.11 (s, 4H), 3.86 (s, 3H), 3.02 (s, 3H), 1.75 (d, j=6.7 hz, 3H).
EXAMPLE 192.5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -6-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3] hept-6-yl) -3-pyridinyl ] -1H-indazole
Step 1.5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3- (6-fluoro-3-pyridinyl) -6-methoxy-1-tetrahydropyran-2-yl-indazole. To 5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]A solution of (3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (150 mg,0.30mmol,1.0 eq) and 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (86 mg,0.38mmol,1.3 eq) in dioxane (4 mL) and water (0.4 mL) was added K 2 CO 3 (122 mg,0.88mmol,3.0 eq) and Pd (dppf) Cl 2 (25 mg,0.030mmol,0.1 eq.). At N 2 The reaction mixture was stirred at 90℃for 3h under protection. After the reaction was completed, the solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM/meoh=30/1) to give a brown solid product (130 mg, 92%). LCMS M/z= 478.4 (m+1).
Step 2:5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-6-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3]]Hept-6-yl) -3-pyridinyl]-1-tetrahydropyran-2-yl-indazole. To the product of step 1 (130 mg,0.27 mmol) and 2-methylsulfonyl-2, 6-diazaspiro [3.3] ]To a solution of heptane TFA salt (95 mg,0.33 mol) in DMSO (5 mL) was added DIEA (176 mg,1.36mmol,5.0 eq). The reaction mixture was stirred at 100℃for 16h. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and washed with brine (20 ml×3). The organic layer is treated by Na 2 SO 4 Drying and concentrating. The crude product was purified by preparative TLC (DCM/meoh=20/1) to give a brown solid (122 mg, 69.6%). LCMS (liquid Crystal Module)m/z＝634.4(M+1)。
Step 3.5- [ (1S) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-6-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3 ]]Hept-6-yl) -3-pyridinyl]-1H-indazole. To a solution of the product of step 2 (100 mg,0.16mmol,1.0 eq) in DCM (4 mL) was added TFA (1 mL) and stirred at rt for 3h. After completion of the reaction, the reaction mixture was concentrated in vacuo. The crude product was treated with MeOH (3 mL) and excess NaHCO was added 3 . The mixture was stirred for 20 min, then DCM (30 mL) was added. The solid was filtered off and the filtrate was concentrated. By preparative HPLC (preparative C18, 5. Mu.M Triart column, 20X 150mm, YMC-Actus; gradient elution of 35% MeCN in water to 50% MeCN in water for 8min, both solvents containing 0.05% NH) 3 .H 2 O) the residue was purified to give a pale red solid (30.4 mg, 35%). LCMS M/z= 550.3 (m+h); 1HNMR (400 MHz, DMSO-d 6) delta 12.78 (s, 1H), 8.84 (s, 1H), 8.48 (d, J=2.0 Hz, 1H), 7.83 (dd, J=8.8 Hz,2.4Hz, 1H), 7.02 (s, 1H), 6.99 (s, 1H), 6.52-6.49 (m, 1H), 5.79 (q, J=6.8 Hz, 1H), 4.17 (s, 4H), 4.11 (s, 4H), 3.87 (s, 3H), 3.03 (s, 3H), 2.77 (s, 3H), 2.43 (s, 3H), 1.65 (d, J=6.8 Hz, 3H).
Example 193.6- [5- [5- [ (1S) -1- (3, 5-dichloro-2-fluoro-4-pyridinyl) ethoxy ] -1H-indazol-3-yl ] -2-pyridinyl ] -2, 6-diazaspiro [3.3] heptane-2-carboxylic acid ethyl ester
Step 1- [6- (2-ethoxycarbonyl-2, 6-diazaspiro [3.3]]Hept-6-yl) -3-pyridinyl]Boric acid. To 2, 6-diazaspiro [3.3]]To a solution of heptane-2-carboxylic acid ethyl ester TFA salt (400 mg,2.35mmol,1.0 eq) and 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (524 mg,2.35mmol,1.0 eq) in DMSO (6 mL) was added DIEA (1.52 g,11.75mmol,5.0 eq). The reaction mixture was stirred at 110℃for 3h. After completion of the reaction, the mixture was diluted with EtOAc (100 mL) and washed with brine (50 ml×3). The organic layer is treated by Na 2 SO 4 Dried and concentrated in vacuo. The crude product was purified by preparative TLC (DCM/meoh=20/1) to give a yellow oil (150 mg, 17%)。LCMS m/z＝292(M+1)。
Step 2.6- [5- [5- [ (1S) -1- (3, 5-dichloro-2-fluoro-4-pyridinyl) ethoxy ]]-1-tetrahydropyran-2-yl-indazol-3-yl]-2-pyridyl group]-2, 6-diazaspiro [3.3]]Heptane-2-carboxylic acid ethyl ester. To 5- [ (1S) -1- (3, 5-dichloro-2-fluoro-4-pyridinyl) ethoxy]-3-iodo-1-tetrahydropyran-2-yl-indazole (138 mg,0.26mmol,1.0 eq) and [6- (2-ethoxycarbonyl-2, 6-diazaspiro [3.3] ]Hept-6-yl) -3-pyridinyl]To a solution of boric acid (75 mg,0.26mmol,1.0 eq) in dioxane (2 mL) and water (0.2 mL) was added K 2 CO 3 (71 mg,0.52mmol,2.0 eq) and Pd (dppf) Cl 2 (19 mg,0.026mmol,0.1 eq). At N 2 The reaction mixture was stirred at 90℃for 2h under protection. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative TLC (DCM/meoh=30/1) to give a yellow oil (75 mg, 44.4%). LCMS M/z= 655.3 (m+1).
Step 3.6- [5- [5- [ (1S) -1- (3, 5-dichloro-2-fluoro-4-pyridinyl) ethoxy ]]-1H-indazol-3-yl]-2-pyridyl group]-2, 6-diazaspiro [3.3 ]]Heptane-2-carboxylic acid ethyl ester. To a solution of the product of step 2 (70 mg,0.11mmol,1.0 eq) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 3h. After completion of the reaction, the mixture was concentrated in vacuo. The crude product was treated with MeOH (3 mL) and NaHCO was added 3 (excess) was added to the solution and stirred at rt for 20 min, then DCM (20 mL) was added. The solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by preparative TLC (DCM/meoh=10/1) to give a white solid (25.3 mg, 41.5%). LCMS M/z= 571.2 (m+h); 1H NMR (400 MHz, DMSO-d 6) delta 13.02 (s, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.34 (s, 1H), 7.88 (dd, J=1.6 Hz,8.8Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.19 (s, 1H), 7.09 (dd, J=8.8 Hz,2.0Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 6.13 (q, J=6.8 Hz, 1H), 4.19-4.09 (m, 8H), 4.01 (q, J=7.2 Hz, 2H), 1.76 (d, J=6.8 Hz, 3H), 1.7 (t, J=7.2 Hz, 3H).
EXAMPLE 194.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -6-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3] hept-6-yl) -3-pyridinyl ] -1H-indazole
Step 1.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3- (6-fluoro-3-pyridinyl) -6-methoxy-1-tetrahydropyran-2-yl-indazole. To 5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy at room temperature]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (135 mg,0.27mmol,1.0 eq) and 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (89 mg,0.40mmol,1.5 eq) in dioxane (2.0 mL) and H 2 K was added to a solution in O (0.2 mL) 2 CO 3 (110 mg,0.81mmol,3.0 eq) and Pd (dppf) Cl 2 (27 mg,20% wt). At N 2 The mixture was stirred at 90℃for 2h under protection. After the reaction was completed, the solid was filtered off and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM/meoh=20/1) to give an off-white solid (120 mg, 94.6%). LCMS M/z= 478.3 (m+1).
Step 2.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-6-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3]]Hept-6-yl) -3-pyridinyl]-1-tetrahydropyran-2-yl-indazole. To example 79c (110 mg,0.230mmol,1.0 eq) and 2-methylsulfonyl-2, 6-diazaspiro [3.3] ]To a solution of heptane TFA salt (100 mg,0.345 mmol) in DMSO (3 mL) was added DIEA (148 mg,1.15 mmol). The reaction mixture was stirred at 110℃for 16h. After completion of the reaction, the mixture was diluted with EtOAc (10 mL) and washed with brine (10 ml×5). The organic layer is treated by Na 2 SO 4 Drying and concentrating. The crude product was purified by preparative TLC (DCM/meoh=20/1) to give a yellow solid (93 mg, 63.7%). LCMS M/z= 634.4 (m+1).
Step 3.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-6-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3 ]]Hept-6-yl) -3-pyridinyl]-1H-indazole. To a solution of the product of step 2 (83 mg,0.131 mmol) in DCM (2 mL) was added TFA (0.4 mL). The solution was stirred at rt for 3h. After completion of the reaction, the mixture was concentrated in vacuo. With saturated NaHCO 3 The solution made the crude basic and was then extracted into DCM (20 mL. Times.3). The combined organic layers were washed with brine (20 mL. Times.2), and dried over Na 2 SO 4 Drying and concentrating in vacuumAnd (5) shrinking. By preparative HPLC (preparative C18, 5. Mu.M Triart column, 20X 150mm, YMC-Actus; gradient elution of 15% MeCN in water to 30% MeCN in water for 11min, both solvents containing 0.05% NH) 3 .H 2 O) to give a white solid (40.6 mg, 56.2%). LCMS: M/z= 550.2 (m+h); 1H NMR (400 MHz, DMSO-d 6) δ12.78 (s, 1H), 8.84 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 7.83 (dd, J=8.4 Hz,2.4Hz, 1H), 7.01 (s, 1H), 6.99 (s, 1H), 6.50 (d, J=8.8 Hz, 1H), 5.79 (q, J=6.8 Hz, 1H), 4.17 (s, 4H), 4.11 (s, 4H), 3.87 (s, 3H), 3.03 (s, 3H), 2.77 (s, 3H), 2.43 (s, 3H), 1.65 (d, J=6.8 Hz, 3H).
Example 200.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -4-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3] hept-6-yl) -3-pyridinyl ] -1H-indazole
Step 1.3-bromo-6-fluoro-2-methoxybenzaldehyde. LDA (2 mol/L,250mL,0.50mol,1.2 eq) was added dropwise to a solution of 1-bromo-4-fluoro-2-methoxy-benzene (85.0 g,0.42mol,1.0 eq) in THF (1L) at-70℃over 30 min. The reaction mixture was stirred at the same temperature for 1h. DMF (42.4 g,0.58mol,1.4 eq) was then added dropwise to the solution at-70 ℃. The reaction mixture was stirred at the same temperature for a further 2h. The reaction mixture was then quenched with aqueous HCl (4 mol/L,300 mL) and extracted with ethyl acetate (300 mL. Times.2). H for combined organic layers 2 O (500 mL), brine (500 mL), washed over Na 2 SO 4 Dried and concentrated in vacuo. The crude product was purified by silica gel chromatography (ethyl acetate/petroleum ether=1/10) to give a pale yellow solid (80.0 g,82.8% yield). LCMS M/z=233 (m+1).
Step 2.5-bromo-4-methoxy-1H-indazole. To a solution of 3-bromo-6-fluoro-2-methoxy-benzaldehyde (38.0 g,0.16 mol) in DMSO (450 mL) was added N 2 H 4 -H 2 O(57.1g,1.14mol,7.0 eq). The mixture was heated to 125 ℃ for 16h. The reaction mixture was cooled to room temperature and taken up with H 2 O (1L) was diluted and extracted with ethyl acetate (500 mL. Times.3). The combined organic layers were purified by Na 2 SO 4 Drying and concentrating. The crude product was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (1/10) to give a brown solid (5.0 g, 13.5%). LCMS M/z=227.1 (m+1).
Step 3.4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole. To a solution of 5-bromo-4-methoxy-1H-indazole (2.5 g,11.0mmol,1.0 eq) in dioxane (50 mL) was added KOAc (3.24 g,33.0mmol,3.0 eq) and Pd (dppf) Cl 2 (1.6 g,2.2mmol,0.2 eq.). The mixture was stirred at 90 ℃ for 24h, then concentrated to give a brown crude (3.5 g); LCMS M/z= 275.2 (m+1). The material was used directly in the next step.
Step 4.4-methoxy-1H-indazol-5-ol. To a solution of 4-methoxy-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (3.5 g) in THF (20 mL) at 0deg.C was added NaOH (0.4 g) and H 2 O 2 (30% aqueous solution, 3.7 g). The resulting mixture was stirred at rt for 2h with 50mL of saturated NaHSO 3 The aqueous solution (30 mL) was quenched and then extracted with ethyl acetate (30 mL. Times.3). The combined organic layers were purified by Na 2 SO 4 Drying and concentrating. The crude product was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (1:1) to give a pale brown solid (700 mg,38.8% yield). LCMS M/z=165 (m+1).
Step 5 t-butyl- [ (4-methoxy-1H-indazol-5-yl) oxy]-dimethyl-silane. To a solution of 4-methoxy-1H-indazol-5-ol (0.86 g,5.2mmol,1.0 eq) in THF (10 mL) was added TBSCl (1.73 g,21mmol,4.0 eq) and imidazole (1.43 g,21mmol,4 eq). The resulting mixture was stirred at 25℃for 16h. The reaction mixture was taken up with 50mL of H 2 O was quenched and extracted with ethyl acetate (50 mL. Times.2). The combined organic layers were washed with brine (30 mL), and dried over Na 2 SO 4 Drying and concentrating. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether=1:1) to give a yellow solid (800 mg,54.9% yield). LCMS M/z= 279.2 (m+1).
Step 6. Tert-butyl- [ (3-iodo-4-methoxy-1H-indazol-5-yl) oxy]-dimethyl-silane. To tert-butyl- [ (4-methoxy-1H-indazol-5-yl) oxy at 0 ℃C]To a solution of dimethyl-silane (0.74 g,2.66mmol,1.0 eq) in DMF (15 mL) was added NIS (598 mg,2.66mmol,1.0 eq). The resulting solution was stirred at 0℃for 3h. The reaction mixture was then taken up in H 2 O (50 mL) was diluted and extracted with ethyl acetate (50 mL. Times.2). The combined organic layers were washed with water (30 mL), brine (30 mL) and then Na 2 SO 4 Drying and concentrating. The combined organic layers were purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (5:1) to give an off-white solid (570 mg, 53%). LCMS M/z=405.1 (m+1).
Step 7. Tert-butyl- (3-iodo-4-methoxy-1-tetrahydropyran-2-yl-indazol-5-yl) oxy-dimethyl-silane. To tert-butyl- [ (3-iodo-4-methoxy-1H-indazol-5-yl) oxy at 25 ℃]To a solution of dimethyl-silane (0.58 g,1.43mmol,1.0 eq) in THF (15 mL) was added 3, 4-dihydro-2H-pyran (241 mg,2.87mmol,2.0 eq) and TsOH (74 mg,0.43mol,0.3 eq). The resulting mixture was stirred at 50℃for 16h, quenched with 50mL of water and extracted with ethyl acetate (30 mL. Times.2). The combined organic layers were washed with water (30 mL), brine (30 mL), and dried over Na 2 SO 4 Drying and concentrating. The crude product was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (10:1) to give an off-white solid (500 mg, 82.8%). LCMS M/z= 489.2 (m+1).
Step 8.3-iodo-4-methoxy-1-tetrahydropyran-2-yl-indazol-5-ol. To a solution of tert-butyl- (3-iodo-4-methoxy-1-tetrahydropyran-2-yl-indazol-5-yl) oxy-dimethyl-silane (0.8 g,1.64mmol,1.0 eq) in THF (15 mL) was added TBAF (1 mol/L in THF, 1.8mL,1.8mmol,1.1 eq) at rt. The resulting mixture was stirred at rt for 5g with H 2 O (50 mL) was diluted and extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with water (50 mL), brine (50 mL), and dried over Na 2 SO 4 Drying and concentrating. The crude product was purified by silica gel chromatography eluting with ethyl acetate/petroleum ether (5:1) to give an off-white solid (450 mg, 73.4%). LCMS M/z=375.1 (m+1).
Step 9.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3-iodo-4-methoxy-1-tetrahydropyran-2-yl-indazole. To a solution of 3-iodo-4-methoxy-1-tetrahydropyran-2-yl-indazol-5-ol (50 mg,0.14mmol,1.0 eq) in DCM (2 mL) at 0deg.C was added PPh 3 (70 mg,0.26mmol,2.0 eq) and DEAD (35 mg,0.2mmol,1.4 eq). The mixture was warmed to rt, stirred for 16h, and then concentrated. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether=1:2) to give a light brown solid (40 mg, 58.9%). LCMS M/z=509.2 (m+1).
Step 10:5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3- (6-fluoro-3-pyridinyl) -4-methoxy-1-tetrahydropyran-2-yl-indazole. At 25℃under N 2 Protected 5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-3-iodo-4-methoxy-1-tetrahydropyran-2-yl-indazole (90 mg,0.18 mmol) in dioxane (4 mL) and H 2 To a solution of 2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (59 mg,0.27mmol,1.5 eq), pd (dppf) Cl was added in O (0.4 mL) 2 (40 mg,0.055mmol,0.3 eq) and K 2 CO 3 (49 mg,0.36mmol,2.0 eq). The resulting mixture was stirred at 100 ℃ for 2h, cooled to rt, diluted with 10mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with water (20 mL), brine (20 mL), and dried over Na 2 SO 4 Drying and concentrating. The crude product was purified by preparative TLC (ethyl acetate/petroleum ether=3:1) to give a light brown solid (70 mg, 82.8%). LCMS M/z= 478.3 (m+1).
Step 11.5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -4-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3] hept-6-yl) -3-pyridinyl ] -1-tetrahydropyran-2-yl-indazole. To a solution of 5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -3- (6-fluoro-3-pyridinyl) -4-methoxy-1-tetrahydropyran-2-yl-indazole (70 mg,0.15mmol,1.0 eq) in DMSO (4 mL) was added 2-methylsulfonyl-2, 6-diazaspiro [3.3] heptane (182 mg,0.66mmol,4.4 eq) and DIEA (190 mg,1.5mmol,10 eq) at 25 ℃. The resulting mixture was stirred at 130 ℃ for 10h, cooled to rt and quenched with water (15 mL). The precipitate was collected by filtration, washed with water and dried in vacuo to give a brown solid (70 mg, 75.4%). LCMS M/z= 634.4 (m+1).
Step 12 5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-4-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3]]Hept-6-yl) -3-pyridinyl]-1H-indazole. At rt, 5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-4-methoxy-3- [6- (2-methylsulfonyl-2, 6-diazaspiro [3.3]]Heptane solution-6-yl) -3-pyridinyl]To a solution of 1-tetrahydropyran-2-yl-indazole (100 mg,0.16mmol,1.0 eq) in DCM (3 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 10h. The solvent was concentrated and the resulting mixture was diluted with DCM/MeOH (5:1, 3 mL). Addition of solid NaHCO 3 And the mixture was stirred for 30 minutes. The solid was filtered off and the filtrate was concentrated in vacuo. The crude product was purified by preparative TLC (DCM: meoh=20:1) to give an off-white solid (22.7 mg, 26.5%). LCMS: M/z= 550.3 (m+h); 1H-NMR (400 MHz, DMSO-d 6) delta 13.09 (s, 1H), 8.88 (s, 1H), 8.52 (d, J=1.6 Hz, 1H), 7.96 (dd, J=8.4 Hz,2.0Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.51 (d, J=8.8 Hz, 1H), 5.65 (q, J=7.2 Hz, 1H), 4.16 (s, 4H), 4.11 (s, 4H), 3.55 (s, 3H), 3.02 (s, 3H), 2.76 (s, 3H), 2.46 (s, 3H), 1.65 (d, J=6.8 Hz, 3H).
EXAMPLE 218 (R) -5- (5- (1- (3, 5-dimethylpyridazin-4-yl) ethoxy) -6-methoxy-1H-indazol-3-yl) -2- (2-oxa-6-azaspiro [3.3] hept-6-yl) nicotinonitrile
Step 1.5- [5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl ] -2-fluoro-pyridine-3-carbonitrile. This intermediate was synthesized using 2-fluoro-5- (4, 5-tetramethyl-1, 3-dioxolan-2-yl) pyridine-3-carbonitrile and 5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy ] -3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole using the conditions previously described.
Step 2.5- [5- [ (1R) -1- (3, 5-Di-methyl)Pyridazin-4-yl) ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile. To 5- [5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2-fluoro-pyridine-3-carbonitrile (150 mg,0.298mmol,1.0 eq) and 2-oxa-6-azaspiro [3.3 ]]To a solution of heptane oxalate (84 mg,0.447 mmol) in DMSO (3 mL) was added DIEA (192 mg,1.49mmol,5.0 eq). The reaction mixture was stirred at 100℃for 6h. After completion of the reaction, the mixture was diluted with EtOAc (60 mL) and washed with brine (20 ml×2). The organic layer is treated by Na 2 SO 4 Drying and concentrating. The crude product was purified by preparative TLC (PE/ea=1/1) to give a yellow solid (100 mg, 57.6%). LCMS M/z= 582.4 (m+1).
(R) -5- (5- (1- (3, 5-dimethylpyridazin-4-yl) ethoxy) -6-methoxy-1H-indazol-3-yl) -2- (2-oxa-6-azaspiro [ 3.3) ]Hept-6-yl) nicotinonitrile. To 5- [5- [ (1R) -1- (3, 5-dimethylpyridazin-4-yl) ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]To a solution of 2-fluoro-pyridine-3-carbonitrile (90 mg,0.155mmol,1.0 eq) in DCM (1 mL) was added TFA (0.4 mL). The solution was stirred at rt for 2h and concentrated in vacuo. The crude product was taken up in saturated NaHCO 3 The aqueous solution was basified and extracted with DCM (30 mL. Times.3). The combined organic layers were washed with brine (20 mL. Times.2), and dried over Na 2 SO 4 Drying and concentrating. By preparative HPLC (preparative C18, 5. Mu.M Triart column, 20X 150mm, YMC-Actus; gradient elution of 20% MeCN in water to 45% MeCN in water for 11min, both solvents contained 0.05% NH) 3 .H 2 O) to give a white solid (20.3 mg, 26.4%). LCMS: M/z=498.2 (m+h); 1H NMR (400 MHz, DMSO-d 6) δ12.96 (s, 1H), 8.82 (s, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 7.01 (d, J=6.0 Hz, 2H), 5.84 (q, J=6.4 Hz, 1H), 4.76 (s, 4H), 4.48 (s, 4H), 3.87 (s, 3H), 2.78 (s, 3H), 2.45 (s, 3H), 1.66 (d, J=6.8 Hz, 3H).
EXAMPLE 279 (R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (3, 5-difluoro-4- (6- (methylsulfonyl) -2, 6-diazaspiro [3.3] hept-2-yl) phenyl) -6-methoxy-1H-indazole
Step 1.6- (4-bromo-2, 6-difluoro-phenyl) -2, 6-diazaspiro [3.3 ]Heptane-2-carboxylic acid tert-butyl ester. To 5-bromo-1, 3-difluoro-2-iodobenzene (1.0 g,3.14mmol,1.0 eq) and 2, 6-diazaspiro [3.3 ]]To a solution of tert-butyl heptanecarboxylate (1.1 g,3.76mmol,1.2 eq) in dioxane (20 mL) was added Xantphos (151 mg,0.31mmol,0.1 eq), pd 2 (dba) 3 (146 mg,0.16mmol,0.05 eq) and Cs 2 CO 3 (2.04 g,6.28mmol,2.0 eq). At N 2 The resulting mixture was stirred at 100℃for 3h under protection. After cooling to room temperature, the reaction mixture was diluted with 50mL of water and extracted with EtOAc (20 ml×3). The combined organic layers were washed with water (30 mL), brine (30 mL), and dried over Na 2 SO 4 Dried and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether/etoac=10/1) to give a white solid (900 mg,73.73% yield). LCMS M/z= 389.2 (m+1).
Step 2.6- [2, 6-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl ]]-2, 6-diazaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester. To 6- (4-bromo-2, 6-difluoro-phenyl) -2, 6-diazaspiro [3.3 ] at 25 ]]To a solution of tert-butyl heptane-2-carboxylate (860 mg,2.21mmol,1.0 eq) and BPD (673 mg,2.65mmol,1.2 eq) in dioxane (20 mL) was added KOAc (433 mg,4.42mmol,2.0 eq) and Pd (dppf) Cl 2 (81 mg,0.11mmol,0.05 eq). At N 2 The resulting mixture was stirred at 100℃for 3h under protection. After cooling to room temperature, the reaction mixture was diluted with 50mL of water and extracted with EtOAc (30 ml×2). The combined organic layers were washed with water (50 mL), brine (50 mL), and dried over Na 2 SO 4 Dried and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether/etoac=10/1) to give an off-white solid (550 mg,57.05% yield). LCMS M/z=437.3 (m+1).
Step 3.6- [4- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ]]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-26-difluoro-phenyl group]-2, 6-diazaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester. To 6- [2, 6-difluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl at 25 ℃C]-2, 6-diazaspiro [3.3 ]]Heptane-2-carboxylic acid tert-butyl ester (176 mg,0.403mmol,1.2 eq) and 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-3-iodo-6-methoxy-1-tetrahydropyran-2-yl-indazole (185 mg,0.336mmol,1.0 eq) in dioxane (6 mL) and H 2 K was added to a solution in O (0.6 mL) 2 CO 3 (93 mg,0.672mmol,2.0 eq) and Pd (dppf) Cl 2 (50 mg,0.067mmol,0.2 eq.) in N 2 The resulting mixture was stirred under protection at 100℃for 2h. After cooling to room temperature, the reaction mixture was diluted with 20mL of water and extracted with EtOAc (10 mL. Times.3). The combined organic layers were washed with brine (20 mL. Times.2), and dried over Na 2 SO 4 Dried, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether/etoac=4/1) to give a white solid (180 mg, 74%). LCMS M/z= 730.3 (m+1).
Step 4.3- [4- (2, 6-diazaspiro [3.3 ]]Hept-2-yl) -3, 5-difluoro-phenyl]-5- [ (1R) -1- (3, 5-dichloro-4) -pyridinyl) ethoxy]-6-methoxy-1-tetrahydropyran-2-yl-indazole. At 0℃to 6- [4- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ]]-6-methoxy-1-tetrahydropyran-2-yl-indazol-3-yl]-2, 6-difluoro-phenyl group]-2, 6-diazaspiro [3.3 ]]To a solution of tert-butyl heptane-2-carboxylate (120 mg,0.165mmol,1.0 eq) in DCM (3 mL) was added TMSOTF (370 mg,1.65mmol,10.0 eq). The resulting mixture was stirred at 25℃for 5h. After completion, the reaction mixture was treated with NaHCO 3 The aqueous solution (20 mL) was quenched and extracted with DCM (10 mL. Times.3). The combined organic layers were washed with brine (20 mL. Times.2), and dried over Na 2 SO 4 Dried and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM/meoh=15/1) to give an off-white solid (120 mg). LCMS M/z= 630.3 (m+1).
Step 5.5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-3- [3, 5-difluoro-4- (2-methylsulfonyl-2, 6-diazaspiro [3.3 ]]Hept-6-yl) phenyl]-6-methoxy-1-tetrahydropyran-2-yl-indazole. At 0 ℃, 3- [4- (2, 6-diazaspiro [3.3 ]) ]Hept-2-yl) -3, 5-difluoro-phenyl]-5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-6-methoxy-1-tetrahydropyridineTo a solution of the pyran-2-yl-indazole (120 mg, crude) in DCM (3 mL) was added MsCl (40 mg,0.35mmol,1.8 eq) and TEA (84 mg,0.83mmol,4.4 eq). The resulting mixture was stirred at 0℃for 3h. After completion, the reaction mixture was taken up with H 2 O (20 mL) was quenched and extracted with DCM (10 mL. Times.3). The combined organic layers were washed with brine (20 mL), and dried over Na 2 SO 4 Dried and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM/meoh=20/1) to give a white solid (78 mg,58.4% yield, two steps). LCMS M/z= 708.20 (m+1).
(R) -5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -3- (3, 5-difluoro-4- (6- (methylsulfonyl) -2, 6-diazaspiro [ 3.3)]Hept-2-yl) phenyl) -6-methoxy-1H-indazole. At 0℃to 5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy]-3- [3, 5-difluoro-4- (2-methylsulfonyl-2, 6-diazaspiro) solution [3.3]Hept-6-yl) phenyl]To a solution of 6-methoxy-1-tetrahydropyran-2-yl-indazole (73 mg,0.103mmol,1.0 eq) in DCM (4 mL) was added TFA (1 mL). The resulting mixture was stirred at 25℃for 3h. After completion, the reaction solution was added dropwise to DCM and NaHCO 3 In a mixed solution of aqueous solutions, the organic layer was separated and the aqueous layer was extracted with DCM (10 ml x 3). The combined organic layers were washed with brine (20 mL. Times.2), and dried over Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM/meoh=15/1) to give a white solid (23.3 mg,36.3% yield). LCMS: M/z= 624.2 (m+h); 1H-NMR (400 MHz, DMSO-d 6) δ8.59 (s, 2H), 7.19 (dd, J=8.8 Hz,2.4Hz, 2H), 6.99 (s, 1H), 6.95 (s, 1H), 5.99 (q, J=6.4 Hz, 1H), 4.34 (s, 4H), 4.10 (s, 4H), 3.87 (s, 3H), 3.02 (s, 3H), 1.76 (d, J=6.4 Hz, 3H).
Example 362.5- [5- [ (1R) -1- (3, 5-dichloro-4-pyridinyl) ethoxy ] -6-fluoro-1H-indazol-3-yl ] -2- (6, 6-dioxo-6λ6-thia-2-azaspiro [3.5] non-2-yl) pyridine-3-carbonitrile
Step 1.5- ((tert-butyldimethylsilyl) oxy) -6-fluoro-1H-indazole. Imidazole (10 g,148 mmol) and t-butyldimethylchlorosilane (10.7 g,71mmol,1.2 eq.) were added sequentially to a solution of 6-fluoro-1H-indazol-5-ol (9 g,59mmol,1.0 eq.) in N, N-dimethylformamide (59 mL) at 0deg.C. After stirring at room temperature for 3 hours. The mixture was diluted with ethyl acetate (120 mL), washed with water (4×60 mL), and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil (15.1 g, 99%). LCMS (ESI) M/z= 267.1 (m+h). The material was used directly in the next step.
Step 2.5- ((tert-butyldimethylsilyl) oxy) -6-fluoro-3-iodo-1H-indazole. 5- ((tert-butyldimethylsilyl) oxy) -6-fluoro-1H-indazole (15.1 g,57mmol,1.0 eq) in methylene chloride (590 mL) was treated with potassium hydroxide (7.5 g,128mmol,2.25 eq) and iodine (22.6 g,85mmol,1.5 eq) at room temperature. After stirring overnight, the reaction was diluted with dichloromethane (1L) and washed with water (1L). The organic layer was separated, filtered through a pad of silica gel (20 g) and washed with a 1:1 mixture of ethyl acetate and heptane (1L). The filtrate was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil (16.5 g,71% crude yield, 2 steps). LCMS M/z=393.0 (m+h). The material was used directly in the next step.
Step 3.5- ((tert-butyldimethylsilyl) oxy) -6-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole. 5- ((tert-butyldimethylsilyl) oxy) -6-fluoro-3-iodo-1H-indazole (16.5 g,42mmol,1.0 eq.) in dichloromethane (420 mL) was treated with 3, 4-dihydro-2H-pyran (7.7 mL,84mmol,2.0 eq.) and p-toluenesulfonic acid (0.4 g,2mmol,0.05 eq.) at room temperature. After stirring overnight, the reaction was diluted with dichloromethane (400 mL) and washed with saturated sodium bicarbonate (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (60 g). In Biotage automated chromatography systems (Biotage HC,200g, silica gel), 0 to 20% ethyl acetate in heptaneGradient elution gave a yellow oil (11.2 g,56% yield, 3 steps). LCMS M/z= 477.1 (m+h).
Step 4.6-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-ol. 5- ((tert-butyldimethylsilyl) oxy) -6-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (11.2 g,23.5mmol,1.0 eq.) in tetrahydrofuran (235 mL) was treated with 1M tetrabutylammonium fluoride in THF (47 mL,47mmol,2.0 eq.) at 0deg.C. After stirring at 0deg.C for 4 hours, the reaction was diluted with dichloromethane (800 mL) and washed with saturated sodium bicarbonate (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (30 g). In Biotage automated chromatography systems (BiotageHC,200g, silica gel) and eluted with a 0 to 10% methanol gradient in dichloromethane to give a white solid (8.07 g, 95%). LCMS M/z= 363.0 (m+h).
Step 5.5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole. 6-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-5-ol (3.0 g,8.3mmol,1.0 eq), (1S) -1- (3, 5-dichloro-4-pyridinyl) ethyl ]A mixture of methanesulfonate (2.3 g,8.3mmol,1.0 eq.) and cesium carbonate (4.1 g,12.4mmol,1.5 eq.) in acetonitrile (82 mL) was heated at 90℃overnight. After cooling to room temperature, the reaction was diluted with ethyl acetate (200 mL) and washed with water (200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (30 g). In Biotage automated chromatography systems (BiotageHC,200g, silica gel) and eluted with a 0 to 100% ethyl acetate gradient in heptane to give a white solid (3.0 g,68% yield). LCMS M/z=m+h).
Step 6.5-bromo-2- (6, 6-dioxo-6-sulphur-2-azaspiro [3.5] non-2-yl) nicotinonitrile. A solution of 5-bromo-2-chloropyridine-3-carbonitrile (327 mg,1.5mmol,1.0 eq), 6λ6-thia-2-azaspiro [3.5] nonane 6, 6-dioxide (318 mg,1.5mmol,1.0 eq) and N, N-diisopropylethylamine (1.21 mL,6.9mmol,4.6 eq) in acetonitrile (8 mL) was heated at 60℃for 16 h and then stirred at room temperature for an additional 16 h. The resulting solid was filtered and washed with cold acetonitrile (4 mL). The solid was dried under vacuum at room temperature overnight to give a white solid (399 mg,74% yield). LCMS M/z=356 (m+h).
Step 7 and step 8.2- (6, 6-dioxo-6λ6-thia-2-azaspiro [3.5] non-2-yl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine-3-carbonitrile and step 8.5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -2- (6, 6-dioxo-6-thiophen-2-azaspiro [3.5] non-2-yl) nicotinonitrile. To a solution of 5-bromo-2- (6, 6-dioxo-6-thia-2-azaspiro [3.5] non-2-yl) nicotinonitrile (243 mg,0.68mmol,1.0 eq), potassium acetate (81 mg,0.83mmol,1.2 eq), bis (pinacolato) diboron (190 mg,0.75mmol,1.10 eq) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (35 mg,0.04mmol,0.07 eq) in 1, 4-dioxane (10 mL) was sparged with nitrogen for 5 min and then heated at 97℃for 18 h. After cooling to room temperature, 5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-fluoro-3-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (200 mg,0.37mmol,1.0 eq.), [1,1' -bis (diphenylphosphino) ferrocene ] -dichloropalladium (II) (19 mg,0.02mmol,0.07 eq.), potassium carbonate (103 mg,0.75mmol,2.0 eq.) and water (1.0 mL) were added. The resulting mixture was purged with nitrogen for 5 minutes and then heated at 90℃for 4 hours. The mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and water (10 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with saturated brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Biotage HC,50g silica gel column), eluting with a 0 to 100% ethyl acetate gradient in heptane, to give an off-white solid (310 mg, >100% yield). LCMS M/z=685 (m+h).
(R) -5- (5- (1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-fluoro-1H-indazol-3-yl) -2- (6, 6-dioxo) -6-thia-2-azaspiro [3.5] non-2-yl) nicotinonitrile. 5- (5- ((R) -1- (3, 5-dichloropyridin-4-yl) ethoxy) -6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-3-yl) -2- (6, 6-dioxo-6-thia-2-azaspiro [3.5] non-2-yl) nicotinonitrile (124 mg,0.18 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (3 mL). After stirring overnight at room temperature, the reaction was quenched with saturated sodium carbonate (25 mL) and 6N sodium hydroxide (20 mL) at 0deg.C. The layers were separated and the aqueous layer was extracted with dichloromethane (2X 25 mL). The combined organic layers were washed with saturated brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (RediSep Rf GOLD 100g HP c18 column), eluting with a 0 to 90% acetonitrile gradient in water. The product fractions were concentrated under reduced pressure and then precipitated from a mixture of ethyl acetate (3 mL), methanol (0.5 mL), MTBE (7 mL) and heptane (15 mL) to give an off-white solid (88 mg,81% yield, 99.3% purity). LCMS M/z=601.1 (m+h); 1H NMR (400 mhz, dmso-d 6) δ=13.23 (s, 1H), 8.75 (d, j=2.3 hz, 1H), 8.60 (s, 2H), 8.14 (d, j=2.3 hz, 1H), 7.47 (d, j=10.9 hz, 1H), 7.24 (d, j=7.9 hz, 1H), 6.18 (q, j=6.6 hz, 1H), 4.29 (d, j=9.0 hz, 2H), 4.07 (d, j=8.9 hz, 2H), 3.51 (s, 2H), 3.11-3.00 (m, 2H), 1.99 (br s, 4H), 1.81 (d, j=6.6 hz, 3H).
The following examples can be prepared using the methods and procedures described herein.
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Kinase assay
Kinase-tagged T7 phage strains were prepared in an e.coli host derived from the BL21 strain. Coli grew to log phase and infected T7 phage and incubated with shaking at 32 ℃ until lysis. The lysate was centrifuged and filtered to remove cell debris. Streptavidin coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to generate affinity resins for kinase assays. Ligand beads were blocked with excess biotin and washed with blocking buffer SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1mM DTT to remove unbound ligand and reduce non-specific binding. The binding reaction was assembled by combining kinase, ligand affinity beads and test compounds in 1 Xbinding buffer (20% SeaBlock, 0.17 XPBS, 0.05% Tween 20, 6mM DTT).
Test compounds were prepared as 111X stock solutions in slaughter 100% DMSO. Kd was determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds used for Kd measurements were distributed in 100% DMSO by acoustic transmission (non-contact dispensing). The compounds were then directly diluted into the assay such that the final concentration of DMSO was 0.9%. All reactions were performed in polypropylene 384 well plates. The final volume was 0.02mL each. Assay plates were incubated for 1 hour with shaking at room temperature and affinity beads were washed with wash buffer (1×pbs,0.05% Tween 20). The beads were then resuspended in elution buffer (1 XPBS, 0.05% Tween 20, 0.5. Mu.M non-biotinylated affinity ligand) and incubated for 30 minutes at room temperature with shaking. The kinase concentration in the eluate was measured by qPCR.
Binding constant (Kd)
Binding constants were calculated by standard dose-response curves using Hill equation:
hill slope is set to-1. A nonlinear least squares fit curve was used using the Levenberg-Marquardt algorithm.
Table 4.
A＝1-20nM
B＝>20to 100nM
C＝>100to 300nM
D＝>300nM
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Cell viability assay
Cell lines for cell viability assays
Ba/F3 cell viability assay
The purpose of the experiment is as follows: recombinant kinase fusions were transduced into the parent Ba/F3, which relied on this constitutive kinase activity to achieve IL3 independent survival. Inhibition of kinase activity leads to cell death, using2.0 (Promega) cell death was monitored and intracellular ATP concentrations were in turn used as markers of viability. FGFR1-BCR Ba/F3 and FGFR3-BAIAP2L1 Ba/F3 are obtained from higher cell kinetics (Seattle, WA)
Cell viability assay procedure:2.0 luminous cell viability assay reagents were purchased from Promega (Madison, wis.). FGFR1-BCR Ba/F3 and FGFR3-BAIAP2L1 Ba/F3 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum. Cultures at 5%The wet environment of CO2 and 95% air was maintained at 37 ℃. />
Cells were inoculated in 100 μl of 10,000 cells/well medium in 96 well clear bottom/white plates (Corning # 3903) and incubated overnight. The next day, a stock solution of test compound DMSO was prepared at a final concentration of 10mM and 2 μm. Then, compounds were added to the cells using an HP 300e digital dispenser in a 9 dose 10-fold dilution series starting at 30 μm (three applications per dose in parallel). DMSO was backfilled into each well until a total volume of 301nL of test compound + DMSO, and a total of 301nL of DMSO was added to the control/no test compound wells, performed in triplicate. Cells and compounds in cell culture plates were incubated at 37℃and 5% CO 2 Incubate for 48 hours under conditions. Then, 50. Mu.l of Cell Titer Glo 2.0 reagent was added to each well of the Cell culture plate. The contents were protected from light and mixed at room temperature on an orbital shaker for 10min. Luminescence was recorded by a Synergy H1 microplate reader (Biotek, winooski, VT). Cells were evaluated as a percentage of control cells treated with DMSO alone. Curves were plotted and IC was calculated based on the sigmoidal dose-effect equation (4 parameters) using GraphPad Prism 8 program 50 Values.
Determination of cell viability of RT112/84, UM-UC-14 and KG-1 cancer cell lines
The purpose of the experiment is as follows: by passing throughDetecting intracellular ATP changes and determining in vitro IC of the compound 50 The inhibition of cancer cell lines by the compounds was evaluated.
2.0 luminous cell viability assay reagents were purchased from Promega (Madison, wis.). RT112/84 and KG-1 cell lines were purchased from the American type culture Collection (Manassas, va.). UM-UC-14 cell line was purchased from Sigma (St. Louis, mo.). RT112/84, UM-UC-14 and KG-1 cells were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum. The culture was maintained at 37℃in a humid environment of 5% CO2 and 95% air.
Cell viability assay procedure: cells were inoculated in 96-well clear bottom/white plate (Corning # 3903) with 100 μl of 10,000 cells/well medium and incubated overnight. The next day, a stock solution of test compound DMSO was prepared at a final concentration of 10mM and 2 μm. Then, compounds were added to the cells using an HP 300e digital dispenser in a 9 dose 10-fold dilution series starting at 30 μm (three applications per dose in parallel). DMSO was backfilled into each well until a total volume of 301nL of test compound + DMSO, and a total of 301nL of DMSO was added to the control/no test compound wells, performed in triplicate. Cells and compounds in cell culture plates were incubated at 37℃and 5% CO 2 Incubate under conditions for 72 hours. Then, 50. Mu.l of Cell Titer Glo 2.0 reagent was added to each well of the Cell culture plate. The contents were protected from light and mixed at room temperature on an orbital shaker for 10min. Luminescence was recorded by a Synergy H1 microplate reader (Biotek, winooski, VT). Cells were evaluated as a percentage of control cells treated with DMSO alone. Curves were plotted and IC was calculated based on the sigmoidal dose-effect equation (4 parameters) using GraphPad Prism 8 program 50 Values. The results are shown in Table 5.
Table 5: FGFR3 selectivity in cell-based assays
A＝1-20nM
B＝>20to 100nM
C＝>100to 300nM
D＝>300nM
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Table 6: FGFR3> FGFR1 selectivity ratio in Ba/F3 FGFR fusion cell-based assays
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The present disclosure also relates to the following aspects:
aspect 1A compound of formula (I)
Or a pharmaceutically acceptable salt thereof,
wherein n=1, 2 or 3;
m=1, 2 or 3;
each R 1 Independently H or optionally substituted C 1 -C 6 An alkyl group;
each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group;
or two R's attached to the same carbon atom 1 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o);
Or two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to different carbon atoms 1 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or two R's attached to different carbon atoms 2 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or R is 1 Radicals and R 2 The groups are connected to form a 6-9 membered bridged bicyclic ring;
a=n or CH;
Z＝S(O) 2 ；S(O)；O、NR 3 or CR (CR) 4 R 4’ ；
R 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b ；
R a Is H or C 1 -C 6 An alkyl group;
R b is H or C 1 -C 6 An alkyl group;
or R is a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R c is optionally substituted C 1 -C 6 Alkyl, or cycloalkyl;
R 4 is H or optionally substituted C 1 -C 6 An alkyl group;
R 4’ is H, -OH or optionally substituted C 1 -C 6 An alkyl group;
or R is 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
y is a 5-or 6-membered heteroaryl ring;
Q 5 、Q 6 、Q 7 、Q 8 and Q 9 Each independently is N or CR 5 Wherein Q is 5 、Q 6 、Q 7 、Q 8 And Q 9 One or two of which are N and the remainder are CR 5 ；
R 5 Is H, halogen, C 1 -C 3 An alkyl group; c (C) 1 -C 3 Alkoxy, or cycloalkyl;
x= O, S or NR, wherein R is H or C 1 -C 3 An alkyl group; and
R 6 is C 1 -C 6 An alkyl group.
Aspect 2 the compound according to aspect 1, wherein Y is a 6 membered heteroaryl ring.
Aspect 3 the compound according to aspect 2, wherein the compound of formula (I) is a compound of formula (IA):
wherein Q is 1 、Q 2 、Q 3 、Q 4 One or two of which are N and the others are each independently CR 5a Wherein CR is 5a Is H, halogen, -CN or C 1 -C 3 An alkyl group.
Aspect 4. The compound according to any one of aspects 1 to 3, wherein X is O.
Aspect 5 the compound according to any one of aspects 3 to 4, wherein the compound of formula (IA) is a compound of formula (IA-1):
aspect 6 the compound according to any one of the preceding aspects, wherein R 6 is-CH 3 。
Aspect 7 the compound according to any one of aspects 3 to 6, wherein Q 3 Is CR (CR) 5a 。
Aspect 8 the compound according to aspect 7, wherein R 5a Is halogen.
Aspect 9. The compound according to aspect 8, wherein halogen is-F.
Aspect 10 the compound according to aspect 5, wherein the compound of formula (IA-1) is a compound of formula (IA-2):
aspect 11 the compound of any one of aspects 1-10, wherein n = 2 and m = 2.
Aspect 12 the compound according to any one of aspects 1-10, wherein n = 1 and m = 1.
Aspect 13 the compound according to any one of aspects 1-10, wherein n = 1 and m = 2.
Aspect 14 the compound according to any one of aspects 1-10, wherein n = 3 and m = 2.
Aspect 15 the compound according to aspect 10, wherein the compound of formula (IA-2) is a compound of formula (IA-3):
aspect 16 the compound according to aspect 15, wherein each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
Aspect 17 the compound according to aspect 15, wherein each R 1 And each R 2 Is H.
Aspect 18 the compound according to aspect 15, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-7 membered spirocycloalkyl ring.
The compound according to aspect 18, wherein the 3-7 membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.
Aspect 20 the compound according to aspect 15, wherein one R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H.
Aspect 21 the compound according to aspect 20, wherein the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
Aspect 22 the compound according to aspect 20, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
Aspect 23 the compound according to aspect 10, wherein the compound of formula (IA-2) is a compound of formula (IA-4):
aspect 24 the compound according to aspect 23, wherein two R's attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
Aspect 25 the compound according to aspect 10, wherein the compound of formula (IA-2) is a compound of formula (IA-5):
aspect 26 the compound according to aspect 25, wherein each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
Aspect 27 the compound according to aspect 25, wherein each R 1 And each R 2 Is H.
Aspect 28 the compound according to aspect 25, wherein each R 1 Is H, and is connected toTwo R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-7 membered spirocycloalkyl ring.
Aspect 29 the compound according to aspect 28, wherein the 3-7 membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.
Aspect 30A compound according to aspect 25, wherein R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H.
Aspect 31 the compound according to aspect 30, wherein the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
Aspect 32 the compound according to aspect 10, wherein the compound of formula (IA-2) is a compound of formula (IA-6):
aspect 33 the compound according to aspect 32, wherein two R's attached to the same carbon atom 1 The group represents a carbonyl group (c=o).
Aspect 34 the compound according to aspect 32 or aspect 33, wherein two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
The compound of aspect 35, aspect 34, wherein two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
The compound according to aspect 35, wherein the optionally substituted 3-7 membered spiroheterocycloalkyl ring is an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, or an optionally substituted piperidinyl ring.
Aspect 37 the compound of aspect 36, wherein the optionally substituted 3-7 membered spiroheterocycloalkyl ring is an azetidinyl ring, a pyrrolidinyl ring, a piperidinyl ring, an N-methylpiperidinyl ring, or an N- (methylsulfonyl) piperidinyl ring.
Aspect 38 the compound according to aspect 10, wherein the compound of formula (IA-2) is a compound of formula (IA-7):
Aspect 39 the compound according to aspect 38, wherein each R 1 Is H.
Aspect 40 the compound according to aspect 38, wherein two R's attached to the same carbon atom 1 The group represents a carbonyl group (c=o).
Aspect 41 the compound according to any one of aspects 38 to 40, wherein each R 2 Is H.
Aspect 42 the compound according to any one of aspects 38 to 40, wherein two R attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
Aspect 43 the compound according to any one of aspects 3 to 42, wherein Q 2 Is N.
Aspect 44 the compound according to any one of aspects 3 to 43, wherein Q 4 Is N.
Aspect 45 the compound according to any one of aspects 3 to 43, wherein Q 4 Is CR (CR) 5a 。
Aspect 46 the compound according to aspect 45, wherein R 5a Is H.
Aspect 47A compound according to aspect 45, wherein R 5a Is halogen.
Aspect 48 the compound according to aspect 47, wherein halogen is-F.
Aspect 49 the compound according to aspect 1, wherein Y is a 5 membered heteroaryl ring.
Aspect 50 the compound according to aspect 49, wherein the compound of formula (I) is a compound of formula IB:
aspect 51 the compound according to aspect 50, wherein the compound of formula (IB) is a compound of formula IB-1:
aspect 52 the compound according to aspect 51, wherein the compound of formula (IB-1) is a compound of formula IB-2:
Aspect 53 the compound according to any one of aspects 49-52, wherein n=2 and m=2.
Aspect 54 the compound according to any one of aspects 49-52, wherein n = 1 and m = 1.
Aspect 55 the compound according to any one of aspects 49-52, wherein n = 1 and m = 2.
Aspect 56 the compound of any one of aspects 49-52, wherein n = 3 and m = 2.
Aspect 57 the compound according to any one of aspects 49 to 56, wherein each R 1 Is H, and each R 2 Is H.
Aspect 58 the compound according to any one of the preceding aspects, wherein a is N.
Aspect 59 the compound according to any one of the preceding aspects, wherein a is CH.
Aspect 60 the compound according to any one of the preceding aspects, wherein Z is S (O) 2 。
Aspect 61 the compound according to any one of aspects 1-59, wherein Z is S (O).
The compound according to any one of aspects 1-59, wherein Z is O.
Aspect 63 the compound of any one of aspects 1-59, wherein Z is NR 3 。
Aspect 64A compound according to aspect 63, wherein R 3 Is H.
Aspect 65A compound according to aspect 63, wherein R 3 is-C (O) NR a R b 。
Aspect 66. According to aspect 63, wherein R is 3 is-S (O) 2 NR a R b
Aspect 67 the compound according to any one of aspects 65 or 66, wherein R a Is H and R b Is H.
Aspect 68 the compound according to any one of aspects 65 or 66, wherein R a Is H and R b Is C 1 -C 6 An alkyl group.
Aspect 69 the compound according to any one of aspects 65 or 66, wherein R a Is C 1 -C 6 Alkyl and R b Is C 1 -C 6 An alkyl group.
Aspect 70 the compound according to any one of aspects 65 or 66, wherein R a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
Aspect 71 the compound according to aspect 70, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted piperidinyl ring, an optionally substituted piperazinyl ring, or an optionally substituted morpholinyl ring.
Aspect 72 the compound according to aspect 71, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is a 4-methylpiperazin-1-yl ring or a morpholinyl ring.
Aspect 73 the compound according to aspect 63, wherein R 3 is-C (O) OR c 。
Aspect 74A compound according to aspect 63, wherein R 3 is-C (O) R c 。
Aspect 75A compound according to aspect 63, wherein R 3 is-S (O) 2 R c 。
Aspect 76 the compound according to any one of aspects 73 to 75, wherein the R c is-CH 3 。
Aspect 77 the compound of any one of aspects 73 to 75, wherein said R c is-CH 2 CH 3 。
Aspect 78 the compound according to aspect 63, wherein R 3 Is C 1 -C 6 An alkyl group.
Aspect 79. The chemistry according to aspect 78A compound, wherein said C 1 -C 6 Alkyl is-CH 3 。
Aspect 80. The compound according to aspect 63, wherein R 3 Is a 3-5 membered heterocycloalkyl.
Aspect 81 the compound according to aspect 80, wherein the 3-5 membered heterocycloalkyl is oxetanyl.
Aspect 82 the compound according to any one of aspects 1 to 59, wherein Z is CR 4 R 4’ 。
Aspect 83 the compound according to aspect 82, wherein R 4 And R is 4’ Each is H.
Aspect 84 the compound according to aspect 82, wherein R 4 And R is 4’ Each is optionally substituted C 1 -C 6 An alkyl group.
Aspect 85 the compound according to aspect 82, wherein R 4 Is H and R 4’ is-OH.
Aspect 86 the compound according to aspect 82, wherein R 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
Aspect 87 the compound according to aspect 86, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 4-membered heterocycloalkyl ring.
Aspect 88 the compound according to aspect 87, wherein the optionally substituted 4-membered heterocycloalkyl ring is an azetidinyl ring.
Aspect 89 the compound of aspect 88, wherein the azetidinyl ring is unsubstituted.
Aspect 90 the compound according to aspect 88, wherein the azetidinyl ring is N-substituted.
Aspect 91 the compound according to aspect 90 wherein the N-substituent is-C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
Aspect 92A compound according to aspect 91 wherein the N-substituent is-CH 3 、-CH(CH3) 2 、-C(O)N(CH 3 ) 2 or-SO 2 CH 3 。
Aspect 93 the compound of aspect 86, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 5-membered heterocycloalkyl ring.
Aspect 94 the compound of aspect 93, wherein the optionally substituted 5-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2, 5-dione ring, an N-substituted pyrrolo-2, 5-dione ring, an unsubstituted imidazolidin-2-one ring, an N-substituted imidazolidin-2-one ring, a tetrahydrofuran ring, or a tetrahydrothiophene-1, 1-dioxide ring.
Aspect 95 the compound according to aspect 94, wherein the N-substituent is-CH 3 。
Aspect 96 the compound according to aspect 86, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 6-membered heterocycloalkyl ring.
Aspect 97 the compound according to aspect 96, wherein the optionally substituted 6-membered heterocycloalkyl ring is an unsubstituted piperazin-2-one ring or an N-substituted piperazin-2-one ring.
The compound according to aspect 98, wherein the N-substituent is-CH 3 。
Aspect 99. A pharmaceutical composition comprising a compound of any one of aspects 1-98, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
Aspect 100. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any one of aspects 1 to 98, or a pharmaceutically acceptable salt thereof.
The method of aspect 101, aspect 100, wherein the cancer is urothelial cancer, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic cancer, oral cancer, prostate cancer, bladder cancer, colorectal cancer, renal cell carcinoma, neuroendocrine cancer, myeloproliferative neoplasms, head and neck (squamous), melanoma, leiomyosarcoma, and/or sarcoma.
Aspect 102 the method of aspect 101, wherein the cancer is intrahepatic cholangiocarcinoma.
Aspect 103 the method of any one of aspects 100 to 102, wherein the cancer is FGFR mutant cancer.
Aspect 104A compound of formula (I)
Or a pharmaceutically acceptable salt thereof,
wherein n=1, 2 or 3;
m=1, 2 or 3;
Each R 1 Independently H, CN or optionally substituted C 1 -C 6 An alkyl group;
each R 2 Independently H, CN or optionally substituted C 1 -C 6 An alkyl group;
or two R's attached to the same carbon atom 1 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to different carbon atoms 1 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or two R's attached to different carbon atoms 2 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or R is 1 Radicals and R 2 The groups are connected to form a 6-9 membered bridged bicyclic ring;
a=n or CH;
Z＝S(O) 2 ；S(O)；O、NR 3 or CR (CR) 4 R 4’ ；
R 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b ；
R a Is H or C 1 -C 6 An alkyl group;
R b is H or C 1 -C 6 An alkyl group;
or R is a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R c is optionally substituted C 1 -C 6 Alkyl, or cycloalkyl;
R 4 is optionally substituted C 1 -C 6 An alkyl group;
R 4’ is H, -OH or optionally substituted C 1 -C 6 An alkyl group;
or R is 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
y is a 5-or 6-membered heteroaryl ring;
Q 5 、Q 6 、Q 7 、Q 8 and Q 9 Each independently is N or CR 5 Wherein Q is 5 、Q 6 、Q 7 、Q 8 And Q 9 One or two of which are N and the remainder are CR 5 ；
R 5 Is H, halogen, C 1 -C 3 An alkyl group; c (C) 1 -C 3 Alkoxy, or cycloalkyl;
x= O, S or NR, wherein R is H or C 1 -C 3 An alkyl group;
R 6 is C 1 -C 6 An alkyl group;
R 7 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl; and
R 8 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl.
Aspect 105 the compound according to aspect 104, wherein Y is a 6 membered heteroaryl ring.
Aspect 106 the compound according to aspect 105, wherein the compound of formula (I) is a compound of formula (IA):
wherein Q is 1 、Q 2 、Q 3 、Q 4 One or two of which are N and the others are each independently CR 5a Wherein CR is 5a Is H, halogen, -CN or C 1 -C 3 An alkyl group.
Aspect 107 the compound according to any one of aspects 104 to 106, wherein X is O.
Aspect 108 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 And Q 8 Each is CR 5 Wherein each R is 5 Is H; and Q is 7 Is N.
Aspect 109 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 Is C 1 -C 3 An alkyl group; and Q is 7 Is N.
Aspect 110 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And Q is 7 Is N.
Aspect 111 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
Aspect 112 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
Aspect 113 the compound according to any of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 114 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 115 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is C 1 -C 3 An alkyl group; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 116 the compound according to any one of aspects 104 to 107, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-CH 3 ；Q 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 117 the compound according to any one of aspects 104 to 107, wherein Q 5 、Q 8 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; and Q is 7 Is N.
Aspect 118 the compound according to any of aspects 104 to 107, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-F; and Q is 7 Is N.
Aspect 119 the compound according to any one of aspects 106-108, wherein the compound of formula (IA) is a compound of formula (IA-1):
aspect 120 the compound according to any one of the preceding aspects, wherein R 6 is-CH 3 。
Aspect 121 the compound according to any one of aspects 106 to 120 wherein Q 3 Is CR (CR) 5a 。
Aspect 122 the compound according to aspect 121, wherein R 5a Is halogen.
Aspect 123 the compound of aspect 122, wherein halogen is-F.
Aspect 124 the compound of aspect 119, wherein the compound of formula (IA-1) is a compound of formula (IA-2):
aspect 125 the compound of any one of aspects 104-124, wherein n = 2 and m = 2.
Aspect 126 the compound of any one of aspects 104-124, wherein n = 1 and m = 1.
Aspect 127 the compound according to any one of aspects 104-124, wherein n=1 and m=2.
Aspect 128 the compound of any one of aspects 104-124, wherein n = 3 and m = 2.
Aspect 129 the compound according to aspect 124, wherein the compound of formula (IA-2) is a compound of formula (IA-3):
aspect 130 the compound according to aspect 129, wherein each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
Aspect 131 the compound according to aspect 129, wherein each R 1 And each R 2 Is H.
Aspect 132A compound according to aspect 129, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-7 membered spirocycloalkyl ring.
Aspect 133. The compound according to aspect 132, wherein the 3-7 membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.
Aspect 134A compound according to aspect 129 wherein R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H.
Aspect 135. The compound according to aspect 134, wherein the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
Aspect 136 the compound of aspect 129, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
Aspect 137 the compound according to aspect 124, wherein the compound of formula (IA-2) is a compound of formula (IA-4):
aspect 138 the compound of aspect 137, wherein two R's attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
Aspect 139 the compound according to aspect 124, wherein the compound of formula (IA-2) is a compound of formula (IA-5):
aspect 140 the compound according to aspect 139, wherein each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
Aspect 141 the compound according to aspect 139, wherein each R 1 And each R 2 Is H.
Aspect 142A compound according to 139, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-7 membered spirocycloalkyl ring.
Aspect 143 the compound according to aspect 142, wherein the 3-7 membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.
Aspect 144 the compound according to aspect 139, wherein one R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H.
Aspect 145 the compound of aspect 144, wherein the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
Aspect 146 the compound according to aspect 124, wherein the compound of formula (IA-2) is a compound of formula (IA-6):
aspect 147 the compound according to aspect 146, wherein two R's attached to the same carbon atom 1 The group represents a carbonyl group (c=o).
Aspect 148 the compound according to aspect 146 or aspect 147, wherein two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted3-7 membered spiroheterocycloalkyl ring.
The compound of aspect 149, aspect 148 wherein two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
Aspect 150 the compound according to aspect 149, wherein the optionally substituted 3-7 membered spiroheterocycloalkyl ring is an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, or an optionally substituted piperidinyl ring.
Aspect 151. The compound of aspect 150, wherein the optionally substituted 3-7 membered spiroheterocycloalkyl ring is an azetidinyl ring, a pyrrolidinyl ring, a piperidinyl ring, an N-methylpiperidinyl ring, or an N- (methylsulfonyl) piperidinyl ring.
Aspect 152 the compound according to aspect 124, wherein the compound of formula (IA-2) is a compound of formula (IA-7):
aspect 153 the compound according to aspect 152, wherein each R 1 Is H.
Aspect 154 the compound according to aspect 152 wherein two R's attached to the same carbon atom 1 The group represents a carbonyl group (c=o).
Aspect 155 the compound according to any of aspects 152 to 154, wherein each R 2 Is H.
Aspect 156 the compound according to any of aspects 152-154, wherein two R attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
Aspect 157 the compound according to one of aspects 117-156, wherein Q 2 Is N.
Aspect 158 the compound according to any of aspects 117-157, wherein Q 4 Is N.
Aspect 159 the compound of any one of aspects 117-157, wherein Q 4 Is CR (CR) 5a 。
Aspect 160A compound according to aspect 159, whichR in (B) 5a Is H.
Aspect 161 the compound according to aspect 159, wherein R 5a Is halogen.
Aspect 162 the compound of aspect 159, wherein halogen is-F.
Aspect 163. The compound of aspect 104, wherein Y is a 5 membered heteroaryl ring.
Aspect 164 the compound according to aspect 163, wherein the compound of formula (I) is a compound of formula IB:
the compound according to any one of aspects 163-164, wherein X is O.
Aspect 166 the compound according to any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 And Q 8 Is CR (CR) 5 Wherein R is 5 Is H; and Q is 7 Is N.
Aspect 167 the compound according to any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 Is C 1 -C 3 An alkyl group; and Q is 7 Is N.
Aspect 168 the compound according to any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And Q is 7 Is N.
Aspect 169. The compound according to any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
Aspect 170 the compound according to any one of aspects 163 to 165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
Aspect 171 the compound according to any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 172 the compound of any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 173 the compound according to any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is C 1 -C 3 An alkyl group; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 174 the compound according to any one of aspects 163-165, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-CH 3 ；Q 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
Aspect 175 the compound according to any one of aspects 163-165, wherein Q 5 、Q 8 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; and Q is 7 Is N.
Aspect 176. The chemical according to any one of aspects 163-165A compound, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-F; and Q is 7 Is N.
Aspect 177. The compound according to aspect 164, wherein the compound of formula (IB) is a compound of formula IB-1:
aspect 178 the compound according to aspect 177, wherein the compound of formula (IB-1) is a compound of formula IB-2:
aspect 179 the compound according to any one of aspects 164-178, wherein n = 2 and m = 2.
Aspect 180 the compound of any one of aspects 164-178, wherein n = 1 and m = 1.
Aspect 181 the compound of any one of aspects 164-178, wherein n = 1 and m = 2.
Aspect 182 the compound according to any one of aspects 164 to 178, wherein n = 3 and m = 2.
Aspect 183 the compound according to any of aspects 164 to 178, wherein each R 1 Is H, and each R 2 Is H.
The compound according to any one of aspects 104-183, wherein a is N.
The compound according to any one of aspects 104-183, wherein a is CH.
Aspect 186 the compound according to any of aspects 104-185, wherein Z is S (O) 2 。
Aspect 187 the compound of any one of aspects 104-185, wherein Z is S (O).
The compound according to any one of aspects 104-185, wherein Z is O.
The compound according to any one of aspects 104-185, wherein Z is NR 3 。
Aspect 190 the compound according to aspect 189, wherein R 3 Is H.
Aspect 191 the compound according to aspect 189, wherein R 3 is-C (O) NR a R b 。
Aspect 192 the compound according to aspect 189, wherein R 3 is-S (O) 2 NR a R b
Aspect 193 the compound according to any one of aspects 191 or 192, wherein R a Is H and R b Is H.
Aspect 194 the compound according to any of aspects 191 or 192, wherein R a Is H and R b Is C 1 -C 6 An alkyl group.
Aspect 195 the compound according to any one of aspects 191 or 192, wherein R a Is C 1 -C 6 Alkyl and R b Is C 1 -C 6 An alkyl group.
Aspect 196 the compound according to any one of aspects 191 or 192, wherein R a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
A compound according to aspect 196, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted piperidinyl ring, an optionally substituted piperazinyl ring, or an optionally substituted morpholinyl ring.
Aspect 198 the compound according to aspect 197, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is a 4-methylpiperazin-1-yl ring or a morpholinyl ring.
199A Compound according to aspect 189, wherein R 3 is-C (O) OR c 。
Aspect 200 the compound according to aspect 186, wherein R 3 is-C (O) R c 。
Aspect 201 the compound according to aspect 186, wherein R 3 is-S (O) 2 R c 。
Aspect 202The compound according to any one of aspects 199 to 201, wherein said R c is-CH 3 。
Aspect 203 the compound according to any one of aspects 199 to 201, wherein the R c is-CH 2 CH 3 3。
Aspect 204 the compound according to aspect 189, wherein R 3 Is C 1 -C 6 An alkyl group.
Aspect 205 the compound of aspect 204, wherein the C 1 -C 6 Alkyl is-CH 3 。
Aspect 206 the compound according to aspect 189, wherein R 3 Is a 3-5 membered heterocycloalkyl.
Aspect 207 the compound of aspect 206 wherein the 3-5 membered heterocycloalkyl is oxetanyl.
Aspect 208 the compound according to any one of aspects 104 to 185, wherein Z is CR 4 R 4’ 。
Aspect 209 the compound of aspect 208, wherein R 4 And R is 4’ Each is H.
Aspect 210 the compound of aspect 208, wherein R 4 And R is 4’ Each is optionally substituted C 1 -C 6 An alkyl group.
Aspect 211 the compound of aspect 208, wherein R 4 Is H and R 4’ is-OH.
Aspect 212 the compound according to aspect 208, wherein R 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
Aspect 213 the compound of aspect 212, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 4-membered heterocycloalkyl ring.
Aspect 214 the compound of aspect 213, wherein the optionally substituted 4-membered heterocycloalkyl ring is an azetidinyl ring.
Aspect 215 the compound of aspect 214, wherein the azetidinyl ring is unsubstituted.
Aspect 216 the compound of aspect 214, wherein the azetidinyl ring is N-substituted.
The compound of aspect 217, aspect 216, wherein the N-substituent is-C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
The compound of aspect 218, aspect 217, wherein the N-substituent is-CH 3 、-CH(CH3) 2 、-C(O)OCH 2 CH 3 、-C(O)N(CH 3 ) 2 、-SO 2 CH 3 、-SO 2 CH(CH 3 ) 2 or-SO 2 CH 2 CH 3 。
Aspect 219 the compound of aspect 213, wherein the optionally substituted 4-membered heterocycloalkyl ring is an optionally substituted thietane 1, 1-dioxide ring.
The compound of aspect 220, aspect 213, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 5-membered heterocycloalkyl ring.
The compound of aspect 221, aspect 220, wherein the optionally substituted 5-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2, 5-dione ring, an N-substituted pyrrolo-2, 5-dione ring, an unsubstituted imidazolidin-2-one ring, an N-substituted imidazolidin-2-one ring, a tetrahydrofuran ring, or a tetrahydrothiophene-1, 1-dioxide ring.
Aspect 222. The compound according to aspect 221, wherein the N-substituent is-C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl or-SO 2 C 1 -C 6 An alkyl group.
Aspect 223 the compound according to aspect 222, wherein the N-substituent is-CH 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、-C(O)OCH(CH 3 ) 2 or-SO 2 CH 3 。
Aspect 224 the compound of aspect 212, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 6-membered heterocycloalkyl ring.
The compound of aspect 225, aspect 224, wherein the optionally substituted 6-membered heterocycloalkyl ring is an unsubstituted piperazin-2-one ring, an N-substituted or unsubstituted piperidine ring, or a tetrahydro-2H-thiopyran 1, 1-dioxide ring.
Aspect 226 the compound according to aspect 225, wherein the N-substituent is-C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl or-SO 2 C 1 -C 6 An alkyl group.
Aspect 227 the compound according to aspect 226 wherein the N-substituent is-CH 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、-C(O)OCH(CH 3 ) 2 or-SO 2 CH 3 。
Aspect 228 a pharmaceutical composition comprising a compound of any one of aspects 104-227, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
Aspect 229. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any one of aspects 104 to 227, or a pharmaceutically acceptable salt thereof.
Aspects 230 the method of aspect 229, wherein the cancer is urothelial cancer, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, exocrine pancreatic cancer, oral cancer, prostate cancer, bladder cancer, colorectal cancer, renal cell carcinoma, neuroendocrine cancer, myeloproliferative neoplasm, head and neck (squamous) carcinoma, melanoma, leiomyosarcoma, and/or sarcoma.
The method of aspect 231, aspect 230, wherein the cancer is intrahepatic cholangiocarcinoma.
The method of any one of aspects 232, 229-231, wherein the cancer is a FGFR mutant cancer.

Claims (135)

1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein n=1, 2 or 3;
m=0, 1, 2 or 3;
each R 1 Independently H, CN or optionally substituted C 1 -C 6 An alkyl group;
each R 2 Independently H, CN or optionally substituted C 1 -C 6 An alkyl group;
or two R's attached to the same carbon atom 1 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o);
Or two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to different carbon atoms 1 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or two R's attached to different carbon atoms 2 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or R is 1 Radicals and R 2 The groups are linked to form a 6-9 membered bridged bicyclic ring;
a=n or CH;
Z＝S(O) 2 ；S(O)；O、NR 3 or CR (CR) 4 R 4’ ；
R 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b ；
Or R is 3 And R is R 1 Or R is 2 Together forming an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R a is H or C 1 -C 6 An alkyl group;
R b is H or C 1 -C 6 An alkyl group;
or R is a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R c is optionally substituted C 1 -C 6 Alkyl, or cycloalkyl;
R 4 is H, -F or optionally substituted C 1 -C 6 An alkyl group;
R 4’ is H, -F, -OH, -CN, -NH 2 、-NH(C 1 -C 3 Alkyl), -N (C) 1 -C 3 Alkyl group 2 、-N(C 1 -C 3 Alkyl) -SO 2 (C 1 -C 3 Alkyl), -C 1 -C 6 Haloalkyl, optionally substituted C 1 -C 6 Alkyl or optionally substituted C 1 -C 6 An alkoxy group;
or R is 4 And R is 4’ Together with the C atom to which they are both attached, form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-to 7-membered cycloalkyl ring;
or R is 4 And R is 4’ Together with the carbon atoms to which they are both attached, form an oxo group;
or R is 4’ And R is R 1 Or R is 2 Together form an optionally substituted 3-to 7-membered heterocycloalkyl ring or an optionally substituted 3-to 7-membered cycloalkyl ring;
y is a 5-or 6-membered heteroaryl ring, or a 6-membered aryl ring;
Q 5 、Q 6 、Q 7 、Q 8 and Q 9 Each independently is N or CR 5 Wherein Q is 5 、Q 6 、Q 7 、Q 8 And Q 9 One or two of which are N and the remainder are CR 5 ；
R 5 Is H, halogen, C 1 -C 3 An alkyl group; c (C) 1 -C 3 Alkoxy, or cycloalkyl;
x= O, S or NR, wherein R is H or C 1 -C 3 An alkyl group;
R 6 is C 1 -C 6 An alkyl group;
R 7 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl; and
R 8 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl.
2. A compound according to claim 1,
wherein n=1, 2 or 3;
m=1, 2 or 3;
each R 1 Independently H or optionally substituted C 1 -C 6 An alkyl group;
each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group;
or two R's attached to the same carbon atom 1 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
Or two R's attached to the same carbon atom 1 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring;
or two R's attached to the same carbon atom 2 The group together with the carbon atom represents a carbonyl group (c=o);
or two R's attached to different carbon atoms 1 Radicals having one carbon atom to which they are attachedForming a 3-7 membered cycloalkyl ring;
or two R's attached to different carbon atoms 2 The groups together with the carbon atom to which they are attached form a 3-7 membered cycloalkyl ring;
or R is 1 Radicals and R 2 The groups are connected to form a 6-9 membered bridged bicyclic ring;
a=n or CH;
Z＝S(O) 2 ；S(O)；O、NR 3 or CR (CR) 4 R 4’ ；
R 3 Is H; optionally substituted C 1 -C 6 Alkyl, 3-5 membered cycloalkyl, 3-5 membered heterocycloalkyl, -C (O) NR a R b ；-C(O)OR c ；-C(O)R c ；-S(O) 2 R c The method comprises the steps of carrying out a first treatment on the surface of the or-S (O) 2 NR a R b ；
R a Is H or C 1 -C 6 An alkyl group;
R b is H or C 1 -C 6 An alkyl group;
or R is a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
R c is optionally substituted C 1 -C 6 Alkyl, or cycloalkyl;
R 4 is H or optionally substituted C 1 -C 6 An alkyl group;
R 4’ is H, -OH or optionally substituted C 1 -C 6 An alkyl group;
or R is 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring;
Y is a 5-or 6-membered heteroaryl ring;
Q 5 、Q 6 、Q 7 、Q 8 and Q 9 Each independently is N or CR 5 Wherein Q is 5 、Q 6 、Q 7 、Q 8 And Q 9 One or two of which are N and the remainder are CR 5 ；
R 5 Is H, halogen, C 1 -C 3 An alkyl group; c (C) 1 -C 3 Alkoxy, or cycloalkyl;
x= O, S or NR, wherein R is H or C 1 -C 3 An alkyl group;
R 6 is C 1 -C 6 An alkyl group;
R 7 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl; and
R 8 is H, halogen, -C 1 -C 6 An alkyl group; -C 1 -C 6 Alkoxy, or-cycloalkyl.
3. The compound of claim 1 or claim 2, wherein Y is a 6 membered heteroaryl ring.
4. A compound according to claim 3, wherein the compound of formula (I) is a compound of formula (IA):
wherein Q is 1 、Q 2 、Q 3 、Q 4 One or two of which are N and the others are each independently CR 5a Wherein CR is 5a Is H, halogen, -CN or C 1 -C 3 An alkyl group.
5. The compound of any one of claims 1-4, wherein X is O.
6. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 And Q 8 Each is CR 5 Wherein each R is 5 Is H; and Q is 7 Is N.
7. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 Is C 1 -C 3 An alkyl group; and Q is 7 Is N.
8. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And Q is 7 Is N.
9. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
10. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
11. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
12. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
13. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 Is C 1 -C 3 An alkyl group; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
14. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each is CR 5 Wherein each R is 5 is-CH 3 ；Q 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
15. The compound of any one of claims 1-5, wherein Q 5 、Q 8 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; and Q is 7 Is N.
16. The compound of any one of claims 1-5, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-F; and Q is 7 Is N.
17. The compound of any one of claims 4-6, wherein the compound of formula (IA) is a compound of formula (IA-1):
18. a method according to any preceding claimSaid compound wherein R 6 is-CH 3 。
19. The compound of any one of claims 4-18, wherein Q 3 Is CR (CR) 5a 。
20. The compound of claim 19, wherein R 5a Is halogen.
21. The compound of claim 20, wherein the halogen is-F.
22. The compound of claim 17, wherein the compound of formula (IA-1) is a compound of formula (IA-2):
23. The compound of any one of claims 1-22, wherein n = 2 and m = 2.
24. The compound of any one of claims 1-22, wherein n = 1 and m = 1.
25. The compound of any one of claims 1-22, wherein n = 1 and m = 2.
26. The compound of any one of claims 1-22, wherein n = 3 and m = 2.
27. The compound of claim 22, wherein the compound of formula (IA-2) is a compound of formula (IA-3):
28. the compound of claim 27, wherein each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
29. The compound of claim 27, wherein each R 1 And each R 2 Is H.
30. The compound of claim 27, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-7 membered spirocycloalkyl ring.
31. The compound of claim 30, wherein the 3-7 membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.
32. The compound of claim 27, wherein one R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H.
33. The compound of claim 32, wherein the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
34. The compound of claim 27, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
35. The compound of claim 22, wherein the compound of formula (IA-2) is a compound of formula (IA-4):
36. the compound of claim 35, wherein two R attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
37. The compound of claim 22, wherein the compound of formula (IA-2) is a compound of formula (IA-5):
38. the compound of claim 37, wherein each R 1 And each R 2 Independently H or optionally substituted C 1 -C 6 An alkyl group.
39. The compound of claim 37, wherein each R 1 And each R 2 Is H.
40. The compound of claim 37, wherein each R 1 Is H, and two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form a 3-7 membered spirocycloalkyl ring.
41. The compound of claim 40, wherein the 3-7 membered spirocycloalkyl ring is a 3-membered spirocycloalkyl ring.
42. The compound of claim 37, wherein one R 1 A group and one R 2 The radicals being joined to form a 6-9 membered bridged bicyclic ring, the other R 1 Is H, and another R 2 Is H.
43. The compound of claim 42, wherein the 6-9 membered bridged bicyclic ring is a 7 membered bridged bicyclic ring.
44. The compound of claim 22, wherein the compound of formula (IA-2) is a compound of formula (IA-6):
45. a compound according to claim 44, wherein two R's attached to the same carbon atom 1 The group represents a carbonyl group (c=o).
46. The compound of claim 44 or claim 45 wherein two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spirocycloalkyl ring or an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
47. A compound according to claim 46, wherein two R's attached to the same carbon atom 2 The groups together with the carbon atoms to which they are both attached form an optionally substituted 3-7 membered spiroheterocycloalkyl ring.
48. The compound of claim 47, wherein the optionally substituted 3-7 membered spiroheterocycloalkyl ring is an optionally substituted azetidinyl ring, an optionally substituted pyrrolidinyl ring, or an optionally substituted piperidinyl ring.
49. The compound of claim 48, wherein the optionally substituted 3-7 membered spiroheterocycloalkyl ring is an azetidinyl ring, a pyrrolidinyl ring, a piperidinyl ring, an N-methylpiperidinyl ring, or an N- (methylsulfonyl) piperidinyl ring.
50. The compound of claim 22, wherein the compound of formula (IA-2) is a compound of formula (IA-7):
51. the compound of claim 50, wherein each R 1 Is H.
52. A compound according to claim 50, wherein two R's attached to the same carbon atom 1 The group represents a carbonyl group (c=o).
53. The compound of any one of claims 50-52, wherein each R 2 Is H.
54. The compound of any one of claims 50-52, wherein two R attached to the same carbon atom 2 The group represents a carbonyl group (c=o).
55. The compound of claim 1 or claim 2, wherein the compound of formula (I) is a compound of formula (IA-8):
wherein R is 9 is-C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C (O) C 1 -C 6 Haloalkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
56. The compound of claim 55, wherein R is 9 is-CH 2 CF 3 、-CH 2 CHF 2 、-C(O)CF 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、-SO 2 CH 2 CH 3 or-SO 2 CH(CH 3 ) 2 。
57. The compound of any one of claims 17-56, wherein Q 2 Is N.
58. The compound of any one of claims 17-56, wherein Q 4 Is N.
59. The compound of any one of claims 17-56, wherein Q 4 Is CR (CR) 5a 。
60. The compound of claim 59, wherein R is 5a Is H.
61. The compound of claim 59, wherein R is 5a Is halogen.
62. The compound of claim 59, wherein said halogen is-F.
63. The compound of claim 1, wherein Y is a 5 membered heteroaryl ring.
64. The compound of claim 63, wherein the compound of formula (I) is a compound of formula IB:
65. the compound of any of claims 63-64, wherein X is O.
66. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 And Q 8 Is CR (CR) 5 Wherein R is 5 Is H; and Q is 7 Is N.
67. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 Is C 1 -C 3 An alkyl group; and Q is 7 Is N.
68. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-CH 3 The method comprises the steps of carrying out a first treatment on the surface of the And Q is 7 Is N.
69. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
70. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is CR (CR) 5 Wherein R is 5 Is H.
71. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
72. The method according to any one of claims 63-65Wherein Q is a compound of formula (I) 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
73. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 Is C 1 -C 3 An alkyl group; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
74. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-CH 3 ；Q 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is N; and Q is 7 Is N.
75. The compound of any of claims 63-65, wherein Q 5 、Q 8 And Q 9 Each independently is CR 5 Wherein each R is 5 Is halogen; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; and Q is 7 Is N.
76. The compound of any of claims 63-65, wherein Q 5 And Q 9 Each independently is CR 5 Wherein each R is 5 is-Cl; q (Q) 6 Is CR (CR) 5 Wherein R is 5 Is H; q (Q) 8 Is CR (CR) 5 Wherein R is 5 is-F; and Q is 7 Is N.
77. The compound of claim 64, wherein the compound of formula (IB) is a compound of formula IB-1:
78. the compound of claim 77, wherein said compound of formula (IB-1) is a compound of formula IB-2:
79. the compound of any of claims 64-78, wherein n = 2 and m = 2.
80. The compound of any of claims 64-78, wherein n = 1 and m = 1.
81. The compound of any of claims 64-78, wherein n = 1 and m = 2.
82. The compound of any one of claims 64-78, wherein n = 3 and m = 2.
83. The compound of any one of claims 64-78, wherein each R 1 Is H, and each R 2 Is H.
84. A compound according to any one of the preceding claims, wherein a is N.
85. A compound according to any one of the preceding claims, wherein a is CH.
86. The compound of any one of the preceding claims, wherein Z is S (O) 2 。
87. The compound of any one of claims 1-85, wherein Z is S (O).
88. The compound of any one of claims 1-85, wherein Z is O.
89. The compound of any one of claims 1-85, wherein Z is NR 3 。
90. The compound of claim 89, wherein R 3 Is H.
91. The compound of claim 89, wherein R 3 is-C (O) NR a R b 。
92. The compound of claim 89, wherein R 3 is-S (O) 2 NR a R b 。
93. The compound of any one of claims 91 or 92, wherein R a Is H and R b Is H.
94. The compound of any one of claims 91 or 92, wherein R a Is H and R b Is C 1 -C 6 An alkyl group.
95. The compound of any one of claims 91 or 92, wherein R a Is C 1 -C 6 Alkyl and R b Is C 1 -C 6 An alkyl group.
96. The compound of any one of claims 91 or 92, wherein R a And R is b Together with the N atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
97. The compound of claim 96, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted piperidinyl ring, an optionally substituted piperazinyl ring, or an optionally substituted morpholinyl ring.
98. The compound of claim 97, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is a 4-methylpiperazin-1-yl ring or a morpholinyl ring.
99. The compound of claim 89, wherein R 3 is-C (O) OR c 。
100. The compound of claim 89, wherein R 3 is-C (O) R c 。
101. The compound of claim 89, wherein R 3 is-S (O) 2 R c 。
102. The compound of any one of claims 99 to 101, wherein the R c is-CH 3 。
103. The compound of any one of claims 99 to 101, wherein the R c is-CH 2 CH 3 。
104. The compound of claim 89, wherein R 3 Is C 1 -C 6 An alkyl group.
105. The compound of claim 104, wherein the C 1 -C 6 Alkyl is-CH 3 。
106. The compound of claim 89, wherein R 3 Is a 3-5 membered heterocycloalkyl.
107. The compound of claim 106, wherein the 3-5 membered heterocycloalkyl is oxetanyl.
108. The compound of any one of claims 1-85An object wherein Z is CR 4 R 4’ 。
109. The compound of claim 108, wherein R 4 And R is 4’ Each is H.
110. The compound of claim 108, wherein R 4 And R is 4’ Each is optionally substituted C 1 -C 6 An alkyl group.
111. The compound of claim 108, wherein R 4 Is H and R 4’ is-OH.
112. The compound of claim 108, wherein R 4 And R is 4’ Together with the C atom to which they are both attached form an optionally substituted 3-to 7-membered heterocycloalkyl ring.
113. The compound of claim 112, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 4-membered heterocycloalkyl ring.
114. The compound of claim 113, wherein the optionally substituted 4-membered heterocycloalkyl ring is an azetidinyl ring.
115. The compound of claim 114, wherein the azetidinyl ring is unsubstituted.
116. The compound of claim 114, wherein the azetidinyl ring is N-substituted.
117. The compound of claim 116, wherein the N-substituent is-C 1 -C 6 Alkyl, -C 1 -C 6 Haloalkyl, -C (O) C 1 -C 6 Haloalkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl radicalsC(O)N(C 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
118. The compound of claim 117, wherein the N-substituent is-CH 2 CF 3 、-CH 2 CHF 2 、-C(O)CF 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、-SO 2 CH 2 CH 3 、-SO 2 CH(CH 3 ) 2 、-CH 3 、-CH(CH 3 ) 2 、-C(O)N(CH 3 ) 2 or-SO 2 CH 3 。
119. The compound of claim 116, wherein the N-substituent is C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl, -C (O) N (C) 1 -C 6 Alkyl group 2 or-SO 2 -C 1 -C 6 An alkyl group.
120. The compound of claim 119, wherein the N-substituent is-CH 3 、-CH(CH3) 2 、-C(O)OCH 2 CH 3 、-C(O)N(CH 3 ) 2 、-SO 2 CH 3 、-SO 2 CH(CH 3 ) 2 or-SO 2 CH 2 CH 3 。
121. The compound of claim 113, wherein the optionally substituted 4-membered heterocycloalkyl ring is an optionally substituted thietane 1, 1-dioxide ring.
122. The compound of claim 112, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 5-membered heterocycloalkyl ring.
123. The compound of claim 122, wherein the optionally substituted 5-membered heterocycloalkyl ring is an unsubstituted pyrrolidinyl ring, an N-substituted pyrrolidinyl ring, an unsubstituted pyrrolidinyl-2-one ring, an N-substituted pyrrolidinyl-2-one ring, an unsubstituted pyrrolo-2, 5-dione ring, an N-substituted pyrrolo-2, 5-dione ring, an unsubstituted imidazolidin-2-one ring, an N-substituted imidazolidin-2-one ring, a tetrahydrofuran ring, or a tetrahydrothiophene-1, 1-dioxide ring.
124. The compound of claim 123, wherein the N-substituent is-C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl or-SO 2 C 1 -C 6 An alkyl group.
125. The compound of claim 124, wherein the N-substituent is-CH 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、-C(O)OCH(CH 3 ) 2 or-SO 2 CH 3 。
126. The compound of claim 112, wherein the optionally substituted 3-to 7-membered heterocycloalkyl ring is an optionally substituted 6-membered heterocycloalkyl ring.
127. The compound of claim 126, wherein the optionally substituted 6-membered heterocycloalkyl ring is an unsubstituted piperazin-2-one ring, an N-substituted or unsubstituted piperidine ring, or a tetrahydro-2H-thiopyran 1, 1-dioxide ring.
128. The compound of claim 127, wherein the N-substituent is-C 1 -C 6 Alkyl, -C (O) OC 1 -C 6 Alkyl, -C (O) C 1 -C 6 Alkyl or-SO 2 C 1 -C 6 An alkyl group.
129. The compound of claim 128, wherein the N-substituent is-CH 3 、-C(O)OCH 3 、-C(O)OCH 2 CH 3 、-C(O)OCH(CH 3 ) 2 、-SO 2 CH 2 CH 3 or-SO 2 CH 3 。
130. The compound of claim 128, wherein the N-substituent is-SO 2 CH 2 CH 3 。
131. A pharmaceutical composition comprising a compound of any one of claims 1-130, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
132. A method of treating cancer in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1 to 130, or a pharmaceutically acceptable salt thereof.
133. The method of claim 132, wherein the cancer is urothelial cancer, breast cancer, endometrial adenocarcinoma, ovarian cancer, primary glioma, cholangiocarcinoma, gastric adenocarcinoma, non-small cell lung cancer, pancreatic exocrine cancer, oral cancer, prostate cancer, bladder cancer, colorectal cancer, renal cell carcinoma, neuroendocrine cancer, myeloproliferative neoplasms, head and neck (squamous) carcinoma, melanoma, leiomyosarcoma, and/or sarcoma.
134. The method of claim 133, wherein the cancer is intrahepatic cholangiocarcinoma.
135. The method of any one of claims 132-134, wherein the cancer is an FGFR mutant cancer.
CN202180092014.9A 2020-12-30 2021-12-30 Indazoles as kinase inhibitors Pending CN116761798A (en)

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US202163216879P 2021-06-30 2021-06-30
US63/216,879 2021-06-30
PCT/US2021/065679 WO2022147246A1 (en) 2020-12-30 2021-12-30 Indazole compounds as kinase inhibitors

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