CN116685596A - Compositions and methods for treating CNS disorders - Google Patents

Compositions and methods for treating CNS disorders Download PDF

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CN116685596A
CN116685596A CN202180090066.2A CN202180090066A CN116685596A CN 116685596 A CN116685596 A CN 116685596A CN 202180090066 A CN202180090066 A CN 202180090066A CN 116685596 A CN116685596 A CN 116685596A
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alkyl
compound
independently selected
pharmaceutically acceptable
acceptable salt
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M·J·布兰科-皮拉多
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Sage Therapeutics Inc
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Sage Therapeutics Inc
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Priority claimed from PCT/US2021/060358 external-priority patent/WO2022115381A1/en
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Abstract

Provided herein are compounds of formula (I)

Description

Compositions and methods for treating CNS disorders
Cross Reference to Related Applications
This PCT application claims the benefit of U.S. provisional patent application Nos. 63/118,089, 63/118,122, 63/118,086, 63/118,107, 63/118,079 and 63/118,092, all filed on 25 months in 2020. These documents are hereby incorporated by reference in their entirety.
Technical Field
The present invention relates to compounds, pharmaceutically acceptable salts and pharmaceutical compositions thereof, which modulate GABA activity and are useful in the treatment of CNS related disorders.
Background
Brain excitability is defined as the level of arousal (which is continuous from coma to convulsions) in an animal and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the potential (or membrane voltage) of the neuronal membrane is about-70 mV, with the cell interior being negative relative to the cell exterior. The potential (voltage) is the ion (K) across the semi-permeable membrane of the neuron + 、Na + 、Cl - Organic anions). Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine will cause membrane depolarization (potential changes from-70 mV to-50 mV). This effect is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine to increase the response to Na + Membrane permeability of ions. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.
In the case of the GABA Receptor Complex (GRC), the effect on brain excitability is mediated by the neurotransmitter gamma-aminobutyric acid (GABA). GABA has a profound effect on overall brain excitability, as up to 40% of neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conductance of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to promote the downward flow of chloride ions into the cell along the electrochemical gradient of the GRC. This intracellular increase in anion levels results in hyperpolarization of the transmembrane potential, rendering the neuron less sensitive to excitatory inputs, i.e., reduced excitability of the neuron. In other words, the higher the chloride ion concentration in the neurons, the lower the brain excitability and arousal level.
GRC has been shown to be responsible for mediating anxiety, seizures and sedation. Thus, GABA and drugs having effects similar to GABA or promoting GABA (e.g., therapeutically useful barbiturates and benzodiazepinesClass of drugs (BZ), such as) Producing a therapeutically useful effect thereof by interacting with specific regulatory sites on the GRC. There is now a lot of evidence that except for benzodiazepine +.>In addition to the drug-like and barbiturates binding sites, GRCs also contain different sites for neuroactive steroids. See, for example, lan, N.C. et al, neurochem.Res. (1991) 16:347-356.
Neuroactive steroids may be produced endogenously. The most potent endogenous neuroactive steroids are 3 alpha-hydroxy-5-reduced pregnan-20-one and 3 alpha-21-dihydroxy-5-reduced pregnan-20-one, the metabolites of the hormones progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al Science232:1004-1007 (1986); harrison, N.L. et al J Pharmacol. Exp. Ther.241:346-353 (1987)).
There is a need for new and improved compounds that act as modulators of brain excitability and as agents for the prevention and treatment of CNS related diseases. The compounds, compositions and methods described herein are directed to this object.
Disclosure of Invention
Provided herein are compounds designed to act, for example, as GABA modulators. In some embodiments, such compounds are useful as therapeutic agents for treating CNS-related disorders.
The present invention provides a compound of formula (I)
Or a pharmaceutically acceptable salt thereof, wherein ring D is selected from
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20a 、R 20b 、R 20c And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together form oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together form oxo, or R 20a And R is 20b Together forming oxo; r is R 5 And R is 20c Each of which is independently selected from-H and optionally substituted C 1-6 An alkyl group; r is R 10 is-H, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 31a And R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl and-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O or S; m is 1 or 2; and n is 0, 1 or 2,
provided that when R 31a And R is 31b One of them is-OR 32 When R is 31a And R is 31b The other of which is-H.
In another aspect, the invention provides a compound of formula (II)
Or a pharmaceutically acceptable salt thereof, wherein ring D, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20a 、R 20b 、R 20c 、R 21 、R 31a 、R 31b M and n are as defined in any one embodiment of the compounds of formula (I).
In some embodiments, ring D is a fused bicyclic ring selected from
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together form oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together form oxo, or R 20a And R is 20b Together forming oxo;R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H or optionally substituted C 1-6 An alkyl group; r is R 13 is-H or optionally substituted C 1-6 An alkyl group; r is R 31a And R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl and-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O or S; and n is 0, 1 or 2, provided that when R 31a And R is 31b One of them is-OR 32 When R is 31a And R is 31b The other of which is-H.
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 1a And R is 1b is-H, and the other is methyl. And in some embodiments, R 1a And R is 1b is-H.
In some embodiments, R 2a And R is 2b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 2a And R is 2b is-H, and the other is methyl. And in some embodiments, R 2a And R is 2b is-H.
In some embodiments, R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 3 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-H or methyl.
In some embodiments, n is 0, and R 4a And R is 4b Is not present. In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H or C optionally substituted with R' 1-6 Alkyl, or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, n is 1, R 4a And R is 4b is-H, and the other is methyl. And in some embodiments n is 1, and R 4a And R is 4b is-H.
In some embodiments, R 5 is-H or methyl. In some embodiments, R 5 is-H.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Three of them are-H, and R 6a 、R 6b 、R 7a And R is 7b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H, and the other is-H or methyl. And in some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. And in some embodiments, R 10 is-H, methyl or methoxymethyl.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b And the other two of them are independently selected from-H or methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of them are-H, and R 11a 、R 11b 、R 12a And R is 12b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H, and the other is-H or methyl. And in some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H.
In some embodiments, R 13 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyAnd (3) a methyl ethyl group. In some embodiments, R 13 is-H, methyl or methoxymethyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Independently selected from-H, methyl or-OH. In some embodiments, R 20a And R is 20b One of them is-OH and the other is-H or methyl. And in some embodiments, R 20a And R is 20b Together forming oxo.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -, -NH-or-CH 2 -CH 2 -CH 2 -; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-NH-; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and is combined withAnd R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, R 30 Is-> X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 Alkyl, orWhen R is 31a And R is 31b When one of them is-H, the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b One of them is-H and the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 An alkyl group. In some embodiments, R 31a And R is 31b One of them is-H and the other is-OH, -O-C 1-6 Alkyl, -O-phenyl or-O-C 3-6 Cycloalkyl groups. And in some embodiments, R 31a And R is 31b is-H.
Another aspect of the present invention provides a compound of formula (II-A) or (II-B)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (II).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H or optionally substituted C 1-3 An alkyl group; and R is 13 is-H or optionally substituted C 1-3 An alkyl group.
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (II-C)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (II).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -C (O) -, -OC (O) -, -C (O) O-, -C (O) C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H or optionally substituted C 1-3 An alkyl group; and R is 13 is-H or optionally substituted C 1-3 An alkyl group.
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-A1) or (II-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (II-A).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-S(O)-、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (II-B1) or (II-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (II-B).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-S(O)-、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-C1) or (II-C2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (II-C).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-A1 a), (II-A1 b), (II-A1 c) or (II-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-A) or (II-A1).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-A2 a), (II-A2 b), (II-A2 c) or (II-A2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-A) or (II-A2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independentIs selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (II-B1 a), (II-B1B), (II-B1 c) or (II-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-B) or (II-B1).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-B2 a), (II-B2B), (II-B2 c) or (II-B2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-B) or (II-B2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-C1 a), (II-C1 b), (II-C1C) or (II-C1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-C) or (II-C1).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-C2 a), (II-C2 b), (II-C2C) or (II-C2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-C) or (II-C2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 Alkyl group；R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl or-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted by-NR ', -S-, -O-, -OC (O) -, -C (O) O-, -C (O) C (O) -, -C (O) NR' -, -NR 'C (O) -, -S (O) -, -NR' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (III)
Or a pharmaceutically acceptable salt thereof, wherein ring D, R 3 、R 5 、R 10 、R 13 、R 15 、R 16 、R 17 、R 20a 、R 20b 、R 20c 、R 21 、R 31a 、R 31b And m is as defined in any one of the embodiments of the compounds of formula (I) or (II).
In some embodiments, ring D is a fused bicyclic ring selected from
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently-H, -OH, C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 Is C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group. In some embodiments, R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-CH 3 。
In some embodiments, R 5 is-H or C 1-3 An alkyl group. In some embodiments, R 5 is-H or methyl.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 10 is-H or methyl.
In some embodiments, R 13 Is C 1-6 An alkyl group. In some embodiments, R 13 Is methyl, ethyl or propyl. In some embodiments, R 13 is-H or methyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b One of them is-H, and R 20a And R is 20b The other one is C 1-6 An alkyl group. In some embodiments, R 20a And R is 20b One of them is C 1-6 Alkyl, and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a And R is 20b One of them being methyl, ethyl or propyl, and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a 、R 20b And the carbon to which it is attached
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In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and R is 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is thatWherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, R 30 Is->X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
Another aspect of the invention provides a compound of formula (III-A) or (III-B)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (III).
In some embodiments, R 3 Is methyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from pyrazolyl, tetrazolyl, and pyridinyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the present invention provides a compound of formula (III-C)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (III).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl;R 20a and R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-A1) or (III-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III) or (III-A).
Another aspect of the invention provides a compound of formula (III-B1) or (III-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III) or (III-B).
Another aspect of the invention provides a compound of formula (III-C1) or (III-C2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 Compounds of the formula (I), (II), (III) or (III-C)As defined in any one of the embodiments of the article.
Another aspect of the invention provides a compound of formula (III-A1 a), (III-A1 b), (III-A1 c) or (III-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-A) or (III-A1).
Another aspect of the invention provides a compound of formula (III-A2 a), (III-A2 b), (III-A2 c) or (III-A2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-A) or (III-A2).
Another aspect of the invention provides a compound of formula (III-B1 a), (III-B1B), (III-B1 c) or (III-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-B) or (III-B1).
Another aspect of the invention provides a compound of formula (III-B2 a), (III-B2B), (III-B2 c) or (III-B2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-B) or (III-B2).
Another aspect of the invention provides a compound of formula (III-C1 a), (III-C1 b), (III-C1C) or (III-C1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-C) or (III-C1).
Another aspect of the invention provides a compound of formula (III-C2 a), (III-C2 b), (III-C2C) or (III-C2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-C) or (III-C2).
Another aspect of the invention provides a compound of formula (IV)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b 、R 21 M and n are as defined in any one of the embodiments of formula (I).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) -, S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Substituted by substituents of (2), or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together withForming oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together form oxo, or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; m is 1 or 2; and n is 0, 1 or 2.
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 1a And R is 1b is-H, and the other is methyl. And in some embodiments, R 1a And R is 1b is-H.
In some embodiments, R 2a And R is 2b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 2a And R is 2b is-H, and the other is methyl. And in some embodiments, R 2a And R is 2b is-H.
In some embodiments, R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 3 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-H or methyl.
In some embodiments, n is 0, and R 4a And R is 4b Is not present. In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, and R 4a And R is 4b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, n is 1, R 4a And R is 4b is-H, and the other is methyl. And in some embodiments n is 1, and R 4a And R is 4b is-H.
In some embodiments, R 5 is-H.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of (3)Independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Three of them are-H, and R 6a 、R 6b 、R 7a And R is 7b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H, and the other is-H or methyl. And in some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. And in some embodiments, R 10 is-H, methyl or methoxymethyl.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b And the other two of (3) are independently selected from-H and methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of them are-H, and R 11a 、R 11b 、R 12a And R is 12b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H, and the other is-H or methyl. And in some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H.
In some embodiments, m is 1, and R 15 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, m is 1, and R 15 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, m is 1, and R 15 is-H or C 1-3 An alkyl group. In some embodiments, m is 1, and R 15 is-H or methyl. And in some embodiments, m is 1, and R 15 is-H.
In some embodiments, R 16 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 16 is-H or optionallyC substituted by R 1-6 An alkyl group. In some embodiments, R 16 is-H or C 1-3 An alkyl group. In some embodiments, R 16 is-H or methyl. And in some embodiments, R 16 is-H.
In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Independently selected from-H, methyl and-OH. In some embodiments, R 20a And R is 20b One of them is-OH and the other is-H or methyl. In some embodiments, R 20a And R is 20b Together forming oxo.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -, -NH-or-CH 2 -CH 2 -CH 2 -; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-NH-; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, R 30 Is-> X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
Another aspect of the present invention provides Sup>A compound of formulSup>A (IV-A)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (IV).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) -, S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 independentlySelected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-3 An alkyl group; and R is 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group.
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 And R is 16 Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-5 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 15 And R is 16 Each of which is independently-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halogenRadicals, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (IV-A1)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV) or (IV-A).
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight or branched chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (IV-A1 a) or (IV-A1 b)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV-A) or (IV-A1).
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of them is selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight or branched chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (IV-A1 A1) or (IV-A1 a 2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV-A1) or (IV-A1 Sup>A).
In some embodiments of the present invention, in some embodiments,R 1a 、R 1b 、R 2a and R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (IV-A1 b 1) or (IV-A1 b 2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV-A1) or (IV-A1 b).
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (V)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (IV).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C(CH 3 ) 3 is substituted with a group of (a).
In some embodiments, R 3 Is C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group. In some embodiments, R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-CH 3 。
In some embodiments, R 5 is-H or C 1-3 An alkyl group. In some embodiments, R 5 is-H or methyl.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 10 is-H or methyl.
In some embodiments, R 13 Is C 1-6 An alkyl group. In some embodiments, R 13 Is methyl, ethyl or propyl. In some embodiments, R 13 is-H or methyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b One of them is-H, and R 20a And R is 20b The other one is C 1-6 An alkyl group. In some embodiments, R 20a And R is 20b One of them is C 1-6 Alkyl, and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a And R is 20b One of them being methyl, ethyl or propyl, and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a 、R 20b And the carbon to which it is attached
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and R is 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a key、-CH 2 -or-N (H) -; and R is 30 Is thatWherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, R 30 Is->X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
Another aspect of the invention provides Sup>A compound of formulSup>A (V-A)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (IV) or (V).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (V-A1) or (V-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV), (V) or (V-A).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (V-A1 a) or (V-A1 b)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV), (V-A) or (V-A1).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or an optionally substituted branchOr straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (V-A2 a) or (V-A2 b)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV), (V-A) or (V-A2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl group,C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (VI)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c 、R 21 、R 31a 、R 31b M and n are as defined in any one of the embodiments of formula (I).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted by-NR ' -, -S-; -O-, -OC (O) -, -C (O) O-, -C (O) -, -C (O) C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together form oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 31a And R is 31b Each (i) of (i) is independently selected from the group consisting of-H, halo, and C 1-6 Alkyl, or (ii) when R 31a And R is 31b When one of them is-H, R 31a And R is 31b The other of them is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S; n is 0, 1 or 2; and m is 1 or2。
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 1a And R is 1b is-H, and the other is methyl. And in some embodiments, R 1a And R is 1b is-H.
In some embodiments, R 2a And R is 2b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 2a And R is 2b is-H, and the other is methyl. And in some embodiments, R 2a And R is 2b is-H.
In some embodiments, R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 3 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . In some embodiments, R 3 is-H or methyl.
In some embodiments, n is 0, and R 4a And R is 4b Is not present. In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, and R 4a And R is 4b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, n is 1, R 4a And R is 4b is-H, and the other is methyl. And in some embodiments n is 1, and R 4a And R is 4b is-H.
In some embodiments, R 5 is-H or methyl. In some embodiments, R 5 is-H.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Three of them are-H, and R 6a 、R 6b 、R 7a And R is 7b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H, and the other is-H or methyl. And in some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. And in some embodiments, R 10 is-H, methyl or methoxymethyl.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b And the other two of (3) are independently selected from-H and methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of them are-H, and R 11a 、R 11b 、R 12a And R is 12b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H, and the other is-H or methyl. And in some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H.
In some embodiments, R 13 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 13 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 13 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). In some embodiments, R 13 is-H. And in some embodiments, R 13 is-CH 3 (methyl group). In some embodiments, R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. In some embodiments, R 13 is-H or C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl or methoxymethyl. And in some embodiments, R 13 Is methyl.
In some embodimentsM is 1, and R 15 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, m is 1, and R 15 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, m is 1, and R 15 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, R 15 is-H.
In some embodiments, R 16 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 16 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 16 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, R 16 is-H.
In some embodiments, R 17 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 17 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 17 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, R 17 is-H.
In some embodiments, R 20c is-H.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -CH 2 -or-CH 2 -CH 2 -; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a hybrid having 0 to 4 heteroatoms independently selected from N, O and SA 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring of a child, wherein said 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, R 30 Is-> X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN,-NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl, or when R 31a And R is 31b When one of them is-H, the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b One of them is-H and the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 An alkyl group. In some embodiments, R 31a And R is 31b One of them is-H and the other is-OH, -O-C 1-6 Alkyl, -O-phenyl or-O-C 3-6 Cycloalkyl groups. In some embodiments, R 31a And R is 31b is-H.
Another aspect of the invention provides a compound of formula (VI-A) or (VI-B)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (VI).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-A1) or (VI-A2)
Or a pharmaceutical thereof Salts of the above acceptable, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI) or (VI-A).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-B1) or (VI-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI) or (VI-B).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R' is,Halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-A1 a), (VI-A1 b), (VI-A1 c) or (VI-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI-A) or (VI-A1) or (VI-A2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or an optionally substituted branchChain or straight-chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-B1 a), (VI-B1B), (VI-B1 c) or (VI-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI-B1) or (VI-B2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-A3 a), (VI-A3B), (VI-B3 a) or (VI-B3B)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 13 、R 17 、R 20c And R is 21 As defined in any of the embodiments of the compounds of formula (I), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c) or (VI-B1 d), where applicable.
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 、R 13 、R 17 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or a straight chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (VII)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (VI).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN,-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 Is C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group. In some embodiments, R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-CH 3 。
In some embodiments, R 5 is-H or C 1-3 An alkyl group. In some embodiments, R 5 is-H or methyl.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 10 is-H or methyl.
In some embodiments, R 13 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 13 is-H or methyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and R is 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is thatWherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, R 30 Is->X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
Another aspect of the invention provides a compound of formula (VII-A) or (VII-B)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI) or (VII).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VII-A1) or (VII-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI), (VII) or (VII-A).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or 3-8 membered saturated with 0-4 heteroatoms independently selected from N, O and S,Partially or fully unsaturated monocyclic ring, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (VII-B1) or (VII-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI), (VII) or (VII-B).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VII-A1 a), (VII-A1 b), (VII-A1 c) or (VII-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI), (VII-A1) or (VII-A2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 Any of the compounds of the formulae (I), (VI), (VII-B1) or (VII-B2)As defined in the embodiments.
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of any of the compounds described herein and a pharmaceutically acceptable carrier, vehicle or excipient.
Another aspect of the invention provides a subject in need of modulationGABA of the patient A A method of treating a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt of any compound or any pharmaceutical composition described herein.
Another aspect of the invention provides a method of modulating GABA in a subject in need thereof A A method of receptor-mediated CNS-related disorder comprising administering to a subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt of any compound or any pharmaceutical composition described herein.
Another aspect of the invention provides a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt of any of the compounds or any of the pharmaceutical compositions described herein.
In some implementations of the above methods, the CNS-related disorder is a sleep disorder, an affective disorder, a schizophrenic lineage disorder, a convulsive disorder, a memory and/or cognition disorder, a movement disorder, a personality disorder, an autism lineage disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and/or withdrawal syndrome, tinnitus, or status epilepticus. In some implementations, the CNS-related disorder is an affective disorder. In some implementations, the affective disorder is depression. In some implementations, the depression is post-partum depression. In some implementations, depression is major depressive disorder. In some implementations, the severe depression is a moderate severe depression. And in some implementations, the severe depression is severe depression.
Detailed Description
As generally described herein, the present invention provides designs to function, for example, as GABA A Neuroactive steroids as receptor modulators. In certain embodiments, it is contemplated that such compounds are useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, e.g., depression, such as post-partum depression or major depressive disorder).
I. Definition of the definition
A. Chemical definition
The definition of specific functional groups and chemical terms is described in more detail below. The chemical elements are identified according to the periodic table of the elements, CAS edition, handbook of Chemistry and Physics, 75 th edition, inner cover, and the specific functional groups are defined generally as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivity are as follows: thomas Sorrell, organic Chemistry, university Science Books, sausalato, 1999; smith and March, march's Advanced Organic Chemistry, 5 th edition, john Wiley & Sons, inc., new York,2001; larock, comprehensive Organic Transformations, VCH Publishers, inc., new York,1989; and Carruthers, some Modern Methods of Organic Synthesis, 3 rd edition, cambridge University Press, cambridge,1987.
Isomers (e.g., stereoisomers) may be separated from the mixtures by methods known to those skilled in the art, including chiral High Performance Liquid Chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, e.g., jacques et al, enantomers, racemates and Resolutions (Wiley Interscience, new York, 1981); wilen et al Tetrahedron 33:2725 (1977); eliel, stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, tables of Resolving Agents and Optical Resolutions, page 268 (E.L.Eliel, et al, univ.of Notre Dame Press, notre Dame, IN 1972). The invention additionally encompasses the compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of the various isomers.
"stereoisomers": it is also understood that compounds of the same formula but with different nature or order of atomic bonding or arrangement of atoms in space are referred to as "isomers". Isomers in which atoms are arranged differently in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers" and stereoisomers that are non-overlapping mirror images of each other are referred to as "enantiomers". For example, when a compound has an asymmetric center, it is bonded to four different groups, possibly as a pair of enantiomers. Enantiomers are characterized by the absolute configuration of their asymmetric centers and can be described by the R-and S-sequencing rules of Cahn and Prelog, or in terms of the plane of molecular rotation polarization and designated as either dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".
As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers (i.e., an isomer excess) of the compound. In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and is thus an enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that a compound comprises more than 75 wt%, more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 91 wt%, more than 92 wt%, more than 93 wt%, more than 94 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, more than 98.5 wt%, more than 99 wt%, more than 99.2 wt%, more than 99.5 wt%, more than 99.6 wt%, more than 99.7 wt%, more than 99.8 wt%, or more than 99.9 wt% of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.
In the compositions provided herein, enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-position/center/carbon compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, enantiomerically pure R-compounds in such compositions may comprise, for example, at least about 95% by weight of the R-compound and up to 5% by weight of the S-compound, based on the total weight of the compounds. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, enantiomerically pure S-compounds in such compositions may comprise, for example, at least about 95% by weight S-compound and up to 5% by weight R-compound, based on the total weight of the compounds. In certain embodiments, the active ingredient may be formulated with little or no excipient or carrier.
The term "diastereomerically pure" means that a compound comprises more than 75 wt%, more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 91 wt%, more than 92 wt%, more than 93 wt%, more than 94 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, more than 98.5 wt%, more than 99 wt%, more than 99.2 wt%, more than 99.5 wt%, more than 99.6 wt%, more than 99.7 wt%, more than 99.8 wt%, or more than 99.9 wt% of a single diastereomer. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity may be determined by any analytical method capable of quantitatively distinguishing a compound from its diastereomers, such as High Performance Liquid Chromatography (HPLC).
The compounds disclosed herein may be "isomerically pure" compounds. As used herein, the term "isomerically pure" refers to a compound in an isomeric form that is substantially free of other isomeric forms of the compound (e.g., substantially free of other stereoisomers (e.g., enantiomers, diastereomers, geometric (or conformational) isomers, etc., structural isomers, isotopic isomers, etc.)). For example, "isomerically pure" compounds having at least one asymmetric center of a particular configuration (i.e., R or S configuration) are substantially free of other isomeric forms of the compounds having a different configuration at the at least one asymmetric center. An "isomerically pure" compound comprises more than 75 wt%, more than 80 wt%, more than 85 wt%, more than 90 wt%, more than 91 wt%, more than 92 wt%, more than 93 wt%, more than 94 wt%, more than 95 wt%, more than 96 wt%, more than 97 wt%, more than 98 wt%, more than 98.5 wt%, more than 99 wt%, more than 99.2 wt%, more than 99.5 wt%, more than 99.6 wt%, more than 99.7 wt%, more than 99.8 wt%, or more than 99.9 wt% of a single isomer of the compound, based on the total weight of all isomers of the compound present.
The articles "a" and "an" may be used herein to refer to one or more than one (as well as to at least one) of the grammatical object of the article. For example, "an analog" means one analog or more than one analog.
When a range of values is recited, each value and subrange within the range is intended to be covered. For example, "C 1-6 Alkyl "is intended to cover C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 And C 5-6 An alkyl group.
The following terms are intended to have the meanings presented below and can be used to understand the description and intended scope of the invention.
"alkyl" refers to a straight or branched chain saturated hydrocarbon radical having 1 to 20 carbon atoms ("C 1-20 Alkyl "). In some embodiments, the alkyl group has 1 to 12 carbon atoms ("C 1-12 Alkyl "). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C 1-10 Alkyl "). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 Alkyl "). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 Alkyl "). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 Alkyl "). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 Alkyl ", and also referred to herein as" lower alkyl "). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 Alkyl "). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 Alkyl "). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 Alkyl "). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 Alkyl "). In some embodiments, the alkyl group has 1 carbon atom ("C 1 Alkyl "). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 Alkyl "). C (C) 1-6 Alkyl groupExamples of (C) include methyl (C) 1 ) Ethyl (C) 2 ) N-propyl (C) 3 ) Isopropyl (C) 3 ) N-butyl (C) 4 ) Tert-butyl (C) 4 ) Sec-butyl (C) 4 ) Isobutyl (C) 4 ) N-pentyl (C) 5 ) 3-pentyl (C) 5 ) Amyl (C) 5 ) Neopentyl (C) 5 ) 3-methyl-2-butyl (C) 5 ) Tert-amyl (C) 5 ) And n-hexyl (C) 6 ). Other examples of alkyl groups include n-heptyl (C 7 ) N-octyl (C) 8 ) Etc. Each instance of alkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent), unless otherwise indicated. In certain embodiments, the alkyl is unsubstituted C 1-10 Alkyl (e.g., -CH) 3 ). In certain embodiments, the alkyl is substituted C 1-10 An alkyl group. Common alkyl abbreviations include Me (-CH) 3 )、Et(-CH 2 CH 3 )、iPr(-CH(CH 3 ) 2 )、nPr(-CH 2 CH 2 CH 3 )、n-Bu(-CH 2 CH 2 CH 2 CH 3 ) Or i-Bu (-CH) 2 CH(CH 3 ) 2 )。
"alkylene" refers to an alkyl group in which two hydrogens are removed to give a divalent group, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), propylene (-CH) 2 CH 2 CH 2 -) and butylene (-CH) 2 CH 2 CH 2 CH 2 -) pentylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 (-), hexylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 2 (-), etc. Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted methylene (-CH (CH) 3 )-、(-C(CH 3 ) 2 (-), substituted ethylene (-CH (CH) 3 )CH 2 -、-CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 3 ) 2 (-), substituted propylene (-CH (CH) 3 )CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 CH 2 C(CH 3 ) 2 (-), etc. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in the divalent chain of linear carbons. The alkylene group may be substituted or unsubstituted with one or more substituents as described herein.
"alkenyl" refers to a group ("C") of a straight or branched hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) 2-20 Alkenyl "). In certain embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, alkenyl groups have 2 to 10 carbon atoms ("C 2-10 Alkenyl "). In some embodiments, alkenyl groups have 2 to 9 carbon atoms ("C 2-9 Alkenyl "). In some embodiments, alkenyl groups have 2 to 8 carbon atoms ("C 2-8 Alkenyl "). In some embodiments, alkenyl groups have 2 to 7 carbon atoms ("C 2-7 Alkenyl "). In some embodiments, alkenyl groups have 2 to 6 carbon atoms ("C 2-6 Alkenyl "). In some embodiments, alkenyl groups have 2 to 5 carbon atoms ("C 2-5 Alkenyl "). In some embodiments, alkenyl groups have 2 to 4 carbon atoms ("C 2-4 Alkenyl "). In some embodiments, alkenyl groups have 2 to 3 carbon atoms ("C 2-3 Alkenyl "). In some embodiments, alkenyl groups have 2 carbon atoms ("C 2 Alkenyl "). One or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C (C) 2-4 Examples of alkenyl groups include vinyl (C) 2 ) 1-propenyl (C) 3 ) 2-propenyl (C) 3 ) 1-butenyl (C) 4 ) 2-butenyl (C) 4 ) Butadiene group (C) 4 ) Etc. C (C) 2–6 Examples of alkenyl groups include the aforementioned C 2–4 Alkenyl and pentenyl (C) 5 ) Pentadienyl (C) 5 ) Hexenyl (C) 6 ) Etc. Other examples of alkenyl groups include heptenyl (C 7 ) Octenyl (C) 8 ) Octenyl (C) 8 ) Etc. Unless otherwise indicated, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted ("substituted alkenyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, the alkenyl group is unsubstituted C 2-10 Alkenyl groups. In certain embodiments, alkenyl is substituted C 2-10 Alkenyl groups.
"alkynyl" refers to a group ("C") of a straight or branched hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) 2-20 Alkynyl "). In certain embodiments, the alkynyl group does not contain any double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2-10 Alkynyl "). In some embodiments, alkynyl groups have 2 to 9 carbon atoms ("C 2-9 Alkynyl "). In some embodiments, alkynyl groups have 2 to 8 carbon atoms ("C 2-8 Alkynyl "). In some embodiments, alkynyl groups have 2 to 7 carbon atoms ("C 2-7 Alkynyl). In some embodiments, alkynyl groups have 2 to 6 carbon atoms ("C 2-6 Alkynyl "). In some embodiments, alkynyl groups have 2 to 5 carbon atoms ("C 2-5 Alkynyl "). In some embodiments, alkynyl groups have 2 to 4 carbon atoms ("C 2-4 Alkynyl "). In some embodiments, alkynyl groups have 2 to 3 carbon atoms ("C 2-3 Alkynyl "). In some embodiments, alkynyl groups have 2 carbon atoms ("C 2 Alkynyl "). The one or more carbon-carbon triple bonds may be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). C (C) 2-4 Examples of alkynyl groups include but are not limited toNot limited to ethynyl (C) 2 ) 1-propynyl (C) 3 ) 2-propynyl (C) 3 ) 1-butynyl (C) 4 ) 2-butynyl (C) 4 ) Etc. C (C) 2-6 Examples of alkynyl groups include the aforementioned C 2-4 Alkynyl and pentynyl (C) 5 ) Hexynyl (C) 6 ) Etc. Other examples of alkynyl groups include heptynyl (C 7 ) Octynyl (C) 8 ) Etc. Unless otherwise indicated, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted ("substituted alkynyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, the alkynyl is unsubstituted C 2-10 Alkynyl groups. In certain embodiments, alkynyl is substituted C 2-10 Alkynyl groups.
As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that also contains 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the backbone chain, with one or more heteroatoms interposed between adjacent carbon atoms within the main carbon chain and/or one or more heteroatoms interposed between a carbon atom and the parent molecule, i.e., between points of attachment. In certain embodiments, heteroalkyl refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-10 Alkyl "). In some embodiments, a heteroalkyl is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-9 Alkyl "). In some embodiments, a heteroalkyl is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-8 Alkyl "). In some embodiments, a heteroalkyl is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-7 Alkyl "). In some embodiments, a heteroalkyl is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1-6 Alkyl "). In some embodiments, a heteroalkyl is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 Alkyl "). In some embodiments, the heteroalkyl group is 1 to 4Saturated radicals having carbon atoms and 1 or 2 hetero atoms (hetero C) 1-4 Alkyl "). In some embodiments, a heteroalkyl is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 Alkyl "). In some embodiments, the heteroalkyl is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2 Alkyl "). In some embodiments, the heteroalkyl is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC 1 Alkyl "). In some embodiments, a heteroalkyl is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Alkyl "). Unless otherwise indicated, each instance of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, the heteroalkyl is an unsubstituted heteroC 1-10 An alkyl group. In certain embodiments, the heteroalkyl is a substituted heteroC 1-10 An alkyl group.
"aryl" refers to a group ("C") of a single or multiple ring (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms in the aromatic ring system and no heteroatoms (e.g., sharing 6, 10, or 14 pi electrons in a cyclic array) 6-14 Aryl "). In some embodiments, the aryl group has six ring carbon atoms ("C 6 Aryl "; i.e. phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C 10 Aryl "; for example naphthyl, such as 1-naphthyl or 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms ("C 14 Aryl "; for example, anthracyl). "aryl" also includes ring systems in which an aryl ring is fused to one or more carbocyclyl or heterocyclyl groups as defined above, wherein the group or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from: acetonthrene (aceanthylene), acenaphthylene (acephthylene), acephetene (acetenanthylene), anthracene, azulene, benzene,(chrysene), coronene, fluoranthene, fluorene, hexabenzene (hexacene), hexacene (hexacene), hexalene, asymmetric introne (as-indacene), symmetric introne (s-indacene), indane, indene, naphthalene, octabenzene (octacene), octacene (octacene), acroleine (octacene), egg benzene (ovaene), pentalene-2, 4-diene, pentacene (pentacene), pentalene (pentalene), perylene (perene), phenanthrene (phenanthrene), picene (picene), heptacene (pleene), pyrene (pyrane), pyranthrene (pyranthrene), rubicene (rucene), triphenylene (triphene) and triphene (triphene). Specifically, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of aryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted by one or more substituents ("substituted aryl"), unless otherwise specified. In certain embodiments, aryl is unsubstituted C 6-14 Aryl groups. In certain embodiments, aryl is substituted C 6-14 Aryl groups.
In certain embodiments, the aryl is substituted with one or more groups selected from halo, C 1-8 Alkyl, C 1-8 Haloalkyl, cyano, hydroxy, C 1-8 Alkoxy and amino groups.
Examples of representative substituted aryl groups include the following:
wherein R is 56 And R is 57 One of which may be hydrogen, and R 56 And R is 57 At least one of which is independently selected from C 1-8 Alkyl, C 1-8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1-8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, -NR 58 COR 59 、-NR 58 SOR 59 、-NR 58 SO 2 R 59 -COOalkyl, -COOaryl, -CONR 58 R 59 、-CONR 58 OR 59 、-NR 58 R 59 、-SO 2 NR 58 R 59 -S-alkyl, -SO 2 Alkyl, -S-aryl, -SO-aryl and-SO 2 An aryl group; or R is 56 And R is 57 May join to form a ring (saturated or unsaturated) having 5 to 8 atoms, optionally containing one or more heteroatoms independently selected from N, O and S. R is R 60 And R is 61 Independently hydrogen, C 1-8 Alkyl, C 1-4 Haloalkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl, substituted C 6-10 Aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl.
"fused aryl" means an aryl group in which two ring carbons of the aryl group are common to a second aryl or heteroaryl ring or to a carbocyclyl or heterocyclyl ring.
"heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms in the aromatic ring system (e.g., sharing 6 or 10 pi electrons in a cyclic array), wherein each heteroatom is independently selected from N, O and S ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, where valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. "heteroaryl" includes ring systems in which a heteroaryl ring is fused to one or more carbocyclyl or heterocyclyl groups as defined above, wherein the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on the aryl or heteroaryl ring, and in such cases the number of ring members indicates the number of ring members in the fused (aryl/heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) having one ring that does not contain a heteroatom may be attached to either ring, such as a ring with a heteroatom (e.g., 2-indolyl) or a ring that does not contain a heteroatom (e.g., 5-indolyl).
In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from N, O and S ("5-10 membered heteroaryl"). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from N, O and S ("5-8 membered heteroaryl"). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from N, O and S ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from N, O and S. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from N, O and S. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from N, O and S. Unless otherwise indicated, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted by one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl is a substituted 5-14 membered heteroaryl.
Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azaRadical, oxazal->Radical and thiazal->A base. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl (cinnolinyl), quinoxalinyl, phthalazinyl (phtalazinyl), and quinazolinyl.
Examples of representative heteroaryl groups include the following:
wherein Z is independently selected from carbonyl, N, NR 65 O and S; and R is 65 Independently hydrogen, C 1-8 Alkyl, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl.
"carbocyclyl" or "carbocycle" refers to a compound having 3 to 10 ring carbon atoms in a non-aromatic ring system ("C 3-10 Carbocyclyl ") and zero heteroatoms. In some embodiments, carbocyclyl has 3 to 8 ring carbon atoms ("C 3-8 Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 6 ring carbon atoms ("C 3-6 Carbocyclyl "). In some embodiments, carbocyclyl has 3 to 6 ring carbon atoms ("C 3-6 Carbocyclyl "). In some embodiments, carbocyclyl has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl "). Exemplary C 3-6 Carbocyclyls include, but are not limited to, cyclopropyl (C 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Etc. Exemplary C 3-8 Carbocyclyls include, but are not limited to, C as previously described 3-6 Carbocyclyl and cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) Cyclooctyl (C) 8 ) Cyclooctenyl (C) 8 ) Bicyclo [2.2.1]Heptyl (C) 7 ) Bicyclo [2.2.2]Octyl (C) 8 ) Etc. Exemplary C 3-10 Carbocyclyls include, but are not limited to, C as previously described 3-8 Carbocyclyl and cyclononyl (C) 9 ) Cyclononenyl (C) 9 ) Cyclodecyl (C) 10 ) Cyclodecenyl (C) 10 ) octahydro-1H-indenyl (C) 9 ) Decalin group (C) 10 ) Spiro [4.5 ]]Decyl (C) 10 ) Etc. As illustrated by the foregoing examples, in certain embodiments, a carbocyclic group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "carbocyclyl" also includes ring systems in which a carbocyclyl group as defined above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases the carbon number continues to indicate the number of carbons in the carbocyclyl system. Each instance of a carbocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted by one or more substituents ("substituted carbocyclyl"), unless otherwise indicated. In certain embodiments, carbocyclyl is unsubstituted C 3-10 Carbocyclyl. In certain embodiments, carbocyclyl is substituted C 3-10 Carbocyclyl.
In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms ("C 3-8 Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 6 ring carbon atoms ("C 3-6 Cycloalkyl "). In some embodiments, cycloalkyl groups haveFrom 5 to 6 ring carbon atoms ("C 5-6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl "). C (C) 5-6 Examples of cycloalkyl groups include cyclopentyl (C) 5 ) And cyclohexyl (C) 5 )。C 3-6 Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl and cyclopropyl (C) 3 ) And cyclobutyl (C) 4 )。C 3-8 Examples of cycloalkyl groups include the aforementioned C 3-6 Cycloalkyl and cycloheptyl (C) 7 ) And cyclooctyl (C) 8 ). Unless otherwise indicated, each instance of cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted by one or more substituents ("substituted cycloalkyl"). In certain embodiments, cycloalkyl is unsubstituted C 3-10 Cycloalkyl groups. In certain embodiments, cycloalkyl is substituted C 3-10 Cycloalkyl groups.
"heterocyclyl" or "heterocycle" refers to a group having a 3 to 10 membered non-aromatic ring system of ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom, when the valence permits. The heterocyclyl may be a monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spiro ring system, such as a bicyclic system ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. The heterocyclyl bicyclic ring system may include one or more heteroatoms in one or both rings. "heterocyclyl" also includes: a ring system wherein the heterocyclyl ring as defined above is fused to one or more carbocyclyls, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring; or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such cases the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Each instance of a heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted by one or more substituents ("substituted heterocyclyl"), unless otherwise indicated. In certain embodiments, the heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl is a substituted 3-10 membered heterocyclyl.
In some embodiments, the heterocyclyl is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen and sulfur.
Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxathiolanyl (oxathiolanyl), dithiofuranyl (disulfuranyl), and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl (thianyl). Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Contains two impurities Exemplary 6-membered heterocyclic groups for atoms include, but are not limited to, triazinyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl (azepanyl), oxepinyl (oxepinyl), and thiepanyl (thiepanyl). Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azacyclooctyl (azocap), oxacyclooctyl (oxecanyl), and thiacyclooctyl (thiocany). And C 6 Exemplary 5-membered heterocyclic groups to which the aryl ring is fused (also referred to herein as 5, 6-bicyclic heterocyclic groups) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinyl, and the like. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6, 6-bicyclic heterocyclic groups) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
"nitrogen-containing heterocyclyl" means a 4-to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine such as N-methylpiperazine. Specific examples include azetidines, piperidones, and piperazinones (piprazones).
When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced with nitrogen, oxygen, or sulfur heteroatoms. Hetero may be applied to any of the hydrocarbon groups described above, such as alkyl (e.g., heteroalkyl), cycloalkyl (e.g., heterocyclyl), aryl (e.g., heteroaryl), cycloalkenyl (e.g., cycloheteroalkenyl), and similar hydrocarbon groups having from 1 to 5, and particularly from 1 to 3 heteroatoms.
"acyl" refers to the group-C (O) R 100 Wherein R is 100 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "alkanoyl" is where R 100 Is a group other than hydrogenAcyl groups of (a). Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C (=o) CH 3 ) Cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C (=O) Ph), phenylmethylcarbonyl (-C (=O) CH 2 Ph)、-C(O)-C 1-8 Alkyl, -C (O) - (CH) 2 ) t (C 6-10 Aryl), -C (O) - (CH 2 ) t (5-10 membered heteroaryl), -C (O) - (CH) 2 ) t (C 3-10 Cycloalkyl) and-C (O) - (CH) 2 ) t (4-10 membered heterocyclyl) wherein t is 0, 1, 2, 3 or 4. In certain embodiments, R 100 Is C 1-8 Alkyl substituted with halo or hydroxy; or C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, C 6-10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is unsubstituted C 1-4 Alkyl, halo, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, or unsubstituted C 1-4 Haloalkoxy or hydroxy substitution.
"alkoxy" means a group-OR 101 Wherein R is 101 Is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1, 2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e. having between 1 and 6 carbon atoms. Other specific alkoxy groups have between 1 and 4 carbon atoms.
In certain embodiments, R 101 Is a group having 1 or more substituents, for example 1 to 5 substituents, and in particular 1 to 3 substituents, especially 1 substituent, selected from the group consisting of: amino, substituted amino, C 6-10 Aryl, aryloxy, carboxyl, cyano, C 3-10 Cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioAryloxy, thiol, alkyl-S (O) -, aryl-S (O) -, alkyl S (O) 2 -and aryl-S (O) 2 -. Exemplary 'substituted alkoxy' groups include, but are not limited to, -O- (CH) 2 ) t (C 6-10 Aryl) -O- (CH) 2 ) t (5-to 10-membered heteroaryl), -O- (CH) 2 ) t (C 3-10 Cycloalkyl) and-O- (CH) 2 ) t (4-10 membered heterocyclyl) wherein t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl present may be unsubstituted C by itself 1-4 Alkyl, halo, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, or unsubstituted C 1-4 Haloalkoxy or hydroxy substitution. Specific exemplary 'substituted alkoxy' groups are-OCF 3 、-OCH 2 CF 3 、-OCH 2 Ph、-OCH 2 -cyclopropyl, -OCH 2 CH 2 OH and-OCH 2 CH 2 NMe 2 。
"amino" means a radical-NH 2 。
"oxo" means =o.
"substituted amino" means a compound of formula-N (R 38 ) 2 Amino group, wherein R is 38 Is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or amino protecting group, wherein R 38 Is not hydrogen. In certain embodiments, each R 38 Independently selected from hydrogen, C 1-8 Alkyl, C 3-8 Alkenyl, C 3-8 Alkynyl, C 6-10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C 3-10 Cycloalkyl; or C 1-8 Alkyl substituted with halo or hydroxy; c (C) 3-8 Alkenyl, which is substituted with halo or hydroxy; c (C) 3-8 Alkynyl substituted with halo or hydroxy; or- (CH) 2 ) t (C 6-10 Aryl) - (CH) 2 ) t (5-to 10-membered heteroaryl), - (CH) 2 ) t (C 3-10 Cycloalkyl) or- (CH) 2 ) t (4-10 membered heterocyclyl) wherein t is an integer between 0 and 8, each of which is unsubstituted C 1-4 Alkyl, halo, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, or unsubstituted C 1-4 Haloalkoxy or hydroxy substitution; or two R 38 The groups join to form an alkylene group.
Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C 1-8 Alkyl, -NR 39 -(CH 2 ) t (C 6-10 Aryl) -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C 3-10 Cycloalkyl) and-NR 39 -(CH 2 ) t (4-10 membered heterocyclyl) wherein t is an integer from 0 to 4, for example 1 or 2; each R 39 Independently represent H or C 1-8 An alkyl group; and any alkyl groups present may themselves be substituted with halo, substituted or unsubstituted amino or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present may themselves be unsubstituted C 1-4 Alkyl, halo, unsubstituted C 1-4 Alkoxy, unsubstituted C 1-4 Haloalkyl, unsubstituted C 1-4 Hydroxyalkyl, or unsubstituted C 1-4 Haloalkoxy or hydroxy substitution. To avoid doubt, the term 'substituted amino' includes alkylamino, substituted alkylamino, alkylaryl amino, substituted alkylaryl amino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below. Substituted amino groups encompass mono-substituted amino groups and di-substituted amino groups.
"carboxy" refers to the group-C (O) OH.
"cyano" refers to the group-CN.
"halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, halo is fluoro or chloro.
"haloalkyl" refers to an alkyl group in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.
"hydroxy" refers to the group-OH.
"nitro" means a group-NO 2 。
"oxo" refers to the group = O.
"thioketone" refers to the group = S.
As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). In general, the term "substituted", whether preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent (e.g., a substituent which upon substitution results in a stable compound (e.g., a compound which spontaneously undergoes conversion without reaction such as by rearrangement, cyclization, elimination, or other reaction)). Unless otherwise specified, a "substituted" group has substituents at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituents described herein which result in stable compounds. The present invention contemplates any and all such combinations to obtain stable compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein that satisfies the valences of the heteroatoms and results in the formation of a stable moiety.
Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OR aa 、-ON(R bb ) 2 、-N(R bb ) 2 、-N(R bb ) 3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(＝O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(＝O)R aa 、-OCO 2 R aa 、-C(＝O)N(R bb ) 2 、-OC(＝O)N(R bb ) 2 、-NR bb C(＝O)R aa 、-NR bb CO 2 R aa 、-NR bb C(＝O)N(R bb ) 2 、-C(＝NR bb )R aa 、-C(＝NR bb )OR aa 、-OC(＝NR bb )R aa 、-OC(＝NR bb )OR aa 、-C(＝NR bb )N(R bb ) 2 、-OC(＝NR bb )N(R bb ) 2 、-NR bb C(＝NR bb )N(R bb ) 2 、-C(＝O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(＝O)R aa 、-OS(＝O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 、-C(＝S)N(R bb ) 2 、-C(＝O)SR aa 、-C(＝S)SR aa 、-SC(＝S)SR aa 、-SC(＝O)SR aa 、-OC(＝O)SR aa 、-SC(＝O)OR aa 、-SC(＝O)R aa 、-P(＝O) 2 R aa 、-OP(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-OP(＝O)(R aa ) 2 、-OP(＝O)(OR cc ) 2 、-P(＝O) 2 N(R bb ) 2 、-OP(＝O) 2 N(R bb ) 2 、-P(＝O)(NR bb ) 2 、-OP(＝O)(NR bb ) 2 、-NR bb P(＝O)(OR cc ) 2 、-NR bb P(＝O)(NR bb ) 2 、-P(R cc ) 2 、-P(R cc ) 3 、-OP(R cc ) 2 、-OP(R cc ) 3 、-B(R aa ) 2 、-B(OR cc ) 2 、-BR aa (OR cc )、C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R dd Group substitution; or two twin hydrogens on carbon atom are represented by groups=o, =s, =nn (R bb ) 2 、＝NNR bb C(＝O)R aa 、＝NNR bb C(＝O)OR aa 、＝NNR bb S(＝O) 2 R aa 、＝NR bb Or=nor cc Replacement; r is R aa Is independently selected from C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa Groups join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution; r is R bb Independently selected from hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 、C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb Groups join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution; r is R cc Is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, or two R cc Groups join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution; r is R dd Independently selected from halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OR ee 、-ON(R ff ) 2 、-N(R ff ) 2 、-N(R ff ) 3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(＝O)R ee 、-CO 2 H、-CO 2 R ee 、-OC(＝O)R ee 、-OCO 2 R ee 、-C(＝O)N(R ff ) 2 、-OC(＝O)N(R ff ) 2 、-NR ff C(＝O)R ee 、-NR ff CO 2 R ee 、-NR ff C(＝O)N(R ff ) 2 、-C(＝NR ff )OR ee 、-OC(＝NR ff )R ee 、-OC(＝NR ff )OR ee 、-C(＝NR ff )N(R ff ) 2 、-OC(＝NR ff )N(R ff ) 2 、-NR ff C(＝NR ff )N(R ff ) 2 、-NR ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R ee 、-S(＝O)R ee 、-Si(R ee ) 3 、-OSi(R ee ) 3 、-C(＝S)N(R ff ) 2 、-C(＝O)SR ee 、-C(＝S)SR ee 、-SC(＝S)SR ee 、-P(＝O) 2 R ee 、-P(＝O)(R ee ) 2 、-OP(＝O)(R ee ) 2 、-OP(＝O)(OR ee ) 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Substituted by a group, or two twin R' s dd Substituents may join to form =o or =s; r is R ee Is independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R gg Group substitution; r is R ff Is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff Groups join to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Group substitution; and R is gg Each instance of (a) is independently halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OC 1-6 Alkyl, -ON (C) 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 3 + X - 、-NH(C 1-6 Alkyl group 2 + X - 、-NH 2 (C 1-6 Alkyl group + X - 、-NH 3 + X - 、-N(OC 1-6 Alkyl) (C) 1-6 Alkyl), -N (OH) (C 1-6 Alkyl), -NH (OH), -SH, -SC 1-6 Alkyl, -SS (C) 1-6 Alkyl), -C (=o) (C 1-6 Alkyl) -CO 2 H、-CO 2 (C 1-6 Alkyl), -OC (=o) (C 1-6 Alkyl), -OCO 2 (C 1-6 Alkyl), -C (=O) NH 2 、-C(＝O)N(C 1-6 Alkyl group 2 、-OC(＝O)NH(C 1-6 Alkyl), -NHC (=o) (C 1-6 Alkyl), -N (C) 1-6 Alkyl) C (=O) (C 1-6 Alkyl), -NHCO 2 (C 1-6 Alkyl), -NHC (=o) N (C) 1-6 Alkyl group 2 、-NHC(＝O)NH(C 1-6 Alkyl), -NHC (=o) NH 2 、-C(＝NH)O(C 1-6 Alkyl), -OC (=nh) (C 1-6 Alkyl), -OC (=nh) OC 1-6 Alkyl, -C (=nh) N (C 1-6 Alkyl group 2 、-C(＝NH)NH(C 1-6 Alkyl), -C (=nh) NH 2 、-OC(＝NH)N(C 1-6 Alkyl group 2 、-OC(NH)NH(C 1-6 Alkyl), -OC (NH) NH 2 、-NHC(NH)N(C 1-6 Alkyl group 2 、-NHC(＝NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl group 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si (C) 1-6 Alkyl group 3 、-OSi(C 1-6 Alkyl group 3 、-C(＝S)N(C 1-6 Alkyl group 2 、C(＝S)NH(C 1-6 Alkyl), C (=S) NH 2 、-C(＝O)S(C 1-6 Alkyl), -C (=S) SC 1-6 Alkyl, -SC (=s) SC 1-6 Alkyl, -P (=o) 2 (C 1-6 Alkyl), -P (=o) (C 1-6 Alkyl group 2 、-OP(＝O)(C 1-6 Alkyl group 2 、-OP(＝O)(OC 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two twin R gg Substituents may join to form =o or =s; wherein X is - Is a counter ion.
A "counterion" or "anionic counterion" is a negatively charged group that associates with the cationic quaternary amino group to maintain electroneutrality. Exemplary counterions include halide (e.g., F - 、Cl - 、Br - 、I - )、NO 3 - 、ClO 4 - 、OH - 、H 2 PO 4 - 、HSO 4 - Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethyl-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).
These and other exemplary substituents are described in more detail in the detailed description and claims. The invention is not intended to be limited in any way by the above list of exemplary substituents.
B. Other definitions
As used herein, the term "modulate" refers to GABA A Inhibition or enhancement of receptor function. The "modulator" (e.g., modulator compound) may be, for example, GABA A Agonists, partial agonists, antagonists or partial antagonists of the receptor.
By "pharmaceutically acceptable" is meant approved by or by a regulatory agency of the federal or a state government or a corresponding agency in a country other than the united states, or listed in the united states pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
By "pharmaceutically acceptable salt" is meant a salt of a compound of the invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and base addition salts. In particular, such salts include: (1) Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) when the acidic proton present in the parent compound is replaced with a metal ion (e.g., an alkali metal ion, alkaline earth ion, or aluminum ion); or salts formed when coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. By way of example only, salts also include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains basic functional groups, salts of non-toxic organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like are included. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion to an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., berge et al, J.Pharm.Sci. (1977) 66 (1): 1-79.
The term "prodrug" is intended to encompass therapeutically inactive compounds that are converted under physiological conditions to the therapeutically active agents of the present invention. One approach for preparing prodrugs is to design selected moieties that are hydrolyzed or cleaved at the site of action in the targeted body under physiological conditions to reveal the desired molecule, which then produces its therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.
In an alternative embodiment, the present invention provides a prodrug of a compound described herein, wherein the prodrug comprises a cleavable moiety on the C3 hydroxyl group as depicted in the formulae depicted herein.
"tautomer" refers to a compound that is an interchangeable form of a particular compound structure and that differs in the substitution of hydrogen atoms and electrons. Thus, the two structures can be balanced by the movement of pi electrons and an atom (typically H). For example, enols and ketones are tautomers in that they are rapidly interconverted by acid or base treatment. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, also formed by acid or base treatment. Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of the compounds of interest.
"subject" for which administration is intended includes humans, i.e., men or women of any age group. Exemplary human subjects include, for example, "pediatric subjects" (e.g., infants, children, adolescents) or "adult subjects" (e.g., young adults, middle-aged adults, or senior adults).
In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -R aa 、-N(R bb ) 2 、-C(＝O)SR aa 、-C(＝O)R aa 、-CO 2 R aa 、-C(＝O)N(R bb ) 2 、-C(＝NR bb )R aa 、-C(＝NR bb )OR aa 、-C(＝NR bb )N(R bb ) 2 、-S(＝O)R aa 、-SO 2 R aa 、-Si(R aa ) 3 、-P(R cc ) 2 、-P(R cc ) 3 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O)(OR cc ) 2 、-P(＝O) 2 N(R bb ) 2 and-P (=O) (NR bb ) 2 Wherein R is aa 、R bb And R is cc As defined herein. Oxygen protecting groups are well known in the art and include Protecting Groups in Organic Synthesis, t.w.greene and p.g.m.Wuts, 3 rd edition, john Wiley&Sons,1999, which are incorporated herein by reference.
Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and toluenesulfonate (Ts).
In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -R aa 、-N(R bb ) 2 、-C(＝O)SR aa 、-C(＝O)R aa 、-CO 2 R aa 、-C(＝O)N(R bb ) 2 、-C(＝NR bb )R aa 、-C(＝NR bb )OR aa 、-C(＝NR bb )N(R bb ) 2 、-S(＝O)R aa 、-SO 2 R aa 、-Si(R aa ) 3 、-P(R cc ) 2 、-P(R cc ) 3 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O)(OR cc ) 2 、-P(＝O) 2 N(R bb ) 2 and-P (=O) (NR bb ) 2 Wherein R is aa 、R bb And R is cc As defined herein. Sulfur protecting groups are well known in the art and include Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, 3 rd edition, john Wiley&Sons,1999, which are incorporated herein by reference.
In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, -OH, -OR aa 、-N(R cc ) 2 、-C(＝O)R aa 、-C(＝O)OR aa 、-C(＝O)N(R cc ) 2 、-S(＝O) 2 R aa 、-C(＝NR cc )R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R dd Group substitution, and wherein R aa 、R bb 、R cc And R is dd As defined herein. Amino protecting groups are well known in the art and include Protecting Groups in Organic Synthesis, T.W.Greene and P.G.M.Wuts, 3 rd edition, john Wiley&Sons,1999, which are incorporated herein by reference.
Exemplary amino protecting groups include, but are not limited to: amide groups (e.g., -C (=o) R aa ) Including, but not limited to, formamide and acetamide; urethane groups (e.g., -C (=o) OR aa ) Including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., -S (=o) 2 R aa ) Including but not limited to p-toluenesulfonamide (Ts), methanesulfonamide (Ms) and N- [2- (trimethylsilyl) ethoxy ]]Methylamine (SEM).
The terms "disease," "disorder," and "condition" are used interchangeably herein.
As used herein, and unless otherwise indicated, the terms "treat" (treat, treating and treatment) contemplate the effect of reducing the severity of a disease, disorder or condition or slowing the progression of a disease, disorder or condition that occurs when a subject is suffering from a specified disease, disorder or condition ("therapeutic treatment") and also consider the effect that occurs before the subject begins to suffer from the specified disease, disorder or condition.
In general, an "effective amount" of a compound refers to an amount sufficient to elicit a desired biological response, e.g., an amount sufficient to treat a CNS-related disorder or to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on factors such as: biological endpoints are desired, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.
As used herein, and unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent alone or in combination with other therapies that provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may encompass an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
In an alternative embodiment, the invention contemplates administering a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutically acceptable composition thereof, before the subject begins to suffer from the indicated disease, disorder, or condition. As used herein, and unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition, or to prevent recurrence thereof. A prophylactically effective amount of a compound means an amount of a therapeutic agent alone or in combination with other agents that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
II compounds
The formulae described herein may mention specific carbon atoms, such as C17, C3, C19, and the like. These references are based on the position of carbon atoms according to steroid nomenclature known and used in the industry, as follows:
for example, C17 refers to carbon at position 17, and C3 refers to carbon at position 3.
A. Compounds of formula (I)
In one aspect, the invention includes a compound of formula (I)
Or a pharmaceutically acceptable salt thereof, wherein ring D is selected from
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl, optionally substituted 3-8 membered saturated, partially unsaturated or having 0-4 heteroatoms independently selected from N, O and SA fully unsaturated monocyclic ring, or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together form oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together form oxo, or R 20a And R is 20b Together forming oxo; r is R 5 And R is 20c Each of which is independently selected from-H and optionally substituted C 1-6 An alkyl group; r is R 10 is-H, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 31a And R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl and-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O or S; m is 1 or 2; and n is 0, 1 or 2, provided that when R 31a And R is 31b One of them is-OR 32 When R is 31a And R is 31b The other of which is-H.
B. Substituent group
1.R 1a And R is 1b
In some embodiments, R 1a And R is 1b Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substitutedC of (2) 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or R 1a And R is 1b Together forming oxo.
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H and optionally halogenated, -CN, -NO 2 、R'、-N(R') 2 or-O-R' substituted C 1-6 An alkyl group; or R is 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b Independently selected from: -H; c (C) 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or phenyl), optionally substituted with 1-3 groups independently selected from halo, -CN, -OH, -NO 2 、C 1-6 Alkoxy (e.g., methoxy, ethoxy, or propoxy), C 3-6 Cycloalkyl, phenyl, a group substituted with 1-3 5-10 membered heteroaryl groups independently selected from N, O and S heteroatoms; -N (H) -C 1-6 An alkyl group; -OH; and-O-C 1-6 An alkyl group.
In some embodiments, R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo.
In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 1a And R is 1b is-H, and the other is: -H; c (C) 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or phenyl), optionally substituted with 1-3 groups independently selected from halo, -CN, -OH, -NO 2 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl or a group substituted with 1-3 5-10 membered heteroaryl groups independently selected from N, O and S heteroatoms; -N (H) -C 1-6 An alkyl group; -OH; or-O-C 1-6 An alkyl group. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 1a And R is 1b is-H, and the other is methyl. And in some embodiments, R 1a And R is 1b is-H.
2.R 2a And R is 2b
In some embodiments, R 2a And R is 2b Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or R 2a And R is 2b Together forming oxo.
In some embodiments, R 2a And R is 2b Each of which is independently selected from the group consisting of-H, -OH and optionally halogenated, -CN, -NO 2 、R'、-N(R') 2 or-O-R' substituted C 1-6 An alkyl group; or R is 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b Independently selected from: -H; c (C) 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or phenyl), optionally substituted with 1-3 groups independently selected from halo, -CN、-OH、-NO 2 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl or a group substituted with 1-3 5-10 membered heteroaryl groups independently selected from N, O and S heteroatoms; -N (H) -C 1-6 An alkyl group; -OH; and-O-C 1-6 An alkyl group.
In some embodiments, R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo.
In some embodiments, R 2a And R is 2b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 2a And R is 2b is-H, and the other is: -H; c (C) 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or phenyl), optionally substituted with 1-3 groups independently selected from halo, -CN, -OH, -NO 2 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, and a group substituted with 1-3 5-10 membered heteroaryl groups independently selected from N, O and S heteroatoms; -N (H) -C 1-6 An alkyl group; -OH; or-O-C 1-6 An alkyl group. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 2a And R is 2b is-H, and the other is methyl. And in some embodiments, R 2a And R is 2b is-H.
3.R 3
In some embodiments, R 3 is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S.
In some embodiments, R 3 is-H or optionally halogenated, -CN, -NO 2 、R'、-N(R') 2 or-O-R' substituted C 1-6 An alkyl group. In some embodiments, R 3 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 3 The method comprises the following steps: -H; c (C) 1-6 Alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or phenyl), optionally substituted with 1-3 groups independently selected from halo, -CN, -OH, -NO 2 、C 1-6 Alkoxy, C 3-6 Cycloalkyl, phenyl, and a group substituted with 1-3 5-10 membered heteroaryl groups independently selected from N, O and S heteroatoms; -N (H) -C 1-6 An alkyl group; -OH; or-O-C 1-6 An alkyl group. In some embodiments, R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . In some embodiments, R 3 is-H or methyl. And in some embodiments, R 3 is-CH 3 。
In some embodiments, R 3 is-H, C 1-6 Alkyl (e.g. methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, phenyl, hexyl or neohexyl) or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl or propoxypropyl). In some embodiments, R 3 Is methyl, ethyl, propyl, isopropyl, butylIsobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-CH 3 。
4.R 4a 、R 4b And n
In some embodiments, n is 0, and R 4a And R is 4b Is not present.
In some embodiments, n is 1 or 2; r is R 4a And R is 4b Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or R 4a And R is 4b Together forming oxo.
In some embodiments, n is 2, and R 4a And R is 4b Each independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, n is 2, and at R 4a And R is 4b In one example on the same carbon atom, R 4a And R is 4b Each of which is independently selected from-H, optionally substituted with R'C of (2) 1-6 Alkyl, -N (R') 2 and-O-R', and at R 4a And R is 4b In another example (i.e., a second example) on the same carbon atom, R 4a And R is 4b Together forming oxo. In some embodiments, n is 2, and R 4a And R is 4b Each independently selected from-H and methyl. In some embodiments, n is 2, and R 4a And R is 4b is-H.
In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, and R 4a And R is 4b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, n is 1, R 4a And R is 4b is-H, and the other is methyl. And in some embodiments n is 1, and R 4a And R is 4b is-H.
5.R 5
In some embodiments, R 5 is-H or optionally substituted C 1-6 An alkyl group. In some embodiments, R 5 is-H or C 1-6 Alkyl (e.g., C 1-3 Alkyl (e.g., methyl)). In some embodiments, R 5 is-H or methyl. For example, R 5 is-H. In other examples, R 5 Is methyl.
6.R 6a 、R 6b 、R 7a And R is 7b
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b And the other two of (3) are independently selected from-H and methyl. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Three of which are-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H, and the other is-H or methyl. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H.
7.R 10
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group. In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 10 is-H, methyl or methoxymethyl. And in some embodiments, R 10 is-H or methyl.
8.R 11a 、R 11b 、R 12a And R is 12b
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently up to two carbon atoms of (C)Ground cover-NR ' -, S-, -O-, -OC (O) -, -C (O) O-, -C (O) -, -C (O) C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b And the other two of (3) are independently selected from-H and methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of which are-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H, and the other is-H or methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H.
9.R 13
In some embodiments, R 13 is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S.
In some embodiments, R 13 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 13 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 13 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group. In some embodiments, R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H or C 1-6 An alkyl group. In some embodiments, R 13 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). In some embodiments, R 13 Is-H. Methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. In some embodiments, R 13 is-H, methyl, ethyl, propyl or isopropyl. In some embodiments, R 13 is-H or methyl. In some embodiments, R 13 is-H, methyl or methoxymethyl. In some embodiments, R 13 is-H. And in some embodiments, R 13 Is methyl (e.g., beta-methyl).
10.R 15 And m
In some embodiments, m is 1 or 2, and R 15 is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S.
In some embodiments, m is 2, and each R 15 Independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, m is 2, and each R 15 Independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodimentsM is 2, and each R 15 Independently selected from-H and C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, m is 2, and each R 15 is-H.
In some embodiments, m is 1, and R 15 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, m is 1, and R 15 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, m is 1, and R 15 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). In some embodiments, m is 1, and R 15 is-H or methyl. In some embodiments, m is 1, and R 15 is-H. In some embodiments, m is 1, and R 15 Is methyl.
11.R 16
In some embodiments, R 16 is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S.
In some embodiments, R 16 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 16 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 16 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). In some embodiments, R 16 is-H or methyl. And in some embodiments, R 16 is-H.
12.R 17
In some embodiments, R 17 is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S.
In some embodiments, R 17 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 17 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 17 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, R 17 is-H.
13.R 20a And R is 20b
In some embodiments, R 20a And R is 20b Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR' -, A method for producing a composite materialS-、-O-、-OC(O)-、-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、-NR'C(O)O-、-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or R 20a And R is 20b Together forming oxo.
In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Each independently selected from-H, methyl and-OH. In some embodiments, R 20a And R is 20b One of them is-OH and the other is-H or methyl. In some embodiments, R 20a And R is 20b Together forming oxo.
In some embodiments, R 20a 、R 20b And the carbon atoms to which they are attached form
In some embodiments, R 20a And R is 20b One of them is-H and the other is C 1-6 Alkyl (e.g., methyl, ethyl, propyl, butyl, phenyl, or hexyl). In some implementationsIn embodiments, R 20a And R is 20b One of them is C 1-6 Alkyl, and the other is-OH. In some embodiments, R 20a And R is 20b One of which is methyl, ethyl or propyl, and the other is-OH. In some embodiments, R 20a And R is 20b One of them is-H and the other is methyl or ethyl.
14.R 20c
In some embodiments, R 20c is-H or optionally substituted C 1-6 An alkyl group. In some embodiments, R 20c is-H or C 1-6 Alkyl (e.g., C 1-3 Alkyl (e.g., methyl)). In some embodiments, R 20c is-H or methyl. For example, R 20c is-H. In other examples, R 20c Is methyl.
15.R 21
In some embodiments, R 21 is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -、-CH 2 -CH 2 -CH 2 -or-NH-; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-NH-; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, R 30 Is thatX 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
In some embodiments, R 21 is-CH 3 、-CH 2 -CH 3 、-O-CH 3 、-O-CH 2 -CH 3 、
In some embodiments, R 21 is-CH 3 、-CH 2 -CH 3 、/>
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and R is 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted by halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH or-C (CH) 3 ) 3 And (3) substitution. In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH or-C (CH) 3 ) 3 And (3) substitution. In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, R 30 Is-> X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
16.R 31a And R is 31b
In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl and-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or having 0 to 4 groups independently selected fromN, O or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring of heteroatoms of S.
In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 Alkyl, or when R 31a And R is 31b When one of them is-H, the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b One of them is-H and the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 An alkyl group. In some embodiments, R 31a And R is 31b One of them is-H and the other is-OH, -O-C 1-6 Alkyl, -O-phenyl or-O-C 3-6 Cycloalkyl groups. In some embodiments, R 31a And R is 31b is-H.
C. Other Compounds of the invention
In another aspect, the invention provides a compound of formula (II)
Or a pharmaceutically acceptable salt thereof, wherein ring D, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20a 、R 20b 、R 20c 、R 21 、R 31a 、R 31b M and n are as defined in any one embodiment of the compounds of formula (I).
In some embodiments, ring D is a fused bicyclic ring selected from
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl (e.g., C 1-3 Alkyl group, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together form oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together form oxo, or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H or optionally substituted C 1-6 An alkyl group; r is R 13 is-H or optionally substituted C 1-6 An alkyl group; r is R 31a And R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl and-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S; and n is 0, 1 or 2, provided that when R 31a And R is 31b One of them is-OR 32 When R is 31a And R is 31b The other of which is-H.
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H, halo, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo.
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H, -OH, C 1-6 Alkyl (e.g., C 1-3 Alkyl) and C 1-6 Alkoxy (e.g., C 1-3 An alkoxy group).
In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, halo, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl or optionally substituted C 1-6 An alkoxy group. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or optionally substituted by R'C 1-6 An alkyl group. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or C 1-3 An alkyl group. In some embodiments, R 1a And R is 1b is-H, and the other is methyl. In some embodiments, R 1a And R is 1b One of which is-H and the other is halo. In some embodiments, R 1a And R is 1b is-H. In some embodiments, R 1a And R is 1b Each of which is a halo group. And in some embodiments, R 1a And R is 1b Each of which is C 1-3 An alkyl group.
In some embodiments, R 2a And R is 2b Each of which is independently selected from-H, halo, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo.
In some embodiments, R 2a And R is 2b Each of which is independently selected from-H, -OH, C 1-6 Alkyl (e.g., C 1-3 Alkyl) and C 1-6 Alkoxy (e.g., C 1-3 An alkoxy group).
In some embodiments, R 2a And R is 2b One of them is-H and the other is-H, halo, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 2a And R is 2b is-H, and the other is methyl. In some embodiments, R 2a And R is 2b One of which is-H and the other is halo. In some embodiments, R 2a And R is 2b is-H. In some embodiments, R 2a And R is 2b Each of which is a halo group. And in some embodiments, R 2a And R is 2b Each of which is C 1-3 An alkyl group.
In some embodiments, R 3 is-H, halo, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 3 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . In some embodiments, R 3 is-H or methyl. In some embodiments, R 3 Is halo.
In some embodiments, n is 0, and R 4a And R is 4b Is not present.
In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, halo, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, and R 4a And R is 4b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 4a And R is 4b Together forming oxo.
In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, -OH, C 1-6 Alkyl (e.g., C 1-3 Alkyl) and C 1-6 Alkoxy (e.g., C 1-3 An alkoxy group).
In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, n is 1, R 4a And R is 4b is-H, and the other is methyl. In some embodimentsWherein n is 1, R 4a And R is 4b One of which is-H and the other is halo. In some embodiments, n is 1, R 4a And R is 4b One of which is-H and the other is-OH. And in some embodiments n is 1, and R 4a And R is 4b is-H.
In some embodiments, R 5 is-H or methyl. In some embodiments, R 5 is-H.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, halo, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, -OH, C 1-6 Alkyl (e.g., C 1-3 Alkyl) and C 1-6 Alkoxy (e.g., C 1-3 An alkoxy group).
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Three of them are-H, and R 6a 、R 6b 、R 7a And R is 7b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H, and the other is-H or methyl. And in some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. And in some embodiments, R 10 is-H, methyl or methoxymethyl.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, -OH, C 1-6 Alkyl (e.g., C 1-3 Alkyl) and C 1-6 Alkoxy (e.g., C 1-3 An alkoxy group).
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b And the other two of (3) are independently selected from-H and methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of them are-H, and R 11a 、R 11b 、R 12a And R is 12b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H, and the other is-H, -OH, halo or methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H, and the other is-H or methyl. And in some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H.
In some embodiments, R 13 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. In some embodiments, R 13 is-H, methyl or methoxymethyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo.
In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, -OH, C 1-6 Alkyl (e.g., C 1-3 Alkyl) and C 1-6 Alkoxy (e.g., C 1-3 An alkoxy group).
In some embodiments, R 20a And R is 20b Independently selected from-H, methyl and-OH. In some embodiments, R 20a And R is 20b One of them is-OH and the other is-H or methyl. And in some embodiments, R 20a And R is 20b Together forming oxo.
In some embodiments, R 20a 、R 20b And the carbon atoms to which they are attached form
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -、-CH 2 -CH 2 -CH 2 -or-NH-; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-NH-; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, R 30 Is thatX 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH。
In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 Alkyl, or when R 31a And R is 31b When one of them is-H, the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b One of them is-H and the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 An alkyl group. In some embodiments, R 31a And R is 31b One of them is-H and the other is-OH, -O-C 1-6 Alkyl, -O-phenyl or-O-C 3-6 Cycloalkyl groups. And in some embodiments, R 31a And R is 31b is-H.
Another aspect of the present invention provides a compound of formula (II-A) or (II-B)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (II).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 independent heteroatomsIs selected from halogen, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H or optionally substituted C 1-3 An alkyl group; and R is 13 is-H or optionally substituted C 1-3 An alkyl group.
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally independently selected from 1-3Halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (II-C)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (II).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -C (O) -, -OC (O) -, -C (O) O-, -C (O) C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl of ROptionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H or optionally substituted C 1-3 An alkyl group; and R is 13 is-H or optionally substituted C 1-3 An alkyl group.
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkane of R' isThe radicals or 3-to 8-membered rings are optionally substituted with 1 to 3 radicals independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-A1) or (II-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (II-A).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally up to two carbon atomsAnd is independently represented by-NR ' - -S-, -O-, -OC (O) -, -C (O) O-, -C (O) -, -C (O) C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (II-B1) or (II-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (II-B).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H、C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-C1) or (II-C2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (II-C).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-S(O)-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-A1 a), (II-A1 b), (II-A1 c) or (II-A1 d)
Or a pharmaceutical thereofSalts of the above acceptable, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-A) or (II-A1).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl group of R' or 3-The 8 membered ring is optionally substituted with 1 to 3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-A2 a), (II-A2 b), (II-A2 c) or (II-A2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-A) or (II-A2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR' -,-S-、-O-、-OC(O)-、-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、-NR'C(O)O-、-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (II-B1 a), (II-B1B), (II-B1 c) or (II-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-B) or (II-B1).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-B2 a), (II-B2B), (II-B2 c) or (II-B2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-B) or (II-B2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-C1 a), (II-C1 b), (II-C1C) or (II-C1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-C) or (II-C1).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo、-OH、-CN、-NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (II-C2 a), (II-C2 b), (II-C2C) or (II-C2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II-C) or (II-C2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 Alkyl), R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or optionally substituted C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl or-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted by-NR' -, -S-; -O-, -OC (O) -, -C (O) O-, -C (O) C ]O)-、-C(O)NR'-、-NR'C(O)-、-NR'C(O)O-、-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (III)
Or a pharmaceutically acceptable salt thereof, wherein ring D, R 3 、R 5 、R 10 、R 13 、R 15 、R 16 、R 17 、R 20a 、R 20b 、R 20c 、R 21 、R 31a 、R 31b And m is as defined in any one of the embodiments of the compounds of formula (I) or (II).
In some embodiments, ring D is a fused bicyclic ring selected from
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently-H, -OH, C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 Is C 1-6 Alkyl (e.g., C 1-3 Alkyl) or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., C 1-3 alkyl-O-C 1-3 Alkyl). In some embodiments, R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-CH 3 。
In some embodiments, R 5 is-H or C 1-3 An alkyl group. In some embodiments, R 5 is-H or methyl.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 10 is-H or methyl.
In some embodiments, R 13 Is C 1-6 Alkyl (e.g., C 1-3 Alkyl). In some embodiments, R 13 Is a armorA group, ethyl or propyl. In some embodiments, R 13 is-H or methyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b One of them is-H, and R 20a And R is 20b The other one is C 1-6 Alkyl (e.g., C 1-3 Alkyl). In some embodiments, R 20a And R is 20b One of them is C 1-6 Alkyl (e.g., C 1-3 Alkyl), and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a And R is 20b One of them being methyl, ethyl or propyl, and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a 、R 20b And the carbon to which it is attached
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and R is 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is thatWherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodimentsWherein R is 30 Is->X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH。
Another aspect of the invention provides a compound of formula (III-A) or (III-B)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (III).
In some embodiments, R 3 is-H, C 1-6 Alkyl (e.g., C 1-3 Alkyl) or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., C 1-3 alkyl-O-C 1-3 An alkyl group); r is R 5 is-H or C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 10 is-H, C 1-6 Alkyl (e.g., C 1-3 Alkyl) or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., C 1-3 alkyl-O-C 1-3 An alkyl group); r is R 13 is-H or C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl (e.g., C 1-3 Alkyl), or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Group substitution of (2). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Is methyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from pyrazolyl, tetrazolyl, and pyridinyl, each of which is optionally halogenated, C 1-6 Alkyl (e.g., C 1-3 Alkyl) or cyano.
Another aspect of the present invention provides a compound of formula (III-C)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II) or (III).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or 3-8 membered having 0-4 heteroatoms independently selected from N, O and SA saturated, partially unsaturated or fully unsaturated monocyclic ring, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1-3 halo, -OH, -CN, -NO 2 、-CF 3 or-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-A1) or (III-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III) or (III-A).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-B1) or (III-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III) or (III-B).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H;R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-C1) or (III-C2)
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Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III) or (III-C).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-A1 a), (III-A1 b), (III-A1 c) or (III-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-A) or (III-A1).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or 5-6 membered saturated, partially unsaturated or fully unsaturated having 1-4 nitrogen atomsA single ring, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-A2 a), (III-A2 b), (III-A2 c) or (III-A2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-A) or (III-A2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-B1 a), (III-B1B), (III-B1 c) or (III-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-B1).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-B2 a), (III-B2B), (III-B2 c) or (III-B2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-B) or (III-B2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-C1 a), (III-C1 b), (III-C1C) or (III-C1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-C) or (III-C1).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridineRadicals, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (III-C2 a), (III-C2 b), (III-C2C) or (III-C2 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (II), (III-C) or (III-C2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 13 is-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In some embodiments, R 3 Methyl, ethyl, propyl or methoxymethyl; r is R 5 is-H; r is R 10 is-H; r is R 13 is-H or methyl; r is R 20a And R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, -NH-, or-CH 2 -；R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
Another aspect of the invention provides a compound of formula (IV)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b 、R 21 M and n are as defined in any one of the embodiments of formula (I).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Substituted by substituents of (2), or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together form oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together form oxo, or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; m is 1 or 2; and n is 0, 1 or 2.
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo.
In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 1a And R is 1b is-H, and the other is methyl. And in some embodiments, R 1a And R is 1b is-H.
In some embodiments, R 2a And R is 2b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 2a And R is 2b is-H, and the other is methyl. And in some embodiments, R 2a And R is 2b is-H.
In some embodiments, R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 3 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-H or methyl.
In some embodiments, n is 0, and R 4a And R is 4b Is not present. In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, and R 4a And R is 4b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, n is 1, R 4a And R is 4b is-H, and the other is methyl. And in some embodiments n is 1, and R 4a And R is 4b is-H.
In some embodiments, R 5 is-H.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo.In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Three of them are-H, and R 6a 、R 6b 、R 7a And R is 7b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H, and the other is-H or methyl. And in some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. And in some embodiments, R 10 is-H, methyl or methoxymethyl.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b And the other two of (3) are independently selected from-H and methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of them are-H, and R 11a 、R 11b 、R 12a And R is 12b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H, and the other is-H or methyl. And in some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H.
In some embodiments, m is 1, and R 15 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, m is 1, and R 15 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, m is 1, and R 15 is-H or C 1-3 An alkyl group. In some embodiments, m is 1, and R 15 is-H or methyl. And in some embodiments, m is 1, and R 15 is-H.
In some embodiments, R 16 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 16 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 16 is-H or C 1-3 An alkyl group. In some embodiments, R 16 is-H or methyl. And in some embodiments, R 16 is-H.
In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Each of which is independently selected from-H, C 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b Independently selected from-H, methyl and-OH. In some embodiments, R 20a And R is 20b One of them is-OH and the other is-H or methyl. In some embodiments, R 20a And R is 20b Together forming oxo.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -、-CH 2 -CH 2 -CH 2 -or-NH-; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-NH-; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered moiety having 1-4 nitrogen atomsA partially or fully unsaturated monocyclic ring, wherein the 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, R 30 Is thatX 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH。
Another aspect of the present invention provides Sup>A compound of formulSup>A (IV-A)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (IV).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 20a And R is 20b Together forming oxo; r is R 5 is-H or C 1-3 An alkyl group; and R is 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group.
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 And R is 16 Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 3 is-H, C 1-6 Alkyl group,C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-5 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 15 And R is 16 Each of which is independently-H or C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 Selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (IV-A1)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV) or (IV-A).
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight or branched chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (IV-A1 a) or (IV-A1 b)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV-A) or (IV-A1).
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of them is selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH、-CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight or branched chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (IV-A1 A1) or (IV-A1 a 2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV-A1) or (IV-A1 Sup>A).
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or having 0 to 4 nitrogen atomsA 3-8 membered partially unsaturated or fully unsaturated monocyclic ring of (2), wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (IV-A1 b 1) or (IV-A1 b 2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV-A1) or (IV-A1 b).
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or C 1-3 An alkyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or a straight chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is-H, C 1-6 Alkyl or 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (V)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (IV).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., C 1-3 alkyl-O-C 1-3 An alkyl group); r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 Is C 1-6 Alkyl (e.g., C 1-3 Alkyl) or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., C 1-3 alkyl-O-C 1-3 Alkyl). In some embodiments, R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-CH 3 。
In some embodiments, R 5 is-H or C 1-3 An alkyl group. In some embodiments, R 5 is-H or methyl.
In some embodiments, R 10 is-H, C 1-6 Alkyl (e.g., C 1-3 Alkyl) or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 10 is-H or methyl.
In some embodiments, R 13 Is C 1-6 Alkyl (e.g., C 1-3 Alkyl). In some embodiments, R 13 Is methyl, ethyl or propyl. In some embodiments, R 13 is-H or methyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 20a And R is 20b Together forming oxo. In some embodiments, R 20a And R is 20b One of them is-H, and R 20a And R is 20b The other one is C 1-6 Alkyl (e.g., C 1-3 Alkyl). In some embodiments, R 20a And R is 20b One of them is C 1-6 Alkyl (e.g., C 1-3 Alkyl), and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a And R is 20b One of them being methyl, ethyl or propyl, and R 20a And R is 20b The other of (C) is-OH. In some embodiments, R 20a 、R 20b And the carbon to which it is attached
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and R is 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is thatWherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, R 30 Is->X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH。
Another aspect of the invention provides Sup>A compound of formulSup>A (V-A)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (IV) or (V).
In some embodiments, R 3 is-H, C 1-6 Alkyl (e.g., C 1-3 Alkyl) or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., C 1-3 alkyl-O-C 1-3 An alkyl group); r is R 5 is-H or C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 10 is-H, C 1-6 Alkyl (e.g., C 1-3 Alkyl) or C 1-6 alkyl-O-C 1-6 Alkyl (e.g., C 1-3 alkyl-O-C 1-3 An alkyl group); r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H orA methyl group; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (V-A1) or (V-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV), (V) or (V-A).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or 3-8 membered saturated, partially unsaturated or fully saturated with 0-4 heteroatoms independently selected from N, O and SA fully unsaturated monocyclic ring, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (V-A1 a) or (V-A1 b)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV), (V-A) or (V-A1).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (V-A2 a) or (V-A2 b)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 20a 、R 20b And R is 21 As defined in any one of the embodiments of the compounds of formulSup>A (I), (IV), (V-A) or (V-A2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 20a And R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (VI)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c 、R 21 、R 31a 、R 31b M and n are as defined in any one of the embodiments of formula (I).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 And R is 21 Each of which is-L A -R 30 The method comprises the steps of carrying out a first treatment on the surface of the Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3Independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Or R 1a And R is 1b Together form oxo, or R 2a And R is 2b Together form oxo, or R 4a And R is 4b Together form oxo, or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together form oxo, or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 31a And R is 31b Each (i) of (i) is independently selected from the group consisting of-H, halo, and C 1-6 Alkyl, or (ii) when R 31a And R is 31b When one of them is-H, R 31a And R is 31b The other of them is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S; n is 0, 1 or 2; and m is 1 or 2.
In some embodiments, R 1a And R is 1b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 1a And R is 1b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 1a And R is 1b One of them is-H, and the other is-HIs methyl. And in some embodiments, R 1a And R is 1b is-H.
In some embodiments, R 2a And R is 2b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, R 2a And R is 2b is-H, and the other is methyl. And in some embodiments, R 2a And R is 2b is-H.
In some embodiments, R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 3 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . In some embodiments, R 3 is-H or methyl.
In some embodiments, n is 0, and R 4a And R is 4b Is not present. In some embodiments, n is 1, and R 4a And R is 4b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, and R 4a And R is 4b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 4a And R is 4b Together forming oxo. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, n is 1, R 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group. In some embodiments, n is 1, R 4a And R is 4b is-H, and the other is methyl. And in some embodiments n is 1, and R 4a And R is 4b is-H.
In some embodiments, R 5 is-H or methyl. In some embodiments, R 5 is-H.
In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b Three of them are-H, and R 6a 、R 6b 、R 7a And R is 7b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H, and the other is-H or methyl. And in some embodiments, R 6a 、R 6b 、R 7a And R is 7b is-H.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. And in some embodiments, R 10 is-H, methyl or methoxymethyl.
In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b And the other two of (3) are independently selected from-H and methyl. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of them are-H, and R 11a 、R 11b 、R 12a And R is 12b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 11a 、R 11b 、R 12a And R is 12b Three of which are-H, and anotherAnd each is-H or methyl. And in some embodiments, R 11a 、R 11b 、R 12a And R is 12b is-H.
In some embodiments, R 13 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 13 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 13 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). In some embodiments, R 13 is-H. And in some embodiments, R 13 is-CH 3 (methyl group). In some embodiments, R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl. In some embodiments, R 13 is-H or C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl or methoxymethyl. And in some embodiments, R 13 Is methyl.
In some embodiments, m is 1, and R 15 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, m is 1, and R 15 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, m is 1, and R 15 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, R 15 is-H.
In some embodiments, R 16 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 16 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 16 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, R 16 is-H.
In some embodiments, R 17 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'. In some embodiments, R 17 is-H or C optionally substituted by R 1-6 An alkyl group. In some embodiments, R 17 is-H or C 1-3 Alkyl (e.g., methyl or ethyl). And in some embodiments, R 17 is-H.
In some embodiments, R 20c is-H.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -CH 2 -or-CH 2 -CH 2 -; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, R 30 Is thatX 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH。
In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 Alkyl, or when R 31a And R is 31b When one of them is-H, the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b One of them is-H and the other is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 Alkyl or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S. In some embodiments, R 31a And R is 31b Each of which is independently selected from-H, halo and C 1-6 An alkyl group. In some embodiments, R 31a And R is 31b One of them is-H and the other is-OH, -O-C 1-6 Alkyl, -O-phenyl or-O-C 3-6 Cycloalkyl groups. In some embodiments, R 31a And R is 31b is-H.
Another aspect of the invention provides a compound of formula (VI-A) or (VI-B)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (VI).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group; r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl group of R' or 3-The 8 membered ring is optionally substituted with 1 to 3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-A1) or (VI-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI) or (VI-A).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-B1) or (VI-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI) or (VI-B).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-A1 a), (VI-A1 b), (VI-A1 c) or (VI-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI-A1) or (VI-A2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-B1 a), (VI-B1B), (VI-B1 c) or (VI-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 5 、R 6a 、R 6b 、R 7a 、R 7b 、R 10 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20c And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI-B1) or (VI-B2).
In some embodiments, R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 Alkyl (e.g., C 1-3 An alkyl group); r is R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VI-A3 a), (VI-A3B), (VI-B3 a) or (VI-B3B)
Or a pharmaceutically acceptable salt thereof, wherein R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 5 、R 10 、R 13 、R 17 、R 20c And R is 21 As defined in any of the embodiments of the compounds of formula (I), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c) or (VI-B1 d), where applicable.
In some embodiments, R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group; r is R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 、R 13 、R 17 And R is 20c Is independently selected from-H and methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or a straight chain C 1-3 An alkylene chain; r is R 30 R', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein the 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
In another aspect, the invention provides a compound of formula (VII)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I) or (VI).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 Is C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group. In some embodiments, R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 . And in some embodiments, R 3 is-CH 3 。
In some embodiments, R 5 is-H or C 1-3 An alkyl group. In some embodiments, R 5 is-H or methyl.
In some embodiments, R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 10 is-H or methyl.
In some embodiments, R 13 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group. In some embodiments, R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl. In some embodiments, R 13 is-H or methyl. And in some embodiments, R 13 Is methyl.
In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and R is 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Group substitution of (2). In some embodiments, R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is thatWherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that (i) X 1 、X 2 、X 3 And X 4 At least one of (i) is N, and (ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, R 30 Is->X 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least one of which is N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH. In some embodiments, X 1 、X 2 、X 3 And X 4 At least two of which are N, and not more than 1 instance of R' is halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 or-CH 2 OH。
Another aspect of the invention provides a compound of formula (VII-A) or (VII-B)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI) or (VII).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VII-A1) or (VII-A2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI), (VII) or (VII-A).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or 0 to 4 are independently selected from N, O and S3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring of heteroatoms of (2), wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the present invention provides a compound of formula (VII-B1) or (VII-B2)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI), (VII) or (VII-B).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a keyBranched or straight-chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VII-A1 a), (VII-A1 b), (VII-A1 c) or (VII-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 As defined in any one of the embodiments of the compounds of formula (I), (VI), (VII-A1) or (VII-A2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H orC 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
Another aspect of the invention provides a compound of formula (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein R 3 、R 5 、R 10 、R 13 And R is 21 Of the formula (I), (VI), (VII-B1) or (VI)Compounds of any one of the embodiments defined for I-B2).
In some embodiments, R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 5 is-H or C 1-6 An alkyl group; r is R 10 And R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
In some embodiments, R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 5 is-H or methyl; r is R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group; r is R 13 is-H or C 1-3 An alkyl group; r is R 21 is-L A -R 30 ；L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and R is 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
D. General synthetic scheme
The compounds of the present invention can be produced according to the following synthetic schemes. In the following general schemes, it is to be understood that all variables used in the schemes have the definitions provided herein. As used in the general scheme, LG represents a "leaving group" and PG represents a "protecting group". Enantiomerically pure compounds of the general scheme are contemplated by using stereospecific reaction conditions or chiral resolution using methods known to those skilled in the art and/or detailed in the specific examples provided herein.
Compounds of the general formulae GB and GD can be prepared according to scheme 1 below. Compounds of formula GA having carbonyl functionality on the C3 carbon of a steroid scaffold are commercially available or are prepared from the corresponding C3 alcohol by using an oxidizing agent such as dess-Martin periodate (DMP). Compounds of formula GB can be prepared by directly exposing a compound of formula GA to an alkyl bromide/magnesium chloride reagent (grignard reagent) such as propyl magnesium bromide (as depicted in scheme 1) or methyl magnesium bromide. Compounds of formula GB can also be prepared by first converting the C3 carbonyl group to an oxirane functional group to produce a compound of formula GC, followed by exposure to a grignard reagent as detailed above. The compounds of the general formula GC can be prepared by reacting a compound of the formula GA with a compound of the formula (I) such as trimethylsulfoxide iodide (Me 3 SOI) is prepared by reacting an oxidizing agent in the presence of a base. The compounds of the general formula GC can also be converted to the corresponding alkoxymethyl compounds by exposure to an appropriate alkoxide, such as the methoxide depicted in scheme 1.
Scheme 1: synthesis of Compounds of the general formula GD
According to scheme 2, a compound of formula GE can be converted to a compound of formula GG, and then a compound of formula GE or GG can be converted to a compound of formula GJ, wherein z is 0 or 1. The compound of formula GG can be prepared by first reacting a compound of formula GE with ethyl diazoacetate to produce a diazo compound of formula GF. The compound of formula GF may then be combined with a reagent such as Rh 2 (OAc) 4 To effect intramolecular carbon insertion reactions to give the compound of formula GG. Compounds of formula GE or GG may be converted to compounds of formula GJ (wherein z is 0 or 1) by first reacting them with a reagent such as methyl benzene sulfinate in the presence of a base to give intermediate compounds of formula GH, and then exposing said intermediate compounds to elimination conditions to giveA compound of formula GI. In the presence of a base, a base such as trimethylsulfoxide iodide (Me 3 SOI) can provide compounds of formula GJ with a fused cyclopropyl moiety.
Scheme 2: synthesis of Compound of general formula GJ
Compounds of general formulae GR and GS can be synthesized according to scheme 3. By reaction with the reagent ethyl triphenylphosphine bromide (EtPh 3 PBr) or other similar reagent in the presence of a base to convert the compound of formula GJ to GK. The resulting compound of formula GK may be converted to a secondary alcohol-type GL compound using a suitable borane reducing agent, optionally in the presence of hydrogen peroxide. The compound of formula GL may be converted to a keto-GM compound using a suitable oxidizing agent such as DMP or pyridinium chlorochromate (PCC). The compounds of formula GN can be prepared from compounds of formula GM by reaction with methyltriphenylphosphine bromide (MePh 3 PBr) or other similar reagents in the presence of a base.
The compound of formula GR may be prepared from a compound of formula GN by first reacting a compound of formula GN with a suitable borane reducing agent, optionally in the presence of hydrogen peroxide, e.g., with BH 3 -Me 2 S is synthesized by reacting it in the presence of hydrogen peroxide and sodium hydroxide to give a compound of formula GO. The alcohol functionality of the compound of formula GO can then be converted to a Leaving Group (LG) using methods known to those skilled in the art, for example, by tosylation, mesylation, or trifluoromethanesulfonyl of the hydroxy functionality to form a compound of formula GQ. The compound of formula GQ can be converted to a compound of formula GR by reaction with a nucleophilic compound such as 4-cyanopyrazole depicted in scheme 3. It will be appreciated that the number of nucleophilic compounds useful in this step to prepare the GR compound of formula (la) is virtually limitless, and that other specific examples are provided herein. Optionally (optionally) Alternatively, the compound of formula GO may be exposed to a casting (Mitsunobu) condition to provide a compound of formula GR, with only the compound of formula GQ formed in situ.
Can be prepared from compounds of formula GN by reaction with suitable oxidizing agents, such as m-CPBA or Me 3 SOI to give oxirane GP compounds to synthesize GS compounds. The compound of formula GP can be converted to the compound of formula GS by reaction with a nucleophilic compound such as 4-cyanopyrazole depicted in scheme 3. As explained above, it should be appreciated that the number of nucleophilic compounds useful in this step to prepare the compound of formula GS is virtually limitless, and other specific examples are provided herein.
Scheme 3: synthesis of Compounds of general formulae GR and GS
Compounds of formulae GU and GX can be synthesized according to scheme 4.
The compounds of formula GU can be synthesized by first reacting a compound of formula GM with a brominating agent such as molecular bromide in the presence of HBr to obtain a compound of formula GT. The GT compound is reacted with a nucleophilic compound such as 4-cyanopyrazole depicted in scheme 3 to provide a compound of formula GU. As explained above, it should be appreciated that the number of nucleophilic compounds that can be used in this step to prepare the GU compounds of formula (la) is virtually limitless, and other specific examples are provided herein.
The compound of formula GX can be synthesized by first reacting a GM compound with a molecular bromide in the presence of sodium hydroxide under aqueous conditions to yield a carboxylic acid compound of formula GV. The conversion of the carboxylic acid functionality of the compound of formula GV to the corresponding carboxamide of formula GW can be accomplished by reaction with ammonium chloride under coupling conditions, or alternatively by first converting the carboxylic acid to the acid chloride and then reacting with ammonium chloride in the presence of a base. The resulting compound of formula GW is reacted with an aryl compound under coupling conditions, such as palladium catalyzed coupling conditions, to yield a compound of formula GX. It will be appreciated that the number of aryl compounds useful in the coupling step to prepare the compound of formula GX is virtually unlimited.
Scheme 4: synthesis of Compounds of the general formulae GU and GX
Alternatively, intermediate compounds of formula GL may be synthesized according to scheme 5 below. By first combining a compound of formula GJ with TMSCH 2 Li or other similar reagent to give a compound of formula GY. The compound of formula GY is reacted with a suitable borane reducing agent, optionally in the presence of hydrogen peroxide, e.g. with BH 3 -Me 2 S is reacted in the presence of hydrogen peroxide and sodium hydroxide to provide the compound of formula GZ. The resulting compound of formula GZ may then be oxidized using an oxidizing agent such as DMP to provide an aldehyde GAA compound, which may then be treated with an alkyl magnesium bromide reagent such as methyl magnesium bromide depicted in scheme 5 to provide a compound of formula GL.
Scheme 5: alternative synthesis of intermediate compounds of general formula GL
The compounds of general formula GA-N can be synthesized according to scheme 6 below. Compounds of the formula GA-B may be used, for example, with trimethylsulfoxide iodide (Me 3 SOI) is treated in the presence of a base to obtain a compound of formula GA-C with a fused cyclopropyl moiety. The resulting GA-C compound may then be treated with ethyl diazoacetate to give the diazonium compound of formula GA-D. The compound of formula GA-D may then be combined with a reagent such as Rh 2 (OAc) 4 To effect intramolecular carbon insertion reactions to give the compounds of formula GA-E. The compounds of formula GA-E are protected using methods known to those skilled in the art to give compounds of formula GA-F, which may then be reduced to compounds of formula GA-G.beta. -hydroxy. The hydroxy moiety of the compound of formula GA-G is converted to a sulfonate compound with a reagent such as methanesulfonyl chloride in the presence of a base to give the elimination product of the compound of formula GA-H. Reduction of the compound of formula GA-H and removal of the protecting groupTo primary alcohol type GA-I compounds. Oxidation of the compound of formula GA-I to the aldehyde compound of formula GA-J and subsequent treatment with an alkyl magnesium bromide reagent such as methyl magnesium bromide depicted in scheme 6 gives the compound of formula GA-K. The secondary alcohol functionality of the formula GA-K compound is oxidized using an oxidizing agent such as DMP to give a ketone GA-L compound, which can then be brominated in the presence of HBr or the like using a brominating reagent such as a molecular bromide to give a compound of formula GA-M. The compounds of formula GA-M may be converted to compounds of formula GA-N by reaction with nucleophilic compounds such as 4-cyanopyrazole depicted in scheme 6. As mentioned above, it will be appreciated that the number of nucleophilic compounds useful in this step to prepare the compounds of formula GA-N is virtually limitless.
Scheme 6: synthesis of Compound of general formula GA-N
Compounds of the general formula GA-W may be prepared from the starting material GA-O according to scheme 7. If the starting material has any unsaturation, the compounds of formula GA-O may be obtained by reduction with a suitable reducing agent such as hydrogen with a palladium catalyst. The compound of formula GA-O may then be reacted with BrCN or an equivalent reagent to produce the dicyano compound of formula GA-P. The compound of formula GA-P may then be exposed to aqueous hydroxide conditions to remove the cyano group and produce the compound of formula GA-Q. The overall conversion from the compound of formula GA-O to the compound of formula GA-Q is the loss of methyl groups on all methylamino moieties of the compound. The compound of formula GA-Q may then be reacted with N-chlorosuccinimide to produce a compound of formula GA-R bis-N-chloro, which may then be converted to a compound of formula GA-S when exposed to methoxide/methoxide conditions. The ring opening and cyclopropane formation necessary to produce the compound of formula GA-T can be accomplished by reacting the compound of formula GA-S with NaNO 2 Or a functionally equivalent reagent reaction. Compounds of formula GA-U can be prepared by directly exposing a compound of formula GA-T to an alkyl bromide/magnesium chloride reagent (grignard reagent) such as methyl magnesium bromide (as depicted in scheme 7) that reacts with the carbonyl functionality on C3.
The compounds of formula GA-W may be synthesized by first reacting a compound of formula GA-U with a brominating agent such as molecular bromide in the presence of HBr to yield a compound of formula GA-V. The GA-V compound is reacted with a nucleophilic compound such as 4-cyanopyrazole depicted in scheme 7 to provide a compound of formula GA-W. It will be appreciated that the number of affinity compounds useful in this step to prepare the compound of formula GA-W is virtually unlimited and that other specific examples are contemplated, such as tetrazole-based nucleophiles.
Scheme 7: synthesis of Compound of general formula GA-W
Can be prepared according to scheme 8 below by first reacting a compound of formula GA-X with methyltriphenylphosphine bromide (MePh 3 PBr) or other similar reagents to give a compound of formula GA-Y, wherein z is 0 or 1. The compounds of formula GA-Y are reacted with a suitable borane reducing agent, optionally in the presence of hydrogen peroxide, for example with 9-BBN dimer in the presence of hydrogen peroxide and sodium hydroxide to give the compounds of formula GA-Z. The resulting compound of formula GA-Z may then be oxidized using an oxidizing reagent such as pyridinium chlorochromate (PCC) to give the aldehyde GA-aA compound, which may then be treated with methyltriphenylphosphine bromide (MePh 3 PBr) or other similar reagent to form olefins from aldehyde functions and to give compounds of formula GA-AB. The formula GA-AD compound can be synthesized by first protecting the alcohol function on C3 of the formula GA-AB compound using methods known to those skilled in the art to give the formula GA-AC compound, and then contacting the formula GA-AC compound with ethyl diazoacetate in the presence of rhodium (ii) acetate dimer to form the cyclopropyl moiety from the olefin function and give the formula GA-AD compound. The compound of formula GA-AD can then be reduced and deprotected to give the compound of formula GA-AE.
The alcohol functionality of the compound of formula GA-AE can then be converted to a Leaving Group (LG) using methods known to those skilled in the art, for example by tosylation, mesylation or trifluoromethanesulfonyl of a hydroxy functionality, to form a compound of formula GA-AF. The compounds of formula GA-AF can be converted to compounds of formula GA-AG by reaction with nucleophilic compounds such as 4-cyanopyrazole depicted in scheme 8. It will be appreciated that the number of nucleophilic compounds useful in this step to prepare the compounds of formula GA-AG is virtually unlimited and other specific examples are contemplated. Optionally, the compound of formula GA-AE may be exposed to casting conditions to obtain a compound of formula GA-AG, with only the compound of formula GA-AF being formed in situ.
Scheme 8: synthesis of Compounds of general formula GA-AG
The above-mentioned synthesis schemes were used to synthesize the compounds in table 1.
Table 1: example compounds of the invention.
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In one aspect, provided herein are compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1), (III-B1C), (III-A2 d), (II-C2B), (II-C1C), (III-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, pharmaceutically acceptable salts of the compounds (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d).
In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C2 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A2B), (III-A) and (III-A2 d) (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), III-A2 d) (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2) Sup>A, V-A2 Sup>A), IV-A1B, V-A2 Sup>A, (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In certain embodiments, the compounds of the present invention are provided in a pharmaceutical composition in an effective amount. In certain embodiments, the compounds of the present invention are provided in a therapeutically effective amount.
In certain embodiments, the compounds of the invention as described herein act to affect GABA, for example, in a positive or negative manner A GAB of receptor A And (3) a regulator. As modulators of excitability of the Central Nervous System (CNS), e.g. by modulating GABA A The ability of the receptor to mediate, such compounds are expected to have CNS activity.
Accordingly, in one aspect, provided herein is a method of modulating GABA in a subject in need thereof A A method of treating a subject, comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
In another aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the invention. In certain embodiments, the CNS-related disorder is a sleep disorder, an affective disorder, a schizophrenic lineage disorder, a convulsive disorder, a memory and/or cognition disorder, a movement disorder, a personality disorder, an autism lineage disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is post-partum depression. In certain embodiments, the CNS-related disorder is severe depression. In certain embodiments, the severe depression is a moderate severe depression. In certain embodiments, the severe depression is severe depression. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, e.g., by continuous intravenous infusion.
The compounds of the present invention may be synthesized from the following known starting materials using methods known to those skilled in the art or some references. In one aspect, provided herein are compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-C1B), (III-A1) and (III-C1 d)) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, pharmaceutically acceptable salts of the compounds (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d).
In one aspect, the invention includes a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt of a compound described herein and a pharmaceutically acceptable carrier, vehicle, or excipient.
III alternative embodiment
In an alternative embodiment, the compounds described herein further comprise one or more isotopic substitutions. For example, the hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example 13 C or 14 C, performing operation; oxygen can be, for example 18 O; the nitrogen may be, for example 15 N, etc. In other embodiments, specific isotopes (e.g., 3 H、 13 C、 14 C、 18 o or 15 N) may represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99% or at least 99.9% of the total isotopic abundance of the elements occupying a particular site of the compound.
A. Pharmaceutical composition
In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C2 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A2B), (III-A) and (III-A2 d) (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), III-A2 d) (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2) Sup>A, V-A2 Sup>A), IV-A1B, V-A2 Sup>A, (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In certain embodiments, the compounds of the present invention are provided in a pharmaceutical composition in an effective amount. In certain embodiments, the compounds of the present invention are provided in a therapeutically effective amount.
In certain embodiments, the pharmaceutical composition comprises an effective amount of an active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.
The pharmaceutical compositions provided herein may be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration.
Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will generally be determined by the physician, based on the relevant circumstances, including the condition to be treated; the route of administration selected; the actual compound administered; age, weight, and response of the individual patient; severity of patient symptoms; etc.
When used to prevent the onset of a CNS disorder, the compounds provided herein will be administered to a subject at risk of developing the disorder, typically at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular disorder generally include subjects having a family history of the disorder or those identified as particularly susceptible to developing the disorder by genetic testing or screening.
The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound over a prolonged period of time (e.g., over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc.), or may continue indefinitely, e.g., for the remainder of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, over a treatment window over a long period of time.
The pharmaceutical compositions of the present invention may be further delivered using a variety of methods of administration. For example, in certain embodiments, the pharmaceutical composition may be administered in a bolus, e.g., to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic level of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose achieves slow release of the active ingredient, whereas a bolus delivered directly to the vein (e.g., by IV infusion) achieves much faster delivery, which rapidly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered in a continuous infusion, for example by IV drip, to provide maintenance of steady state concentration of the active ingredient within the subject's body. Furthermore, in still other embodiments, the pharmaceutical composition may be administered first in a bolus dosage form and then in a continuous infusion form.
Compositions for oral administration may take the form of a bulk liquid solution or suspension or a bulk powder. More commonly, however, the composition is presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to a single dose of physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefills of liquid compositions, pre-measured ampules or syringes or, in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight or preferably about 1 to about 40% by weight), with the remainder being various vehicles or excipients and processing aids that assist in forming the desired form of administration.
In the case of oral administration, a representative regimen is one to five times per day, and especially two to four times per day, and typically three oral doses. Using these modes of administration, each dose provides from about 0.01 to about 20mg/kg of the compounds provided herein, and each preferred dose provides from about 0.1 to about 10mg/kg, and especially from about 1 to about 5mg/kg.
The transdermal dose is generally selected to provide similar or lower blood levels than those achieved using an injected dose, typically in an amount ranging from about 0.01 to about 20 wt%, preferably from about 0.1 to about 10 wt% and more preferably from about 0.5 to about 15 wt%.
The injected dosage level ranges from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all lasting from about 1 to about 120 hours, and especially 24 to 96 hours. A preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered to achieve adequate steady state levels. A maximum total dose of 40 to 80kg of human patients is expected to be no more than about 5 g/day.
Liquid forms suitable for oral administration may include aqueous or non-aqueous vehicles with buffers, suspending and dispersing agents, colorants, flavors, and the like. The solid form may include, for example, any of the following ingredients or compounds of similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, primogel or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based on injectable sterile saline, or phosphate buffered saline, or other injectable excipients known in the art. As previously mentioned, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, the remainder being injectable excipients and the like.
Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as ointments, the active ingredients will typically be combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
The compounds provided herein may also be administered by transdermal means. Accordingly, transdermal administration may be achieved using a patch of the drug storage (reservoir) type or a porous membrane type or a patch of a solid matrix type.
The above components of orally administrable, injectable or topically administrable compositions are merely representative. Other materials and processing techniques, etc., are set forth in Remington's Pharmaceutical Sciences, 17 th edition, section 8 of 1985,Mack Publishing Company,Easton,Pennsylvania, which is incorporated herein by reference.
The compounds of the present invention may also be administered in sustained release form or by sustained release drug delivery systems. A representative sustained release material can be described in Remington' sPharmaceutical Sciences.
The invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the invention. Acids useful in preparing pharmaceutically acceptable salts are acids that form non-toxic acid addition salts (i.e., salts containing pharmacologically acceptable anions such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, and the like).
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection such as Intravenous (IV) administration.
Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersing or suspending aids, surfactants, isotonic agents, preservatives, lubricants, and the like, as appropriate for the particular dosage form desired, such as injection. General considerations for the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, sixteenth edition, e.w. martin (Mack Publishing co., easton, pa., 1980) and remington: the Science and Practice of Pharmacy, 21 st edition (Lippincott Williams & Wilkins, 2005).
For example, injectable formulations, such as sterile injectable aqueous suspensions, may be formulated in accordance with the known art using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that may be employed include, but are not limited to, water, sterile saline or phosphate buffered saline or ringer's solution.
In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α -cyclodextrin, β -cyclodextrin and γ -cyclodextrin, consisting of 6, 7 and 8 α -l,4 linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moiety, including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitutions. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin, such as sulfobutyl ether β -cyclodextrin, also known asSee, for example, U.S.5,376,645. In certain embodiments, the composition comprises hexapropyl-beta-cyclodextrin. In a more specific embodiment, the composition comprises hexapropyl-beta-cyclodextrin (10% -50% in water).
The injectable composition may be sterilized, for example, by: filtering through a bacteria retaining filter; or incorporating the sterilant in the form of a sterile solid composition which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will generally be determined by the physician, based on the relevant circumstances, including the condition to be treated; the route of administration selected; the actual compound administered; age, weight, response of the individual patient; severity of patient symptoms; etc.
The composition is presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to a single dose of physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, pre-measured ampules or syringes of liquid compositions. In such compositions, the compound is typically a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that assist in forming the desired form of administration.
The compounds provided herein may be administered as the sole active agent, or they may be administered in combination with other active agents. In one aspect, the invention provides a combination of a compound of the invention and another pharmacologically active agent. The combined administration may be by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous and alternating administration.
Although the description of pharmaceutical compositions provided herein relates primarily to pharmaceutical compositions suitable for administration to humans, those skilled in the art will appreciate that such compositions are generally suitable for administration to all classes of animals. Modifications to pharmaceutical compositions suitable for administration to humans to render the compositions suitable for administration to a variety of animals are well understood, and common skilled veterinary pharmacologists may use common experimental designs and/or make such modifications. General considerations for the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington, the Science and Practice of Pharmacy, 21 st edition, lippincott Williams & Wilkins,2005.
In one aspect, a kit is provided comprising a kit comprising the formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2C), (III-A), (III-B), (III-C1), (III-A2C), (III-A1), (III-B2 d), (II-C2B), (II-C1C), (II-C1B), (II-C2C), (II-C1 d) (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1C) III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI), V-A2B, VI), A composition (e.g., a solid composition) of the compound (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d).
B. Combination therapy
Compounds or compositions described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (III-A), (III-C) 2 a), (III-C), (III-A1), (III-A2C), (III-A2) and (III-B2B), (III-B1B), (II-C2C), (II-C2B) 1B), (II-C1 d) (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1C) III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI), V-A2B, VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compounds, or pharmaceutically acceptable salts thereof, or compositions comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-A1), (II-B2), (II-C) 1), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), a (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 a), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1) (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 Sup>A), and, the composition of the compounds (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) may be administered in combination with an additional agent or therapy. The subject to whom the compounds disclosed herein are to be administered may have a disease, disorder or condition, or symptoms thereof, that would benefit from treatment with another agent or therapy. Combination therapy may be achieved by administering two or more agents, each formulated and administered separately, or by administering two or more agents in a single formulation. In some embodiments, two or more agents in a combination therapy may be administered simultaneously. In other embodiments, two or more agents in a combination therapy are administered separately. For example, a first dose (or combination of doses) may be administered for minutes, hours, days, or weeks prior to a second dose (or combination of doses). Thus, two or more agents may be administered within minutes of each other, or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other, or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other, or within 2, 3, 4, 5, 6, 7, 8, or 9 weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that two or more agents used in combination therapy be present in the patient at the same time, this is not necessarily so.
Combination therapy may also include the use of different orders of the component agents to administer one or more of the agents used in the combination two or more times. For example, if agent X and agent Y are used in combination, they may be applied sequentially one or more times in any combination, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc. Exemplary additional agents are described below.
1. Selective Serotonin Reuptake Inhibitors (SSRI)
In some embodiments, a compound or composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound or a pharmaceutically acceptable salt thereof) is administered in combination with an SSRI. SSRI include antidepressants that increase serotonin levels in the brain. Exemplary SSRIs include, but are not limited to, citalopram (celesa), escitalopram (Escitalopram) (Lexapro), fluoxetine (fluxetine) (procac), fluvoxamine (Fluvoxamine) (Luvox), paroxetine (Paxil), and Sertraline (selturine) (Zoloft).
2. Norepinephrine reuptake inhibitors (NERI)
In some embodiments, a compound or composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a composition of a pharmaceutically acceptable salt thereof) is administered in combination with NERI. Exemplary NERI include, but are not limited to, atomoxetine (Atomoxetine) (Stratera), reboxetine (Reboxxetine) (Edronate, vestra), bupropion (Bupropion) (Wellbutin, zyban), duloxetine (Duloxxetine), desipramine (Desipramine) (Norpramine), amoxylin (Amedilin) (UK-3540-1), dalidalin (Daledalin) (UK-3557-15), edexetine (Edivoxiline) (LY-2216684), oxazedine (Esrebox) chloro-talamine (Lortalamine) (LM-1404), nisoxetin (Nisoxetin) (Lu-94,939), talopram (tasulopram) (Lu 3-010), talsupram (Lu 5-005), dastine (Tandamine) (AY-23,946) and Vilazine (Vilazine).
3. Antipsychotic
In some embodiments, a compound or composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the composition of (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound or a pharmaceutically acceptable salt thereof) is administered in combination with an antipsychotic agent. Antipsychotics include D2 antagonists that reduce dopaminergic neurotransmission in the dopamine pathway. Exemplary antipsychotics include, but are not limited to, asenapine (saperis), aripiprazole (Aripiprazole) (Abilify), calicheazine (Cariprazine) (Vrayar), clozapine (Clozapine) (Clozaril), haloperidol (Droperidol), haloperidol (Fluperpine), mesoridazine (Mesoridazine), quetiapine hemifumarate (Quetiapine Hemifumarate), triclopride (Racleopide), spiropirone (Spiprone), sulpiride (Sulpiride), trimethobenzamide hydrochloride (Trimethobenzamide hydrochloride), triflurazine dihydrochloride (Trifluoperazine Dihydrochloride), lurasidone (Latuida), olanzapine (Olazapine) (Zyprexa), quetiapine (Quetiapine) (Seroque), zotepine (Zepine), risperidone (Risperidone), risperidone (Risperidone) (62), and norepinephrine (Halodene).
4. Cannabinoids
In some embodiments, a compound or composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is administered in combination with a cannabinoid. Exemplary cannabinoids include, but are not limited to, cannabidiol (ephriol), tetrahydrocannabinol acid (Tetrahydrocannabinolic Acid), tetrahydrocannabinol (Tetrahydrocannabinol), cannabidiol acid (Cannabidolic Acid), cannabinol (cannabainol), cannabigerol (cannabaigerol), cannabigerol (cannabactone), tetrahydrocannabinol (tetrahydrocannabinovarin), and Cannabidiol (cannabatrivarin).
Nmda receptor antagonists
In some embodiments, a compound or composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is administered in combination with an NMDA receptor antagonist. NMDA receptor antagonists are a class of drugs that inhibit the action of the N-methyl-d-aspartate receptor. Exemplary NMDA antagonists include, but are not limited to, ketamine (Ketamine), esketamine (Esketamine), ketone Bei Mitong (ketobemine), ifendopin, 5, 7-dichlorokynurenic acid, licotinine (Licostine), memantine (Memantine), gaulthinine (gavetine), phencyclidine (Phencylindine), dextromethorphan (Dextromethan), lei Momai (Remacemide), selfotel, tiletamine, dextropropoxyphene (Dextroproxyphene), althenate (Aptiganel), desuginosol (Dexanabinol), and Amantadine (Amantadine). NMDA receptor antagonists also include opioid drugs such as Methadone, dextropropoxide, pethidine, levorphanol, tramadol, neramexane, and ketobemisone.
6.GABA A Receptor agonists
In some embodiments, a compound or composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is administered in combination with a GABA receptor agonist. GABA receptor agonists are a class of drugs that are agonists of one or more of the GABA receptors. Exemplary GABA receptor agonists include, but are not limited to, clobazam (Clobazam), topiramate (Topiramate), muscin (Muscovmol), prlufenam (Baclofen), gabapentin (Gabapenin), vigabatrin (Vigatran), valproic acid, tiagabine (Tiagabine), lamotrigine (Latrigine), pregabalin (Pregabalin), phenytoin (Phenylodin), carbamazepine (Carbamazepine), pentathiobarbital (Thiopental), thiobarbital (Thiopennital), pentobarbital (Pentobarbital), butobarbital, isobobab (Ambarbital), methylbazam (Methylzem), methylazepam (Methylazepam), flfuzom (Methylazepam), triazapam (Methylazem), triazapam (Pazom), methylazepam (Methylazepam), methylazepam (Fllazem), methylazepam (Methylazepam), methylazepam (Methoxypam), methoxypam (Przepam), metropupdazole (Przepam), prbarbital, metropapzam, metropobal, cloxazopam (cloxazopam), flutoxazopam (flutozoplam), alprazolam (Alprazolam), escitalopram (Estazopam), bromazepam (Bromazepam), fluoxazepam (Flurazepam), potassium clozapride (Clorazepate Potassium), halo Shalun (Haloxazopam), fluroxypyr Zhuo Yizhi (Ethyl Loflazepate), qazepam, clonazepam (Clonazepam), mexazopam, etizolam (Etizopam), brotizopam (Brotizopam), chlorothiazolam (Clotazopam), propofol, fosfool (Fospopozol), zolpidem (Zolpidem), zopimone (Zopazone), eszofluron (Expiprocolone), fly essence, TFQP/gaboxadol (Ethyl Loflazepate), isozazepam (Isoxadol), zazol-3-co-3, ZAIP-2, ZAIP-3, and ZAIP-3.
7. Cholinesterase inhibitors
In some embodiments, a compound or composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is administered in combination with a cholinesterase inhibitor. In general, cholinergic agents are compounds that mimic the effects of acetylcholine and/or butyrylcholine. Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine. Exemplary cholinesterase inhibitors include, but are not limited to, donepezil (aricet), tacrine (Tacrine) (cognix), rivastigmine (Exelon, exelon Patch), galanthamine (galanthamine), memantine/donepezil (Namzaric), ambenamine (Ambenonium) (Mytelase), neostigmine (Bloxiverz), pyridostigmine (pyredostimine) (Mestinon Timespan, regonol), and galanthamine (Razadyne).
The present disclosure encompasses, among other things, administration of a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C2 d), (II-C2 a), (II-C2C), (II-C2 d), (III-A), (III-B), (III-A2B), (III-A) to a subject) (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), III-A2 d) (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2) Sup>A, V-A2 Sup>A), IV-A1B, V-A2 Sup>A, (V-A2B), (VI-a), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-a), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B) or (VII-B1 d) a compound or a pharmaceutically acceptable salt thereof), said subject having previously been administered an agent selected from the group consisting of: bronchial muscle/airway relaxants, antiviral agents, oxygen, antibodies, and antibacterial agents. In some embodiments, an additional agent is administered to the subject, followed by administration of a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C2 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B) and (III-A2 d), (II-B2C), (II-C2 d) (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), III-A2 d) (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2) Sup>A, V-A2 Sup>A), IV-A1B, V-A2 Sup>A, (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B)), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1B), (VII-B1C) or (VII-B1 d) compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B1), (II-A), (II-B3 a), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), a (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), and (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-a), (VII-B), (VII-A1), (VII-A2), (VII-B1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof), and the additional agent is selected from the group consisting of: bronchial muscle/airway relaxants, antiviral agents, oxygen, antibodies, and antibacterial agents. In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (III-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the compound of (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is co-administered to the subject with an agent selected from the group consisting of bronchomuscular/airway relaxants, anti-viral agents, oxygen and anti-bacterial agents.
C. Methods of use and treatment
In one aspect, compounds described herein are contemplated, for example, of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-C1), (III-A1) and (III-B1 d), (II-C2B), (II-C2 a), (II-C1B), (II-C1C) and (III) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, the compounds of (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) may be used as a medicament for the treatment of a subject in need thereof (e.g. a CNS-related disorder such as depression disorder, depression, or the like in a subject suffering from Lei.g. a Lei syndrome (Rett syndrome), fragile X syndrome or An Geman syndrome (Angelman syndrome) Convulsive disorders, epileptogenesis, memory and/or cognition disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular diseases, substance abuse disorders and/or withdrawal syndromes or tinnitus). Exemplary CNS disorders related to GABA modulation include, but are not limited to, sleep disorders (e.g., insomnia), affective disorders (e.g., depression (e.g., major Depressive Disorder (MDD)), mood disorders (e.g., mild depression), bipolar disorder (e.g., I and/or II), anxiety disorders (e.g., generalized Anxiety Disorder (GAD), social anxiety disorder), stress, post Traumatic Stress Disorder (PTSD), obsessive compulsive disorder (e.g., obsessive Compulsive Disorder (OCD)), schizophrenic disorders (e.g., schizophrenia, schizoaffective disorders), convulsive disorders (e.g., epilepsy (e.g., status Epilepticus (SE)), seizures), disorders of memory and/or cognition (e.g., attention disorders (e.g., attention Deficit Hyperactivity Disorder (ADHD)), dementia (e.g., dementia of the alzheimer's type, dementia of the lewy body type, dementia of the vascular type), movement disorders (e.g., huntington's disease, parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism Spectrum Disorders (ASD) (e.g., autism, monogenic causes of autism (such as synaptic dysfunction) such as ralston syndrome, fragile X syndrome, an Geman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain), chronic pain), traumatic Brain Injury (TBI), vascular diseases (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and/or withdrawal syndromes (e.g., opioid, cocaine, and/or alcohol addiction) and tinnitus.
In certain embodiments, the CNS-related disorder is a sleep disorder, an affective disorder, a schizophrenic lineage disorder, a convulsive disorder, a memory and/or cognition disorder, a movement disorder, a personality disorder, an autism lineage disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is post-partum depression. In certain embodiments, the CNS-related disorder is severe depression. In certain embodiments, the severe depression is a moderate severe depression. In certain embodiments, the severe depression is severe depression.
In one aspect, there is provided a method of reducing or preventing seizures in a subject comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention. In some embodiments, the method reduces or prevents epileptogenesis.
In yet another aspect, a combination of a compound of the invention and another pharmacologically active agent is provided. The compounds provided herein may be administered as the sole active agent or they may be administered in combination with other agents. The combined administration may be by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous and alternating administration.
In another aspect, there is provided a method of treating or preventing brain excitability in a subject susceptible to or suffering from a disorder associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention.
In yet another aspect, there is provided a method of treating or preventing stress or anxiety in a subject comprising administering to a subject in need of such treatment an effective amount of a compound of the invention or a composition thereof.
In yet another aspect, a method of reducing or preventing insomnia in a subject is provided, comprising administering to a patient in need of such treatment an effective amount of a compound of the invention or a composition thereof.
In yet another aspect, a method of inducing sleep and substantially maintaining REM sleep levels found in normal sleep is provided, wherein no significant rebound insomnia is induced, comprising administering an effective amount of a compound of the invention.
In yet another aspect, there is provided a method of reducing or preventing premenstrual syndrome (PMS) or postnatal depression (PND) in a subject comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.
In yet another aspect, there is provided a method of treating or preventing an affective disorder in a subject comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In certain embodiments, the affective disorder is depression.
In yet another aspect, there is provided a method of cognition enhancement or treatment of a memory disorder by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the disorder is alzheimer's disease. In certain embodiments, the disorder is rett syndrome.
In yet another aspect, a method of treating attention deficit is provided by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention deficit is ADHD.
Central Nervous System (CNS) inflammation (neuroinflammation) is considered to be a feature of all neurological disorders. Severe inflammatory neurological conditions include multiple sclerosis (characterized by an immune-mediated response to myelin proteins) and meningoencephalitis (in which infectious agents trigger inflammatory responses). Additional scientific evidence suggests a potential role for inflammatory mechanisms in other neurological disorders such as alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, stroke, and traumatic brain injury. In one embodiment, the compounds of the invention are useful for treating neuroinflammation. In another embodiment, the compounds of the invention are useful for treating neurological disorders including Alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, stroke, and inflammation in traumatic brain injury.
In certain embodiments, the compound is administered to the subject over a prolonged period of time. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intramuscularly or intravenously.
1. Neuroendocrine disorders and dysfunction
Provided herein are methods useful for treating neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to a variety of disorders caused by imbalance in the production of body hormones directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Since the hypothalamus and pituitary are two areas of the brain that regulate hormone production, damage to the hypothalamus or pituitary, such as traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or function is associated with a female health disorder or condition (e.g., a female health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction is associated with a female health disorder or condition (polycystic ovary syndrome).
Symptoms of neuroendocrine disorders include, but are not limited to: behavioral, emotional, and sleep related symptoms; symptoms associated with reproductive function; and somatic symptoms; including but not limited to fatigue, poor memory, anxiety, depression, weight gain or loss, mood swings, lack of concentration, difficulty in attention, lack of libido, infertility, amenorrhea, loss of muscle mass, increased abdominal fat, hypotension, decreased heart rate, hair loss, anemia, constipation, aversion to cold, and dry skin.
2. Neurodegenerative diseases and disorders
The methods described herein are useful for treating neurodegenerative diseases and disorders. The term "neurodegenerative disease" includes diseases and conditions associated with progressive loss of structure or function of neurons or death of neurons. Neurodegenerative diseases and disorders include, but are not limited to: alzheimer's disease (including symptoms associated with mild, severe or severe cognitive impairment); amyotrophic Lateral Sclerosis (ALS); hypoxia and ischemic injury; ataxia and convulsions (including the treatment and prevention of seizures caused by schizoaffective disorders or by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including mcrad's echinocytosis amacrine (McLeod neuroacanthocytosis syndrome, MLS); closed head injury; coma, coma; contusion injury (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; a disturbance of consciousness; down syndrome; drug-induced or drug-therapy-induced parkinsonism (such as antipsychotic drug-induced acute akathisia, acute dystonia, parkinsonism or tardive akinesia, antipsychotic drug malignancy syndrome, or drug-therapy-induced postural tremor); epilepsy; fragile X syndrome; tourette's syndrome (Gilles de la Tourette's syndrome); head trauma; hearing disorders and loss; huntington's disease; lennox syndrome; levodopa-induced dyskinesia; intelligent retardation; dyskinesia, including akinesia and akinesia (ankylosing) syndromes (including basal ganglia calcification, cortical basal ganglia degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, parkinson's disease, postencephalitis parkinsonism, and progressive supranuclear palsy); muscle spasms and conditions associated with muscle spasms or weakness, including chorea (such as benign hereditary chorea, drug-induced chorea, hemiballism (hemiballism), huntington's disease, neuroacanthosis, sienhames chorea (syldenham's chorea) and symptomatic chorea), dyskinesia (including twitches such as complex twitches, simple twitches and symptomatic twitches), myoclonus (including generalized myoclonus and focal myoclonus (cyclonus)), tremors (such as resting tremor, postural tremors and intention tremors) and dystonias (including axonal dystonia, dystonia writers, hemiplegia dystonia, paroxysmal dystonia and focal dystonias such as blepharospasm, oromandibular dystonia and syncope (spasmodic dysphonia) and torticollis; neuronal damage, including ocular damage, retinopathy or macular degeneration of the eye; neurotoxic damage following cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest; parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tuberous sclerosis and viral infection-induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include, but are not limited to, neurotoxic damage following cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and cardiac arrest. Methods of treating or preventing neurodegenerative diseases also include treating or preventing loss of neuronal functional characteristics of a neurodegenerative disorder.
3. Affective disorder
Also provided herein are methods for treating affective disorders such as clinical depression, postnatal or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depression, tension depression (cataonic depression), seasonal affective disorder, mild depression, double depression, depressive personality disorder, recurrent short-term depression, mild depression, bipolar or manic depression, depression caused by long-term medical conditions, treatment-resistant depression, suicidal tendency, suicidal ideation or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect to a subject suffering from depression (e.g., moderate or major depression). In some embodiments, the affective disorder is associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., parkinson's disease), female health disorders or conditions).
Clinical depression is also known as major depression, major Depressive Disorder (MDD), major depression, unipolar disorders, and recurrent depression, and refers to a generalized and persistent mental disorder characterized by low self-esteem and loss of interest or enjoyment of normal pleasant activity. Some people suffering from clinical depression have difficulty falling asleep, lose weight, and often feel excited and irritable. Clinical depression affects the subject's experience, thinking, and behavior, and can cause a variety of emotional and physical problems. Individuals with clinical depression may experience difficulty in performing daily activities and make them feel unqualified for life.
Pre-parturition and post-partum depression refers to depression of pregnancy. Symptoms include irritability, crying, restlessness, sleep difficulties, extreme exhaustion (mood and/or body), appetite changes, difficulty concentrating, anxiety and/or increased fear of increasing, sensory dislocation from the infant and/or fetus, and loss of interest in previously pleasurable activities.
Postnatal depression (PND) is also known as post-natal depression (PPD) and refers to a clinical depression affecting post-natal women. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying events, anxiety and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is refractory depression (e.g., refractory depression as described herein).
In some embodiments, the subject with PND also experiences depression or symptoms of depression during pregnancy. Such depression is referred to herein as perinatal depression. In one embodiment, a subject experiencing perinatal depression is at increased risk of experiencing PND.
Atypical Depression (AD) is characterized by emotional reactivity (e.g., contradictory hedonic deficit (paradoxical anhedonia)) and aggressiveness, significant weight gain, or appetite increase. Patients with AD may also suffer from excessive sleep or somnolence (hypersomnia), feeling heavy limbs, and significant social impairment due to high sensitivity to perceived interpersonal rejection.
Melancholic depression is characterized by loss of pleasure (lack of pleasure), non-response to pleasurable stimuli, emotional depression more pronounced than sad 24696, or loss, excessive weight loss, or excessive guilt in most or all activities.
Psychotic Major Depression (PMD) or psychotic depression refers to major depressive episodes, particularly episodes of melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.
Tension depression refers to major depression involving dyskinesias and other symptoms. The individual may become silent, oligopolistic and immobilized, and either move on one's own or exhibit an unoccupied or bizarre action.
Seasonal Affective Disorder (SAD) refers to a seasonal depression in which the individual has a pattern of seasonal depressive episodes that occur in the autumn or winter.
Mild depression refers to a condition associated with unipolar depression in which the same physical and cognitive problems are evident. They are less severe and tend to last longer (e.g., at least 2 years).
Double depression refers to a fairly depressed mood (mild depression) that persists for at least 2 years and from time to time is major depressive.
Depressive Personality Disorder (DPD) refers to personality disorders characterized by depression.
Recurrent short-term depression (RBD) refers to a condition in which an individual has about one depressive episode per month, each episode lasting 2 weeks or less, and typically less than 2-3 days.
Light depression or light depression refers to depression with at least 2 symptoms within 2 weeks.
Manic depression or manic depression results in extreme mood swings, which include elevated mood (mania or hypomania) and low falls (depression). During mania, an individual may feel or exhibit abnormal pleasure, vigour or irritability. They often make decisions that are considered to be poor, with few consequences considered. Sleep need is generally reduced. During depression, there may be crying, poor contact with the eye of others, and negative attitudes to life. The risk of suicide in 20 years for persons suffering from the condition is high, greater than 6%, with a incidence of disability of 30% -40%. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder.
Depression caused by long-term medical conditions refers to depression caused by long-term medical conditions such as cancer or chronic pain, chemotherapy, long-term stress.
Treatment-resistant depression refers to a condition in which an individual has received treatment for depression, but the symptoms have not been improved. For example, antidepressants or psychological coaching (psychotherapy) do not alleviate the symptoms of depression in individuals with treatment-resistant depression. In some cases, the symptoms of individuals with treatment-resistant depression are improved, but relapse. Refractory depression occurs in patients suffering from depression who are resistant to standard pharmacological therapies (including tricyclic antidepressants, MAOI, SSRI, and dual and triple uptake inhibitors/or anxiolytic drugs) as well as non-pharmacological therapies (e.g., psychotherapy, shock therapy, vagal nerve stimulation, and/or transcranial magnetic stimulation).
Post-operative depression refers to post-operative depression (e.g., due to having to face a person's death). For example, an individual may continue to feel sad or empty, lose pleasure or interest in general enjoyment and activity, or continue to feel worthless or despair.
An affective disorder associated with a disorder or condition of female health refers to an affective disorder (e.g., depression) associated with (e.g., caused by) the disorder or condition of female health (e.g., as described herein).
Suicidal tendency, suicidal ideation, suicidal behavior refer to the tendency of an individual to do suicide. Suicidal ideation involves ideation or unusual concentration on suicide. Suicidal ideation varies widely, for example, from an evanescent idea to an extreme one, detailed planning, role playing, and the onset of an impersonation. Symptoms include talking about suicide, getting a means to make suicide, exiting social contact, concentrating on death, becoming trapped or desperated from a certain situation, increasing drinking or taking up a poison, doing something at risk or self-destructing, and appearing as though they were no longer visible.
Symptoms of depression include persistent anxiety or sadness, helplessness, despair, pessimism, worthlessness, listlessness, restlessness, sleep difficulties, insomnia, irritability, fatigue, dyskinesias, loss of interest in pleasurable activities or hobbies, loss of concentration, weakness, poor self-esteem, lack of positive ideas or plans, excessive sleep, binge eating, loss of appetite, insomnia, self-disability, suicidal ideas, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Symptoms of depression and its relief may be determined by a physician or psychologist (e.g., through mental state examination).
In some embodiments, the method comprises monitoring a subject with a known depression scale, such as the hamiltonian depression (Hamilton Depression, HAM-D) scale, the clinical global impression-improvement scale (CGI), and the Montgomery-epstein depression rating scale (Montgomery-Depression Rating Scale, MADRS). In some embodiments, the therapeutic effect may be determined by a decrease in the total score of hamiltonian depression (HAM-D) exhibited by the subject. The decrease in the total HAM-D score may be at 4, 3, 2, or 1 day; or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours or less. Treatment effects can be assessed over a specified treatment period. For example, therapeutic effects may be achieved by administering a compound described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1)a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), and (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1) (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 a), (III-B1B), (III-B1C), (III-B1 d), (III-B2 a), (III-B2B), (III-B2C), (III-B2 d), (III-C1 a), (III-C1B), III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), V-A1 Sup>A), V-A2 Sup>A (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 Sup>A), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 Sup>A), (VI-A3B), (VI-B3 Sup>A), (VI-B3B), (VII-A), (VII-B) Sup>A, VI-B) Sup>A, the decrease in total HAM-D score from baseline is determined after (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the compound (e.g., 12, 24 or 48 hours, or 24, 48, 72 or 96 hours or longer, or 1 day, 2 days, 14 days, 21 days or 28 days, or 1 week, 2 weeks, 3 weeks or 4 weeks, or 1 month, 2 months, 6 months or 10 months, or 1 year, 2 years or lifetime).
In some embodiments, the subject has mild depression, e.g., mild severe depression. In some embodiments, the subject has a moderate depression, e.g., a moderate severe depression. In some embodiments, the subject has major depressive disorder, e.g., major depressive disorder. In some embodiments, the subject has a major depressive disorder, e.g., a major depressive disorder. In some embodiments, the baseline HAM-D total score of the subject (i.e., in the presence of a compound described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1D), (II-A2 a), (II-A2B), (II-A2C), (II-A2D), (II-B1 a), (II-B1B), (II-B1C), (II-B1D), (II-B2 a), (II-B2B), (II-B2C), (II-B2D), (II-C1 a), (II-C1B), (II-C1C), (II-C1D), (II-C2 a), (II-C2B), (II-C2C), (II-C2D), (III-A), (III-B1 a), (III-B1C), (II-C1D) is obtained) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A), (VI-B) and (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a) and (VII-B1B), (VII-B1 c) or (VII-B1 d) compounds) before treatment of at least 24. In some embodiments, the subject has a baseline sum-D score of at least 18. In some embodiments, the subject's baseline HAM-D total score is between 14 and 18, inclusive. In some embodiments, the subject's baseline HAM-D total score is between 19 and 22, inclusive. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the total HAM-D score of the subject is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-a), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-a), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the total score of the HAM-D of the subject is about 0 to 10 (e.g., less than 10); 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2 or 1.8). In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the HAM-D total score is less than 10, 7, 5 or 3. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1 c) or (VII-B1D) the decrease in the total score of HAM-D from baseline is about 20 to 30 (e.g. 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to about 0 to 10, for example below; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2 or 1.8). In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the reduction in the total score of the baseline HAM-D to the total score of HAM-D is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50 or 100 fold. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-a), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-a), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-B1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the percentage of the total score to the total score of the baseline%) HAM-D is reduced to at least 50% (e.g., 60%, 70%, 80% or 90). In some embodiments, the therapeutic effect is measured as a result of treatment with a compound described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A2C), (II-C2 d) (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), III-A2 d) (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2) Sup>A, V-A2 Sup>A), IV-A1B, V-A2 Sup>A, (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1B), (VII-B1 c) or (VII-B1 d) compounds) after treatment (e.g. 12, 24, 48 hours after administration); or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days, or longer), the decrease in the sum of HAM-D score relative to the baseline sum of HAM-D score is at least 10, 15, or 20 points.
In some embodiments, the method of treating depression (e.g., major depressive disorder) provides a therapeutic effect (e.g., as measured by a decrease in hamilton depression score (HAM-D)) within 14, 10, 4, 3, 2, or 1 days or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, a method of treating depression (e.g., severe depression) is described herein using a compound (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1 d), (III-B) or (II-C2B), (III-A1) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) The first day or second day of treatment of (V-A2 a), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) compound) provides a therapeutic effect (e.g. as determined by statistically significant reduction in the total HAM-D score). In some embodiments, a method of treating depression (e.g., major depressive disorder) begins with a compound described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1 d), (III-B1C), (II-C2 d) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) The treatment of (V-A2 a), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) compound) provides a therapeutic effect (e.g. as determined by statistically significant reduction in the total HAM-D score) for less than or equal to 14 days. In some embodiments, a method of treating depression (e.g., severe depression) begins with a compound (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1 a), (III-III), (III-B1) described herein (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) The treatment of (V-A2 a), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) compound) provides a therapeutic effect (e.g. as determined by statistically significant reduction in the total HAM-D score) for less than or equal to 21 days. In some embodiments, a method of treating depression (e.g., severe depression) begins with a compound (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1 a), (III-III), (III-B1) described herein (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) The treatment of (V-A2 a), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) compound) provides a therapeutic effect (e.g. as determined by statistically significant reduction in the total HAM-D score) for less than or equal to 28 days. In some embodiments, the therapeutic effect is achieved with a compound described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (II-C1C), (II-C2 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) treatment (for example, with a compound of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1) or (VII-B1) as described herein), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), a (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), and (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), VI-A1C), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) once a day for 14 days) and then the total score of HAM-D decreases from baseline. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the total HAM score of the subject is at least 24 prior to treatment. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the total HAM score of the subject is at least 18 prior to treatment. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, the total HAM-D score of the subject before treatment of (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-A), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1 c) or (VII-B1D) compound) is between 14 and 18, inclusive. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1D), (II-A2 a), (II-A2B), (II-A2C), (II-A2D), (II-B1 a), (II-B1B), (II-B1C), (II-B1D), (II-B2 a), (II-B2B), (II-B2C), (II-B2D), (II-C1 a), (II-C1B), (II-C1C), (II-C2D), (II-C2 a), (II-C2B), (II-C2C), (II-C2D), (III-A), (III-B) and (III-A2D), (II-B2D), (II-C2C), (II-C2D) are used in relation to the baseline HAM-D total score) (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), III-A2 d) (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2) Sup>A, V-A2 Sup>A), IV-A1B, V-A2 Sup>A, (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1B), (VII-B1 c) or (VII-B1D) the reduction in the total score of HAM-D after treatment of the subject is at least 10. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1D), (II-A2 a), (II-A2B), (II-A2C), (II-A2D), (II-B1 a), (II-B1B), (II-B1C), (II-B1D), (II-B2 a), (II-B2B), (II-B2C), (II-B2D), (II-C1 a), (II-C1B), (II-C1C), (II-C2D), (II-C2 a), (II-C2B), (II-C2C), (II-C2D), (III-A), (III-B) and (III-A2D), (II-B2D), (II-C2C), (II-C2D) are used in relation to the baseline HAM-D total score) (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), III-A2 d) (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2) Sup>A, V-A2 Sup>A), IV-A1B, V-A2 Sup>A, (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1B), (VII-B1 c) or (VII-B1D) the compound) the reduction in the total score of HAM-D after treatment of the subject is at least 15 (e.g. at least 17). In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1 d), (II-C2B), (II-C1C), (II-C2 d) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the total score of the HAM-D compound) associated with the subject does not exceed a number in the range of 6 to 8. In some embodiments, the compounds described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (III-A1 d), (II-C2B), (II-C1C), (II-C2 d) are used) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1D), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1D), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1D), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1D) the total score of HAM-D in the subject is not more than 7.
In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the clinical global impression-improvement scale (CGI)) within 14, 10, 4, 3, 2, or 1 days or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is depression, e.g., severe depression. In some embodiments, the method of treating depression (e.g., severe depression) provides a therapeutic effect during the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).
In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the montgomery-epstein depression rating scale (MADRS)) for 14, 10, 4, 3, 2, or 1 days or 24, 20, 16, 12, 10, or 8 hours or less. In some embodiments, the CNS disorder is depression, e.g., severe depression. In some embodiments, the method of treating depression (e.g., severe depression) provides a therapeutic effect during the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).
The therapeutic effect of major depressive disorder can be determined by a decrease in the Montgomery-Esberg depression rating scale (MADRS) score exhibited by the subject. For example, the MADRS score may decrease in 4, 3, 2, or 1 day or 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours, or less. Montgomery-Esberg depression rating scale (MADRS) is a ten-item diagnostic questionnaire (about obvious sadness, reported sadness, mental stress, sleep loss, appetite loss, concentration difficulties, tiredness, sensory disability, pessimistic ideas, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with affective disorders.
In some embodiments, the method is at 4, 3, 2, 1 day; 24. the therapeutic effect is provided within 20, 16, 12, 10, 8 hours or less (e.g., as measured by a decrease in the Edinborn depression scale (EPDS)). In some embodiments, the therapeutic effect is an improvement measured by EPDS.
In some embodiments, the method is at 4, 3, 2, 1 day; 24. 20, 16, 12, 10, 8 hours or less (e.g., as measured by a decrease in the generalized anxiety disorder 7 project scale (GAD-7)).
4. Anxiety disorder
Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive compulsive disorder, phobia, post-traumatic stress disorder). Anxiety is a generic term that encompasses several different forms of abnormalities and pathological fear and anxiety. Current diagnostic criteria for psychosis can identify a wide variety of anxiety disorders.
Generalized anxiety disorder is a common chronic condition characterized by long-term anxiety that is not focused on either subject or context. People suffering from generalized anxiety experience non-specific persistent fear and concern, and are overly concerned with daily transactions. Generalized anxiety disorder is the most common anxiety disorder affecting the elderly.
In panic disorder, a person suffers from transient attacks of intense panic and anxiety, often characterized by tremors, confusion, dizziness, nausea, dyspnea. These panic attacks are defined by APA as a fear or discomfort that suddenly appears and peaks in less than ten minutes, can last for several hours and can be triggered by stress, fear, or even exercise; but the specific reasons are often not obvious. In addition to recurrent unexpected panic attacks, diagnosis of panic attacks requires that the attacks have chronic consequences: there is concern about the potential impact of the seizure, a sustained fear of future seizures, or significant changes in seizure-related behavior. Accordingly, even outside a specific panic attack, a person suffering from panic disorder may develop symptoms. Often, panic patients will notice normal changes in the heartbeat, causing them to think that their own heart is problematic or that they are about to panic again. In some cases, a high degree of alertness (excessive vigilance) to physical function occurs during panic attacks, where any perceived physiological change is interpreted as a potentially life-threatening disease (i.e., an extremely suspected condition).
Obsessive-compulsive disorder is an anxiety disorder characterized primarily by repetitive obsessive-compulsive ideas (painful, persistent and invasive ideas or images) and compulsive behaviors (the execution of specific behavioral or ceremonies of impulse). The OCD thinking model is better than the belief because it involves believing that no causal relationship exists in practice. This process is often completely out of logic; for example, forcing to walk in some way may be used to alleviate the forced notion of impending injury. And in many cases the forcing action is totally unexplainable, just completing the impulse of the ceremony triggered by tension. In a few cases, OCD patients may have only obsessive-compulsive ideas, without obvious compulsive behavior; much fewer patients have only compulsive behavior.
The largest class of anxiety disorders is the phobia, which includes all cases of fear and anxiety triggered by specific stimuli or circumstances. Patients often expect dire consequences of encountering their fear of a subject, which may be anything from an animal to a location to bodily fluids.
Post-traumatic stress disorder or PTSD is anxiety disorder caused by traumatic experience. Post-traumatic stress can be caused by extreme situations, such as fighting, rape, man's personality, or even serious accidents. It may also result from prolonged (long term) exposure to severe sources of stress, such as soldiers who are tolerant of individual combat but are unable to deal with continuous combat. Common symptoms include flashback, avoidance behavior, and depression.
5. Female health disorder
Provided herein are methods for treating a disorder or condition associated with female health. Disorders or conditions related to female health include, but are not limited to, gynaecological health and conditions (e.g., premenstrual syndrome (PMS), premenstrual mood disorder (PMDD)), pregnancy problems (e.g., spontaneous abortion, artificial abortion), infertility and related conditions (e.g., polycystic ovary syndrome (PCOS)), other conditions and disorders, and problems related to female overall health (e.g., menopause).
Gynaecological health and disorders affecting women include menstruation and menoxenia; urinary tract health, including urinary incontinence and pelvic floor disorders; and conditions such as bacterial vaginosis, vaginitis, hysteromyoma, and vulvodynia.
Premenstrual syndrome (PMS) refers to physical and emotional symptoms that occur one to two weeks prior to the female's menstrual period. Symptoms vary but may include bleeding, mood swings, breast tenderness, eating impulses, fatigue, irritability, acne, and depression.
Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to PMS, but are more severe and can interfere with work, social activity, and personal relationships. PMDD symptoms include mood swings, depressed or destinated mood, apparent anger, increased interpersonal conflict, tension and anxiety, irritability, reduced interest in daily activities, difficulty concentrating, tiredness, appetite changes, perceived runaway or overwhelming, sleep problems, physical problems (e.g., edema, breast tenderness, swelling, headache, joint or muscle pain).
Pregnancy problems include pre-pregnancy and prenatal care, abortion (spontaneous abortion and stillbirth), premature birth (premature birth), sudden Infant Death Syndrome (SIDS), breast feeding and birth defects.
Spontaneous abortion refers to pregnancy that ends itself within the first 20 weeks of pregnancy.
An artificial abortion refers to an intentional termination of pregnancy that may be made within the first 28 weeks of gestation.
Infertility and related diseases include uterine fibroids, polycystic ovary syndrome, endometriosis and primary ovarian dysfunction.
Polycystic ovary syndrome (PCOS) refers to a disorder of the endocrine system in women of child bearing age. PCOS is a group of symptoms caused by elevated androgens in women. Many small cysts develop on the ovaries of most women with PCOS. Symptoms of PCOS include irregular or no menstruation, menorrhagia, excessive body and facial hair, acne, pelvic pain, pregnancy difficulty and thickened skin, darkening, velvet-like plaques. PCOS may be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.
Other conditions and disorders affecting only women include Turner syndrome, rett syndrome, ovarian cancer and cervical cancer.
Problems associated with the overall health of women include violence for women, disabled women and their unique problems, osteoporosis and skeletal health, and menopause.
Menopause refers to 12 months after the woman's last menstruation and marks the end of the menstrual cycle. Menopause usually occurs in women aged 40 or 50. Physical symptoms such as hot flashes and emotional symptoms in menopause may disturb sleep, reduce energy, or induce anxiety or sadness or a sense of dropouts. Menopause includes natural menopause and surgical menopause, which is one induced menopause resulting from events such as surgery (e.g., hysterectomy, ovariectomy, cancer). Menopause is induced when the ovaries are severely damaged by, for example, radiation, chemotherapy or other drugs.
6. Epilepsy (epilepsy)
Formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-A2C), (III-B1), (III-A2 d), (III-B1), (III-B2C), (III-C1) and (III-C1) (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d) (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), and (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2) (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), the compounds of (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or pharmaceutically acceptable salts or pharmaceutically acceptable compositions thereof may be used in methods described herein, for example in the treatment of a condition described herein such as epilepsy, epileptic status or seizure.
Epilepsy is a disorder of the brain characterized by recurrent seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy such as childhood absence, juvenile myoclonus, seizures with large seizures while awake, westerr's syndrome, lin-go syndrome, partial epilepsy such as temporal lobe, frontal lobe, benign focal childhood.
7. Epileptogenesis
The compounds and methods described herein are useful for treating or preventing epileptogenesis. Epileptogenesis is a gradual process by which the normal brain progresses to epilepsy (a chronic condition in which epileptic seizures develop). Epileptogenesis results from neuronal damage caused by an initial injury (e.g., status epilepticus).
8. Status Epilepticus (SE)
Status Epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, ultra-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; a broad periodic epileptiform discharge; and periodic one-sided epileptiform discharges. Convulsive status epilepticus is characterized by the presence of a convulsive status epilepticus seizure and may include early status epilepticus, established status epilepticus, refractory status epilepticus, ultra-refractory status epilepticus. Early status epilepticus is treated with a first line therapy. Established status epilepticus is characterized by status epilepticus seizures that persist despite treatment with a first line therapy, and administration of a second line therapy. Refractory status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first and second line therapies, and general anesthetics are typically administered. The ultra-refractory status epilepticus is characterized by status epilepticus seizures that persist despite treatment with first-line therapy, second-line therapy, and general anesthetic for 24 hours or more.
The non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simplex partial non-convulsive status epilepticus, cryptogamic non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus or typical absence non-convulsive status epilepticus.
Formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-A2C), (III-B1), (III-A2 d), (III-B1), (III-B2C), (III-C1) and (III-C1) (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d) (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), and (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2) (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), the compound of (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof may also be administered as a prophylactic to a subject suffering from: CNS disorders, such as traumatic brain injury; status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, ultra-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; a broad periodic epileptiform discharge; and periodic one-sided epileptiform discharge; before the onset of seizures.
9. Seizure of epilepsy
Seizures are physiological findings or behavioral changes that occur after the onset of abnormal brain electrical activity. The term "seizure" is often used interchangeably with "convulsions". Convulsions are rapid and uncontrolled tremors of a person's body. During convulsions, the muscles of the person contract and relax repeatedly.
Seizures are divided into two main categories based on behavioral type and brain activity: broad and partial (also known as local or focal). Classifying the seizure type helps a physician to diagnose whether a patient has epilepsy.
The generalized seizures are generated by electrical pulses from the entire brain, while the partial seizures are generated (at least initially) by electrical pulses from a relatively small portion of the brain. The portion of the brain that produces seizures is sometimes referred to as a lesion.
There are six types of generalized seizures. The most common and attractive, and therefore the most widely known, is generalized convulsions, also known as epileptic seizure. In seizures of this type, the patient loses consciousness and often falls short. Loss of consciousness is followed by extensive stiffness (termed the "tonic" phase of the seizure) for 30 to 60 seconds, then by intense twitching ("clonic" phase) for 30 to 60 seconds, after which the patient goes into deep sleep ("postseizure" or late epileptic seizure). During a seizure, injuries and accidents such as biting and urinary incontinence can occur.
Absence seizures cause a short loss of consciousness (only a few seconds), with little or no symptoms. Patients, most often children, typically break the activity and gaze in a lost manner. These seizures begin and end suddenly and may occur several times a day. Patients typically do not know that they are seizures, except that they may know "lost time".
Muscle spastic seizures consist of twitches that occur from time to time, usually on both sides of the body. The patient sometimes describes the whip as a brief shock. When severe, these seizures may cause the object to fall or not be thrown autonomously.
Clonic seizures are repetitive, rhythmic twitches involving both sides of the body.
Tonic seizures are characterized by muscle stiffness.
A seizure with weakness consists of a sudden and complete loss of muscle tone, especially in the arms and legs, which often leads to falls.
Seizures as described herein may include: epileptic seizures; acute repetitive seizures; a cluster seizure; consecutive seizures; uninterrupted seizures; long-term seizures; recurrent seizures; status epilepticus seizures, such as refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; seizure of muscle spasms; tonic seizures; tonic-clonic seizures; simple partial seizure; complex partial seizures; secondary generalized seizures; atypical absence seizure; seizure due to absence of spirit; seizure weakness; benign Rolandic seizures; seizure with febrile disease; emotional seizures; focal seizures; a taeky seizure; broad onset seizures; infantile spasticity; jacksonian seizures; a number of bilateral myoclonus seizures; multifocal seizures; neonatal onset seizures; seizure at night; occipital lobe seizure; post-traumatic seizure; cryptogamic epileptic seizure; sylvan seizure; visually reflex seizures; or withdrawal seizures. In some embodiments, the seizure is a generalized seizure related to: dravet syndrome, lin-go syndrome, tuberous sclerosis complex, rett syndrome or PCDH19 female pediatric epilepsy.
10. Dyskinesia
Methods for treating movement disorders are also described herein. As used herein, "dyskinesia" refers to a variety of diseases and conditions associated with excessive movement disorders and associated abnormal muscle control. Exemplary dyskinesias include, but are not limited to, parkinson's disease and parkinsonism (defined in particular by bradykinesia), dystonia, chorea and huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and convulsions, tic and tourette syndrome, restless leg syndrome, stiff person syndrome, and gait disorders.
The methods described herein can be used to treat tremors, for example of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (III-A), (III-C2 a), (III-A1), (III-A2C), (III-A2) and (III-B2B), (III-B2 d), (II-C1B), (II-C2C), (II-C2 d) (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1C) III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI), V-A2B, VI), the compounds of (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) are useful in the treatment of cerebellar tremor intention tremor, dystonia essential tremor, erectile tremor, parkinsonian tremor, physiological tremor, cardiac tremor or red nucleus tremor. Tremor includes: hereditary, degenerative, and idiopathic disorders such as wilson's disease, parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathy (associated with Xia Ke-Marie-Tooth's disease, roussy-Levy), diabetes, complex regional pain syndrome; toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug induction (cataplexy), tricyclic, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormone, vincristine); and cardiac disorders. Clinical tremors can be categorized into physiological tremors, enhanced physiological tremors, essential tremor syndromes (including typical essential tremors, primary upright tremors, and task and location specific tremors), dystonia tremors, parkinsonian tremors, cerebellar tremors, fulmus tremors (i.e., red nucleus tremors), palatine tremors, neuropathic tremors, toxic or drug-induced tremors, and cardiac tremors.
Tremor is involuntary, sometimes rhythmic, muscle contraction and relaxation that may involve the shaking or tremor of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, torso, legs).
Cerebellar tremor or intention tremor is a slow, extensive tremor of the extremities that occurs after voluntary action. Cerebellar tremor is caused by lesions in or damage to the cerebellum due to, for example, tumors, strokes, diseases (e.g., multiple sclerosis, hereditary degenerative disorders).
Dystonia tremor occurs in individuals affected by dystonia, which is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and/or painful and abnormal postures or positions. Dystonia tremor can affect any muscle of the body. Dystonic tremors occur irregularly and can often be relieved by complete rest.
Essential tremor or benign essential tremor is the most common type of tremor. Some essential tremors can be mild and non-progressive, and can be slowly progressive, starting from one side of the body, but affecting both sides of the body within 3 years. The hands are most often affected, but the head, sound, tongue, legs, and torso may also be affected. With age, tremor frequency may decrease, but severity may increase. Mood hyperactivity, stress, fever, physical fatigue or hypoglycemia may all trigger tremors and/or increase their severity. Symptoms typically develop over time and can be visible and persistent after onset.
Upright tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions that occur in the legs and trunk immediately after standing. When required to stand in a place, the thigh and leg feel cramps and the patient may tremble uncontrollably. Upright tremor can occur in patients with essential tremor.
Parkinsonian tremor is caused by injury to the structure of the brain's control actions. Parkinsonian tremor is often a precursor to parkinsonian disease and is commonly seen as a "pill-like" action of the hand, which may also affect the chin, lips, legs, and torso. The onset of parkinsonian tremor usually begins after the age of 60. The action starts from one limb or body side and may progress to include the other side.
Physiological tremor can occur in normal individuals and is of no clinical significance. It can be found in all voluntary muscle groups. Physiological tremor may be caused by certain drugs, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. Typical frequencies of tremors are about 10Hz.
Cardiac tremor or hysterical tremor can occur at rest or during postural or dynamic actions. Patients with psychogenic tremor may suffer from a conversion or other mental disorder.
Erythronuclear tremor is characterized by coarse slow tremors that can exist at rest, in posing, and with intent. Tremor is associated with a condition that affects the red nucleus in the midbrain (typically unusual stroke).
Parkinson's disease affects dopamine-producing nerve cells in the brain. Symptoms include muscle stiffness, tremors, and changes in language and gait. Parkinson's disease is characterized by tremors, bradykinesia, stiffness and postural instability. Parkinson's disease has symptoms present in parkinson's disease, but it is a symptomatic complex, not a progressive neurodegenerative disease.
Dystonia is a movement disorder characterized by abnormal, often repetitive movements or postures caused by sustained or intermittent muscle contractions. Dystonia actions may be patterned, distorted, and may be Duoble. Dystonia is usually initiated or worsened by voluntary action and is associated with overflow muscle activation.
Chorea is a neurological disorder characterized by involuntary movements of tic nature that generally affect the shoulders, buttocks and face. Huntington's disease is a genetic disease that causes nerve cells in the brain to become debilitating. Symptoms include uncontrolled motion, clumsiness, and balance problems. Huntington's disease may prevent walking, speaking and swallowing.
Ataxia refers to the loss of adequate control of body movements and may affect finger, hand, arm, leg, body, language, and eye movements.
Myoclonus and startle are responses to sudden and unexpected stimuli, which may be auditory, tactile, visual or vestibular stimuli.
Twitch is an involuntary action that is usually sudden, transient, repeatedly ill, but rhythmically absent, which generally mimics normal behavior and often occurs outside of the normal activity context. The twitches can be classified into action type twitches, which are related to actions, or sound type twitches, which are related to sounds. The twitch may be classified as simple or complex. For example, a simple motion type twitch involves only a few muscles that are limited to a specific body part. Tourette's syndrome is a hereditary neuropsychiatric disorder that develops in childhood and is characterized by multiple motor tic twitches and at least one vocal tic twitches.
Restless leg syndrome is a neurosensory dyskinesia characterized by strong impulses moving the legs at rest.
Stiff person syndrome is a progressive movement disorder characterized by involuntary painful spasticity and muscle stiffness, usually involving the lower back and legs. Typically resulting in a straight leg (Stiff-legged) gait with an exaggerated lumbar hyperlordosis. Characteristic abnormalities in EMG recordings with continuous paravertebral motor unit activity are often observed. Variants include "stiff-leg syndrome", which produces focal stiffness that generally affects the distal legs and feet.
Gait disorders refer to abnormal walking patterns or styles, which are caused by neuromuscular, arthritic, or other physical changes. Gait is classified according to the system responsible for abnormal movement and includes hemiplegic gait, paraplegic gait, neuropathic gait, myogenic gait, parkinsonian gait, chorea-like gait, ataxia gait and sensory gait.
11. Anesthesia/sedation
Anesthesia is amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflex, reduced stress response, or all of these simultaneous pharmacologically induced and reversible states. These effects may be obtained from a single drug alone providing the correct combination of effects, or occasionally in combination with drugs (e.g., hypnotics, sedatives, paralyzing agents, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without having to experience the pain and pain they would otherwise experience.
Sedation is the reduction of irritability or agitation by administration of pharmacological agents, often to aid in medical or diagnostic procedures.
Sedation and analgesia encompasses a range of conscious states ranging from minimal sedation (anxiolytics) to general anesthesia.
Minimal sedation is also known as anxiolytic. Minimal sedation is a drug-induced state during which the patient responds normally to oral commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are generally unaffected.
Moderate sedation/analgesia (conscious sedation) is a drug-induced decline in consciousness during which the patient has a conscious response to oral commands (alone or with mild tactile stimulation). No intervention is typically required to maintain airway patency. Spontaneous ventilation is generally sufficient. Cardiovascular function is generally maintained.
Deep sedation/analgesia is a drug-induced decline in consciousness during which the patient cannot easily wake up, but has a conscious response (not reflex withdrawal from painful stimuli) following repeated or painful stimuli. Independent ventilation function may be impaired and the patient may need assistance to maintain airway patency. Spontaneous ventilation may be inadequate. Cardiovascular function is generally maintained.
General anesthesia is a drug-induced loss of consciousness during which the patient cannot be awakened, even with painful stimuli. The ability to maintain independent ventilation is often compromised and assistance is often required to maintain airway patency. Positive pressure ventilation may be required due to reduced spontaneous ventilation or drug-induced reduced neuromuscular function. Cardiovascular function may be impaired.
Sedation in the Intensive Care Unit (ICU) decreases the patient's perception of the environment and decreases their response to external stimuli. It can play a role in the care of critically ill patients and encompasses a wide range of symptomatic control, which will vary from patient to patient and throughout the course of the disease in an individual. Severe sedation in intensive care has been used to promote endotracheal tube tolerance and ventilator synchronization, often with neuromuscular blocking agents.
In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for a long period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives can be very long acting. The elimination half-life of sedatives in the ICU may be very short.
Procedural sedation (procedural sedation) and analgesia (also known as conscious sedation) are techniques in which sedatives or dissociating agents (dissociative agent) are administered with or without analgesics to induce tolerance of a subject to an unpleasant procedure while maintaining cardiopulmonary function.
Also described herein are methods of ameliorating one or more symptoms of a respiratory disorder in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B) III-C2C, II-C2C, (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), sup>A (III-A2B) (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), IV-A1 Sup>A, (V-A1B), (V-A2 a), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-A1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-A) and (II-A1C), (VII-A1) (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), and (II-B2 d) (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A), and (III-B2 d) (IV-A1), (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), VI-A1 Sup>A), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof.
In one aspect, provided herein is a method of treating a subject, wherein the subject exhibits one or more symptoms of a respiratory disorder and/or has been diagnosed with a respiratory disorder, comprising administering to the subject an effective amount of a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2C), (II-C2 d) or (II-B2 d) to the subject (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), and (III-A1 d) (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A), V-A, (V-A1), (V-A2), (V-A1 a), (V-A1B), (V-A2 a), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A2), (VII-B1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I), (VI-B3B), (VII-A) or (VII-B1 d), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-A2), (III-A1), (III-A2C), (III-A1), (III-B2), (III-C1), (III-C2), (III-C1) III-C2) and (III-C1 A1) (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), and (III-C2 Sup>A) (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2) (V), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof.
In some embodiments, the present disclosure encompasses a method of treating a subject comprising administering to the subject a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-III) to the subject) (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), sup>A (III-A2B) (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), IV-A1 Sup>A, (V-A1B), (V-A2 a), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-A1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-A) and (II-A1C), (VII-A1) (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), and (II-B2 d) (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A), and (III-B2 d) (IV-A1), (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), VI-A1 Sup>A), (VI-A1B), (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-a), (VII-B), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof), wherein the subject has a respiratory disorder.
In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A) is administered to a subject exhibiting symptoms of a respiratory disorder) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, the compound (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a combination of pharmaceutically acceptable salts thereof) may result in a reduction in the severity of one or more symptoms of the respiratory condition or in slowing or slowing the progression of one or more symptoms of the respiratory condition.
In some embodiments, the subject suffering from a respiratory disorder has been or is being treated with mechanical ventilation or oxygen. In some embodiments, the subject suffering from a respiratory disorder has been or is being treated with mechanical ventilation.
In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (III-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the composition of the compound (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is administered to a subject who is or has been treated with mechanical ventilation. In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (III-C1B) is administered) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the composition of the compound (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is continued throughout the mechanical ventilation treatment of the subject. In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (III-C1B) is administered) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A1), (III-B), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a) and (III-A2B), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), and (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), and, the composition of the compound (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) is continued after the subject has ended the mechanical ventilation therapy.
In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2 d), (III-A), (III-B), (III-A1C), (II-B2 d), (II-C2 a), (II-C2B), (III-C1 d) (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), III-C1B) (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1) (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), and, (VI), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compounds of formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1 b), (II-A1C), (II-A1 d), (II-A2 a), (II-A) 2b) (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B)), (III-C1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-B1 a), (III-B1B), (III-B1C), (III-B1 d), (III-B2B), (III-B2 a), (III-B2B) and (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 Sup>A 2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), IV-A1 (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A) and (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 Sup>A), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 Sup>A), (VI-A3B), (VI-B3 Sup>A), and, (VI-B3B), (VII-a), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) to a subject being or having received sedative therapy. In some embodiments, the sedative agent is propofol or benzodiazepine And (3) a medicament.
In some embodiments, the disclosure includes administering a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A) to a subject in need thereof (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) in an amount sufficient to increase oxygen saturation in blood. In some embodiments, oxygen saturation in blood is measured using pulse oximetry.
In some embodiments, the disclosure encompasses a method of treating a cytokine storm in a patient. In some embodiments, a method of treating a cytokine storm comprises administering to a patient a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1 d), (III-B1C), (II-C2 d) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a combination of pharmaceutically acceptable salts thereof). In some embodiments, the symptom of the cytokine storm is lung inflammation. In some embodiments, the patient experiencing cytokine storm suffers from Acute Respiratory Distress Syndrome (ARDS).
12. Respiratory disorders
In some embodiments, the subject with a respiratory disorder suffers from respiratory distress. In some embodiments, respiratory distress includes acute respiratory distress.
In some embodiments, a subject with a respiratory disorder may exhibit one or more symptoms selected from the group consisting of: airway hyperresponsiveness, lung tissue inflammation, lung allergy and inflammation-related lung pain.
In some embodiments, a subject with a respiratory disorder may exhibit lung tissue inflammation. In some embodiments, the lung tissue inflammation is bronchitis or bronchiectasis. In some embodiments, the lung tissue inflammation is pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia or intra-hospital-acquired (hospital-acquired) pneumonia. In some embodiments, the pneumonia is ventilator-associated pneumonia.
In some embodiments, administration of a compound or pharmaceutical composition described herein to a subject exhibiting symptoms of a respiratory disorder results in a reduction in the severity of respiratory distress in the subject suffering from the respiratory disorder or slowing the progression of respiratory distress in the subject suffering from the respiratory disorder.
In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A) is administered to a subject exhibiting symptoms of a respiratory disorder) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, the (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound or a pharmaceutically acceptable salt thereof) results in a reduction in the severity of airway hyperreactivity in a subject suffering from a disease associated with coronavirus or in slowing or slowing the progression of airway hyperreactivity in a subject suffering from a respiratory disorder.
In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A) is administered to a subject exhibiting symptoms of a respiratory disorder) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, the (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) results in a reduction in the severity of lung tissue inflammation or slowing the progression of lung tissue inflammation in a subject suffering from a respiratory disorder. In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A) is administered to a subject exhibiting symptoms of a respiratory disorder) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, the (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound or a pharmaceutically acceptable salt thereof) results in a reduction in the severity of pneumonia in a subject suffering from a respiratory disorder or in slowing or slowing the progression of pneumonia in a subject suffering from a respiratory disorder.
In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A) is administered to a subject exhibiting symptoms of a respiratory disorder) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, the (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) compound or a pharmaceutically acceptable salt thereof) results in a reduction in the severity of pulmonary hypersensitivity in a subject suffering from a respiratory disorder or in slowing or slowing the progression of pulmonary allergy in a subject suffering from a respiratory disorder.
In some embodiments, a compound or pharmaceutical composition described herein (e.g., formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B1C), (III-A) is administered to a subject exhibiting symptoms of a respiratory disorder) (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 Sup>A), (III-A1B), (III-A1C), (III-A1 d), (III-A2 Sup>A), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A1 Sup>A), (IV-A1B), (IV-A1 A1B), (IV-A1B 2), (V-A1B), (V-A1 Sup>A), (V-A1B), (V-A1 Sup>A) and (V-A1B) (V-A2 a), (V-A2B), (VI-A1), (VI-A2) and (VI-B1), (VI-B2), (VI-A1 a), (VI-A1B), (VI-A1C), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1C), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1C), (VII-A1 d), (VII-B1 a) or (VII-B1B), (VII-B1C) or (VII-B1 d) compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising formula (I), (II-A), (II-B), (II-C), (II-A1), (II-A2) or (VII-A2), (II-B1), (II-B2), (II-C1), (II-C2), (II-A1 a), (II-A1B), (II-A1C), (II-A1 d), (II-A2 a), (II-A2B), (II-A2C), (II-A2 d), (II-B1 a), (II-B1B), (II-B1C), (II-B1 d), (II-B2 a), (II-B2B), (II-B2C), (II-B2 d), (II-C1 a), (II-C1B), a (II-C1C), (II-C1 d), (II-C2 a), (II-C2B), (II-C2C), (II-C2 d), (III-A), (III-B), (III-C), (III-A1), (III-A2), (III-B1), (III-B2), (III-C1), (III-C2), (III-A1 a), (III-A1B), (III-A1C), (III-A1 d), (III-A2 a), (III-A2B), (III-A2C), (III-A2 d), (III-B1 Sup>A), (III-B1B), (III-B1C), (III-B1 d), (III-B2 Sup>A), (III-B2B), (III-B2C), (III-B2 d), (III-C1 Sup>A), (III-C1B), (III-C1C), III-C1 d), (III-C2 Sup>A), (III-C2B), (III-C2C), (III-C2 d), (IV-A) and (IV-A1) (IV-A1 Sup>A), (IV-A1B), (IV-A1 Sup>A 1), (IV-A1 A2), (IV-A1B 1), (IV-A1B 2), (V-A1), (V-A2), (V-A1 Sup>A), (V-A1B), (V-A2 Sup>A), (V-A2B), (VI-A), (VI-B), (VI-A1), (VI-A2), (VI-B1), (VI-B2), (VI-A1 Sup>A), (VI-A1B), V-A1, the (VI-A1 c), (VI-A1 d), (VI-B1 a), (VI-B1B), (VI-B1 c), (VI-B1 d), (VI-A3 a), (VI-A3B), (VI-B3 a), (VI-B3B), (VII-A), (VII-B), (VII-A1), (VII-A2), (VII-B1), (VII-B2), (VII-A1 a), (VII-A1B), (VII-A1 c), (VII-A1 d), (VII-B1 a), (VII-B1B), (VII-B1 c) or (VII-B1 d) or a pharmaceutically acceptable salt thereof) results in a reduction in the severity of or slowing or progression of inflammation-related pulmonary pain in a subject suffering from a respiratory disorder.
In some embodiments, a subject with a respiratory disorder is experiencing or has undergone treatment for an infection, fibrosis, fibrotic episode, chronic obstructive pulmonary disease, sarcoidosis (or pulmonary sarcoidosis), or asthma/asthma-associated inflammation.
In some embodiments, the subject exhibits symptoms of asthma and/or has been diagnosed with asthma. In some embodiments, the subject is experiencing or has experienced an asthma attack.
In some embodiments, the subject is undergoing or has undergone treatment for fibrosis or a fibrotic episode. In some embodiments, the fibrosis is cystic fibrosis.
In some embodiments, the respiratory disorder is the result of and/or is associated with a disease or disorder selected from the group consisting of: cystic fibrosis, asthma, smoke-induced COPD, chronic bronchitis, sinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral vas deferens (CBAVD), mild lung disease, pulmonary sarcoidosis, idiopathic pancreatitis, allergic Bronchogenic and Pulmonary Aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiency such as protein C deficiency, hereditary angioedema type 1, lipid processing deficiency such as familial hypercholesterolemia, chylomicronemia type 1, beta-free lipoproteinemia, lysosomal storage diseases such as I cell diseases/pseudo Ha Lunzheng (pseudo-Hurler), mucopolysaccharidosis, sandhof/Tay-Sachs, crigler type II-Najjar multiple endocrinopathy/hyperinsulinemia (hyperinsulinemia), diabetes mellitus, la Long Zhuru, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, type 1 glycogenolysis CDG, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes Insipidus (DI), neurogenic (neuroseal) DI, nephrogenic DI, xia Ke-Mali-Tourette syndrome, pachyrhizus (Perlizaeus-Merzbacher disease), neurodegenerative diseases such as Alzheimer's disease, parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear nerve palsy, pick's disease, several polyglutamine neurological disorders (several polyglutamine neurological disorder) such as Huntington's disease, type I spinocerebellar ataxia, spinal cord and medullary muscular atrophy, amyotrophic lateral sclerosis, and the like, dentate red-core pallidum and myotonic dystrophy, as well as spongiform encephalopathies such as hereditary creutzfeldt-jakob disease (due to deficiency in the processing of the ruan viral proteins), fabry disease (Fabry disease), scht-lausle-sargent syndrome (Straussler-Scheinker syndrome), COPD, dry eye or Sjogren's disease.
13. Infection with
The present disclosure encompasses, among other things, treatment of a subject suffering from an infection. The present disclosure encompasses, among other things, treatment of subjects having a disease associated with an infection. In some embodiments, the infection is a viral infection or a bacterial infection. In some embodiments, the infection is a viral infection. In some embodiments, the infection is a bacterial infection.
In some embodiments, the viral infection is a viral infection selected from the group consisting of: coronavirus, influenza virus, human rhinovirus, human parainfluenza virus, human metapneumovirus and hantavirus. In some embodiments, the virus is a coronavirus. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV, SARS-CoV-2, and MERS-CoV.
The present disclosure encompasses, among other things, treatment of subjects having a disease associated with coronavirus. In some embodiments, the disease associated with coronavirus is selected from the group consisting of: coronavirus disease 2019 (covd-19), severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS). In some embodiments, the disease associated with coronavirus is selected from the group consisting of covd-19. In some embodiments, the coronavirus is selected from the group consisting of SARS-CoV-1, SARS-CoV-2, and 2012-nCoV. In some embodiments, the coronavirus is SARS-CoV-2.
In some embodiments, the bacterial infection is a bacterial infection selected from the group consisting of: streptococcus pneumoniae (Streptococcus pneumoniae), chlamydia pneumoniae (Chlamydia pneumoniae), staphylococcus aureus (Staphylococcus aureus), pseudomonas aeruginosa (Pseudomonas aeruginosa) and haemophilus influenzae (Haemophilus influenzae). In some embodiments, the staphylococcus aureus is methicillin-resistant staphylococcus aureus.
IV. examples
The following examples are set forth in order to provide a more thorough understanding of the application described herein. The synthetic and biological examples described in this disclosure are illustrative of the compounds, pharmaceutical compositions and methods provided herein and should not be construed in any way as limiting the scope thereof.
Materials and methods
The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that other process conditions may be used where typical or preferred process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, pressures, etc.) are given unless otherwise indicated. The optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art by routine optimization.
In addition, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions, as will be apparent to those skilled in the art. The selection of suitable protecting groups for a particular functional group and suitable conditions for protection and deprotection are well known in the art. For example, many protecting groups and their introduction and removal are described in T.W.Greene and P.G.M.Wuts, protecting Groups in Organic Synthesis, second edition, wiley, new York,1991 and references cited therein.
The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, milling, column chromatography, HPLC, or Supercritical Fluid Chromatography (SFC). The following protocol details the preparation of representative neuroactive steroids listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns useful for separation/purification of enantiomers/diastereomers provided herein include, but are not limited toAD-10、/>OB、OB-H、/>OD、/>OD-H、/>OF、OG、/>OJ and->OK。
Reported herein 1 H-NMR (e.g., for a region between about 0.5 to about 4ppm of delta (ppm)) is understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integral) of the compound.
LC-ELSD/MS: (mobile phase: 1.5ML/4L TFA in water (solvent a) and 0.75ML/4L TFA in acetonitrile (solvent B), elution gradient 30% -90% (solvent B) was used over 0.9 min and maintained at 90% at a flow rate of 1.2ML/min for 0.6 min; column: xtimate C18.1 x 30mm,3um; wavelength: UV 220nm; column temperature: 50 ℃, MS ionization: ESI; detectors: PDA and ELSD).
Abbreviations:
PE: petroleum ether; etOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridine chlorochromate; TLC: thin layer chromatography; PCC: pyridine chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-boron bicyclo [3.3.1]Nonane; pd (t-Bu) 3 P) 2 : bis (tri-t-butylphosphine) palladium (0); acCl: acetyl chloride; i-PrMgCl: isopropyl magnesium chloride; TBSCl: t-butyl (chloro) dimethylsilane; (i-PrO) 4 Ti: titanium tetraisopropoxide; BHT:2, 6-di-tert-butyl-4-methylbenzoxide; me: a methyl group; i-Pr: an isopropyl group; t-Bu: a tertiary butyl group; ph: a phenyl group; et: an ethyl group; bz: benzoyl; bzCl: benzoyl chloride; csF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMAP: 4-dimethylaminopyridine; DMP: dess-martin periodate; etMgBr: ethyl magnesium bromide; etOAc: ethyl acetate; TEA: triethylamine; alaOH: alanine; boc: t-butyloxycarbonyl. Py: pyridine; TBAF: tetra-n-butyl ammonium fluoride; THF: tetrahydrofuran; TBS: tertiary butyl dimethyl silyl; TMS: trimethylsilyl; TMSCF (TMSCF) 3 : (trifluoromethyl) trimethylsilane; ts: p-toluenesulfonyl; bu: a butyl group; ti (OiPr) 4 : titanium tetraisopropoxide; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; liOH.H 2 O: hydrogen gasLithium oxide hydrate; MAD: methylaluminum bis (2, 6-di-tert-butyl-4-methylbenzoxide); meCN: acetonitrile; NBS: n-bromosuccinimide; na (Na) 2 SO 4 : sodium sulfate; na (Na) 2 S 2 O 3 : sodium thiosulfate; meCN: acetonitrile; meOH: methanol; boc: t-butoxycarbonyl; MTBE: methyl tertiary butyl ether; k-selection: potassium tri (sec-butyl) borohydride; 9-BBN dimer: 9-boron bicyclo (3.3.1) nonane (dimer); DIPEA: diisopropylethylamine; DMF: dimethylformamide; FA: formic acid; SM: starting materials.
The composition of each of the compound numbers 1 to 28 listed in the following examples was verified by mass spectrometry.
Example No. 1:1- (2- ((2R, 4aS,4bR,6aS,7S,7aR,8aR,9aS,9bR,11 aR) -2-hydroxy-2, 6 a-dimethyloctadecenyl-1H-cyclopropa [ b)]-7-yl) -2-oxoethyl) -1H-pyrazole-4-carbonitrile (compound No. 1). />
1.2 Synthesis
LDA (171 mL, 345 mmol,2M in THF) was added to a stirred solution of 1.1 (20 g,68.8 mmol) and ethyl diazoacetate (43.4 g, 345 mmol, 90%) in THF (600 mL) at-70 ℃. The resulting mixture was stirred at-70℃for 2 hours. Acetic acid (19.5 mL, 345 mmol) in THF (60 mL) was then added and the mixture was warmed to 20deg.C for 16 hours. Water (300 mL) was added to the mixture. The aqueous phase was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% to 15% ethyl acetate in petroleum ether) to give 1.2 (25 g, 90%). 1 HNMR(400MHz,CDCl 3 )δ H 4.75-4.60(m,1H),4.29-4.21(m,2H),2.18-2.08(m,1H),1.91-1.76(m,4H),1.73-1.58(m,3H),1.49-1.36(m,6H),1.34-1.28(m,5H),1.26-1.22(m,6H),1.15-0.97(m,5H),0.90(s,3H)。
1.3 Synthesis
Rh was added in one portion to a solution of 1.2 (25 g, crude) in DME (300 mL) at 15℃ 2 (OAc) 4 (680 mg,1.54 mmol). After stirring at 15℃for 12 hours, the mixture was taken up in H 2 O (200 mL) was treated and extracted with EtOAc (3X 200 mL). The combined organic phases were washed with brine (2X 80 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 1.3 (23.2 g) as crude, which was used directly in the next reaction.
1.4 Synthesis
KOH (20.7 g,369 mmol) was added to a solution of 1.3 (23.2 g, 61.6) in MeOH (300 mL) at 15 ℃. After stirring at 70 ℃ for 1 hour, the reaction mixture was poured into saturated brine (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were washed with HCl (1M, 200 mL), saturated NaHCO 3 (200 mL), brine (100 mL), washed over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 1.4 (18.5 g, 99%). 1 HNMR(400MHz,CDCl 3 )δ H 2.67-2.53(m,1H),2.24-2.14(m,1H),2.09-2.03(m,1H),1.93-1.69(m,7H),1.66-1.47(m,6H),1.43-1.31(m,5H),1.31-1.21(m,8H),1.18-0.93(m,7H)。
1.5 Synthesis
At 25 ℃ N 2 Next, 1.4 (18.5 g,60.7 mmol) was added to a solution of t-BuOK (13.5 g,121 mmol) in THF (370 mL). The mixture was stirred for 10 minutes at 25 ℃. Then, methyl benzene sulfinate (18.9 g,121 mmol) was added. After stirring at 30℃for 0.5H, the mixture was taken up in H 2 O (100 mL) was quenched and extracted with EtOAc (3X 80 mL). The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 1.5 (26 g, crude). 1 HNMR(400MHz,CDCl 3 )δ H 7.65-7.62(m,1H),7.52-7.43(m,4H),3.75-3.60(m,1H),2.02-1.95(m,2H),1.88-1.65(m,6H),1.64-1.51(m,8H),1.43-1.29(m,5H),1.26-1.22(m,5H),1.04-0.89(m,4H)。
1.6 Synthesis
To 1.5 (26 g,60.6 mmol) in xylene (300 mL)In (2) adding Na in portions to the mixture 2 CO 3 (96.3 g,909 mol). At 140 ℃ N 2 After stirring for 12 hours, the mixture was filtered and concentrated. The residue was purified by silica gel chromatography (0% -30% ethyl acetate in petroleum ether) to give 1.6 (12 g, 66%). 1 HNMR(400MHz,CDCl 3 )δ H 6.90-6.78(m,1H),5.91(dd,J＝1.6,10.0Hz,1H),2.45(td,J＝5.2,19.2Hz,1H),2.02-1.87(m,3H),1.84-1.73(m,3H),1.66-1.56(m,5H),1.44-1.32(m,6H),1.30-1.24(m,5H),1.21-1.11(m,1H),1.03-0.96(m,4H)。
1.7 Synthesis of
At 60 ℃ N 2 A stirred solution of trimethylsulfoxide iodide (7.26 g,33.0 mmol) and t-BuOK (4.07 g,36.3 mmol) in DMSO (120 mL) was heated for 1.0h. Compound 1.6 (5.0 g,16.5 mmol) was added to the reaction mixture and stirred for 1h at 25 ℃. The reaction was treated with water (30 mL) and extracted with EtOAc (2X 30 mL). The combined organic phases were washed with water (2X 20 mL), brine (20 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 1.7 (3.4 g, 65%). 1 HNMR(400MHz,CDCl 3 )δ H 2.17-2.00(m,2H),1.92-1.83(m,1H),1.79-1.71(m,3H),1.68-1.59(m,3H),1.55-1.46(m,3H),1.44-1.36(m,3H),1.35-1.19(m,8H),1.18-1.04(m,2H),1.03-0.91(m,6H),0.81-0.74(m,1H)。
1.8 Synthesis of
At 15 ℃ N 2 Downward to PPh 3 To a mixture of EtBr (31.7 g,85.6 mmol) in THF (130 mL) was added t-BuOK (9.6 g,85.6 mmol). The resulting mixture was stirred at 40℃for 30min. Compound 1.7 (3.4 g,10.7 mmol) was added in portions at less than 40 ℃. The reaction mixture was stirred at 80 ℃ for 36 hours. At 15℃with saturated NH 4 The reaction mixture was quenched with aqueous Cl (100 mL). The organic layer was then separated. The aqueous layer was extracted with EtOAc (2X 80 mL). The combined organic phases were concentrated in vacuo to give a white solid. The residue was purified by passing through MeOH/H 2 O (1:1, 500 mL) was triturated for purification and then purified by flash column (0% to 12% ethyl acetate in petroleum ether) to give 1.8 (2.36 g, 67%).
1.9 Synthesis of
BH was added to a solution of 1.8 (2.36 g,7.18 mmol) in THF (40 mL) at 0deg.C 3. Me 2 S (2.15 mL,21.5mmol, 10M). After stirring at 20℃for 12 hours, ethanol (7.52 mL) at 15℃was added to the resulting mixture at 0℃followed by aqueous NaOH (25.8 mL, 5.0M). Hydrogen peroxide (12.9 ml,10 m) was added dropwise to the reaction mixture at 0 ℃. The resulting mixture was stirred at 78 ℃ for 1 hour. The mixture was cooled to 15 ℃. Saturated Na 2 S 2 O 3 Aqueous solution (80 mL) was added to the mixture. The aqueous phase was extracted with EtOAc (2X 80 mL). The combined organic phases were washed with brine (2X 50 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 1.9 (1.6 g, 65%).
1.10 Synthesis
To a solution of 1.9 (1.6 g,4.61 mmol) in DCM (20 mL) was added dess-martin reagent (3.9 g,9.22 mmol) at 20deg.C. After stirring the mixture at 20℃for 1 hour, it was stirred at 20℃with saturated NaHCO 3 The mixture was quenched with aqueous solution (30 mL). The DCM phase was separated and saturated NaHCO 3 /Na 2 S 2 O 3 Aqueous (1:1, 2X 50 mL), brine (100 mL), washed with Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% to 25% ethyl acetate in petroleum ether) to give 1.10 (1.3 g, 82%).
1.11 Synthesis
At N 2 Next, to a solution of 1.10 (100 mg,0.290 mmol) in MeOH (10 mL) was added H 2 NaOH (277 mg,8.7 mmol) in O (1 mL). After stirring at 80℃for 16 hours, the mixture was taken up in H 2 O (30 mL) was treated and extracted with EtOAc (3X 40 mL). The combined organic phases were washed with brine (2X 20 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (15% -25% ethyl acetate in petroleum ether) to give 1.11 (90 mg, 90%). 1 HNMR(400MHz,CDCl 3 )δ H 2.23(s,3H),2.18-2.15(m,1H),2.02-1.95(m,1H),1.90-1.82(m,1H),1.78-1.74(m,2H),1.68-1.57(m,4H),1.40-1.11(m,13H),0.99-0.85(m,8H),0.71-0.63(m,1H),0.60-0.50(m,1H),-0.12(q,J＝5.2Hz,1H)。
1.12 Synthesis
HBr (9.37 mg,0.046mmol,40% in water) and Br were added to a solution of 1.11 (80 mg,0.23 mmol) in MeOH (5 ml) at 20 ℃ 2 (44.5 mg,0.27 mmol). After stirring at 20℃for 2h, the mixture was taken up in saturated NaHCO 3 The aqueous solution (10 mL) was quenched, treated with water (20 mL) and extracted with EtOAc (2X 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 1.12 (100 mg) as crude, which is used directly in the next step.
Synthesis of Compound No. 1
To a solution of 1.12 (100 mg,0.23 mmol) in acetone (10 mL) at 20deg.C was added 4-cyano-pyrazole (32.9 mg,0.35 mmol) and K 2 CO 3 (66.2 mg,0.47 mmol) and stirred for 16 hours. H was added to the reaction mixture at 25℃ 2 O (20 ml). The aqueous phase was extracted with EtOAc (2X 50 mL). The combined organic phases were washed with saturated brine (2X 50 mL), dried over anhydrous Na 2 SO 4 Dried, filtered, concentrated and purified by flash column (0% -50% ethyl acetate in petroleum ether) to give 1 (33.8 mg, 33.1%). 1 HNMR(400MHz,CDCl 3 )δ H 7.87(s,1H),7.83(s,1H),5.15-5.05(m,J＝1.0Hz,2H),2.14(d,J＝4.4Hz,1H),2.06-1.97(m,1H),1.88-1.81(m,1H),
1.79-1.58(m,6H),1.43-1.16(m,13H),1.08-0.86(m,8H),0.79-0.70(m,1H),0.63-0.53(m,1H),-0.08(q,J＝4.4Hz,1H)。
Example No. 2:1- ((S) -2-hydroxy-2- ((2R, 4aS,4bR,6aS,7S,7aR,8aR,9aS,9bR,11 aR) -2-hydroxy-2, 6 a-dimethyloctadecenyl-1H-cyclopropyl [ b ]]-7-yl) propyl) -1H-pyrazole-4-carbonitrile (Compound No. 2) and 1- ((S) -2-1- ((R) -2-hydroxy-2- ((2R, 4aS,4bR,6aS,7S,7aR,8aR,9aS,9bR,11 aR) -2-hydroxy-2, 6 a-dimethyloctadecenyl-1H-cyclopropa [ b ]]/>-7-yl) propyl) -1H-pyrazole-4-carbonitrile (Compound No. 3).
2.1 Synthesis
To PPh 3 To a solution of MeBr (4.64 g,13 mmol) in THF (40 mL) was added t-BuOK (1.45 g,13 mmol). The reaction mixture was stirred at 50℃for 0.5h. A solution of 1.11 (450 mg,1.3 mmol) in THF (5 mL) was added to the reaction at 50deg.C. After stirring the reaction mixture at 50℃for 16 hours, the mixture was poured onto saturated NH 4 Cl (100 mL) and extracted with EtOAc (2X 100 mL). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The mixture was purified by flash chromatography (0% to 25% ethyl acetate in petroleum ether) to give 2.1 (300 mg, 67%). 1 HNMR(400MHz,CDCl 3 )δ H 4.88(s,1H),4.75-4.70(m,1H),2.02-1.94(m,1H),1.91-1.72(m,6H),1.53-1.37(m,7H),
1.31-1.19(m,9H),0.95-0.76(m,10H),0.67-0.59(m,1H),0.57-0.48(m,1H),-0.14(q,J＝4.8Hz,1H)。
2.2 Synthesis
To a solution of 2.1 (150 mg,0.43 mmol) in DCM (10 mL) was added m-CPBA (141 mg,0.65mmol, 80%). After stirring for 1h at 20℃the mixture was passed through saturated NaHCO at 20 ℃ 3 The mixture was quenched with aqueous solution (10 mL). The DCM phase was separated and saturated NaHCO 3 /Na 2 S 2 O 3 Aqueous (1:1, 2X 100 mL), brine (10 mL), washed with Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 2.2 (170 mg). 1 HNMR(400MHz,CDCl 3 )δ H 2.73-2.66(m,2H),1.99-1.93(m,1H),1.86-1.62(m,5H),1.42-1.34(m,5H),1.33-1.15(m,11H),1.05-0.91(m,6H),0.89-0.65(m,6H),0.50-0.38(m,1H),0.11--0.19(m,1H)。
Synthesis of Compound No. 2 and Compound No. 3
At 120℃2.2 (200 mg,0.55 mmol), cs 2 CO 3 A solution of (547 mg,1.67 mmol) and 4-cyano-pyrazole (103 mg,1.11 mmol) in DMF (10 mL) was stirred for 16 h. The mixture was poured onto saturated NH 4 Cl (30 mL). The aqueous layer was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with LiCl (100 mL,3% in water), brine (2X 30 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% to 40% ethyl acetate in petroleum ether) to give the mixed product. By SFC (column: DAICEL CHIRALCEL OD-H (250 mm. Times.30 mm,5 um); conditions: 0.1% NH) 3 H 2 O EtOH; start B:35%; end B:35%; flow rate (ml/min): 60; and (3) sample injection: 60 Purification of the residue to give compound No. 2 (7.9 mg, 3%) and compound No. 3 (70.3 mg, 28%).
Compound No. 2: 1 HNMR(400MHz,CDCl 3 )δ H 7.93(s,1H),7.86(s,1H),4.41(d,J＝13.8Hz,1H),4.17(d,J＝13.8Hz,1H),3.62(s,1H),2.31-2.18(m,1H),1.98-1.91(m,1H),1.89-1.82(m,1H),1.78-1.66(m,3H),1.53-1.36(m,5H),1.31-1.21(m,11H),1.02-0.59(m,11H),0.56-0.47(m,1H),0.44-0.34(m,1H),-0.43(q,J＝4.8Hz,1H)。
compound No. 3: 1 HNMR(400MHz,CDCl 3 )δ H 7.96(s,1H),7.80(s,1H),4.48-4.34(m,2H),2.47(s,1H),2.20-2.11(m,1H),2.04-1.96(m,1H),1.91-1.84(m,1H),1.78-1.66(m,3H),1.56-1.23(m,14H),1.12-1.07(m,4H),1.02(s,3H),0.99-0.52(m,8H),-0.09--0.15(m,1H)。
example No. 3:1- ((R) -2- ((2R, 4aS,4bR,6aS,7R,7aR,8aR,9aS,9bR,11 aR) -2-hydroxy-2, 6 a-dimethyloctadecenyl-1H-cyclopropa [ b ]]-7-yl) propyl) -1H-pyrazole-4-carbonitrile (Compound No. 4) and 1- ((S) -2- ((2R, 4aS,4bR,6aS,7R,7aR,8aR,9aS,9bR,11 aR) -2-hydroxy-2, 6 a-dimethyloctadecen-1H-cyclopropa [ b ]]/>-7-yl) propyl) -1H-pyrazole-4-carbonitrile (Compound No. 5).
3.1 Synthesis
At N 2 Next, BH is carried out 3 .Me 2 S (0.3 mL,10M,2.99 mmol) was added to a solution of 2.1 (150 mg,0.43 mmol) in THF (5 mL). After stirring at 20 ℃ for 12 hours, the mixture was cooled to 0 ℃. EtOH (0.771 mL,13.1 mmol) and NaOH (2.61 mL,5M,13.1 mmol) are then added to the mixture followed by dropwise addition of H at 15 ℃ 2 O 2 (1.3 mL,10M,13.1 mmol). The mixture was stirred at 70℃for 1 hour. The mixture was then poured onto Na 2 S 2 O 3 (50 mL, saturated) and stirred for 30min. The aqueous layer was extracted with EtOAc (2X 50 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over anhydrous Na 2 SO 4 And (5) drying. The mixture was filtered and concentrated to give 3.1 (180 mg, crude).
3.2 Synthesis
To a solution of 2.1 (180 mg,0.49 mmol) in DCM (5 mL) were added N-methylimidazole (61.4 mg,0.74 mmol), TEA (206. Mu.L, 1.49 mmol) and TsCl (190 mg,0.99 mmol). After stirring the mixture at 20℃for 1h, the mixture was poured onto NaHCO 3 (10 mL, saturated). The aqueous phase was extracted with DCM (2X 10 mL). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 3.2 (200 mg, crude), which is used directly in the next step.
Synthesis of Compound No. 4 and Compound No. 5
To a solution of 3.2 (200 mg,0.38 mmol) in DMF (10 mL) was added 4-cyano-pyrazole (54.2 mg,0.58 mmol) and Cs 2 CO 3 (255 mg,0.77 mmol). After stirring at 120℃for 16 hours, the mixture was poured into water (20 mL) and stirred for 5min. The aqueous layer was extracted with EtOAc (3X 30 mL). The combined organic layers were washed with saturated brine (2X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% -30% ethyl acetate in petroleum ether). By SFC (column: DAICEL CHIRALCEL OD-H (250 mm. Times.30 mm,5 um); conditions: 0.1% NH) 3 H 2 OEtOH; start B:30%; end B:30%; flow rate (ml/min): 60; and (3) sample injection: 60 Purification of the residue to give compound No. 4 (4 mg, 2%) and compound No. 5 (60.4 mg, 36%).
Compound No. 4: 1 HNMR(400MHz,CDCl 3 )δ H 7.83(s,1H),7.81(s,1H),4.18-3.96(m,2H),2.76-2.65(m,1H),1.99-1.91(m,1H),1.87-1.80(m,1H),1.76-1.68(m,3H),1.45-1.32(m,4H),1.27-1.07(m,9H),0.99-0.55(m,16H),0.40-0.30(m,1H),-0.22--0.36(m,1H)。
compound No. 5: 1 HNMR(400MHz,CDCl 3 )δ H 7.81(s,1H),7.77(s,1H),4.59-4.48(m,1H),3.94-3.81(m,1H),2.66-2.54(m,1H),2.03-1.84(m,3H),1.76-1.60(m,4H),1.55-1.28(m,7H),1.27-1.03(m,7H),0.98-0.83(m,11H),0.76-0.66(m,1H),0.60-0.48(m,2H),-0.10--0.17(m,1H)。
example No. 4:1- (2- ((2R, 4aS,4bR,6aS,7S,7aS,8aS, 9bR,11 aR) -2-hydroxy-2, 6 a-dimethyloctadecenyl-1H-cyclopropa [ b)]-7-yl) -2-oxoethyl) -1H-pyrazole-4-carbonitrile (Compound No. 6) and 1- (2- ((2R, 4aS,4bR,6aS,7R,7aS,8aS, 9bR,11 aR) -2-hydroxy-2, 6 a-dimethyloctadecenyl-1H-cyclopropa [ b ]]/>-7-yl) -2-oxoethyl) -1H-pyrazole-4-carbonitrile (compound No. 7). />
4.1 Synthesis
CeCl was added to a solution of 1.6 (1 g,3.30 mmol) in MeOH (16 mL) and THF (4 mL) at 0deg.C 3 ·7H 2 O(1.46g,3.96 mmol). Stirring at 0deg.C for 10min, adding NaBH 4 (150 mg,3.96 mmol). The mixture was stirred at 0℃for 1h. Adding the mixture to NH 4 Cl (50 mL) and extracted with DCM (2X 100 mL). The combined organic phases were washed with brine (2X 50 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash column (0-50% ethyl acetate in petroleum ether) to give 4.1 (1.3 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 5.77-5.63(m,1H),5.53-5.42(m,1H),3.86(s,1H),2.20-2.08(m,1H),2.01-1.87(m,2H),1.80-1.69(m,3H),1.54-1.48(m,3H),1.44-1.28(m,7H),1.28-1.24(m,4H),1.23-0.89(m,6H),0.79(s,3H)。
4.2 Synthesis
To a solution of 4.1 (1.7 g,5.58 mmol) in toluene (20 mL) were added diethyl zinc (16.7 mL,16.7mmol,1 m) and diiodomethane (1.34 mL,16.7mmol,3.32 g/mL) at 0 ℃ for 30min. The mixture was then stirred at 25 ℃ for 16 hours. The mixture was treated with NH 4 Cl (100 mL) was quenched and extracted with EtOAc (2X 100 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0% to 30% ethyl acetate in petroleum ether) to give 4.1 and 4.2 (1.1 g). 1 H NMR(400MHz,CDCl 3 )δ H 3.82-3.74(m,1H),2.20-1.60(m,7H),1.57-1.30(m,5H),1.28-1.26(m,3H),1.26-1.22(m,4H),1.22-0.79(m,9H),0.69(s,3H),0.60-0.53(m,1H),0.48-0.40(m,1H)。
4.3 Synthesis
To a solution of 4.2 (1.05 g,3.29 mmol) in DCM (15 mL) was added dess-martin (2.78 g,6.58 mmol) at 25 ℃. After stirring at 25℃for 10min, the mixture was passed through saturated NaHCO 3 /Na 2 S 2 O 3 The aqueous solution (1:1, 150 mL) was quenched and extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (2X 50 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 4.3 (1.4 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 2.50-2.40(m,1H),2.32-2.20(m,2H),2.05-1.70(m,9H),1.45-1.30(m,5H),1.28-1.25(m,6H),1.09-0.96(m,6H),0.92(s,3H)。
4.4 Synthesis
TMSCH was added to a solution of 4.3 (700 mg,2.21 mmol) in THF (5 mL) at-30deg.C 2 Li (22.0 mL,11.0mmol, 0.5M). After stirring at 25℃for 16 hours, the mixture was poured onto saturated NH 4 Cl (100 mL) and extracted with EtOAc (3X 100 mL). The combined organic layers were washed with saturated brine (2X 50 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% -20% ethyl acetate in petroleum ether) to give 4.4 (420 mg, 60%). 1 H NMR(400MHz,CDCl 3 )δ H 4.96-4.92(m,1H),4.87-4.84(m,1H),2.25-2.17(m,1H),1.98-1.86(m,3H),1.82-1.58(m,5H),1.53-1.32(m,8H),1.27-1.24(m,7H),0.90-0.88(m,2H),0.84(s,3H),0.82-0.73(m,2H),0.57-0.51(m,1H)。
4.5 Synthesis
At N 2 Next, BH is carried out 3 ·Me 2 S (1.32 mL,10M,13.2 mmol) was added to a solution of 4.4 (420 mg,1.33 mmol) in THF (8 mL). The reaction mixture was stirred at 20 ℃ for 12 hours. The mixture was cooled to 0 ℃. EtOH (4.70 mL,79.8 mmol) and NaOH (15.9 mL,5M,79.8 mmol) are then added to the mixture followed by dropwise addition of H at 15 ℃ 2 O 2 (7.97 mL,10M,79.8 mmol). After stirring at 70℃for 1 hour, the mixture was poured onto Na 2 S 2 O 3 (30 mL, saturated) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (2X 20 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% to 70% ethyl acetate in petroleum ether) to give 4.5 (120 mg, 39%).
4.6 Synthesis
To a solution of 4.5 (180 mg,0.541 mmol) in DCM (5 mL) was added DMP (457 mg,1.08 mmol) at 25 ℃. After stirring at 25℃for 10min, the mixture was poured onto NaHCO 3 /Na 2 S 2 O 3 (20 mL, 1:1) and extracted with DCM (2X 10 mL). The combined organic phases were treated with NaHCO 3 /Na 2 S 2 O 3 (1:1, 2X 10mL, saturated), brine (10 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 4.6 (175 mg, crude).
4.7 Synthesis
To a solution of MeMgBr (573. Mu.L, 1.72 mmol) in THF (2 mL) was added 4.6 (190 mg,0.575 mmol) at 0deg.C. The reaction mixture was stirred at 25℃for 1h. The mixture was poured onto NH 4 Cl (10 mL) and extracted with EtOAc (2X 10 mL). The combined organic layers were washed with brine (2X 10 mL), and dried over Na 2 SO 4 Dried, filtered, concentrated in vacuo and purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 4.7 (130 mg, 65%).
4.8 Synthesis
To a solution of 4.7 (100 mg,0.289 mmol) in DCM (10 mL) was added DMP (244 mg,0.577 mmol) at 25deg.C. The mixture was stirred at 25℃for 1h. The mixture was poured onto NaHCO 3 /Na 2 S 2 O 3 (20 mL, 1:1) and extracted with DCM (2X 10 mL). The combined organic phases were treated with NaHCO 3 /Na 2 S 2 O 3 (1:1, 2X 10mL, saturated), brine (10 mL), washed with anhydrous Na 2 SO 4 Dried and concentrated to give 4.8 (125 mg, crude).
4.9 Synthesis
HBr (40%, 76.2mg,0.377 mmol) and Br2 (66.3 mg, 0.418 mmol) were added dropwise to a solution of 4.8 (130 mg,0.377 mmol) in methanol (3 mL) at 25℃and stirred for 1h. NaHCO was added at 25 ℃to 3 (10 ml of saturated aqueous solution) was added to the reaction mixture. The aqueous phase was extracted with EtOAc (2X 10 mL). The combined organic phases were washed with brine (2X 10 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 4.9 (130 mg, crude).
Synthesis of Compound No. 6 and Compound No. 7
At 25℃4.9 (130 mg,0.30 mmol), K 2 CO 3 A solution of (171 mg,1.22 mmol) and 4-cyano-pyrazole (57.1 mg,0.61 mmol) in acetone (5 mL) was stirred for 16 h. The mixture was poured into saturated H 2 O (20 mL)And extracted with EtOAc (2×20 mL). The combined organic layers were washed with saturated brine (2X 20 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (10% to 15% ethyl acetate in petroleum ether) to give compound No. 7 (30 mg, 22%) and compound No. 6 (45 mg, 34%). Compound No. 7 (30 mg) was purified by HPLC (column: phenomenex Gemini-NX C 18 75 x 30mm x 3um; conditions are as follows: water (0.225% FA) -ACN; start B:60; end B:90; gradient time (min): 7, preparing a base material; 100% B hold time (min) 2; flow rate (ml/min): 30; and (3) sample injection: 4) Purified and lyophilized to give 7 (3.8 mg, 13%). Compound 6 (45 mg,0.103 mmol) was lyophilized to give 6 (25.6 mg, 57%).
Compound No. 6: 1 H NMR(400MHz,CDCl 3 )δ H 7.86(s,1H),7.83(s,1H),5.29-5.23(m,2H),2.84-2.73(m,1H),2.29-2.16(m,1H),1.91-1.74(m,4H),1.45-1.29(m,9H),1.26(s,3H),1.21-1.15(m,2H),1.03-0.87(m,7H),0.83(s,3H),0.79-0.65(m,3H)。
compound No. 7: 1 H NMR(400MHz,CDCl 3 )δ H 7.91(s,1H),7.84(s,1H),5.16(d,J＝18.0Hz,1H),5.03(d,J＝18.0Hz,1H),2.87(s,1H),2.37-2.20(m,1H),1.86-1.58(m,7H),1.40-1.26(m,8H),1.24(s,3H),1.21-0.92(m,6H),0.88(s,3H),0.77-0.62(m,3H),0.51-0.45(m,1H)。
example No. 5:1- (2- ((1S, 2aR, 3bS,3cR,5aR,7R,9aS,9bR,11 aS) -7-hydroxy-7, 11 a-dimethyloctadecenyl-1H-cyclopropa [ c)]-1-yl) -2-oxoethyl) -1H-pyrazole-4-carbonitrile (compound No. 8).
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5.2 Synthesis
To a stirred solution of trimethylsulfoxide iodide (56.3 g,256 mmol) in DMSO (800 mL) was added t-BuOK (31.5 g, 281mmol). At 60 ℃ N 2 After stirring for 1h, 5.1 (37 g,128 mmol) was added and stirred for 2 h at 25 ℃. The reaction was treated with water (500 mL) and extracted with EtOAc (2X 500 mL). The combined organic phases were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by column (0% -20% ethyl acetate in petroleum ether) to give 5.2 (20 g, 52%). 1 H NMR(400MHz,CDCl 3 )δ H 2.04-2.00(m,1H),1.96-1.90(m,1H),1.85-1.70(m,6H),1.65-1.55(m,4H),1.42-1.26(m,12H),1.14-1.03(m,2H),0.95(s,3H),0.90-0.82(m,1H)。
5.3 Synthesis
LDA solution (82.5 mL,2M,165 mmol) was added to a stirred solution of 5.2 (10 g,33 mmol) and ethyl diazoacetate (17.3 mL,165 mmol) in THF (500 mL) at-70 ℃. After stirring at-70℃for 3h, acetic acid (9.42 mL,165 mmol) in THF (10 mL) was added, and the mixture was then warmed to 20℃and stirred for 16h. Water (500 mL) was added to the reaction mixture and combined with another batch from 5.2 (10 g) and extracted with EtOAc (2X 300 mL). The combined organic layers were washed with saturated brine (500 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 5.3 (20 g).
5.4 Synthesis
Rh was added to a solution of 5.3 (20 g,48 mmol) in DME (300 mL) 2 (OAc) 4 (530 mg,1.2 mmol). After stirring at 20℃for 12 hours, H was added 2 O (100 mL) was added to the mixture and extracted with EtOAc (2X 60 mL). The combined organic phases were washed with brine (2X 30 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by silica gel chromatography (0% -40% ethyl acetate in petroleum ether) to give 5.4 (9 g, 48%). 1 H NMR(400MHz,CDCl 3 )δ H 4.24-4.15(m,2H),3.07(s,1H),1.90-1.61(m,9H),1.51-1.31(m,10H),1.30-1.25(m,8H),1.17-1.10(m,1H),1.06-0.98(m,4H),0.93-0.85(m,1H)。
5.5 Synthesis
To a solution of 5.4 (9 g,23.1 mmol) and DMAP (2.82 g,23.1 mmol) in DCM (100 mL) at 20deg.C was added TEA (4.66 g,46.2 mmol) and Ac dropwise 2 O (7.07 g,69.3 mmol). After stirring at 20 ℃ for 16 hours, the mixture was poured into ice water (50 mL) and extracted with DCM (2×100 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 5.5 (10 g, crude).
5.6 Synthesis
HCl (5 mL in 50mL EtOH) was added to a solution of 5.5 (10 g,21.1 mmol) in THF (50 mL). The mixture was stirred at 20 ℃ for 48 and then poured into NaHCO 3 (50 mL). The aqueous layer was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2X 30 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% to 30% ethyl acetate in petroleum ether) to give 5.6 (3.6 g, 40%). 1 H NMR(400MHz,CDCl 3 )δ H 4.19(q,J＝7.2Hz,2H),3.07(s,1H),1.99(s,3H),1.92-1.60(m,12H),1.53-1.30(m,8H),1.29-1.10(m,6H),1.06-0.87(m,6H)。
5.7 Synthesis
To a solution of 5.6 (0.5 g,1.28 mmol) in MeOH/THF (5 mL/5 mL) at 25deg.C was added NaBH 4 (96.8 mg,2.56 mmol). After stirring for 1h at 25℃the reaction mixture was taken up with saturated NH 4 Aqueous Cl (20 mL) was quenched and extracted with ethyl acetate (2X 20 mL). The combined organic layers were washed with brine (50 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 5.7 (500 mg, crude). 1 H NMR(400MHz,CDCl 3 )δ H 4.65(dd,J＝4.0,8.8Hz,1H),4.19-4.10(m,2H),3.65(s,1H),2.11(d,J＝4.0Hz,1H),2.07-1.96(m,5H),1.90-1.58(m,10H),1.53-1.38(m,6H),1.30-1.23(m,7H),1.13-1.03(m,5H),0.92-0.85(m,1H),0.48-0.40(m,1H)。
5.8 Synthesis
To a solution of 5.7 (600 mg,1.38 mmol) in DCM (20 mL) was added TEA (2.77 g,27.5 mmol) and 1-methyl-1H-imidazole (5 mL). The reaction mixture was cooled to 0 ℃. MsCl (1.17 g,10.3 mmol) in DCM (10 mL) was then added. After stirring at 20℃for 16 h, the reaction mixture was quenched with water (50 mL) and extracted with DCM (2X 50 mL). The combined organic phases were washed with brine (50 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash column (0% to 20% ethyl acetate in petroleum ether) to give 5.8 (500 mg, 87%). 1 H NMR(400MHz,CDCl 3 )δ H 7.05(d,J＝5.8Hz,1H),4.18-4.09(m,2H),2.33-2.28(m,1H),2.99-1.94(m,4H),1.88-1.58(m,10H),1.56-1.33(m,10H),1.27(t,J＝7.2Hz,3H),1.18-1.10(m,5H),0.91-0.86(m,2H)。
5.9 Synthesis
At N 2 Down to LiAlH 4 To a solution of (100 mg,2.63 mmol) in THF (5 mL) was added 5.8 (200 mg, 0.480 mmol) in THF (5 mL). The mixture was stirred at 25℃for 1h. H in THF (2 mL) was then added 2 O (0.1 mL), 10% aqueous NaOH (0.1 mL), and H 2 O (0.3 mL). The mixture was filtered and concentrated. The residue was combined with another reaction of 5.9 (200 mg) and purified by flash chromatography (0% to 60% ethyl acetate in petroleum ether) to give 5.9 (250 mg, crude). The crude product was purified 5.9 (50 mg) by preparative HPLC (column: xtime C18 150X 40mm X5 um; conditions: water (0.225% FA) -ACN; start B:52; end B:92; gradient time (min): 10;100% B hold time (min): 5; flow rate (mL/min): 30; sample introduction: 3) to give 5.9 (8 mg, 16%). 1 H NMR(400MHz,CDCl 3 )δ H 3.79(dd,J＝4.0,10.4Hz,1H),3.24(dd,J＝8.0,10.8Hz,1H),2.25-2.11(m,1H),1.90-1.30(m,19H),1.27(s,3H),1.18-0.76(m,6H),0.68(s,3H),0.36-0.23(m,2H)。
5.10 Synthesis
To a solution of 5.9 (200 mg,0.60 mmol) in DCM (5 mL) was added DMP (508 mg,1.2 mmol) at 25 ℃. After stirring at 25℃for 10min, the mixture was poured onto NaHCO 3 /Na 2 S 2 O 3 (50 mL, 1:1) and extracted with DCM (2X 50 mL). The combined organic phases were treated with NaHCO 3 /Na 2 S 2 O 3 (1:1, 2X 50mL, saturated), brine (50 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 5.10 (200 mg, crude).
5.11 Synthesis
To a solution of MeMgBr (1 mL,3 mmol) in THF (5 mL) at 0deg.C was added 5.10 (250 mg,0.75 mmol) in THF (5 mL). After stirring for 1h at 25℃the mixture was poured onto NH 4 Cl (10 mL) and extracted with EtOAc (2X 10 mL). The combined organic phases were washed with brine (2X 10 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash column (0% to 50% ethyl acetate in petroleum ether) to give 5.11 (150 mg, crude).
5.12 Synthesis
To a solution of 5.11 (100 mg,0.28 mmol) in DCM (5 mL) was added DMP (244 mg,0.57 mmol) at 25deg.C. After stirring at 25℃for 10min, the reaction mixture was poured onto NaHCO 3 /Na 2 S 2 O 3 (30 mL, 1:1) and extracted with DCM (2X 30 mL). The combined organic phases were treated with NaHCO 3 /Na 2 S 2 O 3 (1:1, 2X 30mL, saturated), brine (50 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was combined with another batch of 5.12 (50 mg) and purified by flash column (0% to 15% ethyl acetate in petroleum ether) to give 5.12 (100 mg, 67%).
5.13 Synthesis
HBr (11.7 mg,0.058mmol,40% in water) and Br were added to a solution of 5.12 (100 mg,0.29 mmol) in MeOH (5 ml) at 25 ℃ 2 (74.1 mg,0.46 mmol). After stirring at 25℃for 2h, the reaction mixture was taken up in saturated NaHCO 3 The aqueous solution (10 mL) was quenched, treated with water (20 mL) and extracted with EtOAc (2X 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 5.13 (100 mg) as crude, which is used directly in the next step.
Synthesis of Compound No. 8
At 25℃to 8.13 (100 mg,0.23 mmol) inTo a solution in acetone (5 mL) were added 4-cyano-pyrazole (43.9 mg,0.47 mmol) and K 2 CO 3 (66.2 mg,0.47 mmol) and stirred for 16 hours. The reaction mixture was poured onto H 2 O (20 mL) and extracted with EtOAc (2X 50 mL). The combined organic phases were washed with brine (2X 50 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% -50% ethyl acetate in petroleum ether) and lyophilized to give compound No. 8 (25 mg, 25%). 1 H NMR(400MHz,CDCl 3 )δ H 7.81(s,2H),5.06-4.92(m,2H),2.42-2.33(dd,J＝4.8,12.4Hz,1H),2.02-1.63(m,7H),1.53-1.39(m,8H),1.37-1.25(m,4H),1.35-1.25(m,2H),1.24-0.93(m,5H),0.91-0.80(m,4H),0.47-0.38(m,2H)。
Example No. 6:1- ((2R, 4aS,4bR,6aS,7S,7aS,8aR, 8cR,10 aR) -2-hydroxy-2, 6 a-dimethyloctadecanyclopropan [4,5] cyclopenta [1,2-a ] phenanthren-7-yl) ethanone (compound No. 9), 1- ((R) -2- ((2R, 4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10 aR) -2-hydroxy-2, 6 a-dimethyloctadecanyclopropan [4,5] cyclopenta [1,2-a ] phenanthren-7-yl) propyl) -1H-pyrazole-4-carbonitrile (compound No. 10) and 1- ((S) -2- ((2R, 4aS, 6aS, 7aS,8aR,8bR,8cR,10 aR) -2-hydroxy-2, 6 a-dimethyloctadecanyclopropan [4,5] phenanthren-yl) pyrazole (compound No. 11).
6.2 Synthesis
To a stirred solution of trimethylsulfoxide iodide (45 mg,2.07 mmol) in DMSO (20 mL) and THF (20 mL) was added NaH (82.6 mg,2.07mmol,60% in mineral oil) and N at 0deg.C 2 Stirred for 1h. A solution of 6.1 (500 mg,1.73 mmol) in DMSO (10 mL) was added to the resulting mixture at 0deg.C and stirred at 25deg.C for 16h. The reaction mixture was treated with water (50 mL). The resulting mixture was extracted with EtOAc (2X 100 mL). The combined organic phases were washed with water (2X 100 mL), brine (200 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. Passing through column (0% -20% in petroleum ether)Ethyl acetate) to yield 6.2 (360 mg, 69%). 1 H NMR(400MHz,CDCl3)δ H 2.05-1.98(m,1H),1.96-1.91(m,1H),1.87-1.65(m,8H),1.61-1.53(m,4H),1.47-1.22(m,11H),1.12-1.02(m,2H),0.96(s.3H)。
6.3 Synthesis
To PPh 3 To a solution of EtBr (11.0 g,29.7 mmol) in THF (100 mL) was added t-BuOK (3.33 g,29.7 mmol). After stirring the reaction mixture at 40 ℃ for 0.5h, a solution of 6.2 (1.80 g,5.95 mmol) in THF (20 mL) was added to the reaction at 40 ℃. The reaction mixture was stirred at 40 ℃ for 12 hours. The mixture was poured onto saturated NH 4 Cl (100 mL) and extracted with EtOAc (2X 100 mL). The combined organic phases were washed with saturated brine (2X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (0% -10% ethyl acetate in petroleum ether) to give 6.3 (1.20 g, 64.1%). 1 H NMR(400MHz,DMSO)δ H 5.35(q,J＝6.8Hz,1H),2.15-2.09(m,1H),1.86-1.63(m,11H),1.44-1.22(m,14H),1.17-1.06(m,1H),0.99(s,3H),0.93-0.82(m,2H),0.49-0.40(m,1H)。
6.4 Synthesis
At N 2 Next, 9-BBN dimer (1.99 g,8.26 mmol) was added to a solution of 6.3 (1.30 g,4.13 mmol) in THF (20 mL). At 60 ℃ N 2 After stirring the reaction mixture for 2h, the resulting mixture was cooled to 0 ℃. EtOH (2.83 mL,49.5 mmol), naOH (9.9 mL,5M aqueous solution, 49.5 mmol) is added to the mixture. Then H is added dropwise at 15 DEG C 2 O 2 (4.95 mL,10M,49.5 mmol). The mixture was stirred at 60℃for 2 hours. The mixture was then cooled and poured onto Na 2 S 2 O 3 (200 mL, saturated) and stirred for 30min. The aqueous layer was extracted with EtOAc (2X 200 mL). The combined organic layers were washed with saturated brine (2X 100 mL), dried over anhydrous Na 2 SO 4 And (5) drying. The mixture was filtered and concentrated to give 6.4 (1.60 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.87-3.76(m,1H),2.43-2.37(m,2H),1.84-1.70(m,7H),1.45-1.35(m,7H),1.26-1.25(m,6H),1.20-1.10(m,4H),0.92-0.80(m,4H),0.79-0.76(m,1H),0.74(s,3H),0.24-0.14(m,1H)。
Synthesis of Compound No. 9
To a solution of 5.4 (1.60 g,4.81 mmol) in DCM (20 mL) was added dess-martin (4.08 g,9.62 mmol). After stirring the reaction mixture at 40℃for 30min, it was purified by saturated NaHCO 3 The mixture was quenched with aqueous solution (30 mL), the DCM phase was separated and quenched with saturated NaHCO 3 /Na 2 S 2 O 3 Aqueous (1:1, 2X 30 mL), brine (50 mL), washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% to 20% ethyl acetate in petroleum ether) to give compound No. 9 (1.10 g, 69.6%), which was triturated with MeCN (2 mL) to give compound No. 9 (25.6 mg). 1 HNMR(400MHz,CDCl 3 )δ H 2.74(d,J＝4.4Hz,1H),2.21(s,3H),1.96-1.63(m,8H),1.51-1.19(m,16H),1.12-1.00(m,1H),0.89-0.82(m,1H),0.72(s,3H),0.46-0.33(m,1H)。
6.5 Synthesis
To PPh 3 To a solution of MeBr (4.32 g,12.1 mmol) in THF (20 mL) was added t-BuOK (1.35 mg,12.1 mmol). The reaction mixture was stirred at 60℃for 0.5h. A solution of compound No. 1 (800 mg,2.42 mmol) in THF (20 mL) was added to the reaction at 60 ℃. After stirring the reaction mixture at 60℃for 12 hours, the mixture was poured onto saturated NH 4 Cl (300 mL) and extracted with EtOAc (2X 100 mL). The combined organic phases were washed with saturated brine (2X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (0% -15% ethyl acetate in petroleum ether) to give 6.5 (600 mg, 75.4%). 1 H NMR(400MHz,CDCl3)δH5.12-5.08(m,1H),4.87-4.82(m,1H),2.42-2.36(m,1H),1.90-1.60(m,12H),1.52-1.35(m,5H),1.29-0.98(m,11H),0.69-0.65(m,1H),0.64(s,3H),0.28-0.20(m,1H)。
6.6 Synthesis of
At N 2 Next, BH was added to a solution of 6.5 (400 mg,1.21 mmol) in THF (10 mL) 3 .Me 2 S (0.5 mL,10M,5 mmol), N at 25 ℃ 2 The reaction mixture was stirred for 12h. The reaction mixture was cooled to 0 ℃. EtOH (1.38 mL,24.2 mmol) and NaOH (4.84 mL,5M,24.2 mmol) are then added to the mixture. Thereafter, H is added dropwise at 15 ℃ 2 O 2 (2.42 mL,10M,24.2 mmol). After stirring the mixture at 60 ℃ for 2 hours, the mixture was cooled and poured onto Na 2 S 2 O 3 (100 mL, saturated) and stirred for 30min. The aqueous layer was extracted with EtOAc (2X 100 mL). The combined organic layers were washed with brine (2X 100 mL), dried over anhydrous Na 2 SO 4 And (5) drying. The mixture was filtered and concentrated to give 6.6 (400 mg, crude), which was used directly in the next step.
Synthesis of Compound No. 10 and Compound No. 11
To a solution of 6.6 (400 mg,1.15 mmol) and 1H-pyrazole-4-carbonitrile (214 mg,2.3 mmol) in DMF (10 mL) was added Ph 3 P (1.2 g,4.6 mmol), DEAD (0.80 g,4.6 mmol) and the mixture was stirred at 25℃for 2 hours. The mixture was poured into ice water (30 mL). The aqueous phase was extracted with EtOAc (3X 20 mL). The combined organic phases were washed with brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (0% -40% ethyl acetate in petroleum ether) to give 6.7 (400 mg, impurity). The residue was combined with another 100mg of 6.7 by SFC (column: DAICEL CHIRALCEL OD-H (250 mm. Times.30 mm,5 um); conditions: 0.1% NH) 3 H 2 OETOH; start B:35%; end B:35%; flow rate (ml/min): 60; and (3) sample injection: 140 Purification) to give compound No. 10 (24.1 mg,4.03%, peak 3, rt= 3.551 min) and compound No. 11 (83.4 mg,13.9%, peak 4, rt=4.095 min).
Compound No. 10: 1 H NMR(400MHz,CDCl 3 )δ H 7.83-7.76(m,2H),4.60-4.50(m,1H),4.02-3.88(m,1H),2.26-2.14(m,1H),1.85-1.65(m,7H),1.44-1.30(m,7H),1.28-1.06(m,12H),0.79(t,J＝3.2Hz,6H),0.72-0.68(m,1H),0.22-0.14(m,1H)。
compound No. 11: 1 H NMR(400MHz,CDCl 3 )δ H 7.88-7.72(m,2H),4.41-4.33(m,1H),3.76-3.67(m,1H),2.33-2.21(m,1H),1.86-1.57(m,9H),1.42-1.08(m,17H),0.92-0.88(m,6H),0.69-0.64(m,1H),0.19-0.11(m,1H)。
example No. 7: synthesis of 1- ((S) -2-hydroxy-2- ((2R, 4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10 aR) -2-hydroxy-2, 6 a-dimethyloctadecanyclopropyl [4,5] cyclopenta [1,2-a ] phenanthren-7-yl) propyl) -1H-pyrazole-4-carbonitrile (Compound No. 12) and 1- ((R) -2-hydroxy-2- ((2R, 4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10 aR) -2-hydroxy-2, 6 a-dimethyloctadecanyclopropyl [4,5] cyclopenta [1,2-a ] phenanthren-7-yl) propyl) -1H-pyrazole-4-carbonitrile (Compound No. 13)
7.1 Synthesis
m-CPBA (147 mg,0.6847mmol, 80%) was added to a solution of 6.5 (150 mg, 0.458 mmol) in DCM (5 mL). After stirring the mixture at 20℃for 0.5h, it was stirred at 20℃with saturated NaHCO 3 The mixture was quenched with aqueous solution (10 mL). The DCM phase was separated and treated with NaHCO 3 /Na 2 S 2 O 3 Aqueous (1:1, 2X 10 mL), brine (10 mL), washed with Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 7.1 (150 mg, crude). 1 H NMR(400MHz,DMSO)δ H 3.26(d,J＝5.2Hz,1H),2.59(d,J＝5.2Hz,1H),2.26(d,J＝3.6Hz,1H),1.87-1.62(m,7H),1.41-1.35(m,7H),1.31-1.25(m,8H),1.21-1.00(m,6H),0.80(s,3H),0.64-0.57(m,1H),0.18-0.10(m,1H)。
Synthesis of Compound No. 12 and Compound No. 13
At 120℃7.1 (150 mg,0.435 mmol), cs 2 CO 3 A solution of (426 mg,1.3 mmol) and 1H-pyrazole-4-carbonitrile (81.0 mg,0.871 mmol) in DMF (10 mL) was stirred for 16H. The reaction mixture was poured onto saturated NH 4 Cl (30 mL). The aqueous layer was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with LiCl (100 mL,3% in water), saturated brine (2X 50 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was combined with another solution of crude 7.2 and purified by silica gel chromatography (0% to 40% ethyl acetate in petroleum ether) to give 7.2 (120 mg, crude product). By SFC (column: DAICEL CHIRALCEL OJ-H (250 mm. Times.30 mm,5 um); conditions: 0.1% NH) 3 H 2 O ETOH; start B:20% of a base; end B:20% of a base; flow rate (ml/min): 60; and (3) sample injection: 110 Purification of the residue to give compound No. 12 (68.6 mg,57.6%, peak 1, rt= 2.771 min) and compound No. 13 (9.20 mg, peak 2, rt=2.889 min).
Compound No. 12: 1 H NMR(400MHz,CDCl 3 )δ H 7.99(s,1H),7.81(s,1H),4.43(d,J＝14.0Hz,1H),4.24(d,J＝13.6Hz,1H),2.55(s,1H),1.89-1.56(m,10H),1.42-1.17(m,16H),1.15(s,3H),1.05(s,3H),0.93-0.86(m,1H),0.35-0.26(m,1H)。
compound No. 13: 1 H NMR(400MHz,CDCl 3 )7.97(s,1H),7.81(s,1H),4.29(q,J＝14.0Hz,2H),2.61(s,1H),1.93-1.64(m,9H),1.41-1.20(s,15H),1.14(s,3H),1.10-1.03(m,2H),1.00(s,3H),0.92-0.88(m,1H),0.38-0.30(m,1H)。
example No. 8: synthesis of 1- ((R) -2-hydroxy-2- ((2R, 4aS,4bS,6aS,7S,7aS,8aR,8bS,8cR,10 aS) -2-hydroxy-4 a,6 a-dimethyl-2-propyloctadecanhydrocyclopropyl [4,5] cyclopenta [1,2-a ] phenanthren-7-yl) propyl) -1H-pyrazole-4-carbonitrile (Compound No. 14)
8.2 Synthesis
At 60 ℃ N 2 A suspension of trimethylsulfoxide iodide (60.2 g,274 mmol) and t-BuOK (30.6 g,274 mmol) in THF (1000 mL) was heated for 1h. Compound 8.1 (40.0 g,137 mmol) was added to the reaction mixture and stirred for 1h at 25 ℃. The reaction was treated with water (1000 mL) and extracted with EtOAc (2X 1000 mL). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 8.2 (35.0 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.65-3.60(m,1H),2.70-2.50(m,2H),2.21-2.00(m,2H),1.82-1.75(m,3H),1.74-1.48(m,6H),1.47-1.00(m,10H),0.99-0.80(m,4H),0.79-0.72(m,4H)。
8.3 Synthesis of
To a solution of 8.2 (35.0 g,114 mmol) in THF (350 mL) was added CuI (12.9 g,68.4 mmol) in one portion, and then EtMgBr (76 mL,3m,228 mmol) was added dropwise at 0 ℃. The reaction mixture was stirred at 0℃for 1h. The mixture was poured into water (350 mL) and extracted with EtOAc (2×350 mL). The combined organic phases were washed with brine (350 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 8.3 (35.0 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.76-3.52(m,1H),1.80-1.70(m,1H),1.69-1.50(m,6H),1.49-1.30(m,13H),1.29-1.20(m,7H),1.13-0.82(m,4H),0.80-0.70(m,6H)。
8.4 Synthesis
To a solution of 8.3 (35.0 g,104 mmol) in DCM (350 mL) was added dess-martin reagent (88.1 g,208 mmol) at 20deg.C. The reaction mixture was stirred at 20℃for 15min. The mixture was poured into saturated NaHCO 3 /Na 2 S 2 O 3 In aqueous solution (1:1, 400 mL). The aqueous phase was extracted with EtOAc (3X 400 mL). The combined organic phases were washed with saturated brine (2X 400 mL), dried over anhydrous Na 2 SO 4 Dried, filtered, concentrated and purified by flash column (0% to 15% ethyl acetate in petroleum ether) to give 8.4 (29.8 g, crude). 1 HNMR(400MHz,CDCl 3 )δ H 2.47-2.03(m,1H),2.15-2.00(m,1H),1.99-1.80(m,1H),1.79-1.75(m,2H),1.74-1.70(m,1H),1.68-1.48(m,5H),1.46-1.25(m,10H),0.99-0.80(m,9H),0.79-0.76(m,3H),0.75(s,3H)。
8.5 Synthesis
At 15 ℃ N 2 Next, 8.4 (10.0 g,30 mmol) was added to a solution of t-BuOK (6.72 g,60 mmol) in THF (100 mL). After stirring at 15℃for 10min, methyl benzene sulfinate (9.37 g,60 mmol) was added and stirred at 30℃for 0.5h. The mixture was treated with H 2 O (100 mL) was quenched, extracted with EtOAc (2X 100 mL), and quenched with Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 8.5 (12.0 g, crude).
8.6 Synthesis of
To a mixture of 8.5 (12.0 g,27.1 mmol) in xylene (120 mL) at 25deg.CTEA (20 mL) was added in portions. At 125 ℃, N 2 The reaction mixture was stirred for 12 hours. The mixture was filtered, concentrated and purified by silica gel chromatography (0% to 30% ethyl acetate in petroleum ether) to give 8.6 (6.00 g, 70%). 1 H NMR(400MHz,CDCl 3 )δ H 7.58-7.50(m,1H),6.10-5.97(m,1H),2.36-2.26(m,2H),2.01-1.90(m,7H),1.89-1.43(m,6H),1.42-1.00(m,9H),0.99-0.80(m,5H),0.79-0.75(m,3H)。
8.7 Synthesis of
At 0 ℃, N 2 To a stirring solution of trimethylsulfoxide iodide (996 mg,4.53 mmol) in THF (15 mL) was added NaH (180 mg,4.53mmol,60% in oil) and 8.6 (1.00 g,3.02 mmol). The resulting mixture was stirred at 25 ℃ for 2 hours. The reaction was treated with water (10 mL) and extracted with EtOAc (2X 15 mL). The combined organic phases were washed with water (2X 15 mL), brine (15 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 8.7 (1.15 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 2.63-2.56(m,4H),2.00-1.80(m,6H),1.79-1.43(m,10H),1.42-1.00(m,9H),0.99-0.80(m,4H),0.79-0.75(m,3H)。
8.8 Synthesis of
At 25 ℃ N 2 Downward to EtOPh 3 To a mixture of Br (2.46 g,6.66 mol) in THF (15 mL) was added t-BuOK (745 mg,6.66 mmol). After stirring at 50℃for 30min, 8.7 (1.15 g,3.33 mol) was added in portions below 50 ℃. The reaction mixture was stirred at 50 ℃ for 1 hour. At 25℃with 10% NH 4 The reaction mixture was quenched with aqueous Cl (10 mL). The THF layer was separated and the aqueous layer extracted with EtOAc (2X 15 mL). The combined organic phases were taken up in Na 2 SO 4 Dried, filtered, concentrated and purified by silica gel column chromatography (0% to 10% ethyl acetate in petroleum ether) to give 8.8 (760 mg, 64.4%). 1 H NMR(400MHz,CDCl 3 )δ H 3.67-3.52(m,1H),2.00-1.75(m,4H),1.74-1.43(m,10H),1.42-1.00(m,9H),0.99-0.80(m,4H),0.79-0.70(m,6H),0.78-0.72(m,6H)。
8.9 Synthesis of
To 8.8 (760 mg,2.13 mmol) in THF (8 m9-BBN (1.03 g,4.26 mmol) was added to the solution in L). At 50 ℃ N 2 After stirring for 1h, aqueous NaOH (1.27 g,6.37mL,31.9 mmol) was added to the resulting mixture at 0deg.C. Hydrogen peroxide (3.18 mL,10M,31.9 mmol) was added dropwise at 0deg.C. The reaction mixture was stirred at 80℃for 1h. The mixture was cooled to 15℃and taken up in Na 2 S 2 SO 4 (10 mL) quenched and extracted with EtOAc (3X 10 mL). The combined organic phases were washed with brine (2X 10 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated, which was purified by silica gel column chromatography (0% to 45% ethyl acetate in petroleum ether) to give 8.9 (200 mg, 40.1%). 1 H NMR(400MHz,CDCl 3 )δ H 3.85-3.74(m,1H),1.98-1.75(m,2H),1.70-1.43(m,10H),1.42-1.00(m,12H),0.99-0.80(m,4H),0.79-0.70(m,6H),0.78-0.73(m,6H),0.22-0.16(m,1H)。
8.10 Synthesis
To a solution of 8.9 (200 mg,0.53 mmol) in DCM (4 mL) was added silica gel (200 mg) and PCC (172 mg,0.80 mmol) at 0deg.C. After stirring at 10 ℃ for 3h, the resulting mixture was filtered through a pad of silica gel and the filter cake was washed with DCM (10 mL). The filtrate was concentrated and purified by silica gel column chromatography (0% to 10% ethyl acetate in petroleum ether) to give 8.10 (160 mg, 81%). 1 H NMR(400MHz,CDCl 3 )δ H 2.75-2.70(m,1H),2.20(s,3H),1.95-1.80(m,2H),1.75-1.65(m,1H),1.60-1.40(m,9H),1.39-1.30(m,11H),1.29-1.05(m,2H),1.00-0.80(m,4H),0.78-0.73(m,6H),0.43-0.36(m,1H)。
8.11 Synthesis
At 0 ℃, N 2 Down to Me being stirred 3 To a solution of SI (164 mg,0.81 mmol) in THF (4 mL) was added t-BuOK (90.1 mg,0.81 mmol) for 1.0h. The resulting mixture was added to a solution of 8.10 (150 mg,0.40 mmol) at 0℃and stirred at 25℃for 16h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (2X 6 mL). The combined organic phases were washed with water (2X 6 mL), brine (6 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 8.11 (150 mg). 1 H NMR(400MHz,CDCl3)δH 3.27-3.25(m,1H),2.89-2.78(m,2H),2.65-2.60(m,1H),2.51-2.49(m,2H),2.00-1.98(m,2H),1.97-1.80(m,2H),1.77-1.40(m,13H),1.19-1.08(m,6H),1.07-1.00(m,4H),0.99-0.74(m,4H),0.73-0.50(m,2H),0.18-0.12(m,3H)。
Synthesis of Compound No. 14
To a solution of 8.11 (150 mg,0.39 mmol) in DMF (3 mL) at 25deg.C was added 4-cyanopyrazole (72.1 mg,0.78 mmol) and Cs 2 CO 3 (377 mg,1.16 mmol). At 120 ℃, N 2 After stirring for 16 h, the reaction mixture was diluted with water (5X 5 mL) and washed with EtOAc (3X 5 mL). The combined organic layers were concentrated and purified by flash column (0% to 30% ethyl acetate in petroleum ether) to give compound No. 14 (110 mg, crude) by SFC (DAICEL CHIRALCEL OD-H (250 mm. Times. 30mm,5 um), provided that 0.1% NH 3 H 2 O ETOH, start B:40%, end B:40%, flow rate (ml/min): 70, sample injection: 80 Purification) to give 6 (33.5 mg, 31%). 1 H NMR(400MHz,CDCl 3 )δ H 7.97(s,1H),7.80(s,1H),4.35-4.22(m,2H),2.60(s,1H),2.00-1.75(m,3H),1.60-1.45(m,9H),1.44-1.20(m,9H),1.19-1.08(m,6H),1.07-1.00(m,4H),0.99-0.74(m,4H),0.73-0.50(m,4H),0.36-0.31(m,1H)。
Example No. 9: synthesis of (2R, 4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10 aR) -N- (5-cyanopyridin-2-yl) -2-hydroxy-6 a-methyl-2-propyloctadecanyl cyclopropane [4,5] cyclopenta [1,2-a ] phenanthrene-7-carboxamide (Compound No. 15).
9.2 Synthesis
To a solution of BHT (200 g, 328 mmol) in toluene (600 mL) in a three-necked flask (3000 mL) at 0deg.C under nitrogen was added trimethylaluminum (227 mL,2M in toluene, 453 mmol) dropwise. The mixture was stirred at 25 ℃ for 1h and used directly as a solution of MAD. A solution of 9.1 (50.0 g,182 mmol) in DCM (300 mL) was added dropwise to the MAD solution (218 g in toluene, 454 mmol) at-70℃under nitrogen. at-70deg.C, N 2 Stirring for 1 hr, and gradually stirring at-70deg.Cn-PrMgCl (121 mL,3M in diethyl ether, 364 mmol) was added dropwise and stirred for an additional 2 hours. The reaction mixture was slowly poured into saturated aqueous citric acid (1000 mL) at below 10 ℃. The aqueous phase was extracted with DCM (2X 500 mL). The combined organic phases were washed with brine (1000 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The resulting residue was triturated with PE (1500 mL) at 25℃to give 9.2 (110 g, crude). The residue was purified by flash column (5% -12% ethyl acetate in petroleum ether) to give 9.2 (28.0 g). 1 H NMR(400MHz,CDCl 3 )δ H 2.65-2.54(m,1H),2.50-2.39(m,1H),2.31-2.03(m,3H),2.02-1.88(m,2H),1.87-1.60(m,2H),1.56-1.46(m,6H),1.36(br dd,J＝4.4,12.2Hz,8H),1.26-1.18(m,2H),1.16-1.02(m,2H),0.97-0.91(m,4H),0.88(s,3H)。
9.3 Synthesis
At 25 ℃ N 2 To a solution of t-BuOK (7.02 g,62.6 mmol) in THF (400 mL) was added 9.2 (10.0 g,31.3 mmol). After stirring at 25℃for 10min, methyl benzene sulfinate (9.77 g,62.6 mmol) was added and the mixture was stirred at 30℃for 0.5H, the mixture was taken up in H 2 O (200 mL) was quenched and extracted with EtOAc (3X 200 mL). The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 9.3 (20.0 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 7.77-7.46(m,6H),3.26(dd,J＝8.4,10.0Hz,1H),2.44-2.10(m,1H),1.80(br d,J＝13.2Hz,3H),1.68-1.43(m,7H),1.68-1.43(m,7H),1.42-1.23(m,7H),1.21-0.96(m,3H),0.96-0.90(m,3H)。
9.4 Synthesis
To a mixture of 9.3 (20.0 g,45.1 mmol) in xylene (200 mL) was added Na in portions 2 CO 3 (71.6 g,676 mmol). At 140 ℃ N 2 After stirring for 12h, the mixture was filtered and concentrated and the residue was purified by column (0% -15% ethyl acetate in petroleum ether) to give 9.4 (4.50 g). 1 H NMR(400MHz,CDCl 3 )δ H 7.53(dd,J＝1.2,6.0Hz,1H),6.03(dd,J＝3.2,6.0Hz,1H),2.38(br d,J＝7.8Hz,1H),1.85(d,J＝3.6Hz,4H),1.78-1.66(m,3H),1.56(d,J＝16.4Hz,7H),1.41-1.21(m,9H),1.08(s,3H),0.95(t,J＝7.2Hz,3H)。
9.5 Synthesis
At 25 ℃ N 2 Downward Me 3 SOI (3.32 g,15.1 mmol) to a solution of NaH (362 mg,15.1 mmol) in 50ml DMSO was added. After stirring for 1 hour at 25 ℃, 9.4 (4.00 g,12.6 mmol) in 10ml DMSO was added to the mixture. After stirring at 25℃for 3 hours, the mixture was poured into water (100 mL) and extracted with EtOAc (2X 40 mL). The combined organic layers were washed with brine (2X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The mixture was purified by flash column (0% -30% ethyl acetate in petroleum ether) to give 9.5 (2.60 g, 63%). 1 H NMR(400MHz,CDCl 3 )δ H 2.08-1.99(m,1H),1.99-1.89(m,1H),1.73(br d,J＝13.6Hz,7H),1.66-1.45(m,8H),1.44-1.22(m,10H),1.16-1.02(m,2H),0.96(s,3H),0.95-0.91(m,2H)。
9.6 Synthesis
At 25 ℃ N 2 Downward to Ph 3 To a suspension of PEtBur (8.72 g,23.5 mmol) in dry THF (60 mL) was added t-BuOK (2.63 g,23.5 mmol). After stirring at 55℃for 30min, a solution of 9.5 (2.60 g,7.86 mmol) in anhydrous THF (20 mL) was added dropwise. After stirring at 25℃for 16h, the mixture was cooled and poured into ice water (100 mL) and stirred for 10min. The aqueous phase was extracted with EtOAc (2X 50 mL). The combined organic phases were washed with brine (2×200 mL), filtered and concentrated. The mixture was purified by flash column (0% -20% ethyl acetate in petroleum ether) to give 9.6 (2.30 g, 86%). 1 H NMR(400MHz,CDCl 3 )δ H 5.35(q,J＝7.2Hz,1H),2.19-2.09(m,1H),1.91-1.73(m,5H),1.69(d,J＝7.2Hz,4H),1.51-1.30(m,11H),1.27(br t,J＝7.2Hz,5H),1.19-1.02(m,2H),1.00(s,3H),0.94(t,J＝7.2Hz,5H),0.44(dt,J＝5.4,8.1Hz,1H)。
9.7 Synthesis
At N 2 Next, BH was added to a solution of 9.6 (2.80 g,8.17 mmol) in THF (60 mL) 3 THF (24.5 mL,1M,24.5 mmol). At 25 ℃ N 2 After stirring for 2 hours, the mixture was cooled to 0 ℃. Ethanol (7.11 mL,122 mmol) and NaOH (24.4 mL,5M,122 mmol) were added to the reaction mixture. Then at the temperature of 0 deg.c,dropwise addition of H 2 O 2 (12.1 mL,30%,122 mmol). The mixture was stirred at 50℃for 2 hours. Adding saturated Na 2 S 2 O 3 Aqueous solution (200 mL) and the mixture was stirred at 0 ℃ for an additional 1 hour. The aqueous phase was extracted with EtOAc (3X 50 mL). The combined organic phases were washed with brine (2X 200 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 9.7 (2.10 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.93-3.73(m,1H),1.87-1.63(m,5H),1.63-1.42(m,6H),1.41-1.29(m,9H),1.25(br d,J＝6.4Hz,10H),0.94(t,J＝7.2Hz,3H),0.87(s,1H),0.75(s,4H),0.26-0.14(m,1H)。
9.8 Synthesis
At N 2 To a solution of 9.7 (2.80 g,7.76 mmol) in DCM (80 mL) was added DMP (6.57 g,15.5 mmol). At 25 ℃ N 2 After stirring for 2 hours, saturated NaHCO was added 3 Aqueous solution (100 mL) and saturated Na 2 S 2 O 3 An aqueous solution (100 mL) was added to the mixture. The aqueous phase was extracted with DCM (2X 100 mL). The combined organic phases were washed with brine (2X 200 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% -15% ethyl acetate in petroleum ether) to give 9.8 (2.10 g, 76%). 1 HNMR(400MHz,CDCl 3 )δ H 2.75(d,J＝4.0Hz,1H),2.21(s,3H),2.01-1.89(m,1H),1.87-1.63(m,4H),1.62-1.45(m,6H),1.44-1.33(m,8H),1.33-1.17(m,6H),1.13-0.99(m,1H),0.95(t,J＝7.2Hz,3H),0.89-0.83(m,1H),0.73(s,3H),0.50-0.32(m,1H)。
9.9 Synthesis of
Liquid bromine (0.127 ml,399mg,2.50 mmol) was slowly added to vigorously stirred aqueous sodium hydroxide (3.34 ml,8.36mmol, 2.5M) at 0deg.C. After stirring at 25 ℃ for 30min, the mixture was slowly added to a stirred solution of 9.8 (300 mg,0.837 mmol) in dioxane (10 mL). The homogeneous yellow solution slowly became colorless and a white precipitate formed. After stirring for 16 hours at 25℃NaHCO was used 3 The remaining oxidizing reagent was quenched with aqueous solution (20 mL). The reaction mixture was extracted with EtOAc (2X 20 mL) and washed with brine (50 mL)Dried over sodium sulfate, filtered and concentrated to give 9.9 (360 mg, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.72(s,1H),2.80(d,J＝4.4Hz,1H),2.01-1.90(m,1H),1.88-1.60(m,5H),1.59-1.44(m,5H),1.43-1.19(m,13H),1.18-0.99(m,2H),0.95(t,J＝7.2Hz,4H),0.83(s,3H),0.45-0.32(m,1H)。
9.10 Synthesis
To a solution of 9.9 (360 mg,0.998 mmol) in DMF (6 mL) was added HATU (756 mg,1.99 mmol) and DIPEA (515 mg,3.99 mmol). Stirring at 25deg.C for 20min, adding NH 4 Cl (213 mg,3.99 mmol). After stirring at 25 ℃ for 16 hours, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×10 mL), washed with water (2×50 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column (30% -100% ethyl acetate in petroleum ether) to give 9.10 (240 mg, 67%). 1 H NMR(400MHz,CDCl 3 )δ H 6.16(br s,1H),5.43(br s,1H),2.66(d,J＝4.4Hz,1H),2.04-1.95(m,1H),1.89-1.62(m,4H),1.58-1.43(m,5H),1.42-1.17(m,14H),1.15-1.02(m,1H),0.94(t,J＝7.2Hz,5H),0.81(s,3H),0.53-0.29(m,1H)。
Synthesis of Compound No. 15
To 6-chloropyridine-3-carbonitrile (92.4 mg,0.667 mmol), 7.10 (120 mg,0.334 mmol), xantphos (19.3 mg,0.033 mmol) and Cs 2 CO 3 (377 mg,1.16 mmol) A mixture of dioxane (3 mL) was bubbled with nitrogen for 2min, then Pd was added 2 (dba) 3 (30.5 mg,0.033 mmol). After stirring for 16h at 115 ℃, the mixture was filtered through a pad of silica gel, washed with EtOAc (20 mL), over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% -30% ethyl acetate in petroleum ether) to give compound No. 15 (60.0 mg, crude), which was triturated with MeCN (10 ml) at 25 ℃ to give compound No. 15 (49.3 mg, 82%). 1 H NMR(400MHz,CDCl 3 )δ H 8.81(s,1H),8.57(d,J＝1.6Hz,1H),8.44(d,J＝8.8Hz,1H),7.95(dd,J＝2.4,8.7Hz,1H),2.86(d,J＝4.4Hz,1H),2.04-1.96(m,1H),1.90-1.76(m,4H),1.74-1.65(m,3H),1.55-1.35(m,12H),1.35-1.22(m,5H),1.13-1.03(m,2H),0.95(t,J＝7.2Hz,3H),0.80(s,3H),0.66-0.56(m,1H)。
Example No. 10: synthesis of 1- ((2R, 4aS,4bR,6aS,7S,7aS,8aR,8bR,8cR,10 aS) -2-hydroxy-2- (methoxymethyl) -6 a-methyl octadecanycyclopropyl [4,5] cyclopenta [1,2-a ] phenanthren-7-yl) ethanone (Compound No. 16).
10.2 Synthesis
At 25 ℃ N 2 Next, 10.1 (5.00 g,15.6 mmol) was added to a solution of t-BuOK (3.50 g,31.2 mmol) in THF (50 mL). The mixture was stirred at 25℃for 10min. Methyl benzene sulfinate (4.87 g,31.2 mmol) was then added. The mixture was stirred at 30℃for 0.5 h. The mixture was treated with H 2 O (50 mL) was quenched and extracted with EtOAc (3X 50 mL). The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 10.2 (5.90 g, crude).
10.3 Synthesis
Na was added in portions to a mixture of 10.2 (5.90 g,13.2 mmol) in xylene (50 mL) at 25 ℃ 2 CO 3 (20.9 g, 198mol). At 145 ℃ N 2 The reaction mixture was stirred for 16h. The mixture was filtered and concentrated. The mixture was purified by silica gel chromatography (0% -30% ethyl acetate in petroleum ether) to give product 10.3 (2.00 g, 48%). 1 H NMR(400MHz,CDCl 3 )δ H 7.56-7.49(m,1H),6.05-5.98(m,1H),3.39(s,3H),3.19(s,2H),2.36-2.28(m,1H),2.05-2.00(m,1H),1.98-1.62(m,7H),1.55-1.11(m,8H),1.07(s,3H),1.05-0.79(m,3H)。
10.4 Synthesis
At 60 ℃ N 2 A stirred solution of trimethylsulfoxide iodide (2.75 g,12.5 mmol) and t-BuOK (1.54 g,13.8 mmol) in DMSO (20 mL) was heated for 1.0 h. 10.3 (2.00 g,6.28 mmol) was added to the reaction mixture and stirred at 25℃for 1 hour. The reaction was treated with water (30 mL) and extracted with EtOAc (2X 30 mL). The combined organic phases were washed with water (2X 20 mL), brine (20 mL)Washing with anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The mixture was filtered, concentrated and purified by combi-flash (15% -30% ethyl acetate in petroleum ether) to give 10.4 (1.00 g, 48.0%). 1 H NMR(400MHz,CDCl 3 )δ H 3.32(s,3H),3.12(s,2H),1.94-1.75(m,4H),1.68-1.51(m,8H),1.46-1.36(m,1H),1.30-1.20(m,2H),1.17-0.92(m,7H),0.89(s,3H),0.81-0.65(m,2H)。
10.5 Synthesis
At 25 ℃ N 2 Downward to EtOPh 3 To a mixture of Br (3.56 g,9.60 mmol) in THF (12 mL) was added t-BuOK (1.07 g,9.60 mmol). The resulting mixture was stirred at 40℃for 30min. 10.4 (0.40 g,1.20 mmol) was added in portions at below 40 ℃. The reaction mixture was stirred at 40 ℃ for 16 hours to give a yellow suspension. At 25℃with 10% NH 4 The reaction mixture was quenched with aqueous Cl (40 mL). The aqueous phase was extracted with EtOAc (2X 40 mL). The combined organic phases were separated over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% to 35% ethyl acetate in petroleum ether) to give 10.5 (0.40 g, 97%).
10.6 Synthesis
At 0 ℃, N 2 Next, BH was added to a solution of 10.5 (1.00 g,2.90 mmol) in THF (120 mL) 3 .Me 2 S (1.44 mL,10M,14.4 mmol). The mixture was stirred at 25 ℃ for 16 hours. Ethanol (1.70 ml,28.9 mmol), naOH (5.77 ml,5M aqueous solution, 28.9 mmol) and H 2 O 2 (4.34 mL,10M,43.4 mmol) was added dropwise to the mixture. The resulting mixture was stirred at 60℃for 1 hour. With Na 2 S 2 O 3 (20 mL) the mixture was quenched. The mixture was concentrated and filtered. The solid was washed with EA (20 mL), over Na 2 SO 4 Dried, filtered and concentrated to give 10.6 (1.00 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.87-3.77(m,1H),3.38(s,3H),3.18(s,2H),2.05-1.86(m,2H),1.58-1.39(m,3H),1.31-1.08(m,16H),1.06-0.81(m,5H),0.80-0.65(m,5H),0.26-0.13(m,1H)。
Synthesis of Compound No. 16
To a mixture of 8.6 (800 mg, 0.553mmol) in DCM (20 mL) was added silica gel (1.42 g) and PCC (1.42 g,6.60 mmol). The reaction mixture was stirred at 25℃for 1h. PE (10 mL) was added to the reaction mixture. The mixture was filtered and washed with DCM (2X 20 mL). The residue was purified by flash column (15% -30% ethyl acetate in petroleum ether) to give compound No. 16 (500 mg, 63%). 1 H NMR(400MHz,CDCl 3 )δ H 3.39(s,3H),3.19(s,2H),2.76-2.72(m,1H),2.20(s,3H),2.01(s,1H),1.95-1.87(m,2H),1.77-1.60(m,5H),1.46-0.97(m,13H),0.88-0.76(m,2H),0.72(s,3H),0.45-0.35(m,1H)
Example No. 11: synthesis of (2R, 4aS,4bR,6aS,7R,7aS,8aR, 8cR,10 aS) -2- (methoxymethyl) -6 a-methyl-7- ((S) -1- (5-methyl-2H-tetrazol-2-yl) propan-2-yl) octadecano [4,5] cyclopenta [1,2-a ] phenanthren-2-ol (Compound No. 17) and (2R, 4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10 aS) -2- (methoxymethyl) -6 a-methyl-7- ((R) -1- (5-methyl-2H-tetrazol-2-yl) propan-2-yl) octadecano [4,5] cyclopenta [1,2-a ] propan-2-ol (Compound No. 18).
11.1 Synthesis
At 25 ℃ N 2 Down to MePPh 3 To a mixture of Br (1.92 g,5.40 mmol) in THF (8 mL) was added t-BuOK (605 mg,5.40 mmol). The resulting mixture was stirred at 40℃for 30min. Compound No. 16 (0.65 g,1.80 mmol) was added in one portion at 55 ℃. The reaction mixture was stirred at 55 ℃ for 16 hours to give a yellow suspension. At 25℃with 10% NH 4 The reaction mixture was quenched with aqueous Cl (40 mL). The aqueous phase was extracted with EtOAc (2X 40 mL). The combined organic phases were separated over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% to 35% ethyl acetate in petroleum ether) to give 11.1 (1.00 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 5.10(s,1H),4.84(s,1H),3.39(s,3H),3.19(s,2H),2.42-2.37(m,1H),2.04-1.87(m,2H),1.74(s,3H),1.73-1.41(m,7H),1.29-0.98(m,11H),0.81-0.66(m,3H),0.64(s,3H),0.29-0.20(m,1H)。
11.2 Synthesis
At 25 ℃ N 2 Next, BH was added to a solution of 11.1 (1.00 g,2.78 mmol) in THF (10 mL) 3 .Me 2 S (1.11 mL,10M,11.1 mmol). The mixture was stirred at 25 ℃ for 16 hours. Ethanol (1.96 mL,33.3 mmol), naOH (6.65 mL,5M aqueous solution, 33.3 mmol) and H were added dropwise 2 O 2 (4.17 mL,10M,41.7 mmol). The resulting mixture was stirred at 60℃for 1 hour. With Na 2 S 2 O 3 (20 mL) the mixture was quenched. The mixture was concentrated and filtered. The solid was washed with EA (200 mL), over Na 2 SO 4 Dried, filtered and concentrated to give 11.2 (0.52 g, 50%). 1 H NMR(400MHz,CDCl 3 )δ H 3.76-3.66(m,1H),3.45-3.30(m,4H),3.18(s,2H),2.01-1.42(m,13H),1.29-1.17(m,5H),1.14(m,3H),1.12-0.99(m,5H),0.76(s,3H),0.74-0.68(m,2H),0.64-0.58(m,1H),0.14-0.08(m,1H)。
11.3 Synthesis
To a solution of 11.2 (0.52 g,1.38 mmol) in DCM (10 mL) was added N-methylimidazole (226 mg,2.76 mmol), TEA (535. Mu.L, 4.14 mmol) and TsCl (390 mg,2.07 mmol). The mixture was stirred at 25℃for 1h. The mixture was poured onto NaHCO 3 (20 mL, saturated) and washed with 1M HCl (20 mL). The aqueous phase was extracted with DCM (2X 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 Dried and filtered to give 11.3 (0.71 g, 97%). 1 H NMR(400MHz,CDCl 3 )δ H 7.83-7.74(m,2H),7.38-7.30(m,2H),4.14-4.05(m,1H),3.78-3.70(m,1H),3.38(s,3H),3.18(s,2H),2.44(s,3H),2.04-1.62(m,7H),1.57-1.11(m,10H),1.08-1.06(m,3H),1.05-0.80(m,5H),0.76-0.61(m,5H),0.59-0.51(m,1H),0.13-0.01(m,1H)。
Synthesis of Compound No. 17 and Compound No. 18
At 100deg.C, 11.3 (0.30 g,0.56 mmol), cs 2 CO 3 A solution of (736 mg,2.262 mmol) and 5-methyltetrazole (95.0 mg,1.13 mmol) in DMF (5 mL) was stirred for 16 h. The mixture was added to saturated H 2 O (20 mL). The aqueous layer was extracted with EtOAc (2X 20 mL). The combined organic layers were washed with saturated brine (2X 20 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (10% to 30% ethyl acetate in petroleum ether) to give compound number 18 (75.0 mg, 30%) and by SFC (run 1: column DAICEL CHIRALCEL OD-H (250 mm. 30mm,5 um); conditions: 0.1% NH 3 H 2 O ETOH; start B:30%; end B:30%; flow rate (ml/min): 70; and (3) sample injection: 60. run 2: column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 um); conditions are as follows: 0.1% NH 3 H 2 OETOH; start B:40%; end B:40%; flow rate (ml/min): 70; and (3) sample injection: 60 Purified and lyophilized to give compound No. 18 (29.5 mg, 12%) and compound No. 17 (3.20 mg, 1.3%).
Compound No. 17: 1 H NMR(400MHz,CDCl 3 )δ H 4.88-4.75(m,1H),4.59-4.44(m,1H),3.39(s,3H),3.18(s,2H),2.55(s,3H),2.38-2.28(m,1H),1.93-1.86(m,1H),1.74-1.65(m,6H),1.49-1.38(m,1H),1.32-0.96(m,13H),0.83(d,J＝6.4Hz,3H),0.79(s,3H),0.75-0.68(m,3H),0.21-0.14(m,1H)。
compound No. 18: 1 H NMR(400MHz,CDCl3)δH 4.70-4.59(m,1H),4.35-4.18(m,1H),3.39(s,3H),3.19(s,2H),2.54(s,3H),2.44-2.30(m,1H),2.04-1.58(m,10H),1.49-1.42(m,1H),1.27-0.99(m,10H),0.93(d,J＝6.4Hz,3H),0.91(s,3H),0.79-0.65(m,3H),0.20-0.09(m,1H)。
example No. 12: synthesis of (2R, 4aS,4bR,6aS,7R,7aS,8aR, 8cR,10 aS) -2- (methoxymethyl) -6 a-methyl-7- ((S) -1- (5-methyl-2H-tetrazol-2-yl) propan-2-yl) octadecanycyclo [4,5] cyclopenta [1,2-a ] phenanthren-2-ol (Compound No. 19).
12.2 Synthesis
At 15 ℃ N 2 Next, to a solution of t-BuOK (19.3 g,172 mmol) in THF (500 mL) was added12.1 (25.0 g,86.0 mmol) was added. The mixture was stirred at 15℃for 10 minutes. Then, methyl benzene sulfinate (26.8 g,172 mmol) was added. The mixture was stirred at 30℃for 0.5 h. The mixture was treated with H 2 O (300 mL) was quenched and extracted with EtOAc (2X 200 mL). The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 12.2 (45.0 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 7.64-7.56(m,2H),7.55-7.44(m,3H),3.65-3.50(m,1H),3.50-3.20(m,1H),1.90-1.61(m,8H),1.52-1.17(m,10H),1.16-1.02(m,2H),0.95-0.87(m,3H),0.82-0.77(m,3H),0.74-0.55(m,1H)。
12.3 Synthesis
To a mixture of 12.2 (45.0 g,108 mmol) in xylene (450 mL) was added Na in one portion 2 CO 3 (170 g,1.61 mol). At 125 ℃, N 2 The reaction mixture was stirred for 12 hours. The mixture was filtered, concentrated and purified by flash column (0% -30% ethyl acetate in petroleum ether/DCM (1/1)) to give 12.3 (18.8 g, 48%). 1 H NMR(400MHz,CDCl 3 )δ H 7.51(dd,J＝0.8,6.0Hz,1H),6.05-5.97(dd,J＝3.2,6.0Hz,1H),3.66-3.57(m,1H),2.32-2.20(m,1H),2.05-1.94(m,1H),1.90-1.54(m,8H),1.53-1.23(m,7H),1.05(s,3H),1.02-0.94(m,1H),0.87(s,3H),0.83-0.75(m,1H)。
12.4 Synthesis
At 60 ℃ N 2 A stirred solution of trimethylsulfoxide iodide (28.6 g,130 mmol) and t-BuOK (16.0 g,143 mmol) in DMSO (450 mL) was heated for 1.0h. Compound 12.3 (18.8 g,65.1 mmol) was added to the reaction mixture and stirred at 25 ℃ for 1 hour. The reaction was treated with water (300 mL) and then extracted with EtOAc (2X 300 mL). The combined organic phases were washed with water (2X 200 mL), brine (200 mL), and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 12.4 (23.3 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.67-3.52(m,1H),1.97-1.58(m,10H),1.40-1.29(m,5H),1.20-0.99(m,6H),0.94(s,3H),0.84-0.75(m,5H)。
12.5 Synthesis
At 25 ℃ N 2 Down to MePPh 3 To a mixture of Br (78.3 g,211 mmol) in THF (200 mL) was added t-BuOK (23.6 g,211 mmol). The resulting mixture was stirred at 50℃for 30 minutes. Compound 12.4 (21.3 g,70.4 mmol) was added in portions at less than 50 ℃. The reaction mixture was stirred at 50 ℃ for 16 hours. At 15℃with 10% NH 4 The reaction mixture was quenched with aqueous Cl (300 mL). The aqueous phase was extracted with EtOAc (200 mL. Times.3). The combined organic phases were washed with brine (200 ml×2), and dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was triturated with MeOH (780 mL) at 25 ℃ and purified by flash chromatography (0% -25% ethyl acetate in petroleum ether) to give 12.5 (5.81 g, 26%). 1 H NMR(400MHz,CDCl3)δH 5.35(q,J＝7.2Hz,1H),3.65-3.54(m,1H),2.17-2.06(m,1H),1.95-1.71(m,4H),1.71-1.66(m,4H),1.65-1.60(m,2H),1.44-1.24(m,9H),1.02-0.97(m,4H),0.96-0.86(m,2H),0.85-0.79(m,4H),0.78-0.65(m,1H),0.50-0.39(m,1H)。
12.6 Synthesis
To a solution of 12.5 (4.46 g,14.1 mmol) in DCM (45 mL) was added DMP (5.47 g,28.2 mmol). After stirring for 2 hours at 25℃with saturated NaHCO 3 Solution (100 mL) and saturated Na 2 S 2 O 3 (50 mL) quench the reaction mixture. After stirring at 25℃for 15 min, the organic phase was separated and washed with saturated NaHCO 3 (60 mL) and saturated Na 2 S 2 O 3 (30 mL) washing over anhydrous Na 2 SO 4 Dried, filtered, and concentrated to give 12.6 (4.30 g, crude). 1 H NMR(400MHz,CDCl3)δH 5.35(q,J＝7.2Hz,1H),2.46-2.06(m,5H),2.01-1.93(m,2H),1.83-1.71(m,2H),1.70-1.67(m,3H),1.54-1.31(m,5H),1.20-1.07(m,2H),1.06-0.97(m,7H),0.95-0.78(m,4H),0.51-0.41(m,1H)。
12.7 Synthesis
At 60 ℃ N 2 A stirred solution of trimethylsulfoxide iodide (5.63 g,25.6 mmol) and t-BuOK (3.15 g,28.1 mmol) in DMSO (100 mL) was heated for 1.0 h. Compound 12.6 (4.00 g,12.8 mmol) was added to the reaction mixture and stirred at 25 ℃ for 1 hour. The reaction mixture was treated with water (200 mL) and then extracted with EtOAc (2X 150 mL). Will be combinedThe combined organic phases were washed with water (2X 100 mL), brine (100 mL) and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 12.7 (9.00 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 5.39-5.23(m,1H),1.96-1.68(m,6H),1.65(d,J＝7.2Hz,3H),1.63-1.26(m,10H),1.19-0.99(m,5H),0.96(s,3H),0.94-0.86(m,2H),0.84(s,3H),0.46-0.37(m,1H)。
12.8 Synthesis
Sodium metal (6.32 g,275 mmol) was added portionwise to MeOH (180 mL). After stirring at 20℃for 1 hour, a solution of 12.7 (9.00 g,27.5 mmol) in THF (40 mL) was added to the mixture at 25 ℃. The resulting mixture was stirred at 60℃for 24 hours. The mixture was poured onto H 2 O (200 mL). The aqueous layer was extracted with EtOAc (3X 100 mL). The combined organic layers were treated with NH 4 Aqueous Cl (2X 50 mL) was washed with anhydrous Na 2 SO 4 Dried, filtered and concentrated to give 12.8 (5.10 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 5.39-5.29(m,1H),3.38(s,3H),3.18(s,2H),1.94-1.74(m,3H),1.67(d,J＝7.2Hz,3H),1.64-1.05(m,15H),0.97(s,3H),0.93-0.80(m,4H),0.77(s,3H),0.48-0.37(m,1H)。
12.9 Synthesis
BH was added to a solution of 12.8 (5.10 g,66.9 mmol) in THF (50 mL) at 25 ℃ 3 ·Me 2 S (2.83 mL,10M,28.4 mmol). The mixture was stirred at 25 ℃ for 16 hours. Ethanol (4.96 mL,85.2 mmol) was added to the resulting mixture at 25deg.C. Then aqueous NaOH (17.0 mL,5M,85.2 mmol) was added dropwise at 25℃followed by H 2 O 2 (8.52 mL,10M,85.2 mmol). After the addition, the mixture was stirred at 70 ℃ for 1 hour. The mixture was extracted with EtOAc (3X 100 mL). The combined organic phases were washed with saturated brine (2X 80 mL), dried over anhydrous Na 2 SO 4 And (5) drying. The combined organic phases were concentrated in vacuo to give 12.9 (6.08 g, crude). 1 H NMR(400MHz,CDCl 3 )δ H 3.89-3.73(m,1H),3.38(s,3H),3.17(s,2H),1.95-1.87(m,1H),1.78-1.41(m,7H),1.37-1.26(m,8H),1.25-1.21(m,4H),1.20-1.07(m,4H),0.91-0.80(m,3H),0.78-0.70(m,6H),0.24-0.13(m,1H)。
12.10 Synthesis
To a solution of 12.9 (3.08 g,8.17 mmol) in DCM (30 mL) was added DMP (3.16 g,16.3 mmol). After stirring at 25℃for 1 hour, the reaction mixture was taken up in saturated NaHCO 3 Solution (50 mL) and saturated Na 2 S 2 O 3 (50 mL) washed twice with Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash chromatography (0% to 45% ethyl acetate in petroleum ether) to give 12.10 (3.00 g). 1 H NMR(400MHz,CDCl 3 )δ H 3.38(s,3H),3.18(s,2H),2.73(d,J＝4.0Hz,1H),2.25-2.09(m,3H),1.98-1.85(m,2H),1.74-1.60(m,2H),1.57-0.97(m,14H),0.81-0.92(m,2H),0.76(s,3H),0.70(s,3H),0.30-0.45(m,1H)。
12.11 Synthesis
HBr (8.50 mg,0.106mmol,40% aqueous solution) and Br were added to a mixture of 12.10 (0.20 g,0.53 mmol) in MeOH (5 mL) at 20deg.C 2 (93.6 mg,0.586 mmol). The reaction mixture was stirred at 25 ℃ for 2 hours. Addition of NaHCO to the mixture 3 /Na 2 S 2 O 3 (20 mL, 1:1). The aqueous phase was extracted with EtOAc (3X 20 mL). The combined organic phases were washed with saturated brine (2X 10 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 12.11 (0.20 g, crude).
Synthesis of Compound No. 19
To a solution of 12.11 (0.20 g,0.441 mmol) in acetone (5 mL) at 25deg.C was added 4-cyano-pyrazole (82.1 mg,0.882 mmol) and K 2 CO 3 (123 mg,0.882 mmol) and stirred for 16 hours. H was added to the reaction mixture at 25℃ 2 O (10 ml). The aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic phases were washed with saturated brine (2X 10 mL), dried over anhydrous Na 2 SO 4 Drying, filtering, concentrating, and subjecting to flash chromatography (0% -50% ethyl acetate in petroleum ether) and SFC (column: DAICEL CHIRALCEL OD (250 mm. Times. 30mm,10 um)), mobile phase: A: CO 2 B：0.1％ NH 3 H 2 OETOH; gradient: 40% to 40% B, flow rate (mL/min): 80 Purification)And was triturated with PE (5 mL) at 25℃to give compound number 19 (120 mg, 58%). 1 H NMR(400MHz,CDCl 3 )δ H 7.87(s,1H),7.82(s,1H),5.22-5.12(m,2H),3.39(s,3H),3.18(s,2H),2.82(d,J＝2.4Hz,1H),1.95-1.89(m,2H),1.78-1.64(m,2H),1.51-0.80(m,18H),0.76(s,6H),0.51-0.45(m,1H)。
Example No. 13: synthesis of (2R, 4aS,4bR,6aS,7R,7aS,8aR, 8cR,10 aS) -2- (methoxymethyl) -6 a-methyl-7- ((R) -1- (5-methyl-2H-tetrazol-2-yl) propan-2-yl) octadecano [4,5] cyclopenta [1,2-a ] phenanthren-2-ol (Compound No. 20) and (2R, 4aS,4bR,6aS,7R,7aS,8aR,8bR,8cR,10 aS) -2- (methoxymethyl) -6 a-methyl-7- ((R) -1- (5-methyl-2H-tetrazol-2-yl) propan-2-yl) octadecano [4,5] cyclopenta [1,2-a ] propan-2-ol (Compound No. 21).
13.1 Synthesis
At 10 ℃ N 2 A suspension of LiCl (850 mg,20.1mmol, anhydrous) in THF (30 mL, anhydrous) was stirred for 30min. Then FeCl is added at 10 DEG C 3 (1.70 g,10.5mmol, anhydrous). The mixture was cooled to-30 ℃. MeMgBr (12.7 mL,38.4mmol,3M in diethyl ether) was added dropwise to the mixture at-30 ℃. The resulting mixture was stirred at-30℃for 10min. Then 12.6 (1.00 g,3.20 mmol) in THF (10 mL, anhydrous) was added at-30deg.C. The mixture was stirred at-15℃for 4 hours. Citric acid (30 ml,20% aqueous solution) was added to the mixture. The mixture was extracted with EtOAc (3X 50 mL). The combined organic phases were washed with saturated brine (2X 30 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0% to 30% ethyl acetate in petroleum ether) to give 13.1 (850 mg, 81%). 1 H NMR(400MHz,CDCl 3 )δ H 5.35(q,J＝6.8Hz,1H),2.15-2.09(m,1H),1.93-1.88(m,1H),1.81-1.71(m,2H),1.70-1.67(m,3H),1.52-1.44(m,6H),1.32-1.23(m,7H),1.21-1.19(m,4H),0.98(s,3H),0.92-0.83(m,3H),0.80-0.75(m,4H),0.48-0.41(m,1H)。
13.2 Synthesis
At N 2 Next, BH is carried out 3 ·Me 2 S (684. Mu.L, 10M,6.84 mmol) was added to a solution of 13.1 (750 mg,2.28 mmol) in THF (5 mL). At 20 ℃ N 2 The reaction mixture was stirred for 12 hours. EtOH (2.41 mL,41.0 mmol) and NaOH (8.20 mL,5M,41.0 mmol) are added to the mixture. Then H is added dropwise at 15 DEG C 2 O 2 (4.10 mL,10M,41.0 mmol). The mixture was stirred at 70℃for 1 hour. The mixture was then poured onto Na 2 S 2 O 3 (50 mL, saturated) and extracted with EtOAc (3X 50 mL). The combined organic layers were washed with saturated brine (2X 30 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% -45% ethyl acetate in petroleum ether) to give 13.2 (690 mg, 87%).
Synthesis of Compound No. 20
To a solution of 13.2 (300 mg,0.86 mmol) in DCM (10 mL) was added dess-martin reagent (733 mg,1.73 mmol) at 25 ℃. The reaction mixture was stirred at 25℃for 10min. With saturated NaHCO 3 /Na 2 S 2 O 3 The mixture was quenched with aqueous solution (1:1, 20 mL). The mixture was combined with another 13.2 batch (300 mg) and extracted with DCM (3X 50 mL), washed with brine (2X 15 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash column (0% -30% ethyl acetate in petroleum ether) to give compound No. 20 (600 mg). The residue (30.0 mg) was recrystallized from MeCN (8 mL) to give compound No. 20 (7.00 mg, 23%). 1 H NMR(400MHz,CDCl 3 )δ H 2.73(d,J＝4.0Hz,1H),2.20(s,3H),1.97-1.87(m,2H),1.73-1.66(m,1H),1.62-1.57(m,1H),1.53-1.22(m,14H),1.20(s,3H),1.18-1.11(m,2H),0.88-0.81(m,2H),0.76(s,3H),0.71(s,3H),0.43-0.34(m,1H)。
13.3 Synthesis
HBr (7.03 mg,0.087mmol,40% aqueous solution) and Br were added to a mixture of Compound No. 20 (150 mg,0.43 mmol) in MeOH (3 mL) at 20deg.C 2 (83.4mg，0.52 mmol). The reaction mixture was stirred at 25℃for 1h. NaHCO 3 (20 mL) was added to the mixture. The aqueous phase was extracted with EA (3X 30 mL). The combined organic phases were washed with saturated brine (2X 20 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated in vacuo to give 13.3 (200 mg). 1 H NMR(400MHz,CDCl 3 )δ H 4.15-4.05(m,2H),2.99(d,J＝4.4Hz,1H),1.94-1.86(m,2H),1.74-1.69(m,1H),1.49-1.44(m,2H),1.39-1.24(m,11H),1.22-1.19(m,4H),1.17-1.06(m,2H),0.96-0.78(m,3H),0.76(s,3H),0.71(s,3H),0.47-0.39(m,1H)。
Synthesis of Compound No. 21
To a solution of 13.1 (200 mg,0.47 mmol) in acetone (5 mL) at 25deg.C was added 1H-pyrazole-4-carbonitrile (87.8 mg,0.94 mmol) and K 2 CO 3 (132 mg,0.94 mmol) and stirred for 16 hours. H was added to the reaction mixture at 25℃ 2 O (20 ml). The aqueous phase was extracted with EtOAc (2X 50 mL). The combined organic phases were washed with saturated brine (2X 50 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% -50% EtOAc in PE) and recrystallized from MeCN (10 mL) to give compound No. 21 (45.6 mg, 22%). 1 H NMR(400MHz,CDCl 3 )δ H 7.87(s,1H),7.82(s,1H),5.26-5.11(m,2H),2.82(d,J＝2.8Hz,1H),1.99-1.86(m,2H),1.80-1.71(m,1H),1.65-1.57(m,2H),1.53-1.23(m,13H),1.21(s,3H),1.19-1.11(m,2H),1.01-0.95(m,1H),0.89-0.81(m,1H),0.77(s,6H),0.5-0.44(m,1H)。
Example No. 14: synthesis of 1- ((3R, 5S,8R,9S,10S,13S,14S, 17S) -3-hydroxy-3, 10-dimethyldecatetrahydro-1H-13, 14-methylcyclopenta [ a ] phenanthren-17-yl) ethanone (Compound No. 22).
14.2 Synthesis
To a solution of 14.1 (9.50 g,26.6 mmol) in THF (200 mL) was added Pd (OH) 2 C (4.00 g,10%, dry). At 25 ℃, H 2 Under the condition of balloon (15 psi), mixing The mixture was stirred for 16h. The mixture was filtered through a pad of celite and the solid was washed with THF (3×50 mL). The combined filtrates were concentrated to give 14.2 (9.00 g, 94%). 1 H NMR(400MHz,CDCl 3 )δ H 2.95(d,J＝10.0Hz,1H),2.40-2.32(m,1H),2.26(s,6H),2.19(s,3H),2.16-2.07(m,1H),1.83-1.56(m,9H),1.48-1.05(m,11H),1.02(d,J＝6.4Hz,3H),0.99-0.88(m,3H),0.71(s,3H),0.69-0.58(m,1H)。
14.3 Synthesis
To a solution of 14.2 (9.00 g,25.0 mmol) in toluene (800 mL) was added a solution of BrCN (13.2 g,125 mmol) in toluene (100 mL). The mixture was stirred at 80℃for 1h. With Na 2 CO 3 The resulting mixture was quenched with aqueous solution (500 ml, 20%). The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated in vacuo. The residue was purified by flash chromatography (15% -30% ethyl acetate in petroleum ether) to give 14.3 (7.90 g, 83%). 1 HNMR(400MHz,CDCl 3 )δ H 3.78-3.69 (m, 1H), 3.18 (d, j=10.0 hz, 1H), 3.05 (d, j=10.0 hz, 1H), 2.84 (s, 3H), 2.78-2.66 (m, 1H), 1.96-1.61 (m, 9H), 1.57-1.37 (m, 2H), 1.35-1.19 (m, 8H), 1.16-0.87 (m, 6H), 0.75 (s, 3H), 0.72-0.64 (m, 1H). LC-ELSD/MS: purity = 92%, MS ESI C 24 H 37 N 4 [M+H] + Is 381.3 and the experimental value is 381.3.
14.4 Synthesis
To a solution of 14.3 (7.90 g,20.7 mmol) in MeOH (700 mL) was added a solution of KOH (160 g,2.8 mol) in water (120 mL). The mixture was refluxed for 48h at 77 ℃. Water (800 mL) was added to the mixture and concentrated. The residue was extracted with DCM (3X 200 mL). The combined organic layers were washed with brine (100 mL), and dried over Na 2 SO 4 Dried, filtered and concentrated to give 14.4 (6.60 g, 96%). 1 H NMR(400MHz,CDCl 3 )δ H 3.25-3.15 (m, 1H), 2.77 (d, j=11.6 hz, 1H), 2.53 (d, j=12.0 hz, 1H), 2.41 (s, 3H), 2.38-2.27 (m, 1H), 1.87-1.39 (m, 12H), 1.36-1.12 (m, 7H), 1.09 (d, j=6.4 hz, 3H), 1.06-0.88 (m, 5H), 0.71 (s, 3H), 0.69-0.60 (m, 1H). LC-ELSD/MS: purity=97%, MS ESI C 11 H 20 N[M+2H] ++ Calculation of/2A value of 166.2 and an experimental value of 166.2; c (C) 22 H 39 N 2 [M+H] + Calculated for 331.3 and experimental for 331.3.
14.5 Synthesis
At N 2 Next, NCS (6.63 g,49.7 mmol) was added to a solution of 14.4 (6.60 g,19.9 mmol) in DCM (800 mL). The mixture was stirred at 25℃for 1h. The mixture was concentrated in vacuo at below 35 ℃ to afford intermediate 14.5 (15.0 g, crude). LC-ELSD/MS: purity = 96%, MS ESI C 22 H 37 Cl 2 N 2 [M+H] + Is 399.2 and the experimental value is 399.1.
14.6 Synthesis
At N 2 Intermediate 14.5 (15.0 g) was dissolved in THF/MeOH (80 mL/20 mL) and added to MeONa/MeOH solution (10.0 g Na dissolved in 1000mL MeOH) and stirred at 65℃for 1h. The mixture was concentrated in vacuo. H is added to the residue at 0 DEG C 2 SO 4 (1000 mL, 2M) and the mixture was stirred at 25℃for 16h. With NH 3 .H 2 O (400 mL, concentrate 14M) basified the mixture and extracted the mixture with DCM (2X 300 mL). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (10% to 40% ethyl acetate in petroleum ether, 1% TEA added) to give 14.6 (5.50 g, 88%). 1 H NMR(400MHz,CDCl 3 )δ H 3.60-3.52 (m, 1H), 3.46-3.38 (m, 1H), 2.58-2.48 (m, 2H), 2.45-2.22 (m, 3H), 2.12-2.00 (m, 2H), 1.98 (s, 3H), 1.83-1.48 (m, 7H), 1.42-1.18 (m, 6H), 1.11-1.01 (m, 2H), 0.99 (s, 3H), 0.73-0.85 (m, 1H). LC-ELSD/MS: purity = 95%, MS ESI C 21 H 32 NO[M+H] + Is 314.2 and the experimental value is 314.2.
14.7 Synthesis
To a solution of 14.6 (5.50 g,17.5 mmol) in AcOH (500 mL) and water (100 mL) at 5℃NaNO was added dropwise 2 (12.0 g,175mmol in 50mL of water). The mixture was stirred at 10℃for 2h. To the mixture was added water (1000 mL) and extracted with DCM (3×250 mL). The combined organic layers were treated with NaHCO 3 (1000 mL, saturated) washWashing with Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (10% -16% ethyl acetate in petroleum ether) to give 14.7 (1.88 g, 34%). A portion (100 mg) of the product was recrystallized from MeCN/water (20 ml, 1:1) to give 14.7 (54.0 mg). 1 H NMR(400MHz,CDCl 3 )δ H 2.77 (dd, j=8.0, 11.2hz, 1H), 2.43-2.14 (m, 7H), 2.12-1.99 (m, 2H), 1.96-1.62 (m, 7H), 1.56-1.23 (m, 6H), 0.94-0.81 (m, 4H), 0.76 (d, j=5.2 hz, 1H), 0.70-0.59 (m, 1H), 0.21 (d, j=5.2 hz, 1H). LC-ELSD/MS: purity of >99％，MS ESI C 21 H 31 O 2 [M+H] + Is 315.2, and the experimental value is 315.2.
Synthesis of Compound No. 22
At 10 ℃ N 2 A suspension of LiCl (254 mg,6.0mmol, anhydrous) in THF (20 mL, anhydrous) was stirred for 30min. Then FeCl is added at 10 DEG C 3 (509 mg,3.14mmol, anhydrous). The mixture was cooled to-30 ℃. To the mixture was added MeMgBr (3.80 ml,3m in ether, 11.4 mmol) dropwise at-30 ℃. The resulting mixture was stirred at-30℃for 10min. Compound 14.7 (300 mg,0.95 mmol) in THF (5 mL) was added at-30deg.C. The reaction mixture was stirred at-15℃for 1 hour. Citric acid (30 ml,10% aqueous solution) was added to the mixture. The mixture was extracted with EtOAc (2X 20 mL). The combined organic phases were taken up in anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified twice by flash column (10% -20% ethyl acetate in petroleum ether) and lyophilized to give 22 (160 mg, 51%). 1 H NMR(400MHz,CDCl 3 )δ H 2.75 (dd, j=8.0, 11.2hz, 1H), 2.18-2.08 (m, 4H), 1.92-1.72 (m, 3H), 1.69-1.57 (m, 3H), 1.55-1.12 (m, 16H), 0.83-0.58 (m, 6H), 0.17 (d, j=5.2 hz, 1H). LC-ELSD/MS: purity of>99％，MS ESI C 22 H 34 O 2 [M+H-H 2 O] + Is 313.2 and the experimental value is 313.2.
Example No. 15: synthesis of 1- (2- ((3R, 5S,8R,9S,10S,13S,14S, 17S) -3-hydroxy-3, 10-dimethyldecatetrahydro-1H-13, 14-methylcyclopenta [ a ] phenanthren-17-yl) -2-oxoethyl) -1H-pyrazole-4-carbonitrile (Compound No. 2).
15.1 Synthesis
To a solution of Compound No. 22 (105 mg,0.32 mmol) in MeOH (4 mL) were added HBr (6.4 mg,40% aqueous solution, 0.03 mmol) and Br 2 (55.8 mg,0.35 mmol). The mixture was stirred at 20℃for 1h. Addition of NaHCO to the mixture 3 (5 mL, saturated aqueous) and extracted with EtOAc (2X 10 mL). The combined organic layers were separated over Na 2 SO 4 Dried, filtered and concentrated to give 15.1 (130 mg, crude). 1 H NMR(400MHz,CDCl 3 )δ H 4.00(s,2H),3.08(dd,J＝7.6,10.8Hz,1H),2.25-2.05(m,2H),1.90-1.10(m,18H),0.80-0.65(m,6H),0.62(s,3H),0.19(d,J＝5.6Hz,1H)。
Synthesis of Compound No. 23
To a solution of 15.1 (130 mg,0.32 mmol) in acetone (2 mL) was added K 2 CO 3 (131 mg,0.95 mmol) and 4-cyano-pyrazole (35.4 mg,0.38 mmol). The mixture was stirred at 25℃for 16h. To the mixture was added water (10 mL) and extracted with EtOAc (10 mL). The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (30% to 50% ethyl acetate in petroleum ether), recrystallized from MeCN/water (20 ml, 1:1) and lyophilized to give 23 (42.6 mg, 32%). 1 H NMR(400MHz,CDCl 3 )δ H 7.87 (s, 1H), 7.82 (s, 1H), 5.12 (d, j=18.0 hz, 1H), 5.04 (d, j=18.0 hz, 1H), 2.87 (dd, j=8.0, 11.6hz, 1H), 2.23-2.15 (m, 1H), 1.94-1.79 (m, 3H), 1.76-1.57 (m, 4H), 1.51-1.10 (m, 15H), 0.83-0.73 (m, 2H), 0.71-0.59 (m, 4H), 0.25 (d, j=5.2 hz, 1H). LC-ELSD/MS: purity of >99％，MS ESI C 26 H 35 N 3 O 2 [M+H-H 2 O] + Is 404.3, and the experimental value is 404.3.
Example No. 16: synthesis of 1- (((1S, 2R) -2- ((3R, 5R,8R,9R,10S,13S,14S, 17R) -3-hydroxy-3, 13-dimethylhexadecyl-1H-cyclopenta [ a ] phenanthren-17-yl) cyclopropyl) methyl) -1H-pyrazole-4-carbonitrile (Compound No. 24) and 1- (((1R, 2S) -2- ((3R, 5R,8R,9R,10S,13S,14S, 17R) -3-hydroxy-3, 13-dimethylhexadecyl-1H-cyclopenta [ a ] phenanthren-17-yl) cyclopropyl) methyl) -1H-pyrazole-4-carbonitrile (Compound No. 25).
16.2 Synthesis
At 15 ℃ N 2 Downward to PPh 3 To a mixture of MeBr (24.5 g,68.8 mmol) in THF (100 ml) was added t-BuOK (7.70 g,68.8 mmol). The resulting mixture was stirred at 50℃for 60min. At below 50℃16.1 (10 g,34.4 mmol) was added in portions. After stirring at 50℃for 16 hours, the reaction mixture was treated with 10% NH 4 Aqueous Cl (100 ml) was quenched and extracted with EtOAc (2X 100 ml). The combined organic phases were concentrated in vacuo. The residue was purified at 25℃with (MeOH/H 2 O=1/1 (350 ml) }) to give 16.2 (13 g). 1 H NMR(400MHz,CDCl 3 )δ H 4.64-4.62(m,1H),4.62-4.58(m,1H),2.56-2.38(m,1H),2.31-2.17(m,1H),1.93-1.58(m,8H),1.54-1.36(m,6H),1.35-1.24(m,7H),1.15-1.03(m,4H),0.78(s,3H)。
16.3 Synthesis
9-BBN dimer (21.7 g,90.0 mmol) was added to a solution of 16.2 (13 g,45.0 mmol) in THF (250 ml), and the mixture was stirred at 15℃for 16 hours. To the mixture was added EtOH (31 ml,540 mmol) dropwise followed by NaOH (21.6 g in 108ml water, 5M,540 mmol) and H 2 O 2 (54 ml,10M,540 mmol). The mixture was stirred at 78 ℃ for 1h. The mixture was passed through Na 2 S 2 SO 3 (250 ml, 10%) and extracted with EtOAc (2X 200 ml). The organic layer was separated over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% -40% ethyl acetate in petroleum ether) to give 16.3 (22 g). 1 H NMR(400MHz,CDCl 3 )δ H 3.75-3.66(m,1H),3.59-3.48(m,1H),1.84-1.76(m,5H),1.65-1.63(m,3H),1.48-1.43(m,6H),1.33-1.24(m,8H),1.22-0.96(m,7H),0.64(s,3H)。
16.4 Synthesis
To a solution of 16.3 (22 g,71.7 mmol) in DCM (300 ml) was added silica gel (30.7 g) and PCC (30.7 g,143 mmol) at 0deg.C. The mixture was stirred at 10℃for 4 hours. PE (150 ml) was added to the reaction mixture. The resulting mixture was filtered through a pad of silica gel and the filter cake was washed with DCM (3X 200 ml). The residue was filtered and concentrated in vacuo to give the product. The crude product was purified by silica gel chromatography (0% -25% ethyl acetate in petroleum ether) to give 16.4 (8 g). 1 H NMR(400MHz,CDCl 3 )δ H 9.76(d,J＝2.1Hz,1H),2.33-2.27(m,1H),2.01-1.99(m,1H),1.83-1.73(m,7H),1.48-1.31(m,10H),1.26(s,3H),1.23-0.99(m,6H),0.75(s,3H)。
16.5 Synthesis
At 15 ℃ N 2 Downward to PPh 3 To a mixture of MeBr (18.7 g,52.4 mmol) in THF (75 ml) was added t-BuOK (5.86 g,52.4 mmol). The resulting mixture was stirred at 50℃for 60min. Compound 16.4 (8 g,26.2 mmol) was added in portions at less than 50 ℃. After stirring at 50℃for 6 hours, the reaction mixture was treated with 10% NH 4 Aqueous Cl (80 ml) was quenched and extracted with EtOAc (2X 80 ml). The combined organic phases were concentrated in vacuo. The residue was taken up in (MeOH: H) at 25 ℃ 2 O=1:1 (261 ml)) to give 16.5 (8 g). 1 H NMR(400MHz,CDCl 3 )δ H 5.82-5.69(m,1H),4.98(s,1H),4.96-4.89(m,1H),1.96(q,J＝8.9Hz,1H),1.90-1.62(m,8H),1.54-1.28(m,9H),1.26(s,3H),1.24-0.95(m,7H),0.59(s,3H)。
16.6 Synthesis
To a solution of 16.5 (1.1 g,3.63 mmol) in DCM (15 ml) was added DMAP (442 mg,3.63 mmol) and acetic anhydride (1.47 g,1.36ml,14.5 mmol). After stirring at 25 ℃ for 16 hours, the residue was poured into ice water (50 ml) and extracted with DCM (2×50 ml). The combined organic phases were washed with saturated brine (2X 100 ml), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% to 2% ethyl acetate in petroleum ether) to give 16.6 (1.1 g, 88%). 1 H NMR(400MHz,CDCl 3 )δ H 5.82-5.60(m,1H),4.98(s,1H),4.96-4.93(m,1H),1.98(s,5H),1.87-1.73(m,5H),1.70-1.59(m,5H),1.55-1.54(m,3H),1.51-1.23(m,6H),1.16-0.97(m,6H),0.59(s,3H)。
16.7 Synthesis
To a solution of 16.6 (370 mg,1.07 mmol) and rhodium (II) acetate dimer (2.36 mg,0.005 mmol) in refluxing DCM (5 ml) was added dropwise a solution of ethyl diazoacetate (670 mg,5.88 mmol) in DCM (10 ml). After stirring at 45 ℃ for 1 hour and then at 20 ℃ for 16 hours, the residue was poured into water (50 ml) and extracted with DCM (2×50 ml). The combined organic phases were washed with brine (2X 50 ml), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by flash column (0% to 0.5% ethyl acetate in petroleum ether) to give 16.7 (410 mg, 89.1%). 1 H NMR(400MHz,CDCl 3 )δ H 4.19-4.04(m,2H),2.03-1.90(m,4H),1.89-1.57(m,10H),1.54(s,3H),1.49-1.19(m,11H),1.18-0.83(m,8H),0.80-0.60(m,4H)。
16.8 Synthesis
At N 2 Down to LiAlH 4 To a solution of (36.1 mg,0.95 mmol) in THF (10 ml) was added 1.7 (410 mg,0.95 mmol) in THF (5 ml). After stirring at 20℃for 1H, H in THF (10 ml) was added to the mixture 2 O (0.5 ml), 10% aqueous NaOH (0.5 ml) and H 2 O (1.5 ml). The mixture was filtered, concentrated and purified twice by flash column (0% to 45% ethyl acetate in petroleum ether) to give 16.8 (29.6 mg, 9.0%). 1 H NMR(400MHz,CDCl 3 )δ H 3.59-3.35 (m, 2H), 1.90-1.75 (m, 5H), 1.65-1.60 (m, 2H), 1.49-1.33 (m, 7H), 1.26 (m, 6H), 1.19-0.87 (m, 7H), 0.72 (d, j=2.40 hz, 4H), 0.53-0.21 (m, 3H). LC-ELSD/MS purity>99％；MS ESI C 23 H 38 O 2 [M-2H 2 O+H] + Is 311.2 and the experimental value is 311.2.
16.9 Synthesis
To a solution of 16.8 (700 mg,2.01 mmol) in DCM (30 mL) was added N-methylimidazole (247 mg,3.01 mmol), TEA (2.21 mL,16.0 mmol) and TsCl (1.53 g,8.04 mmol). After stirring at 15℃for 6 hours, the mixture was poured into water (100 mL)And extracted with EtOAc (2×50 mL). The combined organic phases were washed with water (2X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated to 16.9 (1 g). 1 H NMR(400MHz,CDCl 3 )δ H 7.78(m,2H)7.33(m,2H)3.14-3.30(m,2H)2.44(s,3H)1.62-1.72(m,8H)1.33-1.40(m,10H)0.91-1.07(m,10H)0.66(s,3H)0.27-0.52(m,4H)。
Synthesis of Compound No. 24 and Compound No. 25
To a solution of 16.9 (1 g,1.99 mmol) in DMF (30 ml) was added Cs 2 CO 3 (1.30 g,3.98 mmol) and 4-cyano-pyrazole (370 mg,3.98 mmol). After stirring at 80℃for 16 hours, the mixture was diluted with EtOAc (2X 60 ml) and washed with water (100 ml), liCl (5%, 100ml aqueous solution) and dried over Na 2 SO 4 Drying and filtering. The residue was purified by flash column (0% to 20% ethyl acetate in petroleum ether) and by SFC (column: chiralpak AD-3 50)D.,3 um); mobile phase: a: CO 2 B: ethanol (0.05% dea); gradient: isocratic: 40% B, flow rate (ml/min): 4) Isolation to give compound No. 24 (97.5 mg, 24%) and compound No. 25 (136.3 mg, 33%).
Compound No. 24: 1 H NMR(400MHz,CDCl 3 )δ H 7.86 (s, 1H) 7.79 (s, 1H) 4.02 (m, 2H) 1.44-1.87 (m, 11H) 1.35-1.40 (m, 6H) 1.25 (s, 3H) 0.87-1.13 (m, 8H) 0.61-0.69 (m, 2H) 0.59 (s, 3H) 0.36-0.50 (m, 2H). LC-ELSD/MS purity>99%, analytical SFC:100% de; MS ESI C 27 H 39 N 3 O[M+H-H 2 O] + Is 404.3, and the experimental value is 404.3.
Compound No. 25: 1 H NMR(400MHz,CDCl 3 )δ H 7.90 (s, 1H) 7.79 (s, 1H) 4.10 (dd, j=14.00, 6.80hz, 1H) 3.93 (dd, j=14.00, 7.60hz, 1H) 1.63-1.91 (m, 7H) 1.28-1.58 (m, 10H) 1.25 (s, 3H) 0.92-1.22 (m, 8H) 0.70 (s, 3H) 0.49-0.68 (m, 4H). LC-ELSD/MS purity>99％，MS ESI C 27 H 39 N 3 O[M+H-H 2 O] + Calculated as 404.3 and experimental as 404.3。
Example No. 17: synthesis of (3R, 5R,8R,9R,10S,13S,14S, 17R) -3, 13-dimethyl-17- ((1S, 2R) -2- ((5-methyl-2H-tetrazol-2-yl) methyl) cyclopropyl) hexadeca-1H-cyclopenta [ a ] phenanthren-3-ol (Compound No. 28) and (3R, 5R,8R,9R,10S,13S,14S, 17R) -3, 13-dimethyl-17- ((1R, 2S) -2- ((5-methyl-2H-tetrazol-2-yl) methyl) cyclopropyl) hexadeca-1H-cyclopenta [ a ] phenanthren-3-ol (17 a)
17.1 and 17.1a Synthesis
To a solution of 16.9 (390 mg,0.79 mmol) in DMF (12 mL) was added Cs 2 CO 3 (508 mg,1.55 mmol) and 5-methyl-2H-1, 2,3, 4-tetrazole (130 mg,1.55 mmol). After stirring at 80℃for 16 h, the mixture was diluted with EtOAc (2X 60 mL) and washed with water (100 mL), liCl (5%, 100mL aqueous solution) and dried over Na 2 SO 4 Dried, filtered and purified by flash column (0% to 60% ethyl acetate in petroleum ether) to give 17.1 (76 mg, mixture) and 17.1a (55 mg, mixture). By SFC (column: chiralpak AD-3 50)D.,3um mobile phase: a: CO 2B: ethanol (0.05% DEA); gradient: isocratic: 40% B, flow rate (ml/min): 4) 17.1 (76 mg,0.184 mmol) was isolated to give compound nos. 28 (40 mg, 53%) and 2a (20 mg, 26%).
Compound No. 28: 1 H NMR(400MHz,CDCl 3 )δ H 4.48 (dd, j=13.60, 6.80hz, 1H) 4.30 (dd, j=13.60, 7.60hz, 1H) 2.53 (s, 3H) 1.75-1.91 (m, 4H) 1.60-1.66 (m, 2H) 1.27-1.57 (m, 9H) 1.25 (s, 4H) 1.14-1.24 (m, 2H) 0.91-1.12 (m, 7H) 0.68 (s, 5H) 0.56-0.63 (m, 1H) 0.47-0.56 (m, 1H). LC-ELSD/MS purity>99%, analytical SFC:100% de; MS ESI C 25 H 40 N 4 O[M+H] + Calculated for (2) is 413.3 and experimental is 413.3.
17a： 1 H NMR(400MHz,CDCl 3 )δ H 4.55(dd,J＝13.60,7.20hz, 1H) 4.26 (dd, j=14.00, 8.40hz, 1H) 2.53 (s, 3H) 1.68-1.89 (m, 4H) 1.59-1.64 (m, 1H) 1.51-1.57 (m, 2H) 1.27-1.47 (m, 9H) 1.25 (s, 3H) 0.80-1.23 (m, 9H) 0.68-0.78 (m, 1H) 0.54 (s, 5H) 0.35-0.44 (m, 1H). LC-ELSD/MS purity >99%, analytical SFC:100% de; MS ESI C 25 H 40 N 4 O[M+H] + Calculated for (2) is 413.3 and experimental is 413.3.
Example No. 18: synthesis of (3R, 5R,8R,9R,10S,13S,14S, 17R) -3, 13-dimethyl-17- ((1R, 2S) -2- ((5-methyl-1H-tetrazol-1-yl) methyl) cyclopropyl) hexadeca-1H-cyclopenta [ a ] phenanthren-3-ol (Compound No. 26) and (3R, 5R,8R,9R,10S,13S,14S, 17R) -3, 13-dimethyl-17- ((1S, 2R) -2- ((5-methyl-1H-tetrazol-1-yl) methyl) cyclopropyl) hexadeca-1H-cyclopenta [ a ] phenanthren-3-ol (Compound No. 27)
Synthesis of Compound No. 26 and Compound No. 27
17.1a (40 mg) was isolated by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm. Times.30 mm,5 um; conditions: 0.1% NH3H2O ETOH; start B:20%; end B: 20%) to give compound No. 26 (4.4 mg, 11%) and compound No. 27 (13.7 mg, 34%).
Compound No. 26: 1 H NMR(400MHz,CDCl 3 )δ H 4.24 (dd, j=14.40, 6.40hz, 1H) 4.07 (dd, j=14.40, 8.00hz, 1H) 2.58 (s, 3H) 1.57-1.85 (m, 6H) 1.27-1.47 (m, 9H) 1.25 (s, 3H) 0.84-1.23 (m, 10H) 0.60-0.76 (m, 2H) 0.57 (s, 3H) 0.40-0.55 (m, 2H). LC-ELSD/MS purity>99%, analytical SFC:100% de; MS ESI C 25 H 40 N 4 O[M-H2O+H] + Is 395.3 and the experimental value is 395.3.
Compound No. 27: 1 H NMR(400MHz,CDCl 3 )δ H 4.22 (dd, j=14.40, 7.20hz, 1H) 4.08 (dd, j=14.40, 8.00hz, 1H) 2.58 (s, 3H) 1.58-1.87 (m, 7H) 1.27-1.55 (m, 9H) 1.25 (s, 3H) 0.92-1.23 (m, 9H) 0.68 (s, 7H). LC-ELSD/MS purity >99%, analytical SFC:100% de; MS ESI C 25 H 40 N 4 O[M+H] + Calculated for (2) is 413.3 and experimental is 413.3.
Example 19: measurement
TBPS-bound steroid inhibition
Use of rat cerebral cortex membrane in the Presence of 5mM GABA [ 35 S]The t-butyl bicyclo phosphorothioate (TBPS) binding assay has been described (Gee et al, J.Pharmacol.Exp. Ther.1987,241,346-353; hawkinson et al, mol. Pharmacol.1994,46,977-985; lewis, A.H et al, mol. Pharmacol.1989,35, 189-194).
Briefly, after carbon dioxide anesthetized Sprague-Dawley rats (200-250 g) were decapitated, the cortex was rapidly removed. The cortex was homogenized in 10 volumes of ice-cold 0.32M sucrose using a glass/teflon homogenizer and centrifuged at 1500x g for 10min at 4 ℃. The resulting supernatant was centrifuged at 10,000Xg for 20min at 4℃to obtain a P2 precipitate. The P2 pellet was resuspended in 200mM NaCl/50mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000Xg for 10min at 4 ℃. This washing procedure was repeated twice and the pellet was resuspended in 10 volumes of buffer. An aliquot of the membrane suspension (100 mL) was combined with 3nM [ in the presence of 5mM GABA 35 S]TBPS was incubated with 5mL aliquots (final 0.5%) of test drug dissolved in dimethyl sulfoxide (DMSO). Incubation was brought to a final volume of 1.0mL with buffer. Nonspecific binding was determined in the presence of 2mM unlabeled TBPS and ranged from 15% to 25%. After incubation for 90min at room temperature, the assay was terminated by filtration through a glass fiber screen (Schleicher and Schuell number 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. The filter screen bound radioactivity was measured by liquid scintillation spectrometry. A non-linear curve fit was performed using Prism (GraphPad) on the overall data for each drug averaged for each concentration. If the sum of squares is significantly lower by the F test, the data is fit to the partial inhibition model, rather than the complete inhibition model. Similarly, if the sum of squares is significantly lower by the F test, the data is fitted to a two-component inhibition model instead of a one-component inhibition model. The 50% inhibition of specific binding by individual experiments was determined with the same model used for the overall data Concentration of test compound (IC 50 ) And maximum inhibition degree (I max ) And then the mean ± SEM of the individual experiments was calculated. Kuotoxin was used as a positive control for these studies, as it has been demonstrated to robustly inhibit TBPS binding.
Screening or screenable of various compounds to determine them as [ 35 S]Potential of modulators of TBPS binding in vitro. These assays are or may be performed according to the above.
In Table 2 below, A indicates TBPS IC 50 (μM)<0.1. Mu.M, B indicates TBPS IC 50 (mu M) of 0.1 mu M to<1.0. Mu.M, and C indicates TBPS IC 50 (μM)≥1.0μM。
Table 2: TBPS assay data.
Equivalent scheme and scope
In the claims, articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise clear from the context. Unless indicated to the contrary or otherwise clear from the context, a claim or specification that includes an "or" between a set of one or more members is considered to satisfy one, more than one, or all of the set of members present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise associated with a given product or process. The present invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise associated with a given product or process.
Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms of one or more listed claims are introduced into another claim. For example, any claim that depends from another claim may be modified to include one or more of the limitations found in any other claim that depends from the same underlying claim. When elements are presented as a manifest, for example, in a Markush group format, each sub-group of elements is also disclosed, and any element may be removed from the group. It should be understood that, in general, where the invention or aspects of the invention are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist of or consist essentially of such elements and/or features. For simplicity, those embodiments are not explicitly described herein in the text (in haec vera). It should also be noted that the terms "comprising" and "including" are intended to be open and allow for the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless indicated to the contrary or otherwise clear from the context and understanding of one of ordinary skill in the art, values expressed as ranges can be assumed to be any specific value or subrange within the illustrated ranges in the different embodiments of the invention, unless the context clearly indicates otherwise, to the tenth of the unit of the lower limit of the range.
The present application relates to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any incorporated reference and this specification, the present specification shall control. In addition, any particular embodiment of the application that belongs to the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are believed to be known to one of ordinary skill in the art, they may be excluded even if not explicitly set forth herein. For any reason, any particular embodiment of the application, whether related to the existence of prior art or not, may be excluded from any claims.
Other embodiments
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the application described herein is not intended to be limited by the foregoing description, but rather is set forth in the following claims. It will be understood by those skilled in the art that various changes and modifications may be made to the present description without departing from the spirit or scope of the application, as defined in the following claims.

Claims (196)

1. A compound of formula (I)
Or a pharmaceutically acceptable salt thereof, wherein
Ring D is selected from
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 、R 20a 、R 20b 、R 20c And R is 21 Each of which is-L A -R 30 ；
Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
each R 30 Independently selected from R', -OH, halo, -CN, -NO 2 and-CF 3 ；
Each R' is independently selected from-H, optionally substituted C 1-6 Alkyl, optionally substituted C 2-6 Alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted C 1-6 alkyl-O-C 1-6 Alkyl and optionally substituted 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, or
R 1a And R is 1b Together form oxo, or
R 2a And R is 2b Together form oxo, or
R 4a And R is 4b Together form oxo, or
R 6a And R is 6b Together form oxo, or
R 7a And R is 7b Together form oxo, or
R 11a And R is 11b Together form oxo, or
R 12a And R is 12b Together form oxo, or
R 20a And R is 20b Together forming oxo;
R 5 and R is 20c Each of which is independently selected from-H and optionally substituted C 1-6 An alkyl group;
R 10 is-H, optionally substituted C 1-6 Alkyl or optionally substituted C 1-6 alkyl-O-C 1-6 An alkyl group;
R 31a and R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl and-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S;
m is 1 or 2; and is also provided with
n is 0, 1 or 2,
provided that when R 31a And R is 31b One of them is-OR 32 When R is 31a And R is 31b The other of which is-H.
2. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (I) is a compound of formula (II)
Or a pharmaceutically acceptable salt thereof, wherein
Ring D is a fused bicyclic ring selected from
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 ；
Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 r', halo, -CN, -NO 2 or-CF 3 ；
Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl of R Or a 3-8 membered ring optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Substituted by a group of (2), or
R 1a And R is 1b Together form oxo, or
R 2a And R is 2b Together form oxo, or
R 4a And R is 4b Together form oxo, or
R 6a And R is 6b Together form oxo, or
R 7a And R is 7b Together form oxo, or
R 11a And R is 11b Together form oxo, or
R 12a And R is 12b Together form oxo, or
R 20a And R is 20b Together forming oxo;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H or optionally substituted C 1-6 An alkyl group;
R 13 is-H or optionally substituted C 1-6 An alkyl group;
R 31a and R is 31b Each of which is independently selected from-H, halo, C 1-6 Alkyl and-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S; and is also provided with
n is 0, 1 or 2,
provided that when R 31a And R is 31b One of them is-OR 32 When R is 31a And R is 31b The other of which is-H.
3. The compound or pharmaceutically acceptable salt of claim 2, wherein R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
4. A compound or pharmaceutically acceptable salt as claimed in claim 2 or claim 3, wherein R 3 is-H or C optionally substituted by R 1-6 An alkyl group.
5. The compound or pharmaceutically acceptable salt of any one of claims 2-4, wherein R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 。
6. The compound or pharmaceutically acceptable salt of any one of claims 2-5, wherein R 13 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
7. The compound or pharmaceutically acceptable salt of any one of claims 2-6, wherein R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
8. The compound or pharmaceutically acceptable salt of any one of claims 2-7, wherein R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl.
9. The compound or pharmaceutically acceptable salt of any one of claims 2-8, wherein R 13 Is methyl.
10. The compound or pharmaceutically acceptable salt of any one of claims 2-9, wherein R 20a And R is 20b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo.
11. The compound or pharmaceutically acceptable salt of any one of claims 2-10, wherein R 20a And R is 20b Each of which is independently selected from-H, C 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo.
12. The compound or pharmaceutically acceptable salt of any one of claims 2-11, wherein R 20a And R is 20b Together forming oxo.
13. The compound or pharmaceutically acceptable salt of any one of claims 2-12, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -、-CH 2 -CH 2 -CH 2 -or-NH-; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
14. The compound or pharmaceutically acceptable salt of any one of claims 2-13, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-NH-; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
15. The compound or pharmaceutically acceptable salt of any one of claims 2-14, wherein R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein theThe 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
16. The compound or pharmaceutically acceptable salt of any one of claims 2-15, wherein R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein the method comprises the steps of
X 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that
(i)X 1 、X 2 、X 3 And X 4 At least one of which is N, and
(ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
17. The compound or pharmaceutically acceptable salt of claim 2, wherein the compound of formula (II) is a compound of formula (II-a) or (II-B)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 ；
Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 ；
Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Substituted by a group of (2), or
R 20a And R is 20b Together forming oxo;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H or optionally substituted C 1-3 An alkyl group; and is also provided with
R 13 is-H or optionally substituted C 1-3 An alkyl group.
18. The compound or pharmaceutically acceptable salt of claim 17, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group;
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 independently selected from R', halo, -CN, -NO 2 and-CF 3 ；
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
19. The compound or pharmaceutically acceptable salt of claim 2, wherein the compound of formula (II) is a compound of formula (II-C)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4a 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 ；
Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 ；
Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Substituted by a group of (2), or
R 20a And R is 20b Together forming oxo;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H or optionally substituted C 1-3 An alkyl group; and is also provided with
R 13 is-H or optionally substituted C 1-3 An alkyl group.
20. The compound or pharmaceutically acceptable salt of claim 19, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H or C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN,-NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
21. The compound or pharmaceutically acceptable salt of claim 17 or claim 18, wherein the compound of formula (II-a) is a compound of formula (II-A1) or (II-A2)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 or-CH 3 Is substituted with a group of (a).
22. The compound or pharmaceutically acceptable salt of claim 17 or claim 18, wherein the compound of formula (II-B) is a compound of formula (II-B1) or (II-B2)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted by-NR', -S-, -O-, -OC (O) -,
-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、-NR'C(O)O-、
-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、
-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
23. The compound or pharmaceutically acceptable salt of claim 19 or claim 20, wherein the compound of formula (II-C) is a compound of formula (II-C1) or (II-C2)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H or C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
24. The compound or pharmaceutically acceptable salt of claim 21, wherein the compound of formula (II-A1) is a compound of formula (II-A1 a), (II-A1 b), (II-A1 c), or (II-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
25. Such asThe compound or pharmaceutically acceptable salt of claim 21, wherein the compound of formula (II-A2) is a compound of formula (II-A2 a), (II-A2 b), (II-A2 c), or (II-A2 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independentlyIs selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 or-CH 3 Is substituted with a group of (a).
26. The compound or pharmaceutically acceptable salt of claim 22, wherein the compound of formula (II-B1) is a compound of formula (II-B1 a), (II-B1B), (II-B1 c), or (II-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H or C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently up to two carbon atoms of (C)Is surrounded by-NR ' -, S-, -O-, -OC (O) -, -C (O) O-, -C (O) -, -C (O) C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 or-CH 3 Is substituted with a group of (a).
27. The compound or pharmaceutically acceptable salt of claim 22, wherein the compound of formula (II-B2) is a compound of formula (II-B2 a), (II-B2B), (II-B2 c), or (II-B2 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
28. The compound or pharmaceutically acceptable salt of claim 23, wherein the compound of formula (II-C1) is a compound of formula (II-C1 a), (II-C1 b), (II-C1C), or (II-C1 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H and C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
29. The compound or pharmaceutically acceptable salt of claim 23, wherein the compound of formula (II-C2) is a compound of formula (II-C2 a), (II-C2 b), (II-C2C), or (II-C2 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H or C 1-6 An alkyl group, a hydroxyl group,
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or optionally substituted C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl or-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 selected from R', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
30. The compound or pharmaceutically acceptable salt of claim 2, wherein the compound of formula (II) is a compound of formula (III)
Or a pharmaceutically acceptable salt thereof, wherein
Ring D is a fused bicyclic ring selected from
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 13 is-H or C 1-6 An alkyl group;
R 20a and R is 20b Each of which is independently-H, -OH, C 1-6 Alkyl, or
R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
31. A compound or pharmaceutically acceptable according to claim 30Acceptable salts, wherein R 13 Is C 1-6 An alkyl group.
32. The compound or pharmaceutically acceptable salt of claim 30 or claim 31, wherein R 13 Is methyl, ethyl or propyl.
33. The compound or pharmaceutically acceptable salt of any one of claims 30-32, wherein R 13 Is methyl.
34. The compound or pharmaceutically acceptable salt of any one of claims 30-33, wherein R 20a And R is 20b Together forming oxo.
35. The compound or pharmaceutically acceptable salt of any one of claims 30-33, wherein R 20a And R is 20b One of them is-H, and R 20a And R is 20b The other one is C 1-6 An alkyl group.
36. The compound or pharmaceutically acceptable salt of any one of claims 30-33, wherein R 20a And R is 20b One of them is C 1-6 Alkyl, and R 20a And R is 20b The other of (C) is-OH.
37. The compound or pharmaceutically acceptable salt of any one of claims 30-33 or 36, wherein R 20a And R is 20b One of them being methyl, ethyl or propyl, and R 20a And R is 20b The other of (C) is-OH.
38. The compound or pharmaceutically acceptable salt of any one of claims 30-33, wherein R 20a 、R 20b And the carbon to which it is attached
39. The compound or pharmaceutically acceptable salt of any one of claims 30-38, wherein R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
40. The compound or pharmaceutically acceptable salt of any one of claims 30-39, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
41. The compound or pharmaceutically acceptable salt of any one of claims 30-40, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
42. The compound or pharmaceutically acceptable salt of any one of claims 30-41, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that
(i)X 1 、X 2 、X 3 And X 4 At least one of which is N, and
(ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
43. The compound or pharmaceutically acceptable salt of claim 41, wherein R 30 Is thatX 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that
(i) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
44. The compound or pharmaceutically acceptable salt of claim 30, wherein the compound of formula (III) is a compound of formula (III-a) or (III-B)
Or a pharmaceutically acceptable salt thereof.
45. The compound or pharmaceutically acceptable salt of claim 44, wherein
R 3 Is methyl;
R 5 is-H;
R 10 is-H;
R 13 is-H or methyl;
R 20a and R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, -NH-, or-CH 2 -；
R 30 Independently selected from pyrazolyl, tetrazolyl, and pyridinyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
46. The compound or pharmaceutically acceptable salt of claim 30, wherein the compound of formula (III) is a compound of formula (III-C)
Or a pharmaceutically acceptable salt thereof.
47. The compound or pharmaceutically acceptable salt of claim 46, wherein
R 3 Methyl, ethyl, propyl or methoxymethyl;
R 5 is-H;
R 10 is-H;
R 13 is-H or methyl;
R 20a and R is 20b Each of which is independently selected from-H, -OH and methyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, -NH-, or-CH 2 -；
R 30 Independently selected from methyl, pyrazolyl, tetrazolyl and pyridyl, each of which is optionally halogenated, C 1-6 Alkyl or cyano substitution.
48. The compound or pharmaceutically acceptable salt of claim 44 or claim 45, wherein the compound of formula (III-A) is a compound of formula (III-A1) or (III-A2)
Or a pharmaceutically acceptable salt thereof.
49. The compound or pharmaceutically acceptable salt of claim 44 or claim 45, wherein the compound of formula (III-B) is a compound of formula (III-B1) or (III-B2)
Or a pharmaceutically acceptable salt thereof.
50. The compound or pharmaceutically acceptable salt of claim 46 or claim 47, wherein the compound of formula (III-C) is a compound of formula (III-C1) or (III-C2)
Or a pharmaceutically acceptable salt thereof.
51. The compound or pharmaceutically acceptable salt of claim 48, wherein the compound of formula (III-A1) is a compound of formula (III-A1 a), (III-A1 b), (III-A1 c), or (III-A1 d)
Or a pharmaceutically acceptable salt thereof.
52. The compound or pharmaceutically acceptable salt of claim 48, wherein the compound of formula (III-A2) is a compound of formula (III-A2 a), (III-A2 b), (III-A2 c), or (III-A2 d)
Or a pharmaceutically acceptable salt thereof.
53. The compound or pharmaceutically acceptable salt of claim 49, wherein the compound of formula (III-B1) is a compound of formula (III-B1 a), (III-B1B), (III-B1 c), or (III-B1 d)
Or a pharmaceutically acceptable salt thereof.
54. The compound or pharmaceutically acceptable salt of claim 49, wherein the compound of formula (III-B2) is a compound of formula (III-B2 a), (III-B2B), (III-B2 c), or (III-B2 d)
Or a pharmaceutically acceptable salt thereof.
55. The compound or pharmaceutically acceptable salt of claim 50, wherein the compound of formula (III-C1) is a compound of formula (III-C1 a), (III-C1 b), (III-C1C), or (III-C1 d)
Or a pharmaceutically acceptable salt thereof.
56. The compound or pharmaceutically acceptable salt of claim 50, wherein the compound of formula (III-C2) is a compound of formula (III-C2 a), (III-C2 b), (III-C2C), or (III-C2 d)
Or a pharmaceutically acceptable salt thereof.
57. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (I) is a compound of formula (IV)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 ；
Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR' -, -S-, -O-,
-OC(O)-、-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、
-NR'C(O)O-、-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、
-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 ；
Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH or-C (CH) 3 ) 3 Substituted by a group of (2), or
R 1a And R is 1b Together form oxo, or
R 2a And R is 2b Together form oxo, or
R 4a And R is 4b Together form oxo, or
R 6a And R is 6b Together form oxo, or
R 7a And R is 7b Together form oxo, or
R 11a And R is 11b Together form oxo, or
R 12a And R is 12b Together form oxo, or
R 20a And R is 20b Together forming oxo;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-)C 1-3 An alkyl group;
m is 1 or 2; and is also provided with
n is 0, 1 or 2.
58. The compound or pharmaceutically acceptable salt of claim 57, wherein R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
59. The compound or pharmaceutically acceptable salt of claim 57 or claim 58, wherein R 3 is-H or C optionally substituted by R 1-6 An alkyl group.
60. The compound or pharmaceutically acceptable salt of any one of claims 57-59, wherein R 3 is-H, -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 。
61. The compound or pharmaceutically acceptable salt of any one of claims 57-60, wherein m is 1 and R 15 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
62. The compound or pharmaceutically acceptable salt of any one of claims 57-61, wherein m is 1 and R 15 is-H or C optionally substituted by R 1-6 An alkyl group.
63. The compound or pharmaceutically acceptable salt of any one of claims 57-62, wherein m is 1 and R 15 is-H or C 1-3 An alkyl group.
64. The compound or pharmaceutically acceptable salt of any one of claims 57-63, wherein R 16 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
65The compound or pharmaceutically acceptable salt of any one of claims 57-64, wherein R 16 is-H or C optionally substituted by R 1-6 An alkyl group.
66. The compound or pharmaceutically acceptable salt of any one of claims 57-65, wherein R 16 is-H or C 1-3 An alkyl group.
67. The compound or pharmaceutically acceptable salt of any one of claims 57-66, wherein R 20a And R is 20b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo.
68. The compound or pharmaceutically acceptable salt of any one of claims 57-67, wherein R 20a And R is 20b Each of which is independently selected from-H, C 1-6 Alkyl, -N (R') 2 and-O-R', or R 20a And R is 20b Together forming oxo.
69. The compound or pharmaceutically acceptable salt of any one of claims 57-68, wherein R 20a And R is 20b Together forming oxo.
70. The compound or pharmaceutically acceptable salt of any one of claims 57-69, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -、-CH 2 -CH 2 -CH 2 -or-NH-; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 3-8 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
71. The compound or pharmaceutically acceptable salt of any one of claims 57-70, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-NH-; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
72. The compound or pharmaceutically acceptable salt of any one of claims 57-71, wherein R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
73. The compound or pharmaceutically acceptable salt of any one of claims 57-72, wherein R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein the method comprises the steps of
X 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that
(i)X 1 、X 2 、X 3 And X 4 At least one of which is N, and
(ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
74. The compound or pharmaceutically acceptable salt of claim 57, wherein the compound of formulSup>A (IV) is Sup>A compound of formulSup>A (IV-A)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 、R 16 、R 20a 、R 20b And R is 21 Each of which is-L A -R 30 ；
Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR' -, -S-, -O-,
-OC(O)-、-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、
-NR'C(O)O-、-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、
-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 ；
Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups having 0 to 4 heteroatoms independently selected from N, O and S3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Substituted by a group of (2), or
R 20a And R is 20b Together forming oxo;
R 5 is-H or C 1-3 An alkyl group; and is also provided with
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group.
75. The compound or pharmaceutically acceptable salt of claim 74, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 15 And R is 16 Each of which is independently selected from-H or C 1-6 An alkyl group;
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-5 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 15 and R is 16 Each of which is independently-H or C 1-6 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -C 1-5 alkyl-OH, C 1-6 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain, whereinL A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-
-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 r', halo, -CN, -NO 2 and-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
76. The compound or pharmaceutically acceptable salt of claim 74 or claim 75, wherein the compound of formulSup>A (IV-Sup>A) is Sup>A compound of formulSup>A (IV-Sup>A 1)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group;
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or a straight or branched C 1-3 An alkylene chain;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R' is-H, C 1-6 Alkyl or a 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein said 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
77. The compound or pharmaceutically acceptable salt of claim 76, wherein the compound of formula (IV-A1) is a compound of formula (IV-A1 a) or (IV-A1 b)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a And R is 2b Each of them is selected from-H and C 1-3 An alkyl group;
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or a straight or branched C 1-3 An alkylene chain;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R' is-H, C 1-6 Alkyl or a 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein said 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
78. The compound or pharmaceutically acceptable salt of claim 77, wherein the compound of formula (IV-A1 a) is a compound of formula (IV-A1) or (IV-A1 a 2)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group;
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or a straight chain C 1-3 An alkylene chain;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R' is-H, C 1-6 Alkyl or a 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein said 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
79. The compound or pharmaceutically acceptable salt of claim 77, wherein the compound of formula (IV-A1 b) is a compound of formula (IV-A1 b 1) or (IV-A1 b 2)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group;
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or C 1-3 An alkyl group;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from-H, -OH, -CH 2 OH、C 1-3 Alkyl and-NH 2 Or R is 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or a straight chain C 1-3 An alkylene chain;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R' is-H, C 1-6 Alkyl or a 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein said 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
80. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (I) is a compound of formula (V)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
81. The compound or pharmaceutically acceptable salt of claim 80, wherein R 20a And R is 20b Together forming oxo.
82. The compound or pharmaceutically acceptable salt of claim 80, wherein R 20a And R is 20b One of them is-H, and R 20a And R is 20b The other one is C 1-6 An alkyl group.
83. The compound of claim 80An agent or pharmaceutically acceptable salt, wherein R 20a And R is 20b One of them is C 1-6 Alkyl, and R 20a And R is 20b The other of (C) is-OH.
84. The compound or pharmaceutically acceptable salt of claim 80 or claim 83, wherein R 20a And R is 20b One of which is methyl, ethyl or propyl, and the other is-OH.
85. The compound or pharmaceutically acceptable salt of claim 80, wherein R 20a 、R 20b And the carbon to which it is attached
86. The compound or pharmaceutically acceptable salt of any one of claims 80-85, wherein R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
87. The compound or pharmaceutically acceptable salt of any one of claims 80-86, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-to 6-membered partially unsaturated or fully unsaturated monocyclic ring having 1 to 4 nitrogen atoms, whereinThe 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
88. The compound or pharmaceutically acceptable salt of any one of claims 80-87, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
89. The compound or pharmaceutically acceptable salt of any one of claims 80-88, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that
(i)X 1 、X 2 、X 3 And X 4 At least one of which is N, and
(ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
90. The assembly of claim 88Wherein R is a compound or pharmaceutically acceptable salt thereof 30 Is thatX 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that
(i) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
91. The compound or pharmaceutically acceptable salt of claim 80, wherein the compound of formulSup>A (V) is Sup>A compound of formulSup>A (V-Sup>A)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
92. The compound or pharmaceutically acceptable salt of claim 91, wherein
R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
93. The compound or pharmaceutically acceptable salt of claim 91, wherein the compound of formulSup>A (V-Sup>A) is Sup>A compound of formulSup>A (V-Sup>A 1) or (V-Sup>A 2)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
94. The compound or pharmaceutically acceptable salt of claim 93, wherein
R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
95. The compound or pharmaceutically acceptable salt of claim 93, wherein the compound of formula (V-A1) is a compound of formula (IV-A1 a) or (IV-A1 b)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or
R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
96. The compound or pharmaceutically acceptable salt of claim 94, wherein R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
97. The compound or pharmaceutically acceptable salt of claim 93, wherein the compound of formula (V-A2) is a compound of formula (V-A2 a) or (V-A2 b)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-6 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
98. The compound or pharmaceutically acceptable salt of claim 97, wherein
R 3 is-H, C 1-3 Alkyl, C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 20a and R is 20b Each of which is independently selected from the group consisting of-H, -OH and C 1-3 Alkyl, or R 20a And R is 20b Together forming oxo;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
99. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (I) is a compound of formula (VI)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 3 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 、R 17 And R is 21 Each of which is-L A -R 30 ；
Each L A Independently selected from bond and optionally substituted branched or straight chain C 1-6 Alkylene chain, wherein L A Optionally and independently substituted with-NR' -, -S-, -O-,
-OC(O)-、-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、
-NR'C(O)O-、-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、
-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
each R 30 Independently selected from R', halo, -CN, -NO 2 and-CF 3 ；
Each R' is independently selected from-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein each alkyl, alkenyl, alkynyl or 3-8 membered ring of R' is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C(CH 3 ) 3 substituted by a group of (2), or
R 1a And R is 1b Together form oxo, or
R 2a And R is 2b Together form oxo, or
R 4a And R is 4b Together form oxo, or
R 6a And R is 6b Together form oxo, or
R 7a And R is 7b Together form oxo, or
R 11a And R is 11b Together form oxo, or
R 12a And R is 12b Together forming oxo;
R 5 and R is 20c Is independently selected from-H and methyl;
R 10 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 31a and R is 31b Each of (3)
(i) Independently selected from-H, halo and C 1-6 Alkyl, or
(ii) When R is 31a And R is 31b When one of them is-H, R 31a And R is 31b The other of them is-H, halo, C 1-6 Alkyl OR-OR 32 Wherein R is 32 is-H, C 1-6 An alkyl group or a 3-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S;
n is 0, 1 or 2; and is also provided with
m is 1 or 2.
100. The compound or pharmaceutically acceptable salt of claim 99, wherein R 3 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
101. The compound or pharmaceutically acceptable salt of claim 99 or claim 100, wherein R 3 is-H or C optionally substituted by R 1-6 Alkyl group。
102. The compound or pharmaceutically acceptable salt of any one of claims 99-101, wherein R 3 is-H or methyl.
103. The compound or pharmaceutically acceptable salt of any one of claims 99-102, wherein R 13 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
104. The compound or pharmaceutically acceptable salt of any one of claims 99-103, wherein R 13 is-H or C optionally substituted by R 1-6 An alkyl group.
105. The compound or pharmaceutically acceptable salt of any one of claims 99-104, wherein R 13 is-H or C 1-3 An alkyl group.
106. The compound or pharmaceutically acceptable salt of any one of claims 99-105, wherein R 13 Is methyl.
107. The compound or pharmaceutically acceptable salt of any one of claims 99-106, wherein m is 1 and R 15 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
108. The compound or pharmaceutically acceptable salt of any one of claims 99-107, wherein m is 1 and R 15 is-H or C optionally substituted by R 1-6 An alkyl group.
109. The compound or pharmaceutically acceptable salt of any one of claims 99-108, wherein m is 1 and R 15 is-H or C 1-3 An alkyl group.
110. Any one of claims 99-109The compound or pharmaceutically acceptable salt thereof, wherein R 16 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
111. The compound or pharmaceutically acceptable salt of any one of claims 99-110, wherein R 16 is-H or C optionally substituted by R 1-6 An alkyl group.
112. The compound or pharmaceutically acceptable salt of any one of claims 99-111, wherein R 16 is-H or C 1-3 An alkyl group.
113. The compound or pharmaceutically acceptable salt of any one of claims 99-112, wherein R 17 is-H, C optionally substituted by R 1-6 Alkyl, -N (R') 2 or-O-R'.
114. The compound or pharmaceutically acceptable salt of any one of claims 99-113, wherein R 17 is-H or C optionally substituted by R 1-6 An alkyl group.
115. The compound or pharmaceutically acceptable salt of any one of claims 99-114, wherein R 17 is-H or C 1-3 An alkyl group.
116. The compound or pharmaceutically acceptable salt of any one of claims 99-115, wherein R 20c is-H.
117. The compound or pharmaceutically acceptable salt of any one of claims 99-116, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -CH 2 -or-CH 2 -CH 2 -; and R is 30 Is a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and SWherein said 3-8 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
118. The compound or pharmaceutically acceptable salt of any one of claims 99-117, wherein R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein the 5-6 membered ring is optionally substituted with 1-3 heteroatoms independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
119. The compound or pharmaceutically acceptable salt of any one of claims 99-118, wherein R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein said 5-6 membered ring is optionally substituted with 1-2 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
120. The compound or pharmaceutically acceptable salt of any one of claims 99-119, wherein R 21 is-L A -R 30 ；L A Is a bond or-CH 2 -; and R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Each of which is independently N or CR ", wherein each R" is independentThe site is selected from-H, halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that
(i)X 1 、X 2 、X 3 And X 4 At least one of which is N, and
(ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
121. The compound or pharmaceutically acceptable salt of claim 99, wherein the compound of formula (VI) is a compound of formula (VI-a) or (VI-B)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group;
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 and R is 20c Is independently selected from-H and methyl;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted by-NR', -S-, -O-, -OC (O) -,-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、-NR'C(O)O-、-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
122. The compound or pharmaceutically acceptable salt of claim 121, wherein the compound of formula (VI-a) is a compound of formula (VI-A1) or (VI-A2)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H or C 1-6 An alkyl group;
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 and R is 20c Is independently selected from-H and methyl;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
123. The compound or pharmaceutically acceptable salt of claim 121, wherein the compound of formula (VI-B) is a compound of formula (VI-B1) or (VI-B2)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H or C 1-6 An alkyl group;
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 and R is 20c Each of (3)-H and methyl;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
124. The compound or pharmaceutically acceptable salt of claim 121, wherein the compound of formula (VI-a) is a compound of formula (VI-A1 a), (VI-A1 b), (VI-A1 c), or (VI-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group;
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 and R is 20c Is independently selected from-H and methyl;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted by-NR', -S-, -O-, -OC (O) -,
-C(O)O-、-C(O)-、-C(O)C(O)-、-C(O)NR'-、-NR'C(O)-、-NR'C(O)O-、
-S(O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、
-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
125. The compound or pharmaceutically acceptable salt of claim 121, wherein the compound of formula (VI-B) is a compound of formula (VI-B1 a), (VI-B1B), (VI-B1 c), or (VI-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a 、R 2b 、R 4a 、R 4b 、R 6a 、R 6b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 13 、R 15 、R 16 And R is 17 Each of which is independently selected from-H and C 1-6 An alkyl group;
R 3 is-H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 and R is 20c Is independently selected from-H and methyl;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 Alkylene chain, wherein L A Optionally and independently substituted with-NR ' -, -S-, -O-, -OC (O) -, -C (O) O-; -C (O) -, -C (O) NR ' -, -NR ' C (O) O-, -S (O) 2 NR'-、-NR'S(O) 2 -、-C(O)NR'NR'-、-NR'C(O)NR'-、-OC(O)NR'-、-NR'NR'-、-NR'S(O) 2 NR' -, -S (O) -or-S (O) 2 -replacement;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein each alkyl or 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
126. The compound or pharmaceutically acceptable salt of claim 99, wherein the compound of formula (VI) is a compound of formula (VI-A3 a), (VI-A3B), (VI-B3 a), or (VI-B3B)
Or a pharmaceutically acceptable salt thereof, wherein
R 1a 、R 1b 、R 2a And R is 2b Each of which is independently selected from-H and C 1-3 An alkyl group;
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 、R 13 、R 17 and R is 20c Is independently selected from-H and methyl;
R 10 is-H, C 1-3 Alkyl or C 1-6 alkyl-O-C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or a straight chain C 1-3 An alkylene chain;
R 30 r', halo, -CN, -NO 2 or-CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R' is independently selected from-H, C 1-6 Alkyl and a 3-8 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 nitrogen atoms, wherein said 3-8 membered ring of R' is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 and-CH 3 Is substituted with a group of (a).
127. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (I) is a compound of formula (VII)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 and R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
128. The compound or pharmaceutically acceptable salt of claim 127, wherein R 13 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
129. The compound or pharmaceutically acceptable salt of claim 127 or claim 128, wherein R 13 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
130. The compound or pharmaceutically acceptable salt of any one of claims 127-129, wherein R 13 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl.
131. The compound or pharmaceutically acceptable salt of any one of claims 127-130, wherein R 13 Is methyl.
132. The compound or pharmaceutically acceptable salt of any one of claims 127-131, wherein R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-3 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
133. The compound or pharmaceutically acceptable salt of any one of claims 127-132, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 is-H or a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
134. The compound or pharmaceutically acceptable salt of any one of claims 127-133, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -、-CH 2 -CH 2 -or-N (H) -; and R is 30 Is a 5-6 membered partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein the 5-6 membered ring is optionally substituted with 1-3 groups independently selected from-CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
135. The compound or pharmaceutically acceptable salt of any one of claims 127-134, wherein R 21 is-L A -R 30 ；L A Is a bond, -CH 2 -or-N (H) -; and is combined withAnd R is 30 Is that Wherein X is 1 、X 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, halo, -OH, -CN, and-NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Provided that
(i)X 1 、X 2 、X 3 And X 4 At least one of which is N, and
(ii) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
136. The compound or pharmaceutically acceptable salt of claim 134, wherein R 30 Is thatX 1 Is N; and X is 2 、X 3 And X 4 Wherein each R' is independently selected from the group consisting of-H, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH, provided that
(i) NO more than 2 instances of R' are independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 and-CH 2 OH。
137. The compound or pharmaceutically acceptable salt of claim 127, wherein the compound of formula (VII) is a compound of formula (VII-a) or (VII-B)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 and R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
138. The compound or pharmaceutically acceptable salt of claim 137, wherein
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
139. The compound or pharmaceutically acceptable salt of claim 137, wherein the compound of formula (VII-a) is a compound of formula (VII-A1) or (VII-A2)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 and R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
140. The compound or pharmaceutically acceptable salt of claim 139, wherein
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
141. The compound or pharmaceutically acceptable salt of claim 137, wherein the compound of formula (VII-B) is a compound of formula (VII-B1) or (VII-B2)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 and R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or 0-4 independent units3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring of heteroatoms selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
142. The compound or pharmaceutically acceptable salt of claim 141, wherein
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
143. The compound or pharmaceutically acceptable salt of claim 137, wherein the compound of formula (VII-a) is a compound of formula (VII-A1 a), (VII-A1 b), (VII-A1 c), or (VII-A1 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 and R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
144. The compound or pharmaceutically acceptable salt of claim 143, wherein
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
145. The compound or pharmaceutically acceptable salt of claim 137, wherein the compound of formula (VII-B) is a compound of formula (VII-B1 a), (VII-B1B), (VII-B1 c), or (VII-B1 d)
Or a pharmaceutically acceptable salt thereof, wherein
R 3 is-H, C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group;
R 5 is-H or C 1-6 An alkyl group;
R 10 and R is 13 Each of which is independently selected from-H, C 1-6 Alkyl and C 1-6 alkyl-O-C 1-6 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond, branched or straight chain C 1-6 Alkylene chains or-N (H) -; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 3-8 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from N, O and S, wherein R 30 Optionally substituted with 1 to 3 of said 3-8 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
146. The compound or pharmaceutically acceptable salt of claim 145, wherein
R 3 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 5 is-H or methyl;
R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group;
R 13 is-H or C 1-3 An alkyl group;
R 21 is-L A -R 30 ；
L A Is a bond or optionally substituted branched or straight chain C 1-3 An alkylene chain; and is also provided with
R 30 is-H, halo, -OH, -CN, -NO 2 、-CF 3 Or a 5-6 membered saturated, partially unsaturated or fully unsaturated monocyclic ring having 1-4 nitrogen atoms, wherein R 30 Optionally substituted with 1 to 3 of said 5-6 membered rings independently selected from halo, -OH, -CN, -NO 2 、-CF 3 、-CH 3 、-CH 2 OH and-C (CH) 3 ) 3 Is substituted with a group of (a).
147. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, or 99-120, wherein R 1a And R is 1b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 1a And R is 1b Together forming oxo.
148. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147, wherein R 1a And R is 1b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 1a And R is 1b Together forming oxo.
149. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147, wherein R 1a And R is 1b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'.
150. The compound or pharmaceutically acceptable salt of any one of claim 2-16, 57-73, 99-120, or 147-149,wherein R is 1a And R is 1b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group.
151. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-150, wherein R 1a And R is 1b is-H.
152. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-151, wherein R 2a And R is 2b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 2a And R is 2b Together forming oxo.
153. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-152, wherein R 2a And R is 2b Is independently selected from-H and C optionally substituted with R 1-6 Alkyl, or R 2a And R is 2b Together forming oxo.
154. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-152, wherein R 2a And R is 2b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'.
155. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, 147-152, or 154, wherein R 2a And R is 2b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group.
156. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-155, wherein R 2a And R is 2b is-H.
157. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-156, wherein n is 1, and R 4a And R is 4b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 4a And R is 4b Together forming oxo.
158. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-157, wherein n is 1, and R 4a And R is 4b Each of which is independently selected from-H or C optionally substituted with R' 1-6 Alkyl, or R 4a And R is 4b Together forming oxo.
159. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-156, wherein n is 1, r 4a And R is 4b One of them is-H and the other is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'.
160. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, 147-156, or 159, wherein n is 1, r 4a And R is 4b One of them is-H and the other is-H or C optionally substituted by R' 1-6 An alkyl group.
161. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-160, wherein n is 1, and R 4a And R is 4b is-H.
162. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-161, wherein R 5 is-H.
163. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-162, wherein R 6a 、R 6b 、R 7a And R is 7b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 6a And R is 6b Together form oxo, or R 7a And R is 7b Together forming oxo.
164. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-163, wherein R 6a 、R 6b 、R 7a And R is 7b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group.
165. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-163, wherein R 6a 、R 6b 、R 7a And R is 7b Two of which are-H, and R 6a 、R 6b 、R 7a And R is 7b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'.
166. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, 147-163, or 165, wherein R 6a 、R 6b 、R 7a And R is 7b Three of them are-H, and R 6a 、R 6b 、R 7a And R is 7b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'.
167. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-166, wherein R 6a 、R 6b 、R 7a And R is 7b is-H.
168. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-167, wherein R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
169. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-168, wherein R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
170. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-169, wherein R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl.
171. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-170, wherein R 11a 、R 11b 、R 12a And R is 12b Each of which is independently selected from-H, C optionally substituted with R' 1-6 Alkyl, -N (R') 2 and-O-R', or R 11a And R is 11b Together form oxo, or R 12a And R is 12b Together forming oxo.
172. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-171, wherein R 11a 、R 11b 、R 12a And R is 12b Is independently selected from-H and C optionally substituted with R 1-6 An alkyl group.
173. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-171, wherein R 11a 、R 11b 、R 12a And R is 12b Two of which are-H, and R 11a 、R 11b 、R 12a And R is 12b Two of which are independently selected from-H, C optionally substituted with R 1-6 Alkyl, -N (R') 2 and-O-R'.
174. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, 147-171, or 173, wherein R 11a 、R 11b 、R 12a And R is 12b Three of them are-H, and R 11a 、R 11b 、R 12a And R is 12b The other of (2) is-H, C optionally substituted by R' 1-6 Alkyl, -N (R') 2 or-O-R'.
175. The compound or pharmaceutically acceptable salt of any one of claims 2-16, 57-73, 99-120, or 147-174, wherein R 11a 、R 11b 、R 12a And R is 12b is-H.
176. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, or 127-136, wherein R 3 Is C 1-6 Alkyl or C 1-6 alkyl-O-C 1-6 An alkyl group.
177. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, or 176, wherein R 3 Is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl.
178. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, 176, or 177, wherein R 3 is-CH 3 、-CH 2 -CH 3 、-CH 2 -CH 2 -CH 3 or-CH 2 -O-CH 3 。
179. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, or 176-178, wherein R 5 is-H or C 1-3 An alkyl group.
180. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, or 176-179, wherein R 5 is-H or methyl.
181. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, or 176-180, wherein R 10 is-H, C 1-6 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
182. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, or 176-181, wherein R 10 is-H, C 1-3 Alkyl or C 1-3 alkyl-O-C 1-3 An alkyl group.
183. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, or 176-182, wherein R 10 is-H, methyl, ethyl, propyl, isopropyl, methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, ethoxyethyl or propoxyethyl.
184. The compound or pharmaceutically acceptable salt of any one of claims 30-43, 80-90, 127-136, or 176-183, wherein R 10 is-H or methyl.
185. A compound selected from
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Or a pharmaceutically acceptable salt thereof.
186. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1-185 and a pharmaceutically acceptable carrier, vehicle, or excipient.
187. Modulating GABA in a subject in need thereof A A method of a subject comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of any one of claims 1-185 or a pharmaceutical composition of claim 186.
188. Modulating GABA in a subject in need thereof A A method of receptor-mediated CNS-related disorder comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-185 or the pharmaceutical composition of claim 186.
189. A method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of any one of claims 1-185 or the pharmaceutical composition of claim 186.
190. The method of claim 188 or claim 189, wherein the CNS related disorder is a sleep disorder, an affective disorder, a schizophrenic lineage disorder, a convulsive disorder, a memory and/or cognition disorder, a movement disorder, a personality disorder, an autism lineage disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and/or withdrawal syndrome, tinnitus or status epilepticus.
191. The method of claim 190, wherein the CNS-related disorder is an affective disorder.
192. The method of claim 191, wherein the affective disorder is depression.
193. The method of claim 192, wherein the depression is post-partum depression.
194. The method of claim 192, wherein the depression is major depressive disorder.
195. The method of claim 194, wherein the severe depression is a moderate severe depression.
196. The method of claim 195, wherein the severe depression is severe depression.
CN202180090066.2A 2020-11-25 2021-11-22 Compositions and methods for treating CNS disorders Pending CN116685596A (en)

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US202063118122P 2020-11-25 2020-11-25
US63/118,089 2020-11-25
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US63/118,086 2020-11-25
US63/118,122 2020-11-25
US63/118,107 2020-11-25
PCT/US2021/060358 WO2022115381A1 (en) 2020-11-25 2021-11-22 Compositions and methods for treating cns disorders cross reference to related application

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