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HK40032660B - Substituted pyrrolizine compounds as hbv replication inhibitors - Google Patents

Substituted pyrrolizine compounds as hbv replication inhibitors Download PDF

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HK40032660B
HK40032660B HK62020022749.9A HK62020022749A HK40032660B HK 40032660 B HK40032660 B HK 40032660B HK 62020022749 A HK62020022749 A HK 62020022749A HK 40032660 B HK40032660 B HK 40032660B
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substituted
pharmaceutically acceptable
acceptable salt
compound
independently
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HK62020022749.9A
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HK40032660A (en
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D·A·古铁雷斯
小林哲也
S·E·拉泽维斯
R·A·李
P·A·莫加内利
边衡正
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吉利德科学公司
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Description

Substituted pyrrolizine compounds as inhibitors of HBV replication
Cross Reference to Related Applications
The present application claims priority from U.S. provisional patent application No. 62/635,262 filed on 26, 02, 2018, the entire contents of which are incorporated herein for all purposes.
Background
Hepatitis B Virus (HBV) is an enveloped, partially double-stranded DNA virus. HBV is an infectious disease affecting the liver. Initial symptoms of infection may include vomiting, jaundice, somnolence, deep urine, and abdominal pain. Chronic HBV infection can lead to cirrhosis and liver cancer. Currently available therapies can inhibit viral replication and minimize liver damage; however, there is currently no therapy that can reliably clear HBV infection.
In view of the continued prevalence of HBV infection, new treatment options are needed, including new inhibitors of HBV replication. In addition, compounds capable of inhibiting HBV replication while having low predicted metabolic clearance are of particular interest.
Disclosure of Invention
In one embodiment, the present disclosure provides a compound of formula (I):
Or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, optionally substituted with 1 to 4R 1B Substituted C 3-8 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R 1A Independently halogen, -OH, -CN, C 1-2 Haloalkyl, -C (O) NR X R Y Optionally by 1 to 3R 1D Substituted C 6-10 Aryl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1A Is optionally substituted with 1 to 3R 1D Substituted C 6-10 Aryl is alternatively a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R 1B independently-CN, halogen, optionally interrupted by 1 to 3-OH or-NR a R b Substituted C 1-6 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, -C (O) NR X R Y Or any of 1 to 3 heteroatoms selected from N, O and SSelected from 1 to 3R 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is C 3-6 Cycloalkyl or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R 1C Independently C 1-6 Alkyl, oxo, C 1-4 Haloalkyl, -C (O) H, -C (O) C 1-4 Alkyl, -C (O) OC 1-4 Alkyl, -C (O) NR X R Y Or optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 12-membered heteroaryl, provided that no more than 1R 1C Is a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R X independently-H, C 3-6 Cycloalkyl, optionally substituted with 1 to 3R Z Substituted C 1-6 Alkyl, optionally substituted with 1 to 3 heteroatoms selected from N, O and S, 1 to 3R Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R Y independently-H or optionally R is 1 to 3 Z Substituted C 1-6 An alkyl group;
or R is X And R is Y Optionally substituted 1 to 3R' S together forming a chain having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
wherein each R is Z Independently halogen, methyl, ethyl, oxo, -OH, -S (O) 2 C 1-3 An alkyl group or a 3 to 8 membered mono-or bicyclic heterocyclic group having 1 to 3 heteroatoms selected from N, O and S;
each R a is-H, C 1-3 Alkyl or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R b is-H or C 1-3 An alkyl group; or alternatively
R a And R is b Taken together to form optionally 1 to 3R Z Substituted 3 to 8 membered mono-or bicyclic heterocycle;
part is optionally substituted with 1-6R 2 Group-substituted pyrrolidines or 5-7 membered bicyclic heterocycles with one nitrogen;
wherein each R is 2 Independently is halogen, C 1-3 Alkyl, -OH or-OC 1-3 An alkyl group;
R 3 is-H, halogen or C 1-4 An alkyl group;
R 4 is optionally substituted with 1 to 5R 4A Substituted C 6-10 Aryl, or optionally substituted 1 to 4R having 1 to 3 heteroatoms selected from N, O and S 4B Substituted 5-to 12-membered heteroaryl; and is also provided with
Each R 1D 、R 4A And R is 4B independently-CN, halogen, optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 Alkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl or C 1-4 A haloalkyl group.
In another embodiment, the present invention provides a compound of formula (II):
or a pharmaceutically acceptable salt thereof,
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-6 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each of which isR 1C independently-C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1D Independently is optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 An alkyl group;
each R X independently-H or C 1-6 An alkyl group;
each R Y independently-H or C 1-6 An alkyl group;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 3 is methyl;
R 4 is covered by 1 to 5R 4A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridinyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group.
In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents.
In certain embodiments, a method of inhibiting HBV replication is provided comprising administering a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to an individual (e.g., a human).
In certain embodiments, a method of treating or preventing HBV infection is provided comprising administering to a subject (e.g., a human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method of treating or preventing HBV infection comprises administering one or more additional therapeutic agents.
In certain embodiments, there is provided the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for medical treatment.
In certain embodiments, there is provided the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of HBV infection.
In certain embodiments, there is provided the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of HBV infection.
Kits comprising the foregoing compounds, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, are also provided. Also provided are articles of manufacture comprising unit doses of the foregoing compounds, or pharmaceutically acceptable salts thereof. Also provided are methods of preparing the compounds of the present disclosure.
Detailed Description
I. General description
The compounds of the present invention include certain 5-oxoacetyl-6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamides which have improved kinetic solubility compared to other substituted pyrrolizines in the art, such as 7-oxoacetyl-6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxamides. The compounds may be combined with pharmaceutically acceptable excipients and one or more additional therapeutic agents to form pharmaceutical compositions. The compounds and pharmaceutical compositions are useful for treating or preventing hepatitis b virus infection.
II. Definition of
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the front or end of the chemical group are convenient to indicate the point of attachment to the parent moiety; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. Such as "C u-v Or (C) u -C v ) The prefix of (a) indicates that the latter group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 Alkyl "means that the alkyl group has 1 to 6 carbon atoms.
"alkyl" is a straight or branched saturated monovalent hydrocarbon. For example, the alkyl group may have 1 to 10 carbon atoms (i.e. (C) 1-10 ) Alkyl) or 1 to 8 carbon atoms (i.e. (C) 1-8 ) Alkyl) or 1 to 6 carbon atoms (i.e. (C) 1-6 Alkyl) or 1 to 4 carbon atoms (i.e. (C) 1-4 ) Alkyl). Examples of alkyl groups include, but are not limited to: methyl (Me, -CH) 3 ) Ethyl (Et, -CH) 2 CH 3 ) 1-propyl (n-Pr, n-propyl, -CH) 2 CH 2 CH 3 ) 2-propyl (i-Pr, isopropyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-1-propyl (i-Bu, isobutyl, -CH) 2 CH(CH3) 2 ) 2-butyl (s-Bu, sec-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH) 3 ) 3 ) 1-pentyl (n-pentyl, -CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) 1-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) And octyl (- (CH) 2 ) 7 CH 3 )。
"alkoxy" refers to the group-O-alkyl, wherein alkyl is as defined above. For example, C 1-4 Alkoxy refers to an-O-alkyl group having 1 to 4 carbons.
"alkynyl" is a straight or branched monovalent hydrocarbon radical having at least one carbon-carbon triple bond. For example, alkynyl groups can have 2 to 8 carbon atoms (i.e., C 2-8 Alkynes) or 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl) or 2 to 4 carbon atoms (i.e. C 2-4 Alkynyl). Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) 2 C.ident.CH) and-CH 2 -C≡C-CH 3 。
The term "halo" or "halogen" as used herein refers to fluoro (-F), chloro (-Cl), bromo (-Br) and iodo (-I).
The term "haloalkyl" as used herein refers to an alkyl group as defined herein wherein one or more hydrogen atoms of the alkyl group are independently replaced by halogen substituents, which may be the same or different. For example, C 1-4 Haloalkyl is wherein C 1-4 C wherein one or more hydrogen atoms of the alkyl radical have been replaced by halogen substituents 1-4 An alkyl group. Examples of haloalkyl include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1-trifluoroethyl and pentafluoroethyl.
The term "aryl" as used herein refers to a single all-carbon aromatic ring or a plurality of fused all-carbon ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, aryl groups have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes phenyl. Aryl groups also include multiple fused ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2,3, or 4 rings), wherein at least one ring is aromatic and wherein the other rings may be aromatic or non-aromatic (i.e., carbocyclic). Such multiple fused ring systems are optionally substituted with one or more (e.g., 1,2, or 3) oxo groups on any carbocyclic moiety of the multiple fused ring systems. The rings of multiple fused ring systems may be linked to each other by fused, spiro, and bridged bonds, as valence requirements allow. It is also understood that when referring to an aryl group of some atom-range member (e.g., a 6-10 membered aryl group), the atom range refers to the total ring atoms of the aryl group. For example, 6-membered aryl groups include phenyl, 10-membered aryl groups include naphthyl and 1,2,3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, anthracenyl, and the like.
The term "heteroaryl" as used herein refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl" also includes multiple fused ring systems having at least one such aromatic ring, the multiple fused ring systems being further described below. Thus, "heteroaryl" includes a single aromatic ring of about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "heteroaryl" also includes a plurality of fused ring systems (e.g., ring systems comprising 2,3, or 4 rings), wherein a heteroaryl group as defined above is fused with one or more rings selected from heteroaryl (to form, for example, 1, 8-naphthyridinyl), heterocycle (to form, for example, 1,2,3, 4-tetrahydro-1, 8-naphthyridinyl), carbocycle (to form, for example, 5,6,7, 8-tetrahydroquinoline), and aryl (to form, for example, indazolyl) to form a plurality of fused ring systems. Thus, heteroaryl groups (single aromatic ring or multiple fused ring systems) have about 1-20 carbon atoms and about 1-6 heteroatoms within the heteroaryl ring. Such multiple fused ring systems may be optionally substituted on the carbocyclic or heterocyclic moiety of the fused ring with one or more (e.g., 1,2,3, or 4) oxo groups. Where valence requirements allow, the rings of multiple fused ring systems may be linked to each other by fused, spiro, and bridged bonds. It is understood that the individual rings of the multiple fused ring systems may be connected in any order relative to one another. It is to be understood that the point of attachment of the heteroaryl or heteroaryl multi-fused ring system may be on any suitable atom of the heteroaryl or heteroaryl multi-fused ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It is also understood that when referring to an atom-range membered heteroaryl (e.g., a 5-to 10-membered heteroaryl), the atom range is the total ring atoms of the heteroaryl and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl group includes thiazolyl and a 10-membered heteroaryl group includes quinolinyl. Exemplary heteroaryl groups include, but are not limited to: pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7, 8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thiaindenyl, pyrrolo [2,3-b ] pyridyl, quinazolin-4 (3H) -one, and triazolyl.
"cycloalkyl" refers to a single saturated or partially unsaturated, fully carbocyclic ring having 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), for example 3 to 12 ring atoms, for example 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 3 to 4 ring atoms. The term "cycloalkyl" also includes a plurality of fused, saturated, and partially unsaturated all-carbon ring systems (e.g., ring systems comprising 2, 3, or 4 carbon rings). Thus, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 ring carbon atoms, such as bicyclo [3.1.0]]Hexane and bicyclo [2.1.1]Hexane) and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles having up to about 20 ring carbon atoms). Where valence requirements allow, the rings of the multiple fused ring systems may be linked to each other by fused, spiro, and bridged bonds. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.
The term "heterocyclyl" or "heterocycle" or "heterocycloalkyl" as used herein refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom in the ring (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise indicated, heterocyclyl has 3 to about 20 ring atoms, for example 3 to 12 ring atoms, for example 3 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3, 4, 5, 6, or 7 membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. Where valence requirements allow, the rings of multiple fused ring (e.g., bicyclic heterocyclyl) systems may be linked to each other by fused, spiro, and bridged bonds. Heterocycles include, but are not limited to: azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro [3.3] hept-6-yl, 6-oxa-1-azaspiro [3.3] hept-1-yl, 2-thia-6-azaspiro [3.3] hept-6-yl, 2, 6-diazaspiro [3.3] hept-2-yl, 2-azabicyclo [3.1.0] hexane-2-yl, 3-azabicyclo [3.1.0] hexyl, 2-azabicyclo [2.1.1] hexyl, 2-azabicyclo [2.2.1] hept-2-yl, 4-azaspiro [2.4] heptyl, 5-azaspiro [2.4] heptyl, and the like.
The term "oxo" as used herein refers to = O.
"Compounds of the present disclosure" include compounds disclosed herein, for example, compounds of the present disclosure include compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), including compounds shown in the examples.
As used herein, "treatment" or "treatment" refers to a method of achieving a beneficial or desired result. For the purposes of this disclosure, beneficial or desired results include, but are not limited to, alleviation of symptoms and/or diminishment of extent of symptoms and/or prevention of exacerbation of symptoms associated with the disease or disorder. In one embodiment, "treatment" or "treatment" includes one or more of the following: a) Inhibiting the disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder, and/or reducing the extent of the disease or disorder); b) Slowing or arresting the development of one or more symptoms associated with the disease or disorder (e.g., stabilizing the disease or disorder, delaying the progression or worsening of the disease or disorder); c) Alleviating a disease or condition, e.g., causing resolution of clinical symptoms, improving a disease state, delaying disease progression, improving quality of life and/or extending survival.
As used herein, "delay" of progression of a disease or disorder means delay, impediment, slowing, delay, stabilization, and/or delay of progression of the disease or disorder. The delay may have different lengths of time depending on the history of the disease and/or the individual being treated. It will be apparent to those skilled in the art that a sufficient or significant delay may actually include prophylaxis, as the individual will not develop a disease or condition.
As used herein, "prevention" or "prophylaxis" refers to a regimen that prevents the onset of a disease or disorder such that the clinical symptoms of the disease do not develop. Thus, "preventing" involves administering a treatment (e.g., administering a therapeutic substance) to an individual before signs of disease can be detected in the individual (e.g., administering a therapeutic substance to an individual without a detectable infectious agent (e.g., virus) in the individual). An individual may be an individual at risk of developing a disease or disorder, such as an individual having one or more risk factors known to be associated with the development or onset of a disease or disorder. Thus, in certain embodiments, the term "preventing HBV infection" refers to administering an anti-HBV therapeutic substance to a subject having no detectable HBV infection. It will be appreciated that the individual for prophylactic treatment against HBV may be an individual at risk of being infected with HBV virus. It should also be appreciated that prevention does not require a 100% success rate. In some cases, prophylaxis may be understood as reducing the risk of infection, but not completely eliminating the occurrence of infection.
As used herein, a "at risk individual" refers to an individual at risk of developing a condition to be treated. An individual at risk may or may not have a detectable disease or condition, and may or may not have displayed a detectable disease prior to treatment by the methods described herein. "at risk" means that an individual has one or more so-called risk factors, which are measurable parameters associated with the development of a disease or disorder and are known in the art. Individuals with one or more of these risk factors have a higher likelihood of developing a disease or disorder than individuals without these risk factors.
As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount effective to elicit the desired biological or medical response, including an amount of a compound that, when administered to an individual to treat a disease, is sufficient to effect such treatment of the disease. The effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. An effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to reach a desired therapeutic endpoint. An effective amount may be considered in the case of administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in combination with one or more other agents, the desired or beneficial result is achieved. Due to the combined effect (e.g., additive or synergistic) of the compounds, the appropriate dosage of any co-administered compounds may optionally be reduced.
"pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock.
As used herein, "co-administration" refers to administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents, e.g., within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of the unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound of the present disclosure within seconds or minutes. In some embodiments, a unit dose of a compound of the present disclosure is administered first, followed by administration of the unit dose of one or more additional therapeutic agents after several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then after a few hours (e.g., 1-12 hours), a unit dose of a compound of the present disclosure is administered. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of the compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient.
The invention also provides pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. By "pharmaceutically acceptable" or "physiologically acceptable" is meant compounds, salts, compositions, dosage forms, and other materials useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.
The compounds described herein may be prepared and/or formulated as pharmaceutically acceptable salts or as the free base where appropriate. Pharmaceutically acceptable salts are non-toxic salts of the compounds in the form of the free base which possess the desired pharmacological activity of the free base. These salts may be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compounds with inorganic or organic acids. Non-limiting examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propanesulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ -hydroxybutyrate, glycolate, tartrate and mandelate. Other suitable pharmaceutically acceptable salts are listed in Remington, the Science and Practice of Pharmacy, 21 st edition, lippincott Wiliams and Wilkins, philiadelphia, pa.,2006.
Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 Alkyl). Also included are base addition salts, such as sodium or potassium salts.
The present invention also provides a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, wherein 1 to n hydrogen atoms attached to a carbon atom can be replaced with a deuterium atom or D, wherein n is the number of hydrogen atoms in the molecule. Deuterium atoms are nonradioactive isotopes of hydrogen atoms, as known in the art. Such compounds may increase resistance to metabolism and thus may be useful when administered to a mammal to increase the half-life of a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof. See, e.g., foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", trends Pharmacol. Sci.,5 (12): 524-527 (1984). These compounds are synthesized by methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.
Examples of isotopes that can be incorporated into the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, for example 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 36 Cl、 123 I and 125 I. with a positron-emitting isotope (e.g., 11 C、 18 F、 15 o and 13 n) substitutions can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the examples, using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously used, as described below.
The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus may produce enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as (R) -or (S) -in terms of absolute stereochemistry or (D) -or (L) -in terms of amino acids. The present disclosure is intended to include all such possible isomers, as well as racemic and optically pure forms thereof. Optically active (+) and (-), (R) -and (S) -, or (D) -and (L) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or of a salt or derivative) using, for example, chiral High Pressure Liquid Chromatography (HPLC). When a compound described herein contains an olefinic double bond or other geometric asymmetric center, the compound includes both the E and Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are also included. When a compound is represented in its chiral form, it is understood that this embodiment includes, but is not limited to, a particular diastereomeric or enantiomerically enriched form. Where no designation is given but chirality is present, it is understood that this embodiment relates to a particular diastereomeric or enantiomerically enriched form; or a racemic or non-proportional (scalemic) mixture of these compounds. As used herein, a "anisometric mixture" is a mixture of stereoisomers in a ratio other than 1:1.
"stereoisomers" as used herein refers to compounds consisting of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are not mirror images of one another.
As used herein, "tautomer" refers to proton transfer from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any of the compounds.
As used herein, a "solvate" is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
As used herein, "prodrug" refers to a derivative of a drug that is converted to the parent drug by some chemical or enzymatic route after administration to the human body.
III. Compounds
The present disclosure provides compounds for the treatment of HBV. In some embodiments, the present disclosure provides compounds of formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, optionally substituted with 1 to 4R 1B Substituted C 3-8 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R 1A Independently halogen, -OH, -CN, C 1-2 Haloalkyl, -C (O) NR X R Y Optionally by 1 to 3R 1D Substituted C 6-10 Aryl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1A Is optionally substituted with 1 to 3R 1D Substituted C 6-10 Aryl is alternatively a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R 1B independently-CN, halogen, optionally interrupted by 1 to 3-OH or-NR a R b Substituted C 1-6 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is C 3-6 Cycloalkyl or 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R 1C Independently C 1-6 Alkyl, oxo, C 1-4 Haloalkyl, -C (O) H, -C (O) C 1-4 Alkyl, -C (O) OC 1-4 Alkyl, -C (O) NR X R Y Or optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 12-membered heteroaryl, provided that no more than 1R 1C Is a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R X independently-H, C 3-6 Cycloalkyl, optionally substituted with 1 to 3R Z Substituted C 1-6 Alkyl, optionally substituted with 1 to 3 heteroatoms selected from N, O and S, 1 to 3R Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R Y independently-H or optionally R is 1 to 3 Z Substituted C 1-6 An alkyl group;
or R is X And R is Y Optionally substituted 1 to 3R' S together forming a chain having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
wherein each R is Z Independently halogen, methyl, ethyl, oxo, -OH, -S (O) 2 C 1-3 An alkyl group or a 3 to 8 membered mono-or bicyclic heterocyclic group having 1 to 3 heteroatoms selected from N, O and S;
each R a is-H, C 1-3 Alkyl or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R b is-H or C 1-3 An alkyl group; or alternatively
R a And R is b Taken together to form optionally 1 to 3R Z Substituted 3 to 8 membered mono-or bicyclic heterocycle;
part is optionally substituted with 1-6R 2 Group-substituted pyrrolidines or 5-7 membered bicyclic heterocycles with one nitrogen;
wherein each R is 2 Independently is halogen, C 1-3 Alkyl, -OH or-OC 1-3 An alkyl group;
R 3 is-H, halogen or C 1-4 An alkyl group;
R 4 is optionally substituted with 1 to 5R 4A Substituted C 6-10 Aryl, or optionally substituted 1 to 4R having 1 to 3 heteroatoms selected from N, O and S 4B Substituted 5-to 12-membered heteroaryl; and is also provided with
Each R 1D 、R 4A And R is 4B independently-CN, halogen, optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 Alkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl or C 1-4 A haloalkyl group.
In certain embodiments of the compounds of formula (I),part is->
Each of which is optionally substituted with 1 to 6R 2 And (3) substitution.
In certain embodiments of the compounds of formula (I),part is->/>
Each of which is optionally substituted with 1 to 6R 2 And (3) substitution.
In certain embodiments of the compounds of formula (I),part is->
Each of which is optionally substituted with 1 to 6R 2 And (3) substitution.
In certain embodiments of the compounds of formula (I),part is->Optionally substituted with 1 to 6R 2 And (3) substitution.
In certain embodiments of the compounds of formula (I),part is->Optionally substituted with 1 to 6R 2 And (3) substitution.
In certain embodiments of the compounds of formula (I),part is->Optionally substituted with 1 to 6R 2 And (3) substitution. />
In some embodiments, whenIn the case of pyrrolidine or a 5-to 7-membered bicyclic heterocycle having one nitrogen in the structure +.>Nitrogen as shown in (a).
In certain embodiments of the compounds of formula (I),part is->
Wherein each R is 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F independently-H, halogen, C 1-3 Alkyl, -OH or-OC 1-3 Alkyl, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group. In certain embodiments of the compounds of formula (I) or (II), each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F independently-H, C 1-3 Alkyl, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group. In certain embodiments of the compounds of formula (I) or (II)In the manner, each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group.
In some embodiments, the compound of formula (I) may be a compound of formula (II):
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, optionally substituted with 1 to 4R 1B Substituted C 3-8 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R 1A Independently halogen, -OH, -CN, C 1-2 Haloalkyl, -C (O) NR X R Y Optionally by 1 to 3R 1D Substituted C 6-10 Aryl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 12-membered heteroaryl, provided that no more than 1R 1A Is optionally substituted with 1 to 3R 1D Substituted C 6-10 Aryl is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 12-membered heteroaryl;
each R 1B Independently halogen, optionally interrupted by 1-3-OH or-NR a R b Substituted C 1-6 Alkyl, C 1-4 Alkoxy, C 1-2 Haloalkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Optionally substituted with 1 to 3R' S having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1C Independently C 1-6 Alkyl, oxo, C 1-4 Haloalkyl, -C (O) H, -C (O) C 1-4 Alkyl, -C (O) OC 1-4 Alkyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R X independently-H, C 3-6 Cycloalkyl, optionally substituted with 1 to 3R Z Substituted C 1-6 Alkyl, optionally substituted with 1 to 3 heteroatoms selected from N, O and S, 1 to 3R Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R Y independently-H or optionally R is 1 to 3 Z Substituted C 1-6 An alkyl group;
or R is X And R is Y Optionally substituted 1 to 3R' S together forming a chain having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
wherein each R is Z Independently halogen, methyl, ethyl, oxo, -OH, -S (O) 2 C 1-3 An alkyl group, or a 3 to 8 membered monocyclic or bicyclic heterocyclic group having 1 to 3 heteroatoms selected from N, O and S;
each R a is-H, C 1-3 Alkyl or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R b is-H or C 1-3 An alkyl group; or alternatively
R a And R is b Taken together to form optionally 1 to 3R Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F independently-H, halogen, C 1-3 Alkyl, -OH or-OC 1-3 Alkyl, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 3 is halogen or methyl;
R 4 is optionally substituted with 1 to 5R 4A Substituted phenyl, or optionally substituted with 1 to 4R 4B Substituted pyridinyl; and
each R 1D 、R 4A And R is 4B independently-CN, halogen, optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 Alkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl or C 1-4 A haloalkyl group.
In some embodiments of the compounds of formula (I) or formula (II), R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, optionally substituted with 1 to 4R 1B Substituted C 3-8 Cycloalkyl, or optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 8-membered monocyclic or bicyclic heterocyclic groups. In some embodiments, R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 An alkyl group. In some embodiments, R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-8 Cycloalkyl, or optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 8-membered monocyclic or bicyclic heterocyclic groups. In some embodiments, R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-8 Cycloalkyl groups. In some embodiments, R 1 Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 8-membered monocyclic or bicyclic heterocyclic groups.
In some embodiments of the compounds of formula (I) or formula (II), R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently halogen, -OH, -CN, C 1-2 Haloalkyl, -C (O) NR X R Y Optionally by 1 to 3R 1D Substituted C 6-10 Aryl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 12-membered heteroaryl, provided that no more than 1R 1A Is optionally substituted with 1 to 3R 1D Substituted C 6-10 Aryl is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5 to 12And (3) a membered heteroaryl group.
In some embodiments of the compounds of formula (I) or formula (II), R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently halogen, -OH, -CN, C 1-2 Haloalkyl, -C (O) NR X R Y . In some embodiments, R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently C 1-2 Haloalkyl or-C (O) NR X R Y . In some embodiments, R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently C 1-2 Haloalkyl or-C (O) NH 2 . In some embodiments, R 1 Is optionally substituted with 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently CF 3 or-C (O) NH 2 。
In some embodiments of the compounds of formula (I) or formula (II), R 1 Is that
In some embodiments of the compounds of formula (I) or formula (II), R 1 Is that
In some embodiments of the compounds of formula (I) or formula (II), R 3 Is halogen. In some embodiments, R 3 Is Cl.
In some embodiments of the compounds of formula (I) or formula (II), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-8 Cycloalkyl, or optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R 1B Independently halogen, optionally interrupted by 1-3-OH or-NR a R b Substituted C 1-6 Alkyl, C 1-4 Alkoxy, C 1-2 Haloalkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Optionally substituted with 1 to 3R' S having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1C Independently C 1-6 Alkyl, oxo, C 1-4 Haloalkyl, -C (O) H, -C (O) C 1-4 Alkyl, -C (O) OC 1-4 Alkyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R X independently-H, C 3-6 Cycloalkyl, optionally substituted with 1 to 3R Z Substituted C 1-6 Alkyl, optionally substituted with 1 to 3 heteroatoms selected from N, O and S, 1 to 3R Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
each R Y independently-H or optionally R is 1 to 3 Z Substituted C 1-6 An alkyl group;
or R is X And R is Y Optionally substituted 1 to 3R' S together forming a chain having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
wherein each R is Z Independently halogen, methyl, ethyl, oxo, -OH, -S (O) 2 C 1-3 An alkyl group, or a 3 to 8 membered monocyclic or bicyclic heterocyclic group having 1 to 3 heteroatoms selected from N, O and S;
each R a is-H, C 1-3 Alkyl or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl;
Each R b is-H or C 1-3 An alkyl group; or alternatively
R a And R is b Taken together to form optionally 1 to 3R Z Substituted 3-to 8-membered monocyclic or bicyclic heterocyclyl; and is also provided with
Each R 1D independently-CN,Halogen, optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 Alkyl, -OC 1-4 Alkyl, -OC 1-4 Haloalkyl or C 1-4 A haloalkyl group.
In some embodiments, the compound of formula (I) may be a compound of formula (II):
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-6 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkenyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1C independently-C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1D Independently is optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 An alkyl group;
each R X independently-H or C 1-6 An alkyl group;
each R Y independently-H or C 1-6 An alkyl group;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 3 is methyl;
R 4 is covered by 1 to 5R 4A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridinyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group.
In some embodiments of the compounds of formula (II), each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group. In some embodiments of the compounds of formula (II), each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H. In some embodiments of the compounds of formula (II), each R 2A And R is 2B Is H, and R 2C Or R is 2D And R is R 2E Or R is 2F Together forming a cyclopropyl group. In some embodiments of the compounds of formula (II), each R 2E And R is 2F is-H, and R 2C Or R is 2D And R is R 2A Or R is 2B Together forming a cyclopropyl group.
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IIa):
wherein R is 1 、R 2C 、R 2D 、R 2E 、R 2F 、R 3 And R is 4 As defined above and below for formulas (I) and (II), or any combination thereof.
In certain embodiments, the compound of formula (I), (II), or (IIa) is a compound of formula (IIb):
wherein R is 1 、R 2C 、R 2D 、R 2E 、R 2F And R is 4 As defined above and below for formulas (I) and (II), or any combination thereof.
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (III):
wherein R is 1 、R 2A 、R 2B And R is 4 As defined above and below for formulas (I) and (II), or any combination thereof. In some embodiments of the compounds of formula (I), (II) or (III), R 2A And R is 2B Are each independently H, halogen, C 1-3 Alkyl, -OH or-OC 1-3 An alkyl group. In some embodiments of the compounds of formula (I), (II) or (III), R 2A And R is 2B Respectively and independently-H and C 1-3 An alkyl group. In some embodiments of the compounds of formula (I), (II) or (III), R 2A And R is 2B respectively-H.
In certain embodiments of the compounds of formula (I), (II) or (III), the compound is a compound of formula (IIIa):
wherein R is 1 、R 2A 、R 2B And R is 4 As defined above and below for formulas (I), (II) and (III), or any combination thereof.
In certain embodiments of the compounds of formula (I), (II) or (III), the compound is a compound of formula (IIIb):
wherein R is 1 、R 2A 、R 2B And R is 4 As defined above and below for formulas (I), (II) and (III), or any combination thereof.
In some embodiments of the compounds of formula (I), (II), (III), (IIIa) or (IIIb), R 2A And R is 2B Are each independently-H, halogen, C 1-3 Alkyl, -OH or-OC 1-3 An alkyl group. In some embodiments of the compounds of formula (I), (II), (III), (IIIa) or (IIIb), R 2A And R is 2B Respectively and independently-H and C 1-3 An alkyl group. In some embodiments of the compounds of formula (I), (II), (III), (IIIa) or (IIIb), R 2A And R is 2B respectively-H.
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IV):
wherein R is 1 、R 2A 、R 2B And R is 4 As defined above and below for formulas (I) and (II), or any combination thereof.
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (V):
wherein R is 1 、R 2E 、R 2F And R is 4 As defined above and below for formulas (I) and (II), or any combination thereof.
In certain embodiments of the compounds of formula (I), (II) or (V), the compound is a compound of formula (Va):
wherein R is 1 、R 2E 、R 2F And R is 4 As defined above and below for formulas (I), (II) and (V), or any combination thereof.
In certain embodiments of the compounds of formula (I), (II) or (V), the compound is a compound of formula (Vb):
wherein R is 1 、R 2E 、R 2F And R is 4 As defined above and below for formulas (I), (II) and (V), or any combination thereof.
In some embodiments of the compounds of formula (I), (II), (V), (Va) or (Vb), R 2E And R is 2F Are each independently-H, halogen, C 1-3 Alkyl, -OH or-OC 1-3 An alkyl group. In some embodiments of the compounds of formula (I), (II), (V), (Va) or (Vb), R 2E And R is 2F Respectively and independently-H and C 1-3 An alkyl group. In some embodiments of the compounds of formula (I), (II), (V), (Va) or (Vb), R 2E And R is 2F respectively-H.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-6 Cycloalkyl, or optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-6 Cycloalkyl groups. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl groups. In the formula (I), (II), (IIa), (I)In some embodiments of compounds Ib), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1B Substituted cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1B Substituted cyclopropyl or cyclobutyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1B Substituted cyclopropyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1R 1B Substituted cyclopropyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1B Substituted cyclobutyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 3R 1B Substituted cyclobutyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1B Substituted cyclopentyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1B Independently halogen, optionally substituted with-OHC of (2) 1-3 Alkyl, C 2-4 Alkynyl, C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 6-membered heteroaryl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1B Independently halogen, optionally-OH-substituted C 1-3 Alkyl, C 2-4 Alkynyl, C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5 membered heteroaryl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), when R 1B independently-C (O) NR X R Y When R is 1B is-C (O) NH 2 -C (O) NHMe or-C (O) NMe 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), when R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D When a substituted 5-to 6-membered heteroaryl group, the heteroaryl group may be pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, thienyl, furanyl, pyranyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), when R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D In the case of a substituted 5-membered heteroaryl group, the heteroaryl group may be pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1B Is triazolyl, thiadiazolyl, oxazolyl, isoxazolyl, or oxadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1B Is triazolyl, thiadiazolyl or oxadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1B Is triazolyl or thiadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1B Is a triazolyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1B Is thiadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 And (3) substitution. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), wherein 2R 1B Optionally F, and 1R 1B is-CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, -C≡CH, triazolyl or thiadiazolyl, wherein the triazolyl and thiadiazolyl are optionally substituted with Me or-CH 2 Si(Me) 3 And (3) substitution. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), wherein 2R 1B Optionally F, and 1R 1B is-C (O) NH 2 or-C (O) NHMe. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), wherein 2R 1B Optionally F, and 1R 1B Is thiadiazolyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1B Independently halogen, optionally-OH-substituted C 1-3 Alkyl, C 2-4 Alkynyl, C (O) NR X R Y Or having 1 to 3 heteroatoms selected from N, O and S and optionally 1 to 3R 1D Substituted5 to 6 membered heteroaryl; each R 1D Independently is optionally covered with Si (C) 1-2 Alkyl group 3 Substituted C 1-3 An alkyl group; r is R X Is C 1-2 An alkyl group; and R is Y is-H.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1D Independently is optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 An alkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1D Independently is optionally-Si (C) 1-2 Alkyl group 3 Substituted C 1-3 An alkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1D Is independently Me or-CH 2 Si(Me) 3 。
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R X independently-H or C 1-6 An alkyl group; and each R Y independently-H or C 1-6 An alkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R X Is C 1-2 An alkyl group; and R is Y is-H. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R X Me; and R is Y is-H.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, wherein each R 1B Independently halogen, C optionally substituted with 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, wherein each R 1B Independently halogen, optionally-OH-substituted C 1-3 Alkyl, C 2-4 Alkynyl, C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5 membered heteroaryl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, wherein each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 And (3) substitution.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 4R 1B Substituted C 3-5 Cycloalkyl, wherein each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl, wherein each R is 1B Independently halogen, optionally-OH-substituted C 1-3 Alkyl, C 2-4 Alkynyl, C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5 membered heteroaryl. In formulae (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb)In some embodiments of the compound, R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl, wherein each R is 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 And (3) substitution. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is F and CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl substituted cyclopropyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 And (3) substitution. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl, wherein 2R 1B Optionally, and 1R 1B Is thiadiazolyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is cyclopropyl substituted by-C.ident.CH, triazolyl or thiadiazolyl, where triazolyl is optionally substituted by Me or-CH 2 Si(Me) 3 And (3) substitution. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is cyclopropyl substituted with thiadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 3R 1B Substituted cyclobutyl, wherein each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 And (3) substitution. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is composed of 2 fluorine atoms and 1-CH 2 OH、-C(O)NH 2 -C (O) NHMe, triazolylOr thiadiazolyl substituted cyclobutyl, wherein the triazolyl is optionally substituted with Me. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is prepared from 2 fluorine atoms and 1-C (O) NH 2 or-C (O) NHMe substituted cyclobutyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is cyclobutyl substituted by 2 fluoro and 1 thiadiazolyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
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In the compounds of the formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb)In some embodiments, R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
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In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is a compound having 1O heteroatom, optionally 1 to 3R 1C Substituted 3-to 6-membered monocyclic heterocyclyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1C Substituted oxiranyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1C Substituted oxiranyl or oxetanyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1R 1C Substituted oxetanyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R 1C Substituted oxetan-2-yl, oxetan-3-yl or oxetan-4-yl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1R 1C Substituted oxetan-3-yl.
In the formulae (I), (II), (IIa), (IIb), (III), (II)In some embodiments of compounds Ia), (IIIb), (IV), (V), (Va) or (Vb), each R 1C independently-C (O) NR X R Y Or optionally 1 to 3C having 1 to 3 heteroatoms selected from N, O and S 1-2 Alkyl substituted 5 to 6 membered heteroaryl; r is R X Is C 1-2 An alkyl group; and R is Y is-H. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), when R 1C independently-C (O) NR X R Y When R is 1C is-C (O) NH 2 -C (O) NHMe or-C (O) NMe 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), when R 1C Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D In the case of substituted 5-or 6-membered heteroaryl groups, the heteroaryl group may be pyrrolyl, pyridyl, imidazolyl, pyrazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, thienyl, furanyl, pyranyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), when R 1C Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D In the case of a substituted 5-membered heteroaryl group, the heteroaryl group may be pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl or oxadiazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 1C independently-C (O) NHMe or triazolyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl wherein each R 1C independently-C (O) NR X R Y Or having 1 to 3 hetero-sources selected from N, O and SOptionally 1 to 3C atoms 1-2 Alkyl substituted 5-to 6-membered heteroaryl, R X Is C 1-2 Alkyl, and R Y is-H. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is a compound having 1O heteroatom, optionally 1 to 3R 1C Substituted 3-to 6-membered monocyclic heterocyclyl wherein each R 1C independently-C (O) NR X R Y Or optionally 1 to 3C having 1 to 3 heteroatoms selected from N, O and S 1-2 Alkyl substituted 5-to 6-membered heteroaryl, R X Is C 1-2 Alkyl, and R Y is-H. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is a compound having 1O heteroatom, optionally 1 to 3R 1C Substituted 3-to 6-membered monocyclic heterocyclyl wherein each R 1C independently-C (O) NH 2 、-C(O)NHMe、-C(O)NMe 2 Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, or oxadiazolyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is C (O) NH 2 、-C(O)NHMe、-C(O)NMe 2 Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl or oxadiazolyl substituted oxiranyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is C (O) NH 2 、-C(O)NHMe、-C(O)NMe 2 Pyrrolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl or oxadiazolyl substituted oxiranyl, oxetanyl, tetrahydrofuranyl or tetrahydropyranyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is oxiranyl or oxetanyl substituted by-C (O) NHMe or triazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is oxetanyl substituted by-C (O) NHMe or triazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is oxetan-2-yl, oxetan-3-yl or oxetan-4-yl substituted by-C (O) NHMe or triazolyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is oxetan-3-yl substituted by-C (O) NHMe or triazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or R 1 Is optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl wherein each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, wherein each R 1C independently-C (O) NR X R Y Or optionally 1 to 3C having 1 to 3 heteroatoms selected from N, O and S 1-2 Alkyl substituted 5-to 6-membered heteroaryl, R X Is C 1-2 Alkyl, and R Y is-H. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl wherein each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substituted, and wherein each R 1C independently-C (O) NHMe or triazolyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl, wherein each R is 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substituted, or R 1 Is oxetanyl substituted by-C (O) NHMe or triazolyl.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is covered by 1 to 5R 4A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally substituted with 1 to 3R 4A Phenyl substituted by a group, or optionally with 1 to 2R 4B A group-substituted pyridyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), when R 4 When pyridinyl, the pyridinyl may be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, each of which is substituted with 1 to 2R 4B And (3) group substitution. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally substituted with 1 to 2R 4A 4-F-phenyl substituted by radicals or by 1 to 2R 4B Pyridin-4-yl substituted with a group.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A independently-CN, halogen or C 1-4 A haloalkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radicals being independently F, cl, CN, CH 2 F、CHF 2 、CF 3 Or CH (CH) 2 CF 3 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radicals being independently F, cl, CN or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radical is F.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A independently-CN, halogen, quilt-OC 1-4 Alkyl or C 1-4 Haloalkyl substituted C 1-4 An alkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radicals being independently F, cl, CN, CH 2 F、CHF 2 、CF 3 、CH 2 OCH 3 Or CH (CH) 2 CF 3 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radicals being independently F, cl, CN, CH 2 OCH 3 Or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radicals being independently F or CH 2 OCH 3 。
In the formulae (I), (II), (IIa), (IIb), (III), (IIIa), (II)In some embodiments of compounds Ib), (IV), (V), (Va) or (Vb), each R 4B Independently halogen or C 1-4 A haloalkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4B The radicals being independently F, cl, CH 2 F、CHF 2 、CF 3 Or CH (CH) 2 CF 3 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4B The radicals being independently F, cl or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4B The radicals being independently F or CHF 2 。
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A independently-CN, halogen or C 1-4 Haloalkyl, and each R 4B Independently halogen or C 1-4 A haloalkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A independently-CN, F, cl, CH 2 F、CHF 2 、CF 3 Or CH (CH) 2 CF 3 And each R 4B Is independently F, cl, CH 2 F、CHF 2 、CF 3 Or CH (CH) 2 CF 3 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And each R 4B The radicals being independently F, cl or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And each R 4B The radicals being independently F or CHF 2 。
In the formulae (I), (II), (IIa), (IIb), (III), (IIIa), (II)In some embodiments of compounds Ib), (IV), (V), (Va) or (Vb), R 4 Is covered by 1 to 5R 4A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridinyl, wherein each R 4A independently-CN, halogen or C 1-4 Haloalkyl, and each R 4B Independently halogen or C 1-4 A haloalkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally substituted with 1 to 3R 4A Phenyl substituted by a group, or optionally with 1 to 2R 4B A group-substituted pyridinyl group, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And each R 4B The radicals being independently F, cl or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally substituted with 1 to 2R 4A 4-F-phenyl substituted by radicals, or by 1 to 2R 4B Pyridin-4-yl substituted with a group, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And each R 4B The radicals being independently F or CHF 2 。
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally substituted with 1 to 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally substituted with 1F, cl, CN or CHF 2 Substituted 4-F-phenyl. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally substituted with 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is optionally 1 to2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radicals are F.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is covered by 1 to 2R 4B Pyridin-4-yl substituted with a group, wherein each R 4B The radicals being independently F, cl or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 4 Is covered by 1 to 2R 4B Pyridin-4-yl substituted with a group, wherein each R 4B The radicals being independently F or CHF 2 。
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb) wherein R 4 Is that
In formulae (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb)In some embodiments of the compound, R 4 Selected from the group consisting of:
in some embodiments, R 4 Selected from the group consisting of:in some embodiments, R 4 Is->/>
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or R 1 Is optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl wherein each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, wherein each R 1C independently-C (O) NR X R Y Or optionally 1 to 3C having 1 to 3 heteroatoms selected from N, O and S 1-2 Alkyl substituted 5-to 6-membered heteroaryl, R X Is C 1-2 Alkyl, R Y is-H, R 4 Is covered by 1 to 3R 4A Substituted phenyl, or substituted with 1 to 2R 4B Substituted pyridinyl, wherein each R 4A independently-CN, halogen or C 1-4 Haloalkyl, and wherein each R 4B Independently halogen or C 1-4 A haloalkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl wherein each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substitution, and wherein each R 1C independently-C (O) NHMe or triazolyl, R 4 Is covered by 1 to 3R 4A Substituted phenyl, or substituted with 1 to 2R 4B Substituted pyridinyl, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 And wherein each R 4B The radicals being independently F, cl or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl, wherein each R is 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substituted, or R 1 Is oxetanyl substituted by-C (O) NHMe or triazolyl, R 4 Is optionally substituted with 1 to 2R 4A 4-F-phenyl substituted by radicals, or by 1 to 2R 4B Pyridin-4-yl substituted with a group, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 And wherein each R 4B The radicals being independently F, cl or CHF 2 。
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, wherein each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl group、C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, R X Is C 1-2 Alkyl, R Y is-H, R 4 Is covered by 1 to 3R 4A Substituted phenyl, and each R 4A independently-CN, halogen or C 1-4 A haloalkyl group. In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, wherein each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substituted, R 4 Is covered by 1 to 3R 4A Substituted phenyl, and each R 4A The radicals being independently F, cl, CN or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl, wherein each R is 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substituted, R 4 Is optionally substituted with 1 to 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 。
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is covered by 1 to 3R 1B Substituted cyclobutyl, wherein each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or thiadiazolyl, respectively-CH 2 Si(Me) 3 Substituted, R 4 Is optionally substituted with 1 to 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is composed of 2 fluorine atoms and 1-CH 2 OH、-C(O)NH 2 -C (O) NHMe, a triazolyl or thiadiazolyl substituted cyclobutyl, wherein triazolyl is optionally substituted by Me, R 4 Is optionally substituted with 1 to 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is prepared from 2 fluorine atoms and 1-C (O) NH 2 or-C (O) NHMe substituted cyclobutyl, R 4 Is optionally substituted with 1 to 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radicals being independently F, cl, CN or CHF 2 . In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is prepared from 2 fluorine atoms and 1-C (O) NH 2 or-C (O) NHMe substituted cyclobutyl, R 4 Is optionally substituted with 1 to 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A The radical is F.
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
And
R 4 is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
And
R 4 is that
In some embodiments of the compounds of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va) or (Vb), R 1 Is that
And
R 4 is that
In some embodiments, the compound of formula (I) may be a compound of formula (II):
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or R 1 Is optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
Each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5 to8 membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, wherein each R 1C independently-C (O) NR X R Y Or optionally 1 to 3C having 1 to 3 heteroatoms selected from N, O and S 1-2 Alkyl substituted 5 to 6 membered heteroaryl;
R X is C 1-2 An alkyl group;
R Y is-H;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 4 is covered by 1 to 3R 4A Substituted phenyl, or substituted with 1 to 2R 4B Substituted pyridinyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group.
In some embodiments, the compound of formula (I) may be a compound of formula (II):
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substitution;
each R 1C independently-C (O) NHMe or triazolyl;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 4 is covered by 1 to 3R 4A Substituted phenyl, or substituted with 1 to 2R 4B Substituted pyridinyl;
each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R 4B The radicals being independently F or CHF 2 。
In some embodiments, the compound of formula (I) may be a compound of formula (II):
/>
wherein the method comprises the steps of
R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl, wherein each R is 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substitution;
or R is 1 Is oxetanyl substituted by-C (O) NHMe or triazolyl;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 4 is optionally substituted with 1 to 2R 4A 4-F-phenyl substituted by radicals, or by 1 to 2R 4B Group-substituted pyridine-4-a radical;
each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R 4B The radicals being independently F or CHF 2 。
In certain embodiments, the compounds of formula (I), (II) or (III) have the following structure:
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-6 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1C independently-C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1D Independently is optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 An alkyl group;
each R X independently-H or C 1-6 An alkyl group;
each R Y independently-H or C 1-6 An alkyl group;
R 4 is covered by 1 to 5R 4A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridinyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group.
In certain embodiments, the compounds of formula (I), (II), (IIa), (IIb), or (III) have the following structure:
wherein the method comprises the steps of
R 1 Is that
And
R 4 is that
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IV):
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-6 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl:
each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1C independently-C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1D Independently is optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 An alkyl group;
each R X independently-H or C 1-6 An alkyl group;
each R Y independently-H or C 1-6 An alkyl group;
R 4 is covered by 1 to 5R 4A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridinyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group.
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IV):
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or R 1 Is optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1C independently-C (O) NR X R Y Or optionally 1 to 3C having 1 to 3 heteroatoms selected from N, O and S 1-2 Alkyl substituted 5 to 6 membered heteroaryl;
R X is C 1-2 An alkyl group;
R Y is-H;
R 4 is covered by 1 to 3R 4A Substituted phenyl, or substituted with 1 to 2R 4B Substituted pyridinyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group.
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IV):
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or optionally substituted with 1 to 3R having 1O heteroatom 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substitution;
each R 1C independently-C (O) NHMe or triazolyl;
R 4 is covered by 1 to 3R 4A Substituted phenyl, or substituted with 1 to 2R 4B Substituted pyridinyl;
Each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R 4B The radicals being independently F, cl or CHF 2 。
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IV):
wherein the method comprises the steps of
R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl;
or R is 1 Is oxetanyl substituted by-C (O) NHMe or triazolyl;
each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein triazolyl and thiadiazolyl are optionally substituted with Me or-CH, respectively 2 Si(Me) 3 Substitution;
R 4 is optionally substituted with 1 to 2R 4A 4-F-phenyl substituted by radicals, or by 1 to 2R 4B Pyridin-4-yl substituted with a group;
each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R 4B The radicals being independently F, cl or CHF 2 。
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IV):
wherein the method comprises the steps of
R 1 Is that
And R is 4 Is that
In certain embodiments, the compound of formula (I) or (II) is a compound of formula (IV):
wherein the method comprises the steps of
R 1 Is that
And
R 4 is that
In certain embodiments, the compounds of formula (I), (II) or (V) have the following structure:
/>
wherein the method comprises the steps of
R 1 Is optionally substituted with 1 to 4R 1B Substituted C 3-6 Cycloalkyl, or optionally substituted 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
Each R 1B C independently being halogen, optionally substituted by 1-OH 1-6 Alkyl, C 2-6 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5 to 8 membered heteroaryl, provided that no more than 1R 1B Is optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1C independently-C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5 to 8 membered heteroaryl;
each R 1D Independently is optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 An alkyl group;
each R X independently-H or C 1-6 An alkyl group;
each R Y independently-H or C 1-6 An alkyl group;
R 4 is covered by 1 to 5R 1A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridinyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group. In certain embodiments, the compound of formula (I) or (II) is:
/>
/>
/>
in certain embodiments, the compound of formula (I) or (II) is:
/>
in certain embodiments, the compound of formula (I), (II) or (III) is:
in certain embodiments, the compound of formula (I), (II) or (IV) is:
/>
/>
/>
in certain embodiments, the compound of formula (I), (II) or (IV) is:
In certain embodiments, the compound of formula (I), (II), or (V) is:
/>
in some embodiments, the compound of formula (I) or (II) is
IV. composition
In certain embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure (e.g., a compound of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), or (Vb), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable excipient.
In certain embodiments, the pharmaceutical composition comprises one or more additional therapeutic agents, as set forth more fully below.
Pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, may be prepared with one or more pharmaceutically acceptable excipients, which may be selected according to conventional practice. The tablets may contain excipients including glidants, fillers, binders, and the like. The aqueous compositions may be prepared in sterile form and, when used for delivery by means other than oral administration, may generally be isotonic. All compositions may optionally contain excipients, for example those described in Rowe et al, handbook of Pharmaceutical Excipients, 6 th edition, american Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrins, hydroxyalkyl celluloses, hydroxyalkyl methylcellulose, stearic acid, and the like. In certain embodiments, the composition is provided in a solid dosage form, including a solid oral dosage form.
The compositions include compositions suitable for use in a variety of routes of administration, including oral administration. The composition may be present in unit dosage form and may be prepared by any method well known in the pharmaceutical arts. Such methods include the step of combining an active ingredient (e.g., a compound of the present disclosure or a pharmaceutically acceptable salt thereof) with one or more pharmaceutically acceptable excipients. The compositions may be prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Techniques and formulations are generally found in Remington, the Science and Practice of Pharmacy, 21 st edition, lippincott Wiliams and Wilkins, philiadelphia, pa., 2006.
Compositions described herein suitable for oral administration may be provided as discrete units (unit dosage forms) including, but not limited to, capsules, cachets or tablets each containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.
The pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with pharmaceutically acceptable excipients and optionally other therapeutic agents. The pharmaceutical composition containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral administration, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more excipients, including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets are acceptable. These excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; a binder such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed alone or with a wax.
The amount of active ingredient that can be combined with inactive ingredients to produce a dosage form can vary depending upon the individual treated and the particular mode of administration desired. For example, in some embodiments, a dosage form for oral administration to the human mouth may contain about 1 to 1000mg of active substance, formulated with a suitable and convenient amount of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutically acceptable excipient comprises about 5 to about 95% (weight: weight) of the total composition.
In certain embodiments, compositions comprising a compound of the present disclosure (e.g., a compound of formula (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (V), (Va), or (Vb)) or a pharmaceutically acceptable salt thereof, in one variant, do not contain an agent that affects the metabolic rate of the active ingredient. Thus, it is understood that in one aspect, a composition comprising a compound of the present disclosure does not comprise an agent that would affect (e.g., slow, hinder, or delay) the metabolism of the compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with the compound of the present disclosure. It is also to be understood that in one aspect, any of the methods, kits, articles of manufacture, etc. detailed herein do not include agents that would affect (e.g., slow, hinder, or delay) the metabolism of the compounds of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with the compounds of the present disclosure.
V. method
In certain embodiments, the present disclosure provides methods of treating HBV infection comprising administering to an individual (e.g., human) infected with a hepatitis b virus a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Although it is within the scope of the present disclosure to treat people with acute infection with HBV, typically, the individual is suffering from chronic hepatitis b infection.
In certain embodiments, methods of inhibiting HBV replication are provided comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (e.g., a human).
In certain embodiments, the present disclosure provides methods for reducing viral load associated with HBV infection, wherein the methods comprise administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (e.g., human) infected with HBV, wherein the therapeutically effective amount is sufficient to reduce HBV viral load in the individual.
As described more fully herein, the compounds of the present disclosure may be administered to an individual (e.g., a human) infected with HBV, along with one or more other therapeutic agents. The other therapeutic agent may be administered to the infected individual (e.g., a human) concurrently with or prior to or subsequent to administration of the compounds of the present disclosure.
In certain embodiments, provided are compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in treating or preventing HBV infection. In certain embodiments, provided are compounds of the present disclosure (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof, for use in the manufacture of a medicament for the treatment or prevention of HBV infection. In certain embodiments, the compounds of the present disclosure
As described more fully herein, the compounds of the present disclosure may be administered to an individual (e.g., a human) infected with HBV, along with one or more other therapeutic agents. Further, in certain embodiments, the compounds of the present disclosure may be administered with one or more (e.g., one, two, three, four, or more) additional therapeutic agents selected from the group consisting of: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulator toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi 4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesol X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-induced gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI 3K) inhibitors, indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymoα -1, bruton's kinase (BTK), HBV antibody, CCR2 chemokine antagonists, arginine inhibitors, and other drugs.
VI application of
The compounds of the present disclosure (also referred to herein as active ingredients) may be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It should be appreciated that the preferred route may vary depending on, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.
The compounds of the present disclosure may be administered to an individual for a desired period or duration, such as for example, for at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, according to an effective dosing regimen. In one variant, the compound is administered daily or intermittently throughout the lifetime of the individual.
Based on the judgment of the administering physician, the dosage or frequency of administration of the compounds of the present disclosure may be adjusted during the course of treatment.
The compound can be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily.
The compounds may be administered by any useful route and manner, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound may include from about 0.00001mg/kg body weight per day to about 10mg/kg body weight per day, such as from about 0.0001mg/kg body weight per day to about 10mg/kg body weight per day, or such as from about 0.001mg/kg body weight per day to about 1mg/kg body weight per day, or such as from about 0.01mg/kg body weight per day to about 1mg/kg body weight per day, or such as from about 0.05mg/kg body weight per day to about 0.5mg/kg body weight per day, or such as from about 0.3mg to about 30mg per day, or such as from about 30mg to about 300mg per day.
The compounds of the present disclosure may be combined with one or more additional therapeutic agents at any dose of the compounds of the present disclosure (e.g., 1mg to 1000mg of the compound). A therapeutically effective amount may comprise from about 1mg per dose to about 1000mg per dose, for example from about 50mg per dose to about 500mg per dose, or for example from about 100mg per dose to about 400mg per dose, or for example from about 150mg per dose to about 350mg per dose, or for example from about 200mg per dose to about 300mg per dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100 mg/dose, 125 mg/dose, 150 mg/dose, 175 mg/dose, 200 mg/dose, 225 mg/dose, 250 mg/dose, 275 mg/dose, 300 mg/dose, 325 mg/dose, 350 mg/dose, 375 mg/dose, 400 mg/dose, 425 mg/dose, 450 mg/dose, 475 mg/dose, or about 500 mg/dose. Other therapeutically effective amounts of the compounds of the present disclosure are about 100mg per dose, or about 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 350mg, 400mg, 450mg, or about 500mg per dose. A single dose may be administered hourly, daily or weekly. For example, a single dose may be administered every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose may also be administered every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or every 7 days. A single dose may also be administered every 1 week, 2 weeks, 3 weeks, or 4 weeks. In certain embodiments, a single dose may be administered once a week. A single dose may also be administered once a month.
Other therapeutically effective amounts of the compounds of the present disclosure are about 20 mg/dose, 25 mg/dose, 30 mg/dose, 35 mg/dose, 40 mg/dose, 45 mg/dose, 50 mg/dose, 55 mg/dose, 60 mg/dose, 65 mg/dose, 70 mg/dose, 75 mg/dose, 80 mg/dose, 85 mg/dose, 90 mg/dose, 95 mg/dose, or about 100 mg/dose.
The frequency of administration of the compounds of the present disclosure will be determined by the needs of the individual patient and may be, for example, once a day or two or more times a day. Administration of the compound continues as long as needed to treat HBV infection. For example, the compound may be administered to a person infected with HBV for a period of 20 to 180 days, or for a period of time such as 20 to 90 days, or for a period of time such as 30 to 60 days.
The administration may be intermittent for a period of days or more during which the patient receives a daily dose of a compound of the present disclosure, and then for a period of days or more during which the patient does not receive a daily dose of the compound. For example, the patient may receive a dose of the compound every other day or three times a week. As another example, a patient may receive a dose of the compound daily for a period of 1 to 14 days, then 7 to 21 days, during which the patient does not receive a dose of the compound, and for a subsequent period of time (e.g., 1 to 14 days), during which the patient receives a daily dose of the compound again. Alternate dosing cycles of compound administration followed by no compound administration may be repeated as needed to clinically treat the patient.
In one embodiment, a pharmaceutical composition is provided comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one or four) additional therapeutic agents.
In one embodiment, a kit is provided comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.
In certain embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
In certain embodiments, the compounds of the present disclosure are administered to a patient in a single dosage form concurrently with one or more additional therapeutic agents, e.g., as a solid dosage form for oral administration.
In certain embodiments, the compounds of the present disclosure are co-administered with one or more additional therapeutic agents.
Combination therapy
In certain embodiments, methods of treating or preventing HBV infection in a human suffering from or at risk of infection are provided comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, there is provided a method of treating HBV infection in a human suffering from or at risk of infection comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.
In certain embodiments, the present disclosure provides methods of treating HBV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents suitable for treating HBV infection.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.
Administration of HBV combination therapy
In certain embodiments, as described above, when a compound disclosed herein is combined with one or more additional therapeutic agents, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of each agent is present in the patient.
Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents. The compounds disclosed herein may be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of the unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of the unit dose of one or more additional therapeutic agents after a period of hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of the unit dose of a compound disclosed herein after a period of hours (e.g., 1-12 hours).
In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, e.g., as a solid dosage form for oral administration.
In certain embodiments, the compounds of formula (I) are formulated as tablets, which may optionally contain one or more other compounds for the treatment of HBV. In certain embodiments, the tablet may contain another active ingredient for the treatment of HBV.
In certain embodiments, such tablets are suitable for once-daily administration.
HBV combination therapy
The compounds described herein may be used or combined with one or more of the following: chemotherapeutic agents, immunomodulators, immunotherapeutic agents, therapeutic antibodies, therapeutic vaccines, bispecific antibodies, and "antibody-like" therapeutic proteins (e.gFab derivatives), antibody-drug conjugates (ADCs), genetic modifiers or gene editing agents (e.g., CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs), cell therapies (e.g., CAR-T (chimeric antigen receptor T cells) and TCR-T (engineered T cell receptor) agents), or any combination thereof.
In the above embodiments, the additional therapeutic agent may be an anti-HBV agent. For example, the additional therapeutic agent may be selected from the group consisting of: HBV combination drugs, other drugs for the treatment of HBV, 3-dioxygenase (IDO) inhibitors, antisense oligonucleotides targeting viral mRNA, apolipoprotein A1 modulators, arginase inhibitors, B-and T-lymphocyte attenuation factor inhibitors, bruton's Tyrosine Kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), covalently closed circular DNA (cccDNA) inhibitors, cyclophilin inhibitors, cytokines, cytotoxic T lymphocyte-associated protein 4 (ipi 4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesyl X receptor agonists Gene modifier or editor, HBsAg inhibitor, HBsAg secretion or assembly inhibitor, HBV antibody, HBV DNA polymerase inhibitor, HBV replication inhibitor, HBV ribonuclease inhibitor, HBV vaccine, HBV virus entry inhibitor, HBx inhibitor, hepatitis B large envelope protein modulator, hepatitis B large envelope protein stimulator, hepatitis B structural protein modulator, hepatitis B surface antigen (HBsAg) inhibitor, hepatitis B surface antigen (HBsAg) secretion or assembly inhibitor, hepatitis B virus E antigen inhibitor, hepatitis B virus replication inhibitor, hepatitis virus structural protein inhibitor, HIV-1 reverse transcriptase inhibitor, hyaluronidase inhibitor, IAP inhibitor, IL-2 agonist, IL-7 agonist, immunoglobulin G modulator, immunomodulators, indoleamine-2, ribonucleotide reductase inhibitors, interferon agonists, interferon alpha 1 ligands, interferon alpha 2 ligands, interferon alpha 5 ligand modulators, interferon alpha ligands, interferon alpha ligand modulators, interferon alpha receptor ligands, interferon beta ligands, interferon receptor modulators, interleukin-2 ligands, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM5 inhibitors, KDM1 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin beta receptor activators, microRNA (miRNA) gene therapeutics, axl modulators, B7-H3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators CD27 modulator, CD47 modulator, CD70 modulator, GITR modulator, HEVEM modulator, ICOS modulator, mer modulator, NKG2A modulator, NKG2D modulator, OX40 modulator, SIRPalpha modulator, TIGIT modulator, tim-4 modulator, tyro modulator, na+ -taurine co-transporter polypeptide (NTCP) inhibitor, natural killer cell receptor 2B4 inhibitor, NOD2 gene stimulator, nucleoprotein inhibitor, nucleoprotein modulator, PD-1 inhibitor, PD-L1 inhibitor, PEG-interferon lambda, peptidyl prolyl isomerase inhibitor, phosphatidylinositol-3 kinase (PI 3K) inhibitor, recombinant Scavenger Receptor A (SRA) protein, recombinant thymosin alpha-1, retinoic acid-inducing gene 1 stimulator, reverse transcriptase inhibitor, ribonuclease inhibitor, RNA DNA polymerase inhibitor, RNA polymerase inhibitor, short interfering RNAs (sirnas), short synthetic hairpin RNAs (sshrnas), SLC10A1 gene inhibitors, SMAC mimics, src tyrosine kinase inhibitors, interferon gene Stimulators (STING) agonists, NOD1 stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 ligands, tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors, zinc finger nucleases or synthetic nucleases (talens) and combinations thereof.
In certain embodiments, the compounds of formula (I) are formulated as tablets, which may optionally contain one or more other compounds for the treatment of HBV. In certain embodiments, the tablet may contain another active ingredient for the treatment of HBV, such as 3-dioxygenase (IDO) inhibitors, apolipoprotein A1 modulators, arginase inhibitors, B-and T-lymphocyte attenuation factor inhibitors, bruton's Tyrosine Kinase (BTK) inhibitors, CCR2 chemokine antagonists, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonists and modulators, compounds targeting HBcAg, compounds targeting hepatitis B core antigen (HBcAg), modulators of core protein allosteric, inhibitors of covalently closed circular DNA (cccDNA), cyclophilin inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi 4) inhibitors, DNA polymerase inhibitors, endonuclease modulators, epigenetic modifiers, farnesol X receptor agonists, HBsAg inhibitors inhibitors of HBsAg secretion or assembly, inhibitors of HBV DNA polymerase, inhibitors of HBV replication, inhibitors of HBV ribonuclease, inhibitors of HBV viral entry, inhibitors of HBx, modulators of hepatitis B large envelope protein, stimulators of hepatitis B large envelope protein, modulators of hepatitis B structural protein, inhibitors of hepatitis B surface antigen (HBsAg) secretion or assembly, inhibitors of hepatitis B virus E antigen, inhibitors of hepatitis B viral replication, inhibitors of hepatitis virus structural protein, inhibitors of HIV-1 reverse transcriptase, inhibitors of hyaluronidase, IAP inhibitors, IL-2 agonists, IL-7 agonists, immunomodulators, indoleamine-2 inhibitors, inhibitors of ribonucleotide reductase, interleukin-2 ligand, ipi4 inhibitor, lysine demethylase inhibitor, histone demethylase inhibitor, KDM1 inhibitor, KDM5 inhibitor, killer lectin-like receptor subfamily G member 1 inhibitor, lymphocyte activation gene 3 inhibitor, lymphotoxin beta receptor activator, axl modulator, B7-H3 modulator, B7-H4 modulator, CD160 modulator, CD161 modulator, CD27 modulator, CD47 modulator, CD70 modulator, GITR modulator, HEVEM modulator, ICOS modulator, mer modulator, NKG2A modulator, NKG2D modulator, OX40 modulator, SIRP alpha modulator, GIT modulator, tim-4 modulator, tyro modulator, na+ -taurine co-transporter polypeptide (NTCP) inhibitor, natural killer cell receptor 2B4 inhibitor NOD2 gene stimulators, nucleoprotein inhibitors, nucleoprotein modulators, PD-1 inhibitors, PD-L1 inhibitors, peptidyl prolyl isomerase inhibitors, phosphatidylinositol-3 kinase (PI 3K) inhibitors, retinoic acid-induced gene 1 stimulators, reverse transcriptase inhibitors, ribonuclease inhibitors, RNA DNA polymerase inhibitors, SLC10A1 gene inhibitors, SMAC mimetics, src tyrosine kinase inhibitors, interferon gene Stimulators (STING) agonists, NODI stimulators, T cell surface glycoprotein CD28 inhibitors, T cell surface glycoprotein CD8 modulators, thymosin agonists, thymosin alpha 1 ligands, tim-3 inhibitors, TLR-3 agonists, TLR-7 agonists, TLR-9 agonists, TLR9 gene stimulators, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitors and combinations thereof.
In certain embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents selected from the group consisting of: HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulator toll-like receptor (TLR) modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, hepatitis b surface antigen (HBsAg) inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi 4) inhibitors, cyclophilin inhibitors, HBV viral entry inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA) and ddRNAi endonuclease modulators, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesol X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-induced gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI 3K) inhibitors, indoleamine-2, 3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymoα -1, bruton's kinase (BTK), HBV antibody, CCR2 chemokine antagonists, arginine inhibitors, and other drugs.
HBV combination medicine
Examples of combination drugs for treating HBV include(tenofovir disoproxil fumarate and emtricitabine); ABX-203, lamivudine, and PEG-IFN- α; ABX-203 adefovir and PEG-ifnα; and INO-1800 (INO-9112 and RG 7944).
Other HBV drugs
Examples of other drugs for the treatment of HBV include alpha-hydroxy tropolone, amadori, beta-hydroxy cytidine, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporin A, gentiopicroside (gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV-205 (molixan, BAM-205), oligonucleotides, mivotilate, feron, GST-HG-131, levamisole, casutin, alloferon, WS-007Y-101 (tefenadine), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, hepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, hepbarna, IBPB-006IA, hepuyinfen, dasKloster 0014-01, ISA-204, jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, dasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO-6864018, RG-7834, UB-551 and ZH-2N, and compounds disclosed in US20150210682 (Roche), US 2016/012344 (Roche), WO2015173164, WO2016023877, US2015252057a (Roche), WO16128335A1 (Roche), WO16120186A1 (Roche), US2016237090a (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US2016176899a (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US2016220586a (Roche) and US2015031687a (Roche).
HBV vaccine
HBV vaccines include prophylactic and therapeutic vaccines. Examples of HBV preventive vaccines include Vaxelis, hexaxim, heplisav, mosquirix, DTwP-HBV vaccine, bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwp-Hepb-Hib-IPV vaccine, heberpenta L, DTwp-Hepb-Hib, V-419, CVI-HBV-001, tetra bha, hepatitis B preventive vaccine (Advax Super D), hepatrol-07, GSK-223192A, ENGERIXRecombinant hepatitis B vaccine (intramuscular, kangtai biological preparation), recombinant hepatitis B vaccine (Hansenula, intramuscular, wallace biological engineering), recombinant hepatitis B surface antigen vaccine, bimmugen, euforavac, eutravac, anrix-DTaP-IPV-Hep B, HBAI-20, infinix-DTaP-IPV-Hep B-Hib, pentabio Vaksin DTP-HB-Hib, comvac 4, twinrix, euvax-B, tritanrix HB, infinix Hep B, comvax, DTP-Hib-HBV vaccine, DTP-HBV vaccine, YI Tai, heberthovac HB, trivac HB, gervax, DTwP-Hep B-Hib vaccine, bilive, hepavax-Gene, SUPERVAX, comvac, shanvac-B, hebsulin, recombivax, revac B mcf, revac B+, fendrix, DTwP-HepB-Hib, DNA-001, shan5, shan6, rhG, LBsA, HBsA-Hev vaccine, HBsA-Hev 78 and HBsA vaccine.
Examples of HBV therapeutic vaccines include HBsAG-HBIG complex, ARB-1598, bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, tetra bha, GX-110E, GS-4774, peptide vaccine (epsilon PA-44), hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, revac B mcf, revac B+, MGN-1333, KW-2, CVI-HBV-002, altraHepB, VGX-6200, FP-02, FP-02.2, TG-1050, NU-500, HBVax, im/Trigrid/antigen vaccine, mega-CD 40L-adjuvanted vaccine, hepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine (HBV infection, biotech), adTG-17909, adTG-17910, TG-18202, chronc-B, TG-and LVam.
HBV DNA polymerase inhibitors
Examples of HBV DNA polymerase inhibitors include adefovirEmtricitabineTenofovir disoproxil fumarate +.>Tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, tenofovir disoproxil fumarate, tenofovir Wei Shiba alkoxyethyl ester, CMX-157, besifovir, entecavir, and jejunal>Entecavir maleate, telbivudine +.>Pradefovir, clavudine, ribavirin, lamivudine ++ >Azidothalamine, famciclovir, spindle protein, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil asparate, tenofovir disoproxil orotate and HS-10234. Other examples of HBV DNA polymerase inhibitors include fluoclovir.
Immunomodulators
Examples of immunomodulators include ritatolimod, emidol hydrochloride, ingaron, dermaVir, paradol (hydroxychloroquine), aldesleukin (proleukin), hydroxyurea, mycophenolate Mofetil (MPA) and its ester derivatives Mycophenolate Mofetil (MMF), WF-10, ribavirin, IL-12, INO-9112, polymeric Polyethylenimine (PEI), gepon, VGV-1, MOR-22, BMS-936559, RO-7011785, RO-6871765, AIC-649 and IR-103. Other examples of immunomodulators include JNJ-440, AB-452, CRV-431, JNJ-0535, TG-1050, ABI-H2158, GS-9688, RG-7854 and AB-506.
Toll-like receptor (TLR) modulators
Modulators of TLR include modulators of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR 13. Examples of TLR3 modulators include ritimod, poly-ICLC,Apoxxim、/>IPH-33, MCT-465, MCT-475, GS-9688 and ND-1.1.
Examples of TLR7 modulators include GS-9620, GSK-2245035, imiquimod, raximod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, limtop, TMX-30X, TMX-202, RG-7863, RG-7795, RG-7854, and the compounds disclosed in US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), and US20090047249 (Gilead Sciences). Other examples of TLR7 modulators include terlamote, SP-0509 and LHC-165.
Examples of TLR8 modulators include motolimod, raschimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and compounds in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO 2014/023613 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array biopha), US20100029585 (venteirx Pharma), US20110092485 (venteirx Pharma), US20110118235 (ventex Pharma), US20120082658 (venteirx) US20120219615 (venteirx), US20140066432 (venteirx) pharmaceutical x, US 4 (ventex) pharmaceutical applications (ventex 393), US 4635/692, US patent application No. 692 (US patent application No. 35, US patent application No. 69215/692, and US patent application No. 69215.
Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, left O Li Mote (MGN-1703), li Nimo T and CYT-003-QbG.
Other examples of TLR7, TLR8 and TLR9 modulators include those described in WO (Teika Seiyaku), WO (Janssen), WO (Roche), WO (Jiangsu constant rayleigh Pharmaceutical inc.), and WO (Roche), WO (Roche), WO (Novartis), WO () WO (Pharmaceutical), WO (Merck), WO (Roche) WO (Roche), WO (3M Co), WO (Gilead Sciences), WO (Eisai Co Ltd), WO (Roche), WO (3M Co), WO ((India)), WO (Novartis) WO (Roche), WO (Novartis), WO (Roche), WO (3M Co), WO (Eisai Co Ltd), WO (Roche) WO (), WO (Merck), WO (Roche), WO (), US (), WO (), compounds disclosed in WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO2017184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas) and WO2015023958 (University of Kansas).
Interferon alpha receptor ligands
Examples of interferon alpha receptor ligands include interferon alpha-2 b (INTRON) Pegylated interferon alpha-2 aPEGylated interferon alpha-1 b, interferon alpha 1 b->Veldona, infradure, luo Raosu-A, YPEG-Interferon alpha-2 a (YPHEG-rhIFN alpha-2 a), P-1101, algeron, alfarona, ingaron (Interferon gamma), rSIFN-co (recombinant super-consensus interferon), ypeg Interferon alpha-2 b (YPHEG-rhIFN alpha-2 b), MOR-22, polyethylene glycol Interferon alpha-2 b->Bioferon、Novaferon、Inmutag(Inferon)、Interferon alpha-n 1->Interferon beta-1 a->Sheferon, interferon alpha-2B (Axxo), alfaferone, interferon alpha-2B (BioGeneric Pharma), interferon alpha-2 (CJ), laferonum, VIPEG, BLAUFERON-A, BLAUFERON-B, intermax alpha, realdiron, lanstion, pegaferon, PDferon-B, PDferon-B, interferon alpha-2B (IFN, laboratorios Bioprofarma), interferon alpha 2B, kalferon, pegnano, feronsure, pegiHep, interferon alpha 2B (Zydus-Cadila), interferon alpha 2a, optipeg A, realfa 2B, reliferon, interferon alpha-2B (Amega)) Interferon alpha-2 b (Virchow), rog interferon alpha-2 b, rHSA-IFN alpha-2 a (recombinant human serum albumin interferon alpha 2a fusion protein), rHSA-IFN alpha 2b, recombinant human interferon alpha- (1 b, 2a, 2 b), peg interferon alpha-2 b (Amega), peg interferon alpha-2 a, reaferon-EC, proquiferon, uniferon, urifron, interferon alpha-2 b (Changchun Institute of Biological Products), anterferon, shanferon, layfferon, shang Sheng Lei Tai, INTEFEN, SINOGEN, fukangtai, pegstat, rHSA-IFN alpha-2 b, SFR-9216 and Interapo (Interapa).
Hyaluronidase inhibitor
Examples of hyaluronidase inhibitors include astondrimer.
Hepatitis b surface antigen (HBsAg) inhibitors
Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP-9AC, REP-9C, REP-9, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006, and REP-9AC'.
Examples of HBsAg secretion inhibitors include BM601.
Cytotoxic T-lymphocyte-associated protein 4 (ipi 4) inhibitors
Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi 4) inhibitors include AGEN-2041, AGEN-1884, yiprimumab, berazepine, PSI-001, PRS-010, probody mAb, texi Li Mshan antibody, and JHL-1155.
Cyclophilin inhibitors
Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175 and the compounds disclosed in US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences) and US20130344029 (Gilead Sciences).
Inhibitors of HBV viral entry
Examples of HBV viral entry inhibitors include myrculdex B.
Antisense oligonucleotides targeting viral mRNA
Examples of antisense oligonucleotides targeting viral mRNA include ISIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.
Short interfering RNA (siRNA) and ddRNAi
Examples of siRNA include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, hepB-nRNA and ARC-520, ARC-521, ARB-1740, ARB-1467.
Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.
Endonuclease modulators
Examples of endonuclease modulators include PGN-514.
Ribonucleotide reductase inhibitors
Examples of ribonucleotide reductase inhibitors include Trimidox.
HBV E antigen inhibitors
Examples of HBV E antigen inhibitors include wogonin.
Covalently closed circular DNA (cccDNA) inhibitors
Examples of cccDNA inhibitors include BSBI-25 and CHR-101.
Fanisol X receptor agonists
Examples of farnesol X receptor agonists are EYP-001. Other examples of farnesoid x receptor agonists include GS-9674, EDP-305, MET-409, tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX-023-1, EP-024297 and GS-8670.
HBV antibodies
Examples of HBV antibodies targeting hepatitis B virus surface antigens include GC-1102, XTL-17, XTL-19, KN-003, IV hepibulin SN and fully human monoclonal antibody therapy (hepatitis B virus infection, humabs BioMed).
Examples of HBV antibodies include monoclonal and polyclonal antibodies, including Zutectra, shang Sheng Gan Di, uman Big (hepatitis B hyperimmune), omri-Hep-B, nabi-HB, hepatectCP, hepaGam B, igantibe, niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, shanghai RAAS blood product) and Fovepta (BT-088).
Fully human monoclonal antibodies, such as HBC-34.
CCR2 chemokine antagonists
Examples of CCR2 chemokine antagonists include propargyl germanium.
Thymosin agonists
Examples of thymosin agonists include thymalfasin and recombinant thymosin alpha 1 (GeneScience).
Cytokines and methods of use
Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24, and Western Mo Baijie.
Nuclear protein modulators
The nucleoprotein modulator may be an HBV core or capsid protein inhibitor. Examples of nucleoprotein modulators include AB-423, AT-130, GLS4, NVR-1221, NVR-3778, BAY 41-4109, moxadine sulfonate, JNJ-379, RG-7907, ABI-H0731, ABI-H2158 and DVR-23. Other examples of nucleoprotein modulators include GS-4882, AL-3778, ARB-168786, ARB-880, HEC-72702, AB-506 and JNJ-440.
Examples of capsid inhibitors include compounds disclosed in US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), WO2015/059212 (Janssen), WO2015118057 (Janssen), WO2015011281 (Janssen), WO2014184365 (Janssen), WO2014184350 (Janssen), WO2014161888 (Janssen), WO2013096744 (Novira), US20150225355 (Novira), US20140178337 (Novira), US20150315159 (Novira), US20150197533 (Novira), US20150274652 (Novira), US20150259324 (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche). Other examples of capsid inhibitors include compounds disclosed in WO2017198744 (Roche), US 20170334882 (Novira), US 20170334898 (Roche), WO2017202798 (Roche), WO2017214395 (Enanta), WO2018001944 (Roche), WO2018001952 (Roche), WO2018005881 (Novira), WO2018005883 (Novira), WO2018011100 (Roche), WO2018011160 (Roche), WO2018011162 (Roche), WO2018011163 (Roche), WO2018036941 (Roche), WO2018043747 (Kyoto Univ), US20180065929 (Janssen), WO2016168619 (Indiana University), WO2016195982 (The Penn State Foundation), WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira) and US20170121329 (Novira).
Examples of transcript inhibitors include compounds disclosed in WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (enata), WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (new Pharma), US20180030053 (Novartis), WO2018045911 (Zhejiang Pharma).
Retinoic acid-induced gene 1 stimulators
Examples of retinoic acid-inducing gene 1 stimulators include SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 and ORI-7170, RGT-100.
NOD2 stimulators
Examples of NOD2 stimulators include SB-9200.
Phosphatidylinositol 3-kinase (PI 3K) inhibitors
Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, piciliside, lenatinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI-549, UCB-5857, tasselisib, XL-765, gedatolisib, ME-401, VS-5584, copanlisib, CAI orotate, pirifaxine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-40093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, SAR-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib, and CLR-1401.
Indolylamine-2, 3-dioxygenase (IDO) pathway inhibitors
Examples of IDO inhibitors include epacoadostat (INCB 24360), resminostat (4 SC-201), indomod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218 and the compounds disclosed in US20100015178 (Incyte), US2016137652 (Flexus Biosciences, inc.), WO2014073738 (Flexus Biosciences, inc.) and WO2015188085 (Flexus Biosciences, inc.).
PD-1 inhibitors
Examples of PD-1 inhibitors include nivolumab, pembrolizumab, pidilizumab, BGB-108, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, and mDX-400. Other examples of PD-1 inhibitors include Semilbezumab, STI-A1014, JNJ-63723283, CA-170, dewaruzumab, alemtuzumab, JS-001, camrelizumab, sintilimab, sintilimab, tislelizumab, BCD-100, BGB-A333, JNJ-63723283, GLS-010 (WBP-3055), CX-072, AGEN-2034, GNS-1480 (epidermal growth factor receptor antagonist; programmed cell death ligand 1 inhibitor), CS-1001, M-7824 (PD-L1/TGF-beta bifunctional fusion protein), genolimizumab and BMS-936559.
PD-L1 inhibitors
Examples of PD-L1 inhibitors include alemtuzumab, avstuzumab, AMP-224, MEDI-0680, RG-7446, GX-P2, dewaruzumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, CX-072, and BMS-936559. Other examples of PD-L1 inhibitors include GS-4224.
Other examples of PD-1/PD-L1 inhibitors include those found in WO (Incyte Corp), WO (), WO (Incyte Corp) WO (Incyte Corp), WO (Incyte Corp) WO (), WO (Eisai Co Ltd; WO (), WO (; individual), WO (Incyte Corp), WO (), WO (, co), WO (,), WO (, etc.) WO (), WO (Incyte Corp), WO (, compounds disclosed in WO2015134605 (BristolMyers Squibb Co), WO2018051255 (Aurigene Discovery Technologies Ltd), WO2018051254 (Aurigene Discovery Technologies Ltd), WO2017222976 (Incyte Corp), WO2017070089 (Incyte Corp), WO2018044963 (BristolMyers Squibb Co), WO2013144704 (Aurigene Discovery Technologies Ltd), WO2018013789 (Incyte Corp), WO2017176608 (BristolMyers Squibb Co), WO2018009505 (BristolMyers Squibb Co), WO2011161699 (Aurigene Discovery Technologies Ltd), WO2015119944 (Incyte Corp; merck Sharp & Dohme Corp), WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317 (Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene Discovery Technologies Ltd), WO2015036927 (Aurigene Discovery Technologies Ltd), WO2015044900 (Aurigene Discovery Technologies Ltd) and WO2018026971 (Arising International).
Recombinant thymosin alpha-1
Examples of recombinant thymosin alpha 1 include NL-004 and PEGylated thymosin alpha 1.
Bruton's Tyrosine Kinase (BTK) inhibitors
Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS-986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC-2364447, RDX-022, X-022, AC-058, RG-7845, spebrutinib, TAS-5315, TP-0158, TP-4207, HM-71224, KBP-7516, M-2951, TAK-020, AC-0025 and the compounds disclosed in US20140330015 (Ono Pharmaceutical), US20130079327 (Ono Pharmaceutical) and US20130217880 (Ono Pharmaceutical).
KDM inhibitors
Examples of KDM5 inhibitors include the compounds disclosed in WO2016057924 (Genntech/Constellation Pharmaceuticals), US20140275092 (Genntech/Constellation Pharmaceuticals), US20140371195 (Epitherapeutics) and US20140371214 (Epitherapeutics), US20160102096 (Epitherapeutics), US20140194469 (Quanticel), US20140171432, US20140213591 (Quanticel), US20160039808 (Quanticel), US20140275084 (Quanticel), WO2014164708 (Quanticel).
Examples of KDM1 inhibitors include the compounds disclosed in US9186337B2 (Oryzon Genomics) and GSK-2879552, RG-6016, ORY-2001.
STING agonists
Examples of STING agonists include SB-11285, adVCA0848 and STING vax. Other examples of STING agonists include the compounds disclosed in WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (invitogen), WO 2017161349 (Immune Sensor), WO 2017106740 (Aduro Biotech), US 20170158724 (Glaxo Smithkiline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO2018098203 (Janssn), WO2018118665 (Merck), WO2018118664 (Merck), WO2018100558 (Takeda), WO2018067423 (Merck) and WO2018060323 (Boehringer).
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Examples of NNRTIs include the compounds disclosed in WO2018118826 (Merck), WO2018080903 (Merck), WO2018119013 (Merck), WO2017100108 (Idenix), WO2017027434 (Merck), WO2017007701 (Merck) and WO2008005555 (Gilead).
Inhibitors of HBV replication
Examples of hepatitis B virus replication inhibitors include isothiaflodine, IQP-HBV, RM-5038 and Xingentie.
Arginase inhibitors
Examples of arginase inhibitors include CB-1158, C-201 and reminisstat.
Gene therapy and cell therapy
Gene therapies and cell therapies include genetic modifications for silencing a gene; genetic methods for directly killing infected cells; immune cell infusions designed to replace a majority of the patient's autoimmune system to enhance the immune response to the infected cells or activate the patient's autoimmune system to kill the infected cells or seek and kill the infected cells; genetic methods for modifying cellular activity to further alter an endogenous immune response to an infection.
Gene editing agent
The gene editing system is selected from the group consisting of: CRISPR/Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems; cccDNA elimination and alteration of one or more Hepatitis B Virus (HBV) viral genes, for example, by targeted cleavage. Altering (e.g., knocking out and/or knocking down) PreC, C, X, preSI, preS, S, P or SP gene means (1) reducing or eliminating PreC, C, X, preSI, preS2, S, P or SP gene expression, (2) interfering with the intracellular, serum and/or intraparenchymal levels of a pre-Core, X protein, long surface protein, middle surface protein, S protein (also known as HB antigen and HBsAg), polymerase protein and/or hepatitis b splice protein function (HBe, HBc, HBx, preS1, preS2, S, pol and/or HBSP) or (3) reducing or eliminating HBe, HBc, HBx, LHB, MHB, SHB, pol and/or HBSP protein. One or more of the PreC, C, X, preSI, preS, S, P and/or SP genes are knocked down by targeting one or more genes in HBV cccDNA and/or integrated HBV DNA.
CAR-T cell therapy
The population of immune effector cells is engineered to express a Chimeric Antigen Receptor (CAR), wherein the CAR comprises an HBV antigen binding domain. The immune effector cells are T cells or NK cells. In some embodiments, the T cell is a cd4+ T cell, a cd8+ T cell, or a combination thereof. The cells may be autologous or allogeneic.
TCR-T cell therapy
T cells express HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-derived peptides presented on the surface of virus-infected cells.
T cells express HBV surface antigen (HBsAg) specific TCRs.
TCR-T therapy involves the treatment of HBV, such as LTCR-H2-1.
HBV combination therapy
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, or four additional therapeutic agents selected from the group consisting of: adefovirTenofovir disoproxil fumarate +.>Tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->Tibifadin->Or lamivudine->In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovir- >Tenofovir disoproxil fumarate +.>Tenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->Tibifadin->Or lamivudineIn one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, four, one or two, or oneTo three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.
Combination therapy with HBV DNA polymerase inhibitors
In a specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and at least one additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapeutics, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis b virus E antigen inhibitors, recombinant SRA proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies including HBV antibodies and bispecific antibodies targeting hepatitis b virus surface antigens, and "antibody-like" therapeutic proteins (e.g. Fab derivatives or TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBV core or capsid protein modulators), retinoic acid-inducing gene 1 stimulators, RIG-I-like receptor stimulators, NOD2 stimulators, NOD1 stimulators, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activating gene 3 inhibitors, CD160 inhibitors, cytotoxic T lymphocyte-associated protein 4 (ipi 4) inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B-and T-lymphocyte senescenceAn attenuation inhibitor, a CD305 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a PEG-interferon lambda, a recombinant thymosin alpha-1, a BTK inhibitor, a TIGIT modulator, a CD47 modulator, a sirpa modulator, an ICOS modulator, a CD27 modulator, a CD70 modulator, an OX40 modulator, an epigenetic modifier, a NKG2D modulator, a Tim-4 modulator, a B7-H3 modulator, a NKG2A modulator, a GITR modulator, a CD160 modulator, a HEVEM modulator, a CD161 modulator, an Axl modulator, a Mer modulator, a Tyro modulator, a gene modifier or an editing agent such as CRISPR (including CRISPR Cas 9), a zinc finger nuclease or a synthetic nuclease (TALEN), an IAP inhibitor, a SMAC mimetic, a KDM5 inhibitor, an IDO inhibitor, and a hepatitis B virus replication inhibitor.
In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HBV DNA polymerase inhibitor, one or two additional therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies and bispecific antibodies targeting hepatitis b virus surface antigens, and "antibody-like" therapeutic proteins (e.gFab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducing gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators, and one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis b viral surface antigens, siRNA, miRNA gene therapeutics, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).
In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBV therapeutic vaccines, including targeted b HBV antibodies to hepatitis virus surface antigen and HBV antibodies to bispecific antibodies and "antibody-like" therapeutic proteins (e.g/>Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators.
In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis b virus surface antigens, siRNA, miRNA gene therapeutics, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core protein or capsid protein inhibitors).
HBV drug combination therapy
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovirTenofovir disoproxil fumarateTenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir- >TibifdineOr lamivudine->And in combination with at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, interferon alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, compounds targeting HBcAg, cyclophilin inhibitors, HBV vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, siRNA, miRNA gene therapeutics, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis b virus E antigen inhibitors, recombinant SRA proteins, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, sshRNA, HBV antibodies including HBV antibodies and bispecific antibodies targeting hepatitis b virus surface antigens, and "antibody-like" therapeutic proteins (e.g.Fab derivatives or TCR-like antibodies), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators (HBV core or capsid protein modulators), retinoic acid inducing gene 1 stimulators, RIG-I-like receptor stimulators, NOD2 stimulators, NOD1 stimulators, IDOl inhibitors, recombinant thymosin alpha-1, arginase inhibitors, STING agonists, PI3K inhibitors, lymphotoxin beta receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activating gene 3 inhibitors, CD160 inhibitors, ipi4 inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B-and T-lymphocyte attenuation factor inhibitors, epigenetic modifiers, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon lambda, BTK inhibitors, TIGIT modulators, CD47 modulators, sirpa modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, TIM-4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, axl modulators, mer modulators, tyro modulators, Genetic modifiers or editors such as CRISPR (including CRISPR Cas 9), zinc finger nucleases or synthetic nucleases (TALENs), IAP inhibitors, SMAC mimics, KDM5 inhibitors and hepatitis b virus replication inhibitors.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovirTenofovir disoproxil fumarateTenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->TibifdineOr lamivudine->And in combination with at least a second additional therapeutic agent selected from the group consisting of: polyethylene glycol interferon alpha-2 b->Interferon alpha 1 b->Interferon alpha-2 b (INTRON->) Pegylated interferon alpha-2 aInterferon alpha-n 1->Ribavirin, interferon beta-1 aBioferon, ingaron, inmutag (Inferon), algeron, luo Raosu-A, oligotide, zutectra, shaferon, interferon alpha-2B (AXXO), alfaferone, interferon alpha-2B (BioGeneric Pharma), ferron, interferon alpha-02 (CJ), BEVAC, laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, intermax alpha, realdiron, lanstion, pegaferon, PDferon-B, interferon alpha-2B (IFN, laboratorios Bioprofarma), alpha interferon 2B, kalferon, pegnano, feronsure, pegiHep, interferon alpha 2B (Zydus-Cadila), optipeg A, realfa 2B, reliferon, interferon alpha-2B (Amega), interferon alpha-2B (Virchow), polyethylene glycol interferon alpha-2B (Amega), reaferon-EC, proquiferon, uniferon, urifron, interferon alpha-2B (Changchun Institute of Biological Products), anterferon, shanferon, MOR-22, interleukin-2 (IL-2, immunex), recombinant human interleukin-2 (Shenzhen Neptunus), layfferon, kacelsho Ning, shang Sheng Lei Tai, INTEFEN, SINOGEN, fukangtai, alloferon and molekin.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovirTenofovir disoproxil fumarateTenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->TibifdineOr lamivudine->And in combination with at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies targeting hepatitis b virus surface antigens and bispecific antibodies, and "antibody-like" therapeutic proteins (e.g.>Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, arginase inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors, IDO inhibitors, and NOD2 stimulators.
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovir Tenofovir disoproxil fumarateTenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->TibifdineOr lamivudine->And in combination with at least a second additional therapeutic agent selected from the group consisting of: HBV viral entry inhibitor, NTCP inhibitor, HBx inhibitor, cccDNA inhibitorAgents, HBV antibodies targeting hepatitis b virus surface antigen, siRNA, miRNA gene therapeutics, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core protein or capsid protein modulators).
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovirTenofovir disoproxil fumarateTenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->TibifdineOr lamivudine->And one, two or three additional therapeutic agent combinations selected from the group consisting of: immunomodulators, TLR modulators, inhibitors of HBsAg secretion or assembly, HBV therapeutic vaccines, HBV antibodies including HBV antibodies and bispecific antibodies targeting hepatitis b virus surface antigens, and "antibody-like" therapeutic proteins (e.g. >Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-induced gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, and NOD2 stimulators; and in combination with one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitor, NTCP inhibitor, HBx inhibitor, cccDNAInhibitors, HBV antibodies targeting hepatitis b virus surface antigen, siRNA, miRNA gene therapeutics, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core protein or capsid protein modulators).
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovirTenofovir disoproxil fumarateTenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->TibifdineOr lamivudine->In combination with one or two additional therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, inhibitors of HBsAg secretion or assembly, HBV therapeutic vaccines, HBV antibodies including HBV antibodies and bispecific antibodies targeting hepatitis b virus surface antigens, and "antibody-like" therapeutic proteins (e.g. >Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, retinoic acid-inducing gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators; to be used forAnd in combination with one or two additional therapeutic agents selected from the group consisting of: HBV viral entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis b viral surface antigens, siRNA, miRNA gene therapeutics, sshRNA, KDM5 inhibitors and nucleoprotein modulators (HBV core protein or capsid protein modulators).
In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: adefovirTenofovir disoproxil fumarateTenofovir alafenamide, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, entecavir->TibifdineOr lamivudine->And one, two, three or four additional therapeutic agent combinations selected from the group consisting of: immunomodulators, TLR7 modulators, TLR8 modulators, HBsAg inhibitors, HBsAg secretion or assembly inhibitors, HBV therapeutic vaccines, HBV antibodies including HBV antibodies and bispecific antibodies targeting hepatitis b virus surface antigens, and "antibody-like" therapeutic proteins (e.g.) >Fab derivatives or TCR-like antibodies), cyclophilin inhibitors, tretinoinAcid-induced gene 1 stimulators, RIG-I like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors, NOD2 HBV viral entry inhibitor stimulators, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, siRNA, miRNA gene therapeutics, sshrs, KDM5 inhibitors, and nucleoprotein modulators (HBV core protein or capsid protein modulators). />
In a particular embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and the compounds, as in U.S. publication No. 2010/0143301 (Gilead Sciences), U.S. publication No. 2011/0098248 (Gilead Sciences), U.S. publication No. 2009/0047249 (Gilead Sciences), U.S. patent No. 8722054 (Gilead Sciences), U.S. publication No. 2014/0045849 (Janssen), U.S. publication No. 2014/0073242 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), U.S. publication No. 2014/0350031 (Janssen), WO 2014/023913 (Janssen), U.S. publication No. 2008/0234251 (Array Biopharma), U.S. publication No. 2008/0306050 (Array biophma), U.S. publication No. 2010/0029585 (venteirx), U.S. publication No. 2008/0306050 (jansmay biopharmac); U.S. publication No. 2011/0092485 (Ventirx Pharma), US 2011/0110235 (Ventirx Pharma), US publication No. 2012/0082658 (Ventirx Pharma), US publication No. 2012/0219615 (Ventirx Pharma), US publication No. 2014/0066432 (Ventirx Pharma), US publication No. 2014/0088085 (Ventirx Pharma), US publication No. 2014/0275167 (Novira Therapeutics), US publication No. 2013/0251673 (Novira Therapeutics), US patent No. 8513184 (Gilead Sciences), US publication No. 2014/0030221 (Gilead Sciences), US publication No. 2013/0344030 (Gilead Sciences), US publication No. 2013/0344029 (Gilead Sciences), US20140275167 (Novira Therapeutics), US publication No. 2013/0344029 (Gilead Sciences), US20130251673 (Novira Therapeutics), US publication No. 2014/0343032 (Roche), WO2014037480 (Roche), US publication No. 2013/0267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2015/059212 (Janssen), a WO2014033170 (Janssen), WO2014033170 (Novira), US 2014033170, (Novira), US 2014033170 (Novira), WO2014033170 (Janssen), WO2014033170 (Roche), US 2014033170 (Incyte), US 2014033170 (2014033170, inc.), WO2014033170 (2014033170, inc.), US publication No. 2014/0330015 (2014033170), US publication No. 2013/0079327 (2014033170), US publication No. 2013/0217880 (2014033170), WO2014033170 (Genentech/2014033170), US 2014033170 (epherapeutics) and US 2014033170 (epherapeutics), US 2014033170 (quantel), WO2014033170 (quantel), US 2014033170B 2 (Oryzon Genomics), and other drugs for the treatment of HBV, and combinations thereof.
In certain embodiments, a compound disclosed herein (e.g., any compound of formula I) can be combined with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents at any dose of a compound of formula I (e.g., 10mg to 1000mg of a compound).
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with inartiivir.
In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a PD-1 inhibitor. In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a PD-L1 inhibitor. In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor. In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor and a PD-1 inhibitor. In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor and a PD-L1 inhibitor. In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor, a TLR8 agonist, and a PD-1 inhibitor. In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor, a TLR8 agonist, and a PD-L1 inhibitor. In a particular embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is combined with a TLR7 modulator (e.g., GS-9620). In a particular embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is combined with a TLR8 modulator (e.g., GS-9688).
In a particular embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a TLR8 modulator and an IDO inhibitor. In a particular embodiment, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is combined with a TLR8 modulator (e.g., GS-9688) and an IDO inhibitor (e.g., epacadostat).
In certain embodiments of the combinations described herein, the TLR8 modulators are TLR8 agonists disclosed in U.S. patent No. 9,670,205, which are incorporated herein by reference in their entirety, and in particular relate to the disclosed compounds (e.g., without limitation, the compounds of examples 59, 61, 62, 63, 65, 66, 80, and 98 or pharmaceutically acceptable salts thereof) and methods of making and using the same. In some embodiments, a Toll-like receptor 8 (TLR 8) agonist is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof. In some embodiments, the TLR8 agonist is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
In certain embodiments of the combinations described herein, the PD-1 inhibitor is selected from the group consisting of: nivolumab, lanreoxygenatab (lambrolizumab), pembrolizumab, pidilizumab, PDR001 and TSR-001, or pharmaceutically acceptable salts thereof. In some embodiments, the PD-L1 inhibitor is selected from the group consisting of: the alemtuzumab, dewaruzumab or Avstuzumab, or a pharmaceutically acceptable salt thereof.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30mg tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof, is mixed with 5-10;5-15;5-20 parts; 5-25;25-30 parts of a base; 20-30 parts; 15-30 parts; or 10-30mg tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate or tenofovir alafenamide combination. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10mg tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, or tenofovir alafenamide. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25mg tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, or tenofovir alafenamide. The compounds disclosed herein (e.g., compounds of formula I) can be combined with the agents provided herein in any dose of the compounds (e.g., from 50mg to 500mg of the compounds), as if each dose of the combination were specifically and independently listed.
In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 100-400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemi-fumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is mixed with 100-150;100-200 parts; 100-250;100-300 parts; 100-350;150-200;150-250;150-300;150-350;150-400;200-250;200-300 parts; 200-350;200-400;250-350;250-400;350-400 or 300-400mg tenofovir disoproxil fumarate, tenofovir disoproxil hemi-fumarate or tenofovir disoproxil combination. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300mg tenofovir disoproxil fumarate, tenofovir disoproxil hemi-fumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 250mg tenofovir disoproxil fumarate, tenofovir disoproxil hemi-fumarate, or tenofovir disoproxil. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 150mg tenofovir disoproxil fumarate, tenofovir disoproxil hemi-fumarate, or tenofovir disoproxil. The compounds disclosed herein (e.g., compounds of formula I) can be combined with the agents provided herein in any dose of the compounds (e.g., from 50mg to 500mg of the compounds), as if each dose of the combination were specifically and independently listed.
In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.
VIII kit
The present disclosure provides kits comprising compounds of the present disclosure, or pharmaceutically acceptable salts thereof. The kit may further comprise instructions for use, for example, in the treatment of HBV infection. The instructions for use are typically written instructions, although electronic storage media (e.g., magnetic or optical) containing instructions are also acceptable.
The present disclosure also provides pharmaceutical kits comprising one or more containers comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Optionally, associated with such containers may be a notification in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceuticals, which notification reflects approval by the agency of manufacture, use or sale for human administration. Each component (if there is more than one component) may be packaged in a separate container, or some components may be combined in one container allowed by cross-reactivity and shelf-life. The kit may be in unit dosage form, bulk package (e.g., multi-dose package), or subunit dose. The kit may also include a plurality of unit doses of the compound and instructions for use, and the amount of packaging is sufficient for storage and use in a pharmacy (e.g., hospital pharmacy and pharmacy).
Also provided are articles of manufacture comprising a unit dose of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in a suitable package for use in the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The article may be further sterilized and/or sealed.
IX. embodiment
Embodiments also relate to processes and intermediates useful for preparing the compounds of the invention or pharmaceutically acceptable salts thereof.
Numerous general references can be found that provide well-known chemical synthesis schemes and conditions that can be used to synthesize the disclosed compounds (see, e.g., smith, march's Advanced Organic Chemistry: reactions, mechanisms, and structures, 7 th edition, wiley-Interscience, 2013).
The compounds described herein may be purified by any method known in the art, including chromatographic methods, such as High Performance Liquid Chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase may be used, including normal and reverse phases, as well as ion resins. Most typically, the disclosed compounds are purified by silica gel and/or alumina chromatography. See, e.g., introduction to Modern Liquid Chromatography, 2 nd edition, l.r. snyder and j.j. Kirkland, john Wiley and Sons,1979; and Thin Layer Chromatography, E.Stahl (ed.), springer-Verlag, new York,1969.
In any method of preparing the subject compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules. This can be achieved by conventional protecting groups as described in the standard works, for example T.W.Greene and P.G.M.Wuts, "Protective Groups in Organic Synthesis", 4 th edition, wiley, new York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.
Exemplary chemical entities useful in the methods of the embodiments will now be described by reference to the exemplary synthetic schemes of the general preparations herein and the specific examples that follow. The skilled artisan will recognize that in order to obtain the various compounds herein, the starting materials may be appropriately selected such that the final desired substituents are carried out by the reaction scheme with or without protection as desired to yield the desired product. Alternatively, it may be necessary or desirable to use a suitable group at the position of the final desired substituent, which group may be carried out by the reaction scheme and appropriately substituted with the desired substituent. Furthermore, one skilled in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant group. Each reaction described in the general scheme is preferably carried out at a reflux temperature of about 0 ℃ to the organic solvent used.
The examples provided herein describe the synthesis of the compounds disclosed herein and intermediates useful in the preparation of the compounds. It should be understood that the various steps described herein may be combined. It will also be appreciated that individual batches of the compounds may be combined and then carried out in the next synthesis step.
In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the disclosure. Other embodiments may be utilized and logic and other changes may be made without departing from the scope of the present disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure.
The process of the present invention generally provides a particular enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, even though the compound may be substantially enantiomerically pure or diastereomerically pure, the compound is depicted without showing any stereochemistry at the particular stereocenter.
Representative syntheses of compounds of the present disclosure are described in the following schemes, as well as in the specific examples that follow.
Example 1:5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl Phenyl) -6-methyl-N- (3, 4, 5-trifluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide
To a solution of tert-butyl 5- (2-methoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylate (619 mg,2.01 mmol) in methanol (16 mL) was added 2N aqueous lithium hydroxide (3 mL). The reaction mixture was stirred for 90 minutes, at which time it was diluted with water, acidified with aqueous hydrogen chloride and extracted into ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- (7- (tert-butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid which was allowed to continue to react without further purification.
2- (7- (tert-Butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid (503 mg,2.21 mmol), 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine hydrochloride (503 mg,2.21 mmol), N-methylmorpholine (0.75 mL,6.8 mmol) and (hexafluorophosphoric acid 1- [ bis (dimethylamino) methylene]-1H-1,2, 3-triazolo [4,5-b ]A solution of pyridinium 3-oxide) (985 mg,2.59 mmol) in N-methyl-2-pyrrolidone (8 mL) was stirred at room temperature for 30 minutes, at which time the reaction mixture was diluted with ethyl acetate and washed sequentially with 1M aqueous hydrogen chloride, 5% aqueous sodium bicarbonate, 5% aqueous lithium chloride, and saturated aqueous sodium chloride. The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure to give 5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl-6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester, which continues to react without further purification. 1 H NMR (400 MHz, chloroform-d) δ9.11 (s, 1H), 7.53 (s, 1H), 4.24 (t, j=7.4 hz, 2H), 3.67 (dd, j=14.1, 12.0hz, 2H), 3.33 (dd, j=13.0, 7.8hz, 2H), 3.07 (t, j=7.6 hz, 2H), 2.49 (d, j=13.9 hz, 5H), 1.54 (s, 9H).
Tert-butyl 5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylate (0.94 g,2.0 mmol) in 4M hydrogen chloride in dioxane (10 mL) was stirred at 40 ℃ for 3.5H, at which point the reaction mixture was cooled to room temperature and diethyl ether was added to initiate precipitation. The resulting precipitate was collected by filtration and triturated with ether to give 5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid which was allowed to continue the reaction without further purification. 1 H NMR(400MHz，DMSO-d6)δ10.26(s,1H),9.57(s,1H),4.18(t,J＝7.3Hz,2H),3.58-3.50(m,2H),3.31(dd,J＝14.1,8.0Hz,2H),2.98(t,J＝7.6Hz,2H),2.41(t,J＝7.3Hz,2H),2.34(s,3H)。
A solution of 5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid (40.6 mg,0.1 mmol), 3,4, 5-trifluoroaniline (96 mg,0.65 mmol), N-methylmorpholine (0.05 mL,0.45 mmol) and (hexafluorophosphoric acid 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide) (59 mg,0.16 mmol) in N-methyl-2-pyrrolidone (0.5 mL) was stirred at 100℃for 24H at which time the reaction mixture was cooled to room temperature, filtered through a syringe filter and purified by preparative HPLC (10-100% acetonitrile/water, 0.1% TFA buffer) to give 5- (2- ((3, 3-difluoro-1- (1, 4-triazolo [4,5-b ] pyridinium 3-oxide) (59 mg,0.16 mmol) in N-methyl-2-pyrrolidone (0.5 mL).
Synthesis of 5- (2-methoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester:
(2-ethoxy-2-oxoacetyl) -L-proline (30.5 g,142 mmol) and t-butyl-2-alkynoate (22.5 g,161 mmol) were stirred in acetic anhydride (150 mL,1.6 mol) at 120℃for 18h. Most of the acetic anhydride was removed under reduced pressure and the crude reaction mass was adsorbed on silica gel. After purification by silica gel chromatography (0-15% ethyl acetate: hexane), the desired cycloaddition regioisomer 7- (tert-butyl) 5-ethyl 6-methyl-2, 3-dihydro-1H-pyrrolizine-5, 7-dicarboxylic acid ester was isolated as the main product. 1 H NMR (400 MHz, chloroform-d) delta 4.32-4.16 (m, 4H), 3.10-2.97 (m, 2H), 2.57 (s, 3H), 2.43 (dq, j=8.5, 7.4hz, 2H), 1.56 (s, 9H), 1.32 (t, j=7.1 hz, 3H).
7- (tert-butyl) 5-ethyl 6-methyl-2, 3-dihydro-1H-pyrrolizine-5, 7-dicarboxylic acid ester (11.7 g,39.9 mmol) was dissolved in ethanol (130 mL) and treated with 4N aqueous sodium hydroxide solution (20 mL). The reaction mixture was stirred at 60 ℃ for 18h and the reaction volume was concentrated under reduced pressure to half. The mixture was then cooled to 0 ℃ and acidified with dilute aqueous hydrochloric acid. The resulting precipitate was collected by filtration and triturated with water, ethanol, and diethyl ether, sequentially to give 7- (tert-butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid. 1 H NMR(400MHz,DMSO-d6)δ4.14(t,J＝7.3Hz,2H),2.92(t,J＝7.6Hz,2H),2.44(s,3H),2.42-2.28(m,2H),1.45(s,9H)。
To a suspension of 7- (tert-butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid (10.6 g,39.9 mmol) in dichloromethane (340 mL) was added 2- (1H-benzotriazol-1-yl) -1, 3-tetramethylammonium tetrafluoroborate (15.0 g,50 mmol), N-diisopropylethylamine (25 mL,144 mmol) and 1- (cyanomethyl) tetrahydro-1H-thiophen-1-ium bromide (10.2 g,49.0 mmol). After 2H an additional 3.3g of 1- (cyanomethyl) tetrahydro-1H-thiophen-1-ium bromide and 13mL of N, N-diisopropylethylamine are added, after which the reaction mixture is partitioned between dichloromethane and saturated aqueous ammonium chloride. The aqueous phase was extracted three times into dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. Silica gel column chromatography (0-10% methanol: dichloromethane) gives tert-butyl 5- (2-cyano-2- (tetrahydro-1λ4-thiophen-1-ylidene) acetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylate An ester. 1 H NMR (400 MHz, chloroform-d) delta 4.08 (t, j=7.2 hz, 2H), 3.47 (q, j=6.3 hz, 2H), 3.38 (dt, j=13.1, 6.7hz, 2H), 3.00 (dd, j=13.8, 6.4hz, 2H), 2.66-2.52 (m, 2H), 2.46 (s, 3H), 2.41 (t, j=7.3 hz, 2H), 2.18-2.01 (m, 2H), 1.52 (s, 9H).
To a solution of 5- (2-cyano-2- (tetrahydro-1λ4-thiophen-1-ylidene) acetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester (15.0 g,39.9 mmol) in 1:1N, N-dimethylformamide: methanol (340 mL) was added potassium peroxymonosulfate (61.4 g,100 mmol) and stirred for 2H. The reaction mixture was partially concentrated under reduced pressure, followed by partitioning between 5% aqueous sodium bicarbonate and ethyl acetate. The aqueous phase was extracted three times into ethyl acetate and the combined organic phases were washed with 5% aqueous lithium chloride solution followed by brine. The organic phase is then dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (20-100% dichloromethane: hexane) afforded 5- (2-methoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, chloroform-d) delta 4.37-4.26 (m, 2H), 3.93 (s, 3H), 3.06 (t, j=7.7 hz, 2H), 2.55-2.45 (m, 2H), 2.42 (s, 3H), 1.54 (s, 9H).
Synthesis of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutane-1-amine hydrochloride:
To a solution of 1-amino-3, 3-difluorocyclobutane-1-carboxylic acid (990 mg,6.55 mmol) in methanol (8 mL) at 0deg.C was added 1M aqueous sodium hydroxide (7 mL,7 mmol) followed by di-tert-butyl dicarbonate (1.8 g,8.2 g). The reaction mixture was warmed to ambient temperature, stirred for 14h, acidified with dilute aqueous hydrogen chloride, and extracted to diethyl ether. The ether phase was quenched with 1:1 water: washing with brine, drying over sodium sulfate, filtration and concentration under reduced pressure gives 1- ((tert-butoxycarbonyl) amino) -3, 3-difluorocyclobutane-1-carboxylic acid, which continues to react without further purification.
To a solution of 1- ((tert-butoxycarbonyl) amino) -3, 3-difluorocyclobutane-1-carboxylic acid (1.95 g,7.75 mmol), formylhydrazine (1.26 g,20.1 mmol) and 1-hydroxybenzotriazole (1.06 g,7.81 mmol) in dichloromethane (60 mL) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (3.69 g,19.2 mmol). The reaction mixture was stirred at room temperature for 60h, at which time it was diluted with ethyl acetate, filtered through a celite pad, and the organic phase was washed with 1M aqueous hydrogen chloride, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride in this order to give tert-butyl (3, 3-difluoro-1- (2-formylhydrazine-1-carbonyl) cyclobutyl) carbamate, which was allowed to continue to react without further purification.
To a solution of tert-butyl (3, 3-difluoro-1- (2-formylhydrazine-1-carbonyl) cyclobutyl) carbamate (1.87 g,6.36 mmol) in dioxane (80 mL) was added the lawsen reagent (2.65 g,6.55 mmol). After heating the reaction mixture to 85 ℃ for 2h, it was cooled to room temperature, diluted with ethyl acetate, and sequentially taken up in 1:1 saturated sodium carbonate: aqueous washing followed by washing with brine. The organic phase was then dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography on silica gel (0-60% ethyl acetate: hexanes) to give tert-butyl (3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) carbamate.
Tert-butyl (3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) carbamate (1.1 g,3.8 mmol) was stirred in 4M hydrogen chloride in dioxane (20 mL) at 60 ℃ for 1 hour, at which time the reaction mixture was concentrated under reduced pressure and the resulting solid was collected by filtration, ether trituration to give 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobut-1-amine hydrochloride. 1 H NMR(400MHz，DMSO-d6)δ9.74(s,1H),3.65-3.41(m,4H)。
Example 2: n- (3-cyano-4-fluorophenyl) -5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutane) Group) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (2)
This product was synthesized in analogy to example 1 using 3-cyano-4-fluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 3:5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl Phenyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (3)
The product was synthesized in analogy to example 1 using 3, 4-difluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 4:5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-) Oxo acetyl) -6-methyl-N- (3, 4, 5-trifluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (4)
This product was synthesized in analogy to example 1, using 3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutan-1-amine bis (hydrochloride) instead of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine hydrochloride.
Synthesis of 3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobut-1-amine bis (hydrochloride):
to a solution of tert-butyl (3, 3-difluoro-1-formylcyclobutyl) carbamate (1.66 g,7.04 mmol) in methanol (50 mL) was added potassium carbonate (3.12 g,22.6 mmol), followed by dropwise dimethyl (1-diazonium-2-oxopropyl) phosphonate (1.6 mL,10.7 mmol). The reaction mixture was stirred at room temperature for 18h, at which time it was concentrated under reduced pressure through a pad of celite, and purified by column chromatography on silica gel (0-10% ethyl acetate: hexanes) to give tert-butyl (1-ethynyl-3, 3-difluorocyclobutyl) carbamate. 1 H NMR(400MHz, chloroform-d) delta 3.06 (t, j=11.1 Hz, 4H), 2.44 (s, 1H), 1.46 (s, 9H).
A solution of tert-butyl (1-ethynyl-3, 3-difluorocyclobutyl) carbamate (739 mg,3.2 mmol), (trimethylsilyl) methyl azide (0.7 mL,4.7 mmol) and copper (I) thiophene-2-carboxylate (610 mg,3.2 mmol) in N, N-dimethylformamide (20 mL) was stirred at 80℃for 45 min, at which time it was cooled to room temperature, passed through a pad of celite, and successively washed with 5% aqueous lithium chloride followed by aqueous saturated sodium chloride to give tert-butyl (3, 3-difluoro-1- (1- ((trimethylsilyl) methyl) -1H-1,2, 3-triazol-4-yl) cyclobutyl) carbamate which was allowed to continue the reaction without further purification. 1 H NMR (400 MHz, chloroform-d) delta 7.48 (d, j=28.7 hz, 1H), 3.89 (s, 2H), 3.22 (s, 4H), 1.41 (s, 9H), 0.13 (s, 9H).
To a solution of tert-butyl (3, 3-difluoro-1- (1- ((trimethylsilyl) methyl) -1H-1,2, 3-triazol-4-yl) cyclobutyl) carbamate (1.11 g,3.09 mmol) in tetrahydrofuran (40 mL) was added a 1M solution of n-tetrabutylammonium fluoride in tetrahydrofuran (4 mL). The reaction mixture was stirred for 40 minutes at which time it was partitioned between ethyl acetate and water and the aqueous phase was extracted to ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) carbamate which was allowed to continue the reaction without further purification. 1 H NMR (400 MHz, chloroform-d) delta 7.54 (s, 1H), 4.08 (s, 3H), 3.20 (t, j=11.8 hz, 4H), 1.42 (s, 9H).
A solution of tert-butyl (3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutyl) carbamate (892 mg,3.09 mmol) in dioxane (6 mL) was treated with dioxane (8 mL) containing 4M hydrogen chloride and stirred at room temperature for 18H, at which time the reaction mixture was concentrated under reduced pressure and the resulting solid, ether, was collected by filtration and triturated to give 3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutan-1-amine bis (hydrochloride). 1 H NMR(400MHz，DMSO-d6)。δ9.17(s,3H),8.34(s,1H),4.08(s,3H),3.48-3.33(m,2H),3.25(td,J＝15.6,14.5,4.2Hz,2H)。
Example 5: n- (3-cyano-4-fluorophenyl) group5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazole-) 4-yl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (5)
This product was synthesized in analogy to example 4 using 3-cyano-4-fluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 6:5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-) Oxo acetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (6)
The product was synthesized in analogy to example 4 using 3, 4-difluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 7:5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-5-yl) cyclobutyl) amino) -2-) Oxo acetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (7)
Example 9:5- (2- ((3, 3-difluoro-1- (2-methyl-2H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2- Oxo acetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (9)
Example 10:5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-) Oxo acetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (10)
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A solution of 5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (example 17) (29.7 mg,0.06 mmol) in N, N-dimethylformamide (1 mL) was treated with potassium carbonate (12 mg,0.09 mmol), followed by methyl iodide (0.05 mL,0.8 mmol) and stirred at room temperature for 48H at which time the reaction mixture was filtered through a syringe and purified by preparative HPLC (10-100% acetonitrile/water, 0.1% TFA buffer), the peak mixture (first elution) of 5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-5-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (7) and the peak mixture (first elution) of 5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (example 10) of 5- (2- ((3, 3-difluoro-1- (2-methyl-2H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (example 9) was obtained. Compounds 7 and 10 were subjected to supercritical fluid chromatography (30% methanol: CO) 2 IC-5 μm-4.6X100 mm column) was further separated from each other, 5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (example 10) was eluted first as the major product and 5- (2- ((3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-5-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (example 7) was eluted second as the minor product.
Example 8:5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl Phenyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (8)
The product was synthesized in analogy to example 1 using 4-fluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 11: n- (3, 4-difluorophenyl) -6-methyl-5- (2- ((1- (1-methyl-1H-1, 2, 3-triazol-4-yl) radical) Cyclopropyl) amino) -2-oxoacetyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (11)
To a solution of N- (3, 4-difluorophenyl) -6-methyl-5- (2-oxo-2- ((1- (1- ((trimethylsilyl) methyl) -1H-1,2, 3-triazol-4-yl) cyclopropyl) amino) acetyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (example 12) (28.8 mg,0.05 mmol) in tetrahydrofuran (1.8 mL) was added a 1M solution of N-tetrabutylammonium fluoride in tetrahydrofuran (0.2 mL). The reaction mixture was stirred for 20 min, at which time it was concentrated under reduced pressure, dissolved in N, N-dimethylformamide, passed through a syringe filter, and purified by preparative HPLC (10-100% acetonitrile/water, 0.1% tfa buffer) to give the product.
Example 12: n- (3, 4-difluorophenyl) -6-methyl-5- (2-oxo-2- ((1- (1- ((trimethylsilyl) methyl) 1H-1,2, 3-triazol-4-yl) cyclopropyl) amino) acetyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (12)
A solution of N- (3, 4-difluorophenyl) -5- (2- ((1-ethynylcyclopropyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (example 13) (55.8 mg,0.14 mmol), (trimethylsilyl) methyl azide (0.03 mL,0.2 mmol) and copper (I) thiophene-2-carboxylate (26.4 mg,0.14 mmol) in N, N-dimethylformamide (2 mL) was stirred at 80℃for 40 min, at which time it was cooled to room temperature and partitioned between water and ethyl acetate. The organic phase was washed successively with 5% aqueous lithium chloride solution and then with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-7% methanol: dichloromethane) to give the product.
Example 13: n- (3, 4-difluorophenyl) -5- (2- ((1-ethynylcyclopropyl) amino) -2-oxoacetyl) o-acetyl- 6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (13)
Tert-butyl 5- (2-methoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrazine-7-carboxylate (763 mg,2.48 mmol) in 4M hydrogen chloride in dioxane (20 mL) was stirred at 40 ℃ for 2.5H, at which time the reaction mixture was concentrated under reduced pressure to give 5- (2-methoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrazine-7-carboxylic acid which was reacted further without further purification.
A solution of 5- (2-methoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid (624 mg,2.48 mmol), 3, 4-difluoroaniline (1.5 mL,15.1 mmol), N-methylmorpholine (1.2 mL,10.9 mmol) and (hexafluorophosphoric acid 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide) (1.10 g,2.89 mmol) in N-methyl-2-pyrrolidone (1.5 mL) was stirred at 100deg.C for 1H, at which time the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed sequentially with 1N aqueous hydrogen chloride, 5% aqueous lithium chloride and brine, then dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate: hexanes) to give methyl 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetate.
To a solution of methyl 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetate (751mg, 2.07 mmol) in methanol (16 mL) was added an aqueous 2N lithium hydroxide solution (2.6 mL). The reaction mixture was stirred for 15 minutes, at which time it was diluted with water, acidified with aqueous hydrogen chloride, and the product extracted into dichloromethane. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid which was reacted further without further purification.
A solution of 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid (85.6 mg,0.25 mmol), ethynyl cyclopropylamine hydrochloride (62 mg,0.53 mmol), N-methylmorpholine (0.1 mL,0.91 mmol) and (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide of hexafluorophosphate) (123 mg,0.32 mmol) in N-methyl-2-pyrrolidone (1 mL) was stirred at room temperature for 10 minutes, at which time the reaction mixture was diluted with ethyl acetate and washed sequentially with 1M aqueous hydrogen chloride, 5% aqueous sodium bicarbonate, 5% aqueous lithium chloride and saturated aqueous sodium chloride. Subsequently, the organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-100% ethyl acetate: hexanes) to give N- (3, 4-difluorophenyl) -5- (2- ((1-ethynylcyclopropyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (13).
Example 14: (1 aS,6 bR) -4- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) ammonia) Phenyl) -2-oxoacetyl-N- (4-fluorophenyl) -5-methyl-1, 1a,2,6 b-tetrahydrocyclopropa [ a ]]Pyrrolizine-6-carboxamide (14)
This product was synthesized in analogy to example 34, using (1 r,2s,5 s) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid instead of (1 r,3s,5 r) -3- (hydroxy (oxo) - λ5-methyl) -2-azabicyclo [3.1.0] hexane and 4-fluoroaniline instead of 3, 4-difluoroaniline.
Example 15: n- (3-cyano-4-fluoro)Phenyl) -5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclic) Butyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (15)
This product was synthesized in analogy to example 1, using 3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutan-1-amine hydrochloride instead of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine hydrochloride and using 3-cyano-4-fluoroaniline instead of 3,4, 5-trifluoroaniline.
Synthesis of 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobut-1-ammonium chloride:
benzyl (2, 5-dioxopyrrolidin-1-yl) carbonate (696 mg,2.79 mmol) was added as a solid to a stirred mixture of 3, 3-difluoro-1- (hydroxymethyl) cyclobutan-1-ammonium chloride (481mg, 2.79 mmol) and N-ethyl-N-isopropyl-propan-2-amine (1.22 mL,6.99 mmol) in dichloromethane (20 mL) at ambient temperature. After 19h, water (5 mL) and diethyl ether (100 mL) were added sequentially. The organic layer was washed with aqueous hydrogen chloride (2×70 mL) and water (70 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and the resulting solution was stirred at ambient temperature. Dess-Martin periodate (1.78 g,4.19 mmol) was added as a solid. After 4h, aqueous sodium thiosulfate (1.0M, 25 mL) and diethyl ether (100 mL) were added sequentially and washed. The organic layer was washed with saturated aqueous sodium bicarbonate (2×100 mL) and water (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in methanol (20 mL), potassium carbonate (1.16 g,8.38 mmol) was added in solid state, and the resulting heterogeneous mixture was stirred at 0 ℃. Dimethyl (1-diazo-2-oxopropyl) phosphonate (629 μl,4.19 mmol) was added via syringe. After 5min, the reaction mixture was warmed to ambient temperature. After 15h, the reaction mixture was filtered through celite and the filter cake was extracted with ethyl acetate (80 mL). The filtrate was concentrated under reduced pressure, and the residue was dissolved in diethyl ether (100 mL). The organic layer was washed with water (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 10% ethyl acetate/hexanes) to give benzyl (1-ethynyl-3, 3-difluorocyclobutyl) carbamate.
Azidometrimethylsilane (344 μl,2.59 mmol) was added by syringe to a stirred mixture of benzyl (1-ethynyl-3, 3-difluorocyclobutyl) carbamate (491 mg,1.85 mmol) and copper (I) iodide (17.6 mg,92.5 μl) in N, N-dimethylformamide (3.5 mL) and methanol (0.4 mL) at ambient temperature, and the resulting mixture was heated to 100 ℃. After 6h, the reaction mixture was cooled to ambient temperature and diethyl ether (130 mL) was added. The organic layer was washed with brine and water in this order to give a mixture (1:1, 100 mL) and water (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0 to 40% ethyl acetate/hexanes) to give benzyl (3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) carbamate.
A heterogeneous mixture of benzyl (3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) carbamate (307 mg,0.995 mmol) and palladium on activated carbon (10% wt/wt,248mg, 23.3. Mu. Mol) in ethanol (10 mL) was placed under 1atm hydrogen at ambient temperature and vigorously stirred. After 1.5h, the reaction mixture was filtered through celite and the filter cake was extracted with ethyl acetate (80 mL). A hydrogen chloride solution (4M in 1, 4-dioxane, 0.5 mL) was added to the filtrate via syringe and the resulting mixture was swirled vigorously for 1min and then concentrated under reduced pressure to give 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-ammonium chloride.
Example 16: n- (3-chloro-4-fluorophenyl) -5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutane) Group) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (16)
The product was synthesized in analogy to example 15 using 3-chloro-4-fluoroaniline instead of 3-cyano-4-fluoroaniline.
Example 17:5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoethyl) Acyl) -N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (17)
The product was synthesized in analogy to example 15 using 4-fluoroaniline instead of 3-cyano-4-fluoroaniline.
Example 18:5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoethyl) Acyl) -6-methyl-N- (3, 4, 5-trifluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (18)
This product was synthesized in analogy to example 15 using 3,4, 5-trifluoroaniline instead of 3-cyano-4-fluoroaniline.
Example 19:5- (2- ((3, 3-difluoro-1- (hydroxymethyl) cyclobutyl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
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A flame-dried microwave vial was charged with 1-amino-3, 3-difluorocyclobutane-1-carboxylic acid (250 mg,1.65 mmol) and subsequently purged with nitrogen and dissolved in anhydrous THF and cooled to 0 ℃. Then, lithium aluminum hydride (1M in THF, 0.8 mL) was added. The mixture was stirred in an ice bath and after the addition was complete the ice bath was removed and the reaction mixture was warmed to room temperature and then heated to 50 ℃ overnight. Subsequently, the reaction mixture was cooled again and diluted with THF. The reaction was quenched with water, 15% aqueous sodium hydroxide solution and water over a period of 30 min. The solution was stirred for 30min and the white precipitate was filtered. The filter cake was washed with diethyl ether (3×150 mL) and the organic filtrates were combined and the filtrate concentrated to azeotrope water using ACN. The crude material was then used in the next reaction.
2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid (40 mg 0.072 mmol), HATU (20 mg 0.086 mmol) were dissolved in 0.5mL DMF followed by NMM (0.05mL 44mg 0.431mmol). (1-amino-3, 3-difluorocyclobutyl) methanol (40 mg 0.287 mmol) was dissolved in 0.25mL DMF and added to the reaction mixture. It was stirred at room temperature for 3h until no further reaction was achieved by LCMS. The reaction was diluted in EtOAc using 1N (aq) HCl (3×), naHCO 3 (3X) and brine (1X), the organic layer was washed with MgSO 4 Drying, filtering, and concentrating. The crude material was then purified on preparative HPLC to give 5- (2- ((3, 3-difluoro-1- (hydroxymethyl) cyclobutyl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (15 mg 28%). ES/MS m/z: calculated for C22H21F4N3 o4+h: 468.1541, found: m+h 468.18. 1 H NMR (400 MHz, acetonitrile-d) 3 )δ8.10(s,1H),7.78(ddd,J＝13.2,7.4,2.5Hz,1H),7.42(s,1H),7.31(d,J＝8.8Hz,1H),7.28-7.18(m,1H),4.31-4.19(m,2H),3.73(d,J＝1.0Hz,2H),3.10(t,J＝7.5Hz,3H),3.02-2.75(m,5H),2.54(q,J＝7.4Hz,2H),2.48(s,3H)。
Example 20:5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) amino) N- (2- (difluoromethyl) -3-fluoropyridin-4-yl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
Step 1: 5- (2-methoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester (0.150 g,0.488 mmol) was dissolved in 1.5mL EtOH. NaOH (0.048 g,1.220 mmol) was added and the reaction stirred at 60℃for 2h. The reaction mixture was cooled to 0 ℃, acidified to pH about 3 using HCl (aq), then extracted with EtOAc, washed with brine, and dried over MgSO 4 Drying, filtering and concentrating. Isolation of 2- (7- (tert-butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetic acid. ES/MS m/z: calculated for C15H19NO5+ H: 294.1336, found: m+h294.1.
Step 2: 2- (7- (tert-Butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetic acid (132 mg,0.450 mmol), 3-difluoro-1- (methylcarbamoyl) cyclobut-1-ammonium 4-methylbenzenesulfonate (166 mg, 0.495mmol) and HATU (240 mg 0.633 mmol) were charged into a 5mL microwave vial, capped and sealed. NMP (1.5 ml) was then added. NMM (0.2 mL 1.77 mmol) was then added and the reaction mixture was stirred at room temperature for 2h. TLC in 6/4/1/Hex/EtOAc/MeOH showed complete conversion. The reaction mixture was diluted in ethyl acetate and washed with water and brine. The organic layer was dried over MgSO 4 Drying, filtering, and concentrating. 5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester was recovered and the reaction was continued as crude product. ES/MS m/z: calculated for C21H27F2N3 o5+h: 440.1992, found: M+H2440.2
Step 3: 5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester (274 mg,0.623 mmol) was dissolved in DCM (2 mL) and the reaction was cooled to 0 ℃. TFA (0.3 mL) was then added and the reaction stirred for 2h. TLC 1/1 Hex/EtOAc showed no SM. The reaction mixture was concentrated to give 5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid. ES/MS m/z: calculated for C17H19F2N3 o5+na: 406.1185, found: m+h 406.21.
Step 4: 5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid (75 mg,0.196 mmol), 2- (difluoromethyl) -3-fluoropyridine-4-ammonium chloride (213 mg,1.07 mmol) and EtOAc (140 mg,0.274 mmol) containing 50wt% 1-propanephosphonic anhydride solution (74.7 mg,0.23 mmol) were charged to a microwave vial and dissolved in DMF 1 mL. Then, NMM 0.2mL was added and the reaction stirred at 100deg.C for 5h. No initial reaction was detected by LCMS. The reaction was diluted with EtOAc and 1N HCl (2×), naHCO 3 (2 x) and brine (1 x). The organic layer was dried over MgSO4, filtered, then concentrated and purified by preparative HPLC to give the desired product. ES/MS m/z: calculated for C23H22F5N5 o4+na: 528.1665, found: m+h 528.11. 1 H NMR (400 MHz, acetone-d 6) delta 8.88 (s, 1H), 8.77 (s, 1H), 8.59 (t, j=5.7 hz, 1H), 8.40 (d, j=5.4 hz, 1H), 6.93 (t, j=53.6 hz, 1H), 4.31 (t, j=7.3 hz, 2H), 3.38 (td, j=15.4, 11.6hz, 2H), 3.27 (t, j=7.5 hz, 2H), 3.00 (td, j=14.7, 6.6hz, 2H), 2.77 (d, j=4.7 hz, 3H), 2.65-2.57 (m, 2H), 2.55 (s, 3H).
Example 21: (1 aR,6 bS) -4- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutyl) ammonia) Phenyl) -2-oxoacetyl-N- (3, 4-difluorophenyl) -5-methyl-1, 1a,2,6 b-tetrahydrocyclopropa [ a ]]Pyrrolizine-6-A Amide (21)
This product was synthesized in analogy to example 34, using (1 s,2s,5 r) -3-azabicyclo [3.1.0] hexane-2-carboxylic acid instead of (1 r,3s,5 r) -3- (hydroxy (oxo) - λ5-methyl) -2-azabicyclo [3.1.0] hexane.
Example 22: (1 aR,6 bS) -4- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxo Acetoacetyl) -N- (3, 4-difluorophenyl) -5-methyl-1, 1a,2,6 b-tetrahydrocyclopropylAnd [ a ]]Pyrrolizine-6-carboxamide (22)
This product was synthesized in analogy to example 21, using 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride instead of 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-ammonium chloride.
Synthesis of 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride:
to a solution of 1-amino-3, 3-difluorocyclobutane-1-carboxylic acid (990 mg,6.55 mmol) in methanol (8 mL) at 0deg.C was added 1M aqueous sodium hydroxide (7 mL,7 mmol) followed by di-tert-butyl dicarbonate (1.8 g,8.2 g). The reaction mixture was warmed to ambient temperature, stirred for 14 hours, acidified with dilute aqueous hydrogen chloride, and extracted to diethyl ether. The ether phase was quenched with 1:1 water: washing with brine, drying over sodium sulfate, filtration and concentration under reduced pressure gives 1- ((tert-butoxycarbonyl) amino) -3, 3-difluorocyclobutane-1-carboxylic acid, which continues to react without further purification.
To a solution of 1- ((tert-butoxycarbonyl) amino) -3, 3-difluorocyclobutane-1-carboxylic acid (1.65 g,6.6 mmol), methylamine hydrochloride (2.28 g,33.8 mmol) and triethylamine (7.4 mL,53 mmol) in N, N-dimethylformamide (24 mL) at 0deg.C was added 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide (3.75 g,9.86 mmol) of hexafluorophosphoric acid. The reaction was warmed to ambient temperature and stirred for 20h, at which time the reaction mixture was diluted with diethyl ether and washed with saturated aqueous sodium bicarbonate, 5% aqueous lithium chloride and brine. The ether phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl (3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) carbamate, which was reacted further without further purification.
Will (3, 3-Difluoro-1- (methylcarbamoyl) cyclobutyl) carbamic acid tert-butyl ester (1.3 g,4.92 mmol) was dissolved in 4M hydrogen chloride in dioxane (20 mL,80 mmol) and stirred at 90℃for 90 min. The solvent was removed under reduced pressure, azeotroped twice with toluene, and the resulting material was dried under high vacuum to give 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride: 1 H NMR(400MHz，DMSO-d6)δ8.86(s,3H),8.44(s,1H),3.27(dd,J＝13.3,7.5Hz,2H),3.05(q,J＝14.3Hz,2H),2.69(d,J＝4.5Hz,3H)。
example 23: (1 aS,6 aS) -3- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutyl) ammonia) Phenyl) -2-oxoacetyl-N- (3, 4-difluorophenyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]pyrrolizine-5-A Amide (23)
This product was synthesized in analogy to example 34, using (1 s,3s,5 s) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid instead of (1 r,3s,5 r) -3- (hydroxy (oxo) - λ5-methyl) -2-azabicyclo [3.1.0] hexane.
Example 24: (1 aS,6 aS) -3- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxo Acetoacetyl) -N- (3, 4-difluorophenyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b]Pyrrolizine-5-carboxamide (24)
This product was synthesized in analogy to example 23, using 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride instead of 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-ammonium chloride.
Example 25: (1 aS,6 bR) -4- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutyl) ammonia) Phenyl) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -5-methyl-1, 1a,2,6 b-tetrahydrocyclopropa [ a ]]Pyrrolizine-6-A Amide (25)
The product was synthesized in analogy to example 14 using 3, 4-difluoroaniline instead of 4-fluoroaniline.
Example 26: (1 aS,6 bR) -4- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxo Acetoacetyl) -N- (3, 4-difluorophenyl) -5-methyl-1, 1a,2,6 b-tetrahydrocyclopropa [ a ] ]Pyrrolizine-6-carboxamide (26)
This product was synthesized in analogy to example 25, using 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride instead of 3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutan-1-amine hydrochloride.
Example 27:5- (2- ((1- (1H-1, 2, 3-triazol-4-yl) cyclopropyl) amino) -2-oxoacetyl) -N- (3- (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
Methyl 2- (7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetate was prepared as described in example 1 using 3- (difluoromethyl) -4-fluoroaniline instead of 3,4, 5-trifluoroaniline. ES/MS m/z: calculated for C19H18F3N2O 4: 395.11, found: 395.42.
2- (7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid was prepared as described in example 1. ES/MS m/z: calculated for C18H16F3N2O 4: 381.10, found: 381.36.
the product was prepared as described in example 1 using 1- (1H-1, 2, 3-triazol-4-yl) cyclopropan-1-amine dihydrochloride instead of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine. 1 H NMR (400 MHz, acetone-d 6) delta 8.88 (s, 1H), 8.57 (s, 1H), 8.08 (d, j=6.4 hz, 1H), 7.90 (s, 1H), 7.68 (s, 1H), 7.27 (t, j=9.4 hz, 1H), 7.10 (t, j=54.5 hz, 1H), 4.27 (t, j=7.5 hz, 2H), 3.18 (t, j=7.5 hz, 2H), 2.55 (quintuples, j=7.5 hz, 2H), 2.46 (s, 3H), 1.50-1.28 (m, 4H). ES/MS m/z: calculated for C23H22F3N6O 3: 487.16, found: 487.54.
Synthesis of 1- (1H-1, 2, 3-triazol-4-yl) cyclopropan-1-amine dihydrochloride:
step 1: tert-butyl (1-ethynylcyclopropyl) carbamate (200.0 mg,1.104 mmol) was treated with azido trimethylsilane (508.6 mg,4.414mmol,4 eq.) in the presence of copper iodide (21.0 mg,0.11 mmol) in N, N-dimethylformamide (1 mL) and methanol (1 mL) and stirred at 110℃for 2h. After cooling, purification by preparative HPLC gave tert-butyl (1- (1H-1, 2, 3-triazol-4-yl) cyclopropyl) carbamate. LCMS-esi+ (m/z): [ M+H ]] + C 10 H 17 N 4 O 2 Is calculated by the following steps: 225.1; actual measurement value: 225.1.
step 2: tert-butyl (1- (1H-1, 2, 3-triazol-4-yl) cyclopropyl) carbamate (243.2 mg,1.084 mmol) was treated with hydrogen chloride (4N in 1, 4-dioxane, 4 mL) in methanol (2 mL) and stirred at 110℃for 1H. The organic solvent was removed under reduced pressure to give 1- (1H-1, 2, 3-triazol-4-yl) cyclopropan-1-amine dihydrochloride. LCMS-esi+ (m/z): [ M+H ]] + C 5 H 9 N 4 Is calculated by the following steps: 125.1; actual measurement value: 125.1.
example 28: n- (3-cyano-4-fluorophenyl) -5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) Amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid (75 mg,0.196 mmol), 5-amino-2-fluorobenzonitrile (146 mg,1.07 mmol) and HATU (64 mg,0.274 mmol) were charged to a microwave vial and dissolved in DMF 1mL then NMM 0.2mL was added and the reaction stirred for 5H at 100 ℃. No starting material was detected by LCMS. The reaction was diluted with EtOAc and washed with 1N HCl (2 x), naHCO3 (2 x) and brine (1 x). The organic layer was dried over MgSO 4 Drying, filtration, and then concentration, and purification by preparative HPLC gave the desired product. ES/MS m/z: calculated for C24H22F3N5 o4+na: 524.1516, found: m+h524.1. 1 H NMR (400 MHz, acetonitrile-d 3) delta 8.16 (s, 1H), 8.04 (dd, j=5.7, 2.7hz, 1H), 7.97 (s, 1H), 7.87-7.79 (m, 1H), 7.28 (t, j=9.0 hz, 1H), 4.22 (t, j=7.3 hz, 2H), 3.35-3.23 (m, 2H), 3.07 (t, j=7.5 hz, 2H), 2.88 (dd, j=14.8, 7.3hz, 2H), 2.68 (d, j=4.7 hz, 3H), 2.50 (q, j=7.2 hz, 2H), 2.42 (s, 3H).
Example 29:5- (2- ((1- (1, 3, 4-thiadiazol-2-yl) cyclopropyl) amino) -2-oxoacetyl) -6-methyl 1-dihydro-2, 3-1H-pyrrolizine-7-carboxamide (29) and N- (3, 4, 5-trifluorophenyl) -yl-N- (2-methyl-N-vinyl acetate)
This product was synthesized in analogy to example 1, using 1- (1, 3, 4-thiadiazol-2-yl) cyclopropan-1-amine instead of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine hydrochloride.
Example 30:5- (2- ((1- (1, 3, 4-thiadiazol-2-yl) cyclopropyl) amino) -2-oxoacetyl) -N- (4- Fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (30)
The product was synthesized in analogy to example 29, using 4-fluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 31:5- (2- ((1- (1, 3, 4-thiadiazol-2-yl) cyclopropyl) amino) -2-oxoacetyl) -N- (3- (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (31)
This product was synthesized in analogy to example 29, using 3- (difluoromethyl) -4-fluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 32:5- (2- ((1-carbamoyl-3, 3-difluorocyclobutyl) amino) -2-oxoacetyl) -N- (3-) (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (32)
This product was synthesized in analogy to example 1 using 3- (difluoromethyl) -4-fluoroaniline instead of 3,4, 5-trifluoroaniline and 1-amino-3, 3-difluorocyclobutane-1-carboxamide instead of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine hydrochloride.
Synthesis of 1-amino-3, 3-difluorocyclobutane-1-carboxamide:
to a solution of 1-amino-3, 3-difluorocyclobutane-1-carboxylic acid (5.09 g,33.7 mmol) and N, N-diisopropylethylamine (14 mL) in dichloromethane (100 mL) was added N- (benzyloxycarbonyloxy) succinimide (7.1 mL,34.1 mmol), and the reaction mixture was stirred at room temperature for 2h, at which time the reaction volume was concentrated under reduced pressure for two-thirds. The solution was then diluted with diethyl ether and washed with 1M aqueous hydrogen chloride followed by water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 1- (((benzyloxy) carbonyl) amino) -3, 3-difluorocyclobutane-1-carboxylic acid which was reacted further without further purification.
To a solution of 1- (((benzyloxy) carbonyl) amino) -3, 3-difluorocyclobutane-1-carboxylic acid (9.61 g,35.4 mmol), ammonium chloride (9.52 g,178 mmol) and triethylamine (40 mL,287 mmol) in N, N-dimethylformamide (100 mL) at 0deg.C was added 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide (20.4 g,53.8 mmol) hexafluorophosphate. The reaction was warmed to ambient temperature and stirred for 3h, at which time the reaction mixture was partially concentrated under reduced pressure, diluted with diethyl ether, washed successively with 0.25M aqueous hydrogen chloride, 5% aqueous sodium bicarbonate, 5% aqueous lithium chloride and saturated aqueous sodium chloride, resulting in precipitation of the product in the organic phase. This precipitate was collected by filtration to give benzyl (1-carbamoyl-3, 3-difluorocyclobutyl) carbamate, which was allowed to continue the reaction without further purification.
To a solution of benzyl (1-carbamoyl-3, 3-difluorocyclobutyl) carbamate (1.2 g,4.44 mmol) in ethanol (20 mL) was added 10% palladium on charcoal (510 mg,0.48 mmol). The reaction mixture was placed under hydrogen at one atmosphere and stirred for 2h. The reaction mixture was then filtered through celite and the resulting filtrate was concentrated under reduced pressure to give 1-amino-3, 3-difluorocyclobutane-1-carboxamide, which was allowed to continue to react without further purification. 1 H NMR(400MHz，DMSO-d6)δ7.40(s,1H),7.15(s,1H),3.06-2.91(m,2H),2.54(s,2H),2.44-2.27(m,2H)。
Example 33: (1 aR,6 aR) -3- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxo Acetoacetyl) -N- (3, 4-difluorophenyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b]Pyrrolizine-5-carboxamide
The compound was synthesized in analogy to example 34, except that 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide 4-methylbenzenesulfonate was used instead of 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-amine dihydrochloride. 1 H NMR(400MHz，DMSO-d6)δ9.67(d,J＝19.2Hz,2H),7.85-7.74(m,2H),7.44-7.32(m,2H),4.34(d,J＝6.2Hz,1H),3.54(s,3H),3.36(dd,J＝18.1,6.8Hz,1H),3.21(t,J＝14.1Hz,2H),3.10(d,J＝18.2Hz,1H),2.59(d,J＝4.5Hz,3H),2.29(s,3H),2.14(d,J＝7.6Hz,1H),1.14-1.04(m,1H),0.23(d,J＝4.7Hz,1H)。LCMS-ESI+(m/z)：[M+H] + ：507.13
Example 34: (1 aR,6 aR) -3- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutyl) ammonia) Phenyl) -2-oxoacetyl-N- (3, 4-difluorophenyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]pyrrolizine-5-A Amides and their use
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Step 1: to a solution of (1R, 3S, 5R) -2- (tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid (10 g,44 mmol) and cesium carbonate (21.5 g,66 mmol) in DMF (100 mL) was added bromobenzyl (6.4 mL,53.7 mmol). The mixture was stirred at ambient temperature for 10h. The reaction was then partitioned with ethyl acetate (500 mL) and water (500 mL). The aqueous solution was then taken up and extracted with ethyl acetate (300 mL), followed by drying the organics over magnesium sulfate and subsequent purification by normal phase chromatography with 0-40% ethyl acetate/hexane to give 3-benzyl 2- (tert-butyl) (1 r,3s,5 r) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid ester.
Step 2: 3-benzyl 2- (tert-butyl) (1R, 3S, 5R) -2-azabicyclo [3.1.0] hexane-2, 3-dicarboxylic acid ester was dissolved in DCM (120 mL). TFA (26 mL,345 mmol) was added thereto. It was allowed to stir at ambient temperature for 1 hour. The reaction was then concentrated and co-evaporated twice with toluene (100 mL) to give benzyl (1 r,3s,5 r) -2- (2-methoxy-2-oxoacetyl) -2-azabicyclo [3.1.0] hexane-3-carboxylate as crude product for the next step.
Step 3: benzyl (1 r,3s,5 r) -2- (2-methoxy-2-oxoacetyl) -2-azabicyclo [3.1.0] hexane-3-carboxylate was dissolved in DCM (120 mL) and DIPEA (53 mL,304 mmol) was added thereto. The reaction was cooled to 0 ℃ in an ice bath. Subsequently, methyl oxalyl chloride (4.3 mL,47 mmol) was added dropwise over 30 minutes. The reaction was stirred for 1 hour. The reaction was then diluted with water (300 mL) and the organic phase was separated. The reaction was washed with ethyl acetate (200 mL) and the organic phases were combined and dried over magnesium sulfate, followed by concentration to an oil. The oil was purified by normal phase chromatography with 0-60% ethyl acetate/hexane and concentrated to an oil. The material was then treated with 10wt% palladium on charcoal (50% water, 1g,1.5 mmol) in ethanol (250 mL) and stirred under an atmospheric pressure of hydrogen for 2h. After completion of the reaction, the crude mixture was filtered through celite, washed with ethanol, and concentrated under reduced pressure to give (1 r,3s,5 r) -2- (2-methoxy-2-oxoacetyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid, which was allowed to continue the reaction without further purification.
Step 4: to a solution of oxalyl chloride (16.4 mL,192 mmol) and toluene (60 mL) containing 1% DMF (0.5 mL) was added dropwise a solution of (1R, 3S, 5R) -2- (2-methoxy-2-oxoacetyl) -2-azabicyclo [3.1.0] hexane-3-carboxylic acid (37.2 mmol) in dichloromethane (80 mL). The resulting solution was stirred at ambient temperature for 1h. The solution was concentrated and the residue was co-evaporated with toluene (100 mL). The resulting residue was dried in vacuo to give crude methyl 2- ((1 r,3s,5 r) -3- (chlorocarbonyl) -2-azabicyclo [3.1.0] hex-2-yl) -2-oxoacetate.
In the course of the above procedure 2- ((1R, 3S, 5R) -3- (chlorocarbonyl) -2-azabicyclo [ 3.1.0)]After methyl hex-2-yl) -2-oxoacetate was dissolved in acetonitrile (50 mL), 2, 6-di-tert-butylpyridine (12.7 mL,57 mmol) was added followed by ethyl 2-oxopent-3-ynoate (10.8 mL,84 mmol). The resulting solution was stirred at ambient temperature for 2h. The mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with 0-50% ethyl acetate/hexanes)The residue is left to give (1 aR,6 aR) -5- (2-ethoxy-2-oxoacetyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]Pyrrolizine-3-carboxylic acid methyl ester. LCMS-esi+ (m/z): [ M+H ]] + ：291.98
Step 5: (1 aR,6 aR) -5- (2-ethoxy-2-oxoacetyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropo [ b ] ]Methyl pyrrolizine-3-carboxylate (7.7 g,26.5 mmol) was dissolved in (1:1) MeOH/THF (40 mL), cooled to 0deg.C, 1N LiOH (40 mL) was added, the reaction stirred for 30min until complete, the reaction concentrated and evaporated twice with toluene to give 2- ((1 aR,6 aR) -3- (methoxycarbonyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropo [ b ]]Pyrrolizin-5-yl) -2-oxoacetic acid, which continues to react without further purification. LCMS-esi+ (m/z): [ M+H ]] + ：264.00
Step 6: 2- ((1 aR,6 aR) -3- (methoxycarbonyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b)]Pyrrolizin-5-yl) -2-oxoacetic acid (2 g,7.6 mmol) was dissolved in EtOAc (100 mL) to which TBAI (0.14 g,0.38 mmol) was added followed by 5.0-6.0M t-butyl hydroperoxide (1.7 mL,8.4 mmol). The reaction was heated to 80 ℃ for 38h. The reaction was cooled to ambient temperature, then concentrated to a volume of about 40mL, cooled to 0 ℃, and the material was filtered to give (1 ar,6 ar) -3- (methoxycarbonyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]Pyrrolizine-5-carboxylic acid, which is used in the next step without further purification. LCMS-esi+ (m/z): [ M+H ]] + ：236.07
Step 7: (1 aR,6 aR) -3- (methoxycarbonyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropo [ b ] pyrrolizine-5-carboxylic acid (1.2 g,5.1 mmol) was dissolved in DMF (15 mL) to which HATU (2.3 g,6.1 mmol) and DIPEA (3.6 mL,20.4 mmol) were added. The reaction was stirred at room temperature for 30min and then diluted with EtOAc (200 mL), washed twice with saturated ammonium chloride (50 mL), twice with saturated sodium bicarbonate (50 mL) and with saturated sodium chloride (50 mL). The organics were dried over magnesium sulfate and concentrated. The resulting oil was purified by normal phase chromatography EtOAc/hexanes (0-70%) to give 5- (3H- [1,2,3] triazolo [4,5-b ] pyridin-3-yl) 3-methyl (1 ar,6 ar) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ] pyrrolizine-3, 5-dicarboxylic acid ester which was used in the next step without further purification.
Step 8: 5- (3H- [1,2, 3)]Triazolo [4,5-b ]]Pyridin-3-yl) 3-methyl (1 aR,6 aR) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]Pyrrolizine-3, 5-dicarboxylic acid ester (350 mg,0.99 mmol), 3, 4-difluoroaniline (0.3 mL,3 mmol), 2, 6-dimethylpyridine (0.45 mL,3.9 mmol) were dissolved in dioxane (2 mL) in a sealed vial. Then, it was heated at 100℃for 32 hours. Subsequently, the reaction was diluted with DCM (5 mL) and purified by normal phase chromatography with EtOAc/hexane (0-80%) to give (1 aR,6 aR) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b]Pyrrolizine-3-carboxylic acid methyl ester. 1 H NMR(400MHz，DMSO-d6)δ9.52(s,1H),7.83-7.72(m,1H),7.41-7.27(m,2H),4.31(s,1H),3.37(d,J＝6.8Hz,1H),3.33(d,J＝6.8Hz,1H),3.06(d,J＝17.7Hz,1H),2.39(s,3H),2.11(s,1H),1.08(dt,J＝8.5,5.8Hz,1H),0.21(td,J＝5.3,2.1Hz,1H)。LCMS-ESI+(m/z)：[M+H] + ：347.14
Step 9: (1 aR,6 aR) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropo [ b ] pyrrolizine-3-carboxylic acid methyl ester (300 mg,0.87 mmol) was dissolved in (1:1) MeOH/THF (6 mL), to which was added 1N LiOH (2.6 mL,2.6 mmol). The reaction was heated at 60℃for 11h. The reaction was then neutralized with 1N HCl (2.6 mL) and concentrated to give (1 ar,6 ar) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropo [ b ] pyrrolizine-3-carboxylic acid which was used in the next step without further purification.
Step 10: (1 aR,6 aR) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropo [ b ] pyrrolizine-3-carboxylic acid (258 mg,0.78 mmol) was dissolved in DMF (3 mL) to which was added 1- (cyanomethyl) tetrahydro-1H-thiophen-1-ium bromide (210 mg,1.0 mmol), DIPEA (0.96 mL,5.5 mmol) and HBTU (330 mg,0.85 mmol). The reaction was stirred at ambient temperature and then filtered to give (1 ar,6 ar) -3- (2-cyano-2- (tetrahydro-1 l 4-thiophen-1-ylidene) acetyl) -N- (3, 4-difluorophenyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ] pyrrolizine-5-carboxamide, which was used in the next step without further purification.
Step 11: (1 aR,6 aR) -3- (2-cyano-2- (tetrahydro-1 l 4-thiophen-1-ylidene) acetyl) -N- (3, 4-difluorophenyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ] pyrrolizine-5-carboxamide (340 mg,0.77 mmol) and OXONE (1.0 g,1.7 mmol) were suspended in DMF (4 mL) and MeOH (4 mL) and stirred at ambient temperature for 1h. The reaction was diluted with DCM (25 mL) and washed with saturated sodium bicarbonate (20 mL), and the organics were then dried over magnesium sulfate and concentrated to an oil. The oil was then purified by normal phase chromatography of EtOAc/hexanes (0-70%) to give methyl 2- ((1 ar,6 ar) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ] pyrrolizin-3-yl) -2-oxoacetate.
Step 12: 2- ((1 aR,6 aR) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]Pyrrolidin-3-yl) -2-oxoacetic acid methyl ester (199mg, 0.5 mmol) was dissolved in (1:1) MeOH/THF (4 mL) to which was added 1N LiOH (1.0 mL). It was stirred at ambient temperature for 30min. 1N HCl (1.0 mL) was added thereto, and the reaction was concentrated to give 2- ((1 aR,6 aR) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]Pyrrolizin-3-yl) -2-oxoacetic acid, which is used in the next step without further purification. LCMS-esi+ (m/z): [ M+H ] ] + ：361.09
Step 13: 2- ((1 aR,6 aR) -5- ((3, 4-difluorophenyl) carbamoyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b ]]Pyrrolizin-3-yl) -2-oxoacetic acid (95 mg,0.26 mmol) and 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-amine dihydrochloride (65 mg,0.26 mmol) were dissolved in DMF (10 mL), to which HATU (200 mg,0.52 mmol) and DIPEA (0.32 mL,20 mmol) were added. The reaction was stirred for 1H at ambient temperature and then purified by reverse phase HPLC to give (1 ar,6 ar) -3- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -4-methyl-1, 1a,6 a-tetrahydrocyclopropa [ b)]Pyrrolizine-5-carboxamide. 1 H NMR(400MHz,DMSO-d6)δ9.87(s,1H),9.69(s,1H),7.84-7.72(m,2H),7.44-7.27(m,2H),4.28(s,1H),3.27(d,J＝9.9Hz,4H),3.11(s,1H),3.06(s,1H),2.17(s,4H),1.13-0.99(m,1H),0.23(d,J＝4.7Hz,1H)。LCMS-ESI+(m/z)：[M+H] + ：517.17
Example 35: n- (3-chloro-4-fluorophenyl) -5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) ammonia) Phenyl) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
The product was prepared as described in example 16 using 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide instead of 3, 3-difluoro-1- (1H-1, 2, 3-triazol-5-yl) cyclobutan-1-amine. 1 H NMR (400 MHz, acetone-d) 6 ) Delta 8.85 (s, 1H), 8.69 (s, 1H), 8.05 (ddd, j=6.8, 2.6,1.7hz, 1H), 7.64 (ddd, j=8.5, 4.2,2.7,1.4hz, 1H), 7.40 (m, 1H), 7.26 (t, j=9.0 hz, 1H), 4.27 (t, j=7.3 hz, 2H), 3.38 (td, j=15.2, 11.5hz, 2H), 3.17 (t, j=7.5 hz, 2H), 3.00 (td, j=14.7, 6.6hz, 2H), 2.77 (d, j=4.2 hz, 3H), 2.54 (quincuncial peak, j=7.5 hz, 2H), 2.47 (s, 3H). ES/MS m/z: calculated for C23H23ClF3N4O 4: 511.13, real side values: 511.1.
Example 36:5- (2- ((3- (1H-1, 2, 3-triazol-4-yl) oxetan-3-yl) amino) -2-oxoethyl) Acyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
Step 1: a solution of methyl pivalate (4- (3- ((tert-butylsulfinyl) amino) oxetan-3-yl) -1H-1,2, 3-triazol-1-yl) methyl ester (69.7 mg,0.194 mmol) in methanol (0.7 mL) was stirred at 0deg.C, followed by addition of a solution of dioxane (0.3 mL,1.20 mmol) containing 4N hydrochloric acid along the sides of the flask. After about 3min, the mixture was concentrated without heating. The residue was treated with diethyl ether and then concentrated again and dried overnight in vacuo to give the crude pivalic acid (4- (3-aminooxetan-3-yl) -1H-1,2, 3-triazol-1-yl) methyl ester hydrochloride.
Step 2: 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid (62 mg,0.18 mmol), methyl (4- (3-aminooxetan-3-yl) -1H-1,2, 3-triazol-1-yl) pivalate salt as described aboveAcid salt (0.19 mmol) 1- [ bis (dimethylamino) methylene hexafluorophosphate]-1H-1,2, 3-triazolo [4,5-b]A solution of pyridinium 3-oxide (82 mg,0.21 mmol) in dimethylformamide (1.5 mL) was stirred at ambient temperature followed by the addition of N, N-diisopropylethylamine (0.2 mL,1.148 mmol). After 30min at room temperature, the reaction mixture was diluted with ethyl acetate (30 mL), with aqueous ammonium chloride (x 2), naHCO 3 The aqueous solution (x 2) and brine (x 1) were washed. After extraction of the aqueous component with ethyl acetate (×1), the organic components were combined, dried (MgSO 4 ) And concentrated. The residue was purified by preparative HPLC (column, gemini 10u C18 110A, AXI/;250X 21.2 mm) (10-70% acetonitrile (0.1% TFA)/water (0.1% TFA) elution) to give pivalic acid (4- (3- (2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetamido) oxetan-3-yl) -1H-1,2, 3-triazol-1-yl) methyl ester: 1 h NMR (400 MHz, chloroform-d) delta 8.24 (s, 1H), 7.98 (s, 1H), 7.70-7.58 (m, 2H), 7.17-7.01 (m, 2H), 6.22 (s, 2H), 5.10 (d, j=6.9 hz, 2H), 5.03 (d, j=6.9 hz, 2H), 4.20 (t, j=7.3 hz, 2H), 3.05 (t, j=7.5 hz, 2H), 2.49 (p, j=7.5 hz, 2H), 2.36 (s, 3H), 1.18 (s, 9H). 19 F NMR (376 MHz, chloroform-d) delta-136.19 (ddd, J=21.9, 12.2,7.7 Hz), -141.81-144.80 (m). ES/MS m/z: calculated for C28H31F2N6O6 (m+h): 585.23, real side values: 585.27.
step 3: a solution of pivalic acid (4- (3- (2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetamido) -1H-1,2, 3-triazol-1-yl) methyl ester (73 mg,0.13 mmol) in methanol (2 mL) was stirred at room temperature followed by the addition of 2M sodium hydroxide (0.2 mL,0.4 mmol). After 30min, the mixture was acidified with 1N hydrochloric acid (about 0.08 mL) and the resulting mixture concentrated. The resulting residue was purified by preparative HPLC (synergy 4u Polar-RP 80A, axia;10% acetonitrile in water-60% acetonitrile in water with 0.1% TFA over 30min, gradient), followed by purification with another preparative HPLC without trifluoroacetic acid modifier and freeze-drying to give 5- (2- ((3- (1H-1, 2, 3-triazol-4-yl) oxetan-3-yl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide: 1 H NMR (400 MHz, acetonitrile-d) 3 )δ8.17(s,1H),8.10(s,1H),7.78(s,1H),7.79-7.70(m,1H),7.33-7.26(m,1H),7.22(dt,J＝10.6,8.8Hz,1H),5.02(d,J＝6.7Hz,2H),4.96(d,J＝6.7Hz,2H),4.23(t,J＝7.2Hz,2H),3.07(t,J＝7.5Hz,2H),2.50(p,J＝7.4Hz,2H),2.39(s,3H)。 19 F NMR (376 MHz, acetonitrile-d) 3 ) Delta-139.21 (ddd, j=21.5, 13.2,8.8 hz), -146.32-146.83 (m). ES/MS m/z: C22H21F2N6O4 (m+h) gives the calculated value: 471.16, experimental values: 471.22.
example 37:5- (2- ((3- (1H-1, 2, 3-triazol-4-yl) oxetan-3-yl) amino) -2-oxoethyl) Acyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
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Step 1: in analogy to example 40 step 4, 7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid methyl ester was synthesized using 3- (difluoromethyl) -4-fluoroaniline instead of 3, 4-difluoroaniline: 1 h NMR (400 MHz, chloroform-d) delta 7.82-7.75 (m, 1H), 7.68 (dd, j=6.0, 2.7hz, 1H), 7.35 (s, 1H), 7.15-7.08 (m, 1H), 6.88 (t, j=54.9 hz, 1H), 4.30 (dd, j=8.1, 6.5hz, 2H), 3.86 (s, 3H), 3.15 (dd, j=8.0, 7.1hz, 2H), 2.68 (s, 3H), 2.54 (ddd, j=14.9, 8.0,6.8hz, 2H). 19 F NMR (376 MHz, chloroform-d) delta-114.59 (d, j=55.4 hz, 2F), -125.61-125.98 (m, 1F). ES/MS m/z: calculated for C18H18F3N2O3 (m+h): 367.13, real side values: 367.16.
step 2: 7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid was synthesized in analogy to example 40 step 5 using 7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid methyl ester.
Step 3: step of example 406A similar procedure was used to synthesize 5- (2-cyano-2- (tetrahydro-1 l 4-thiophen-1-ylidene) acetyl) -N- (3- (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide using 7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid: ES/MS m/z: c (C) 23 H 23 F 3 N 3 O 2 Calculated value of S (m+h): 462.15, real side values: 462.27.
step 4: synthesis of 2- (7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetic acid methyl ester using 5- (2-cyano-2- (tetrahydro-1 l 4-thiophen-1-ylidene) acetyl) -N- (3- (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide in analogy to example 40 step 7: 1 h NMR (400 MHz, chloroform-d) delta 7.82-7.73 (m, 1H), 7.68 (dd, j=6.0, 2.7hz, 1H), 7.44 (s, 1H), 7.17-7.07 (m, 1H), 6.88 (t, j=54.9 hz, 1H), 4.33 (t, j=7.3 hz, 2H), 3.94 (s, 3H), 3.13 (t, j=7.6 hz, 2H), 2.58 (p, j=7.6 hz, 2H), 2.44 (s, 3H). 19 F NMR (376 MHz, chloroform-d) delta-114.72 (d, j=55.0 Hz), -125.27 (dt, j=10.3, 5.2 Hz). ES/MS m/z: calculated for C19H18F3N2O4 (m+h): 395.12, real side values: 395.20.
step 5: 2- (7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetic acid was synthesized in analogy to example 40 step 8 using methyl 2- (7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetic acid: ES/MS m/z: c (C) 18 H 16 F 3 N 2 O 4 Calculated value of (m+h): 381.11, real side values: 381.06.
step 6: 5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (3- (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (21) was synthesized in analogy to example 40 step 9 using 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-amine dihydrochloride instead of 1- (1H-1, 2, 3-triazol-4-yl) cyclopropan-1-amine dihydrochloride and 2- (7- ((3- (difluoromethyl) -4-fluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (21): 1 H NMR(400MHz, chloroform-d) delta 7.82-7.73 (m, 1H), 7.68 (dd, j=6.0, 2.7hz, 1H), 7.44 (s, 1H), 7.17-7.07 (m, 1H), 6.88 (t, j=54.9 hz, 1H), 4.33 (t, j=7.3 hz, 2H), 3.94 (s, 3H), 3.13 (t, j=7.6 hz, 2H), 2.58 (p, j=7.6 hz, 2H), 2.44 (s, 3H). 19 F NMR (376 MHz, chloroform-d) delta-114.72 (d, j=55.0 Hz), -125.27 (dt, j=10.3, 5.2 Hz). ES/MS m/z: c (C) 24 H 22 F 5 N 6 O 3 Calculated value of (m+h): 537.17, real side values: 537.13.
example 38: n- (3, 4-difluorophenyl) -6-methyl-5- (2- ((3- (methylcarbamoyl) oxetane-3-) Base) amino) -2-oxoacetyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (38)
The product was synthesized in analogy to example 13, using 3-amino-N-methyloxetane-3-carboxamide instead of ethynyl cyclopropylamine hydrochloride.
Synthesis of 3-amino-N-methyloxetane-3-carboxamide:
to a solution of 3-aminooxetane-3-carboxylic acid (4.99 g,42.6 mmol) and N, N-diisopropylethylamine (18 mL) in dichloromethane (120 mL) was added N- (benzyloxycarbonyloxy) succinimide (9.21 mL,34.1 mmol), and the reaction mixture was stirred at room temperature for 24h, at which point the reaction volume was concentrated under reduced pressure for two-thirds. This solution was then diluted with diethyl ether and washed with 1M aqueous hydrogen chloride, followed by washing with water, drying over sodium sulfate, filtration and concentration under reduced pressure to give 3- (((benzyloxy) carbonyl) amino) oxetane-3-carboxylic acid, which was used in the next step without further purification.
To a solution of 3- (((benzyloxy) carbonyl) amino) oxetane-3-carboxylic acid (9.2 g,36.6 mmol), methylamine hydrochloride (12.9 g,191.5 mmol) and N-methylmorpholine (25 mL,230 mmol) in N, N-dimethylformamide (100 mL) was added 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide (21.4 g,56.3 mmol) hexafluorophosphate. The reaction mixture was stirred for 18h, at which time most of the N, N-dimethylformamide was removed under reduced pressure, the remaining material was diluted with diethyl ether, washed sequentially with 1M aqueous hydrogen chloride, 5% aqueous sodium bicarbonate, 5% aqueous lithium chloride and saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-10% methanol: dichloromethane) to give benzyl (3- (methylcarbamoyl) oxetan-3-yl) carbamate.
To a solution of benzyl (3- (methylcarbamoyl) oxetan-3-yl) carbamate (4.9 g,18.5 mmol) in ethanol (80 mL) was added 10% palladium on charcoal (1.95 g,0.92 mmol). The reaction mixture was placed under hydrogen at atmospheric pressure and stirred for 3h. The reaction mixture was then filtered through celite and the resulting filtrate was concentrated under reduced pressure to give 3-amino-N-methyloxetane-3-carboxamide. 1 H NMR(400MHz，DMSO-d6)δ7.82(s,1H),4.70(d,J＝5.8Hz,2H),4.26(d,J＝5.7Hz,2H),2.61(d,J＝4.7Hz,3H)。
Example 39:5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoethyl) Acyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
This product was synthesized in analogy to example 1, step 9, using 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-amine dihydrochloride instead of 1- (1H-1, 2, 3-triazol-4-yl) cyclopropan-1-amine dihydrochloride: 1 h NMR (400 MHz, acetonitrile-d) 3 )δ8.08(s,1H),7.97(s,1H),7.76(s,1H),7.75(ddd,J＝12.8,7.5,2.6Hz,1H),7.28(dddd,J＝9.0,4.2,2.6,1.3Hz,1H),7.22(dt,J＝10.5,8.8Hz,1H),4.25-4.17(m,2H),3.42-3.21(m,4H),3.07(t,J＝7.5Hz,2H),2.49(p,J＝7.5Hz,2H),2.34(s,3H)。 19 F NMR(376MHz，Acetonitrile-d 3 )δ-77.32(d,J＝15.1Hz),-90.19--90.89(m,1F),-90.98--91.69(m,1F),-139.21(ddd,J＝21.6,13.2,8.5Hz,1F),-146.56(ddd,J＝14.9,10.9,7.3Hz,1F)。ES/MS m/z：C 23 H 21 F 4 N 6 O 3 Calculated value of (m+h): 505.16, real side values: 505.19.
example 40:5- (2- ((1- (1H-1, 2, 3-triazol-4-yl) cyclopropyl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
Step 1: a solution of 7- (2-ethoxy-2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid methyl ester (10.4126 g,37.28 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) was stirred at 0deg.C followed by 1N lithium hydroxide (56 mL). After stirring at 0deg.C for 45min, the reaction mixture was washed with diethyl ether (200 mL x 1), acidified with 1N hydrochloric acid, and the product extracted with ethyl acetate (100 mL x 2). The combined extracts were dried (MgSO 4 ) And concentrating to give 2- (5- (methoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-7-yl) -2-oxoacetic acid: ES/MS m/z: c (C) 12 H 14 NO 5 Calculated value of (m+h) = 252.09, real side value: 251.97.
step 2: to a mixture of 2- (5- (methoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-7-yl) -2-oxoacetic acid (300 mg,1.2 mmol) and tetrabutylammonium iodide (44 mg,0.12 mmol) in ethyl acetate (12 mL) was added decane (0.27 mL,1.350-1.620 mmol) containing 5.0-6.0M tert-butyl peroxide at room temperature. The reaction mixture was stirred at 80℃for 16h. The resulting solution was washed with water (50 mL), acidified with 1N hydrochloric acid, and the two components separated by adding ethyl acetate (40 mL) and heating the solids dissolved in the reaction mixture. After extraction of the aqueous component with ethyl acetate (-30 mL), the two organic components were washed with water (containing 1-2 drops of 1N hydrochloric acid), combined, dried (MgSO 4 ) And concentrating to obtain crude 5- (methoxycarbonyl)) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid: ES/MS m/z: calculated = 224.09 for C11H14NO4 (m+h), found: 224.03.
step 3: mixing the crude acid with 1- [ bis (dimethylamino) methylene hexafluorophosphate]-1H-1,2, 3-triazolo [4,5-b ]Pyridinium 3-oxide (46 mg,1.44 mmol) was stirred in dimethylformamide (3 mL) at 0deg.C with the addition of N, N-diisopropylethylamine (0.9 mL,5.2 mmol). After 1h at 0deg.C, the reaction mixture was diluted with ethyl acetate (40 mL) and saturated NH 4 Cl solution (x 2), saturated NaHCO 3 The solution (x 2) and brine (x 1) were washed. After extraction of the aqueous component with ethyl acetate (-30 mL x 1), the organic components were combined, dried (MgSO 4 ) And concentrated. Purification of the residue by CombiFlash (40 g column) eluting with 0-100% ethyl acetate/hexane gave 7- (3H- [1,2, 3)]Triazolo [4,5-b ]]Pyridin-3-yl) 5-methyl 6-methyl-2, 3-dihydro-1H-pyrrolizine-5, 7-dicarboxylic acid ester: 1 h NMR (400 MHz, chloroform-d) δ8.72 (dd, j=4.5, 1.4hz, 1H), 8.43 (dd, j=8.4, 1.4hz, 1H), 7.43 (dd, j=8.4, 4.5hz, 1H), 4.45-4.33 (m, 2H), 3.88 (s, 3H), 3.35 (t, j=7.6 hz, 2H), 2.64-2.54 (m, 2H), 2.61 (s, 3H). ES/MS m/z: calculated for C16H16N5O4 (m+h): 342.12, found: 341.77.
step 4: 7- (3H- [1,2, 3)]Triazolo [4,5-b ]]Pyridin-3-yl) 5-methyl 6-methyl-2, 3-dihydro-1H-pyrrolizine-5, 7-dicarboxylic acid ester (230 mg,0.67 mmol), 3, 4-difluoroaniline (0.2 mL 2.0 mmol), 2, 6-dimethylpyridine (0.3 mL,2.6 mmol) and 1, 2-dichloroethane (0.5 mL) were mixed in a flask and stirred at 70℃for 24H. The reaction mixture was purified by CombiFlash (40 g column) eluting twice with 0-85% ethyl acetate/hexane and further purified by preparative HPLC (synergy 4u Polar-RP 80a, axia;10% acetonitrile in water-70% acetonitrile in water with 0.1% tfa over 30min, gradient). The fractions containing the main UV peak were combined, concentrated to remove most of the acetonitrile, by adding a certain amount of saturated NaHCO 3 The solution was neutralized and the product extracted with ethyl acetate (×2). After washing the organic components with water (x 1), combining and concentrating, the residue was dried over the weekend in vacuo to give methyl 7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylate: 1 h NMR (400 MHz, chloroform-d) delta 7.77-7.62 (m, 1H), 7.29 (s, 1H), 7.15-7.05 (m, 2H), 4.39-4.21 (m, 2H), 3.86 (s, 3H), 3.13 (t, j=7.5 hz, 2H), 2.66 (s, 3H), 2.53 (p, j=7.3 hz, 2H). 19 F NMR (376 MHz, chloroform-d) delta-136.09- -136.53 (m), -143.53- -143.94 (m). ES/MS m/z: calculated for C17H17F2N2O3 (m+h): 335.12, found: 335.10.
step 5: to a suspension of 7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrazine-5-carboxylic acid methyl ester (252 mg,0.754 mmol) in methanol (3 mL) and tetrahydrofuran (3 mL) was added 1N LiOH (2.25 mL), and the resulting suspension was stirred at 60℃for 12H. The reaction mixture was acidified by addition of 1N hydrochloric acid (-2.3 mL), concentrated to remove organic solvent, diluted with water (40-50 mL) and the residual aqueous suspension was filtered, washed with water and dried in vacuo to give crude 7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid.
Step 6: a suspension of the above crude acid, O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (317 mg,0.84 mmol) and 1- (cyanomethyl) tetrahydro-1H-thiophen-1-ium bromide (209 mg,1.0 mmol) in dimethylformamide (3 mL) was stirred at ambient temperature followed by the addition of N, N-diisopropylethylamine (0.94 mL,5.4 mmol). The reaction mixture was stirred for 17h, and quenched with water (30 mL) and some saturated NH 4 And (5) diluting the Cl solution. The remaining solid was filtered and the collected solid was washed with water and then dichloromethane. The resulting solid was collected and dried in vacuo for 1H to give 5- (2-cyano-2- (tetrahydro-1 l 4-thiophen-1-ylidene) acetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide: 1 H NMR(400MHz，DMSO-d 6 )δ9.39(s,1H),7.91-7.73(m,1H),7.43-7.26(m,2H),4.01(t,J＝7.2Hz,2H),3.74-3.55(m,2H),3.19(dt,J＝12.5,6.3Hz,2H),3.02(t,J＝7.4Hz,2H),2.40(p,J＝7.4Hz,2H),2.33(m,2H),2.30(s,3H),2.07(m,2H)。 19 F NMR(376MHz,DMSO-d6)δ-138.09--138.58(m),-146.15--146.66(m)。ES/MS m/z：C 22 H 22 F 2 N 3 O 2 calculated value of S (m+h): 430.14, found: 430.16.
step 7: 5- (2-cyano-2- (tetrahydro-)1l 4-thiophen-1-ylidene) acetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (250 mg,0.58 mmol) and OXONE, monopersulfate compound (2 KHSO 5 -KHSO 4 -K 2 SO 4 A suspension of 724mg,1.2 mmol) in dimethylformamide (2 mL) and methanol (2 mL) was stirred at room temperature. After 15min, additional solvents dimethylformamide (2 mL) and methanol (2 mL) were added. After 22h, the reaction mixture was taken up with ethyl acetate (15 mL), dichloromethane (30 mL) and saturated NaHCO 3 And (5) diluting the solution. After separation of the two layers, the organic component was washed with 5LiCl solution (x 1) and brine (x 1). After extraction of the aqueous component with dichloromethane (-20 mL x 1), the two organic components were combined, dried (MgSO 4 ) And concentrated. The residue was purified by CombiFlash (24 g column) eluting with 0-70% ethyl acetate/hexanes to give methyl 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetate: 1 h NMR (400 MHz, chloroform-d) delta 7.66 (ddd, j=12.0, 7.2,2.4hz, 1H), 7.18 (s, 1H), 7.16-7.02 (m, 2H), 4.36 (t, j=7.4 hz, 2H), 3.95 (s, 3H), 3.13 (t, j=7.6 hz, 2H), 2.59 (p, j=7.5 hz, 2H), 2.47 (s, 3H). 19 F NMR (376 MHz, chloroform-d) delta-135.74- -136.19 (m), -142.87- -143.19 (m). ES/MS m/z: c (C) 18 H 17 F 2 N 2 O 4 Calculated value of (m+h): 363.12, found: 363.15.
step 8: a solution of methyl 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetate (181 mg,0.50 mmol) in tetrahydrofuran (1 mL) and MeOH (1 mL) was stirred at ambient temperature followed by the addition of 1N LiOH (1.0 mL). After 30min at ambient temperature, the reaction mixture was concentrated to remove most of the organic solvent, diluted with water, acidified and the product extracted with ethyl acetate (×2). The combined extracts were dried (MgSO 4 ) And concentrated to give crude 2- (7- ((3, 4-difluorophenyl) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid: ES/MS m/z: c (C) 17 H 15 F 2 N 2 O 4 Calculated value of (m+h): 349.10, found: 349.11.
step 9: crude 2- (7- ((3, 4-difluorobenzene)Radical) carbamoyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid (49 mg,0.14 mmol), 1- (1H-1, 2, 3-triazol-4-yl) cyclopropan-1-amine dihydrochloride (40 mg,0.20 mmol) and 1- [ bis (dimethylamino) methylene hexafluorophosphate]-1H-1,2, 3-triazolo [4,5-b]A solution of pyridinium 3-oxide (150 mg,0.39 mmol) in dimethylformamide (1.2 mL) was stirred at ambient temperature followed by the addition of N, N-diisopropylethylamine (0.2 mL,1.15 mmol). After 30min at room temperature, methanol (1 mL) was added to the reaction mixture and stirred at ambient temperature for 2h. The reaction mixture was diluted with ethyl acetate (20 mL), with aqueous ammonium chloride (x 2), naHCO 3 The aqueous solution (x 2) and brine (x 1) were washed. After extraction of the aqueous component with ethyl acetate (x 1), the organic components were combined and dried (MgSO 4 ) And concentrated. The residue was purified by preparative HPLC (column, gemini 10u C18 110A, AXI/;250X 21.2 mm) eluting with 10-80% acetonitrile (0.1% TFA)/water (0.1% TFA) and lyophilized to give 5- (2- ((1- (1H-1, 2, 3-triazol-4-yl) cyclopropyl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide: 1 H NMR (400 MHz, acetonitrile-d) 3 )δ8.08(s,1H),7.87(s,1H),7.76(ddd,J＝13.2,7.5,2.5Hz,1H),7.59(s,1H),7.33-7.26(m,1H),7.22(dt,J＝10.5,8.8Hz,1H),4.30-4.19(m,2H),3.07(t,J＝7.5Hz,2H),2.50(p,J＝7.5Hz,2H),2.39(s,3H),1.43-1.34(m,2H),1.34-1.25(m,2H)。 19 F NMR (376 MHz, acetonitrile-d) 3 ) Delta-77.34 (s, 3F), -139.21 (ddd, j=21.3, 12.9,8.6hz, 1F), -146.26-147.01 (m, 1F). ES/MS m/z: calculated for C22H21F2N6O3 (m+h): 455.16, found: 455.13.
example 41:5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) amino) N- (3- (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
1- (1H-1, 2, 3-triazole-4) was replaced with 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide as described in example 27-yl) cyclopropyl-1-amine dihydrochloride. 1 H NMR(400MHz，DMSO-d 6 ) δ9.79 (br s, 1H), 9.62 (br s, 1H), 8.01 (dd, j=6.6, 2.6hz, 1H), 8.75-8.82 (m, 1H), 7.38-7.29 (m, 1H), 7.22 (t, j=54.3 hz, 1H), 4.21 (t, j=7.3 hz, 2H), 3.24 (q, j=14.1 hz, 2H), 3.08 (t, j=7.5 hz, 2H), 3.01-2.82 (m, 2H), 2.62 (d, j=4.5 hz, 3H), 2.45 (quincuncial peaks, j=7.4 hz, 1H), 2.36 (s, 3H). ES/MS m/z: calculated for C24H24F5N4O 4: 527.16, found: 527.1.
example 42:5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) amino) 6-methyl-N- (3, 4, 5-trifluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide
This product was prepared as described in example 1 using 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide instead of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine. 1 H NMR (400 MHz, acetone-d) 6 ) Delta 8.99 (br s, 1H), 8.73 (br s, 1H), 7.62 (s, 2H), 7.39 (br s, 1H), 4.26 (br s, 2H), 3.37 (br s, 2H), 3.16 (br s, 2H), 2.99 (br s, 2H), 2.76 (s, 3H), 2.50 (br s, 2H), 2.48 (s, 3H). ES/MS m/z: calculated for C23H22F5N4O 4: 513.15, found: 513.1.
example 43:5- (2- ((1- (1, 3, 4-thiadiazol-2-yl) cyclopropyl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (43)
The product was synthesized in analogy to example 29, using 3, 4-difluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 44:5- (2- ((1-carbamoyl-3, 3-difluorocyclobutyl) amino) -2-oxoacetyl) -N- (3, 4-) Difluorophenyl) -6-methyl-23-dihydro-1H-pyrrolizine-7-carboxamide (44)
The product was synthesized in analogy to example 32 using 3, 4-difluoroaniline instead of 3- (difluoromethyl) -4-fluoroaniline.
Example 45:5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) amino) N- (4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide
The product was prepared as described in example 7 using 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide instead of 3, 3-difluoro-1- (1-methyl-1H-1, 2, 3-triazol-5-yl) cyclobutan-1-amine. 1 H NMR(400MHz，DMSO-d 6 ) δ9.18 (s, 1H), 9.16 (s, 1H), 7.32 (q, j=4.6 hz, 1H), 7.28-7.12 (m, 2H), 6.70 (t, j=7.0 hz, 2H), 3.75 (t, j=7.3 hz, 2H), 2.79 (q, j=14.1 hz, 2H), 2.61 (t, j=7.3 hz, 2H), 2.46 (td, j=14.5, 7.7hz, 2H), 2.16 (d, j=4.6 hz, 1H), 2.00 (quincuncial peak, j=7.5 hz, 2H), 1.89 (s, 3H). ES/MS m/z: calculated for C23H24F3N4O 4: 477.17, found: 477.1.
example 46:5- (2- ((3, 3-difluoro-1- (methylcarbamoyl) cyclobutyl) amino) -2-oxoacetyl) amino) N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (46)
This product was synthesized in analogy to example 1 using 1-amino-3, 3-difluoro-N-methylcyclobutane-1-carboxamide hydrochloride instead of 3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutan-1-amine hydrochloride and 3, 4-difluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 47: (R) -5- (2- ((3-amino-1, 1-trifluoro-2-methyl-3-oxopropan-2-yl) amino) -2-oxo Substituted acetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (47)
Step 1: a solution of (R) -2-amino-3, 3-trifluoro-2-methylpropanoic acid hydrochloride (116 mg,0.60 mmol) in dichloromethane (5 mL) was treated with trimethylamine (0.2 mL,1.47 mmol) and concentrated under reduced pressure. The resulting residue was redissolved in N-methyl-2-pyrrolidone (2 mL), treated with trimethylchlorosilane (0.1 mL,0.8 mmol), and stirred for 20 min. Then, the mixture was added to a premixed solution of 2- (7- (tert-butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid (102 mg,0.35 mmol), trimethylamine (0.20 mL,1.5 mmol) and HATU (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide) hexafluorophosphate (159 mg,0.42 mmol) in N-methyl-2-pyrrolidone (1 mL) and then stirred at room temperature for 60 minutes, at which time the reaction mixture was diluted with ethyl acetate and washed with 1M aqueous hydrogen chloride, 5% aqueous lithium chloride and saturated aqueous sodium chloride in this order. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure, followed by silica gel chromatography (0-20% ethanol: dichloromethane) and preparative HPLC (10-100% acetonitrile/water, 0.1% tfa buffer) to give (R) -2- (2- (7- (tert-butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolazin-5-yl) -2-oxoacetamido) -3, 3-trifluoro-2-methylpropanoic acid.
Step 2: a solution of (R) -2- (2- (7- (tert-butoxycarbonyl) -6-methyl-2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetamido) -3, 3-trifluoro-2-methylpropanoic acid (33 mg,0.08 mmol), ammonium chloride (23 mg,0.43 mmol), N-methylmorpholine (0.10 mL,0.91 mmol), 4-dimethylaminopyridine (11 mg,0.09 mmol) and HATU (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide of hexafluorophosphoric acid) (94 mg,0.25 mmol) in N-methyl-2-pyrrolidone (1 mL) was stirred at room temperature for 20 minutes at which time the reaction mixture was diluted with ethyl acetate and washed sequentially with 1M aqueous hydrogen chloride, 5% aqueous sodium bicarbonate, 5% aqueous lithium chloride and saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate, filtered and concentrated under reduced pressure to give (R) -5- (2- ((3-amino-1, 1-trifluoro-2-methyl-3-oxopropan-2-yl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester which was allowed to continue to react without further purification.
Step 3: a solution of (R) -5- (2- ((3-amino-1, 1-trifluoro-2-methyl-3-oxopropan-2-yl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid tert-butyl ester (33 mg,0.08 mmol) in dioxane (1 mL) containing 4M hydrogen chloride was stirred at 40℃for 45 min, at which time the reaction mixture was cooled to room temperature and the solvent removed under reduced pressure to give (R) -5- (2- ((3-amino-1, 1-trifluoro-2-methyl-3-oxopropan-2-yl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid which was continued to react without further purification.
Step 4: a solution of (R) -5- (2- ((3-amino-1, 1-trifluoro-2-methyl-3-oxopropan-2-yl) amino) -2-oxoacetyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxylic acid (29 mg,0.08 mmol), 3, 4-difluoroaniline (0.1 mL,1.0 mmol), N-methylmorpholine (0.05 mL,0.45 mmol) and HATU (hexafluorophosphate 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide) (41 mg,0.11 mmol) in N-methyl-2-pyrrolidone (1 mL) was stirred at 100℃for 3H, at which time the reaction mixture was cooled to room temperature, filtered through a syringe filter and purified by preparative HPLC (10-100% acetonitrile/water, 0.1% TFA buffer) to give (R) -5- (2-amino-1, 1-trifluoro-2-triazolo [4,5-b ] pyridinium 3-oxide) (41 mg,0.11 mmol) in N-methyl-2-pyrrolidone (1 mL).
Example 48: (S) -5- (2-)(3-amino-1, 1-trifluoro-2-methyl-3-oxopropan-2-yl) amino) -2-oxo Substituted acetyl) -N- (3, 4-difluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (48)
This product was synthesized in analogy to example 47 using (S) -2-amino-3, 3-trifluoro-2-methylpropanoic acid hydrochloride instead of (R) -2-amino-3, 3-trifluoro-2-methylpropanoic acid hydrochloride.
Example 49:5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl Phenyl) -N- (3- (difluoromethyl) -4-fluorophenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (49)
This product was synthesized in analogy to example 1 using 3- (difluoromethyl) -4-fluoroaniline instead of 3,4, 5-trifluoroaniline.
Example 50:5- (2- ((3, 3-difluoro-1- (1, 3, 4-thiadiazol-2-yl) cyclobutyl) amino) -2-oxoacetyl Phenyl) -N- (4-fluoro-3- (methoxymethyl) phenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (50)
This product was synthesized in analogy to example 1 using 4-fluoro-3- (methoxymethyl) aniline instead of 3,4, 5-trifluoroaniline.
Example 51:5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoethyl) Acyl) -N- (4-fluoro-3- (methoxymethyl) phenyl) -6-methyl-2, 3-dihydro-1H-pyrrolizine-7-carboxamide (51)
The product was synthesized in analogy to example 15 using 4-fluoro-3- (methoxymethyl) aniline instead of 3-cyano-4-fluoroaniline.
Example 52:5- (2- ((1- (1, 3, 4-thiadiazol-2-yl) cyclopropyl) amino) -2-oxoacetyl) -6-chloro-o-i-c-i N- (3, 4-difluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (52)
Step 1: to a solution of aluminum chloride (557 mg,4.2 mmol) in methylene chloride (16 mL) at 0deg.C was added methyl 6-chloro-2, 3-dihydro-1H-pyrrolizine-5-carboxylate (399mg, 2.0 mmol) followed by trichloroacetyl chloride (0.5 mL,4.5 mmol). Then, the reaction solution was warmed to room temperature and stirred for 18h, at which time it was partitioned between dichloromethane and ice water. The aqueous phase was extracted three times to dichloromethane and the combined organic phases were dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel (0-10% ethyl acetate: hexanes) to give methyl 6-chloro-7- (2, 2-trichloroacetyl) -2, 3-dihydro-1H-pyrrolizine-5-carboxylate. 1 H NMR (400 MHz, chloroform-d) delta 4.48-4.35 (m, 2H), 3.94 (s, 3H), 3.33 (t, j=7.6 hz, 2H), 2.54 (p, j=7.5 hz, 2H).
Step 2: methyl 6-chloro-7- (2, 2-trichloroacetyl) -2, 3-dihydro-1H-pyrrolizine-5-carboxylate (356 mg,1.0 mmol) was dissolved in a mixture of methanol (24 mL) and tetrahydrofuran (16 mL) and then treated with 4N aqueous sodium hydroxide solution (1 mL). The reaction mixture was stirred at room temperature for 1h and acidified with dilute aqueous hydrochloric acid. The aqueous mixture was extracted into ethyl acetate and the combined organic phases were washed with water, with sulfurSodium acid is dried, filtered and concentrated under reduced pressure to give dimethyl 6-chloro-2, 3-dihydro-1H-pyrrolizine-5, 7-dicarboxylate which is reacted further without further purification. 1 H NMR (400 MHz, chloroform-d) delta 4.41-4.28 (m, 2H), 3.91 (s, 3H), 3.86 (s, 3H), 3.20-3.07 (m, 2H), 2.55-2.44 (m, 2H).
Step 3: dimethyl 6-chloro-2, 3-dihydro-1H-pyrrolizine-5, 7-dicarboxylate (260 mg,1.0 mmol) was dissolved in methanol (6 mL) and treated with 4N aqueous sodium hydroxide (0.6 mL). The reaction mixture was stirred at 60 ℃ for 24h, diluted with water and acidified with dilute aqueous hydrochloric acid. The aqueous mixture was extracted to dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 6-chloro-7- (methoxycarbonyl) -2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid which was allowed to continue to react without further purification.
Step 4: to a solution of 6-chloro-7- (methoxycarbonyl) -2, 3-dihydro-1H-pyrrolizine-5-carboxylic acid (160 mg,0.62 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (0.75 mL,9.8 mmol). The reaction mixture was stirred at 40 ℃ for 4h, diluted with EtOAc, and washed with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride in sequence. The organic phase is then dried over sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel (0-30% ethyl acetate: hexane) to give methyl 6-chloro-2, 3-dihydro-1H-pyrrolizine-7-carboxylate. 1 H NMR (400 MHz, chloroform-d) delta 6.61 (s, 1H), 3.97 (t, j=7.2 hz, 2H), 3.82 (s, 3H), 3.15-2.98 (m, 2H), 2.49 (p, j=7.3 hz, 2H).
Step 5: to a solution of methyl 6-chloro-2, 3-dihydro-1H-pyrrolizine-7-carboxylate (26 mg,0.13 mmol) and 3, 4-difluoroaniline (39 mg,0.30 mmol) in tetrahydrofuran (1 mL) was added a 1M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (0.25 mL,0.25 mmol). The reaction mixture was stirred at room temperature for 2H, at which time it was diluted with ethyl acetate, washed sequentially with dilute hydrochloric acid and then with saturated aqueous sodium chloride, dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (0-30% ethyl acetate: hexanes) to give 6-chloro-N- (3, 4-difluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide. 1 H NMR (400 MHz, chloroform-d) delta 8.46(s),1H),7.79(ddd,J＝12.5,7.3,2.5Hz,1H),7.21-7.04(m,2H),6.67(s,1H),3.99(t,J＝7.2Hz,2H),3.26-3.16(m,2H),2.53(tt,J＝8.0,6.9Hz,2H)。
Step 6: to a solution of 6-chloro-N- (3, 4-difluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (24 mg,0.08 mmol) in ethyl acetate (1 mL) was added methyl 2-chloro-2-oxoacetate (0.1 mL,1.0 mmol). The reaction mixture was stirred at 40 ℃ for 3h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted to ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 2- (6-chloro-7- ((3, 4-difluorophenyl) carbamoyl) -2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetate which was allowed to continue the reaction without further purification.
Step 7: a solution of methyl 2- (6-chloro-7- ((3, 4-difluorophenyl) carbamoyl) -2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetate (30 mg,0.08 mmol) in methanol (1 mL) was treated with a 2M lithium hydroxide solution (0.1 mL,0.2 mmol). After stirring at room temperature for 40min, the reaction mixture was diluted with water, acidified with dilute hydrochloric acid and extracted three times to ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2- (6-chloro-7- ((3, 4-difluorophenyl) carbamoyl) -2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid which was allowed to continue the reaction without further purification.
Step 8: 2- (6-chloro-7- ((3, 4-difluorophenyl) carbamoyl) -2, 3-dihydro-1H-pyrrolizin-5-yl) -2-oxoacetic acid (20 mg,0.09 mmol), 1- (1, 3, 4-thiadiazol-2-yl) cyclopropyl-1-amine hydrochloride (30 mg,0.14 mmol), N-methylmorpholine (0.05 mL,0.45 mmol) and HATU (1- [ bis (dimethylamino) methylene hexafluorophosphate)]-1H-1,2, 3-triazolo [4,5-b]A solution of pyridinium 3-oxide) (43 mg,0.11 mmol) in N, N-dimethylformamide (1 mL) was stirred at room temperature for 2H, at which time the reaction mixture was passed through a syringe filter and purified by preparative HPLC (10-100% acetonitrile/water, 0.1% TFA buffer) to give 5- (2- ((1- (1, 3, 4-thiadiazol-2-yl) cyclopropyl) amino) -2-oxoacetyl) -6-chloro-N- (3, 4-difluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (52).Example 53:5- (2- ((1- (1H-1, 2, 3-triazol-4-yl) ring)Propyl) amino) -2-oxoacetyl) -6-chloro-N- (3, 4-difluorophenyl) -p-henyl- 2, 3-dihydro-1H-pyrrolizine-7-carboxamide (53)
This product was synthesized in analogy to example 52, using 1- (1H-1, 2, 3-triazol-4-yl) cyclopropan-1-amine bis (hydrochloride) instead of 1- (1, 3, 4-thiadiazol-2-yl) cyclopropan-1-amine hydrochloride.Example 54: 6-chloro-5- (2- ((3, 3-di) Fluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxoacetyl) -N- (3, 4-difluorophenyl) -2, 3-di-N-ethyl Hydrogen-1H-pyrrolizine-7-carboxamide (54)
This product was synthesized in analogy to example 52, using 3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutan-1-amine bis (hydrochloride) instead of 1- (1, 3, 4-thiadiazol-2-yl) cyclopropan-1-amine hydrochloride.
Example 55: 6-chloro-5- (2- ((3, 3-difluoro-1- (1H-1, 2, 3-triazol-4-yl) cyclobutyl) amino) -2-oxo Acetoacetyl) -N- (3- (difluoromethyl) -4-fluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (55)
This product was synthesized in analogy to example 54 using 3- (difluoromethyl) -4-fluoroaniline instead of 3, 4-difluoroaniline.
Example 56:5- (2- ((1- (1H-1, 2, 3-triazol-4-yl) cyclopropyl) amino) -2-oxoacetyl) -6- chloro-N- (3- (difluoromethyl) -4-fluorophenyl) -2, 3-dihydro-1H-pyrrolizine-7-carboxamide (56)
The product was synthesized in analogy to example 53 using 3- (difluoromethyl) -4-fluoroaniline instead of 3, 4-difluoroaniline.
Table 1: data on characterization of the Compounds
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Example 57: quantitative HBV DNA assay
HepG2 cell line overexpressing HBV viral attachment receptor sodium-taurocholate cotransporter polypeptide (NTCP) DMEM growth medium in T175 flasks, free of sodium pyruvate (Life Technologies, rockville, MD) and supplemented with 10% fbs (Thermo Scientific, waltham, MD), 1% penicillin/streptomycin (Life Technologies, rockville, MD) and 2mM L-glutamine (Life Te) Technologies, rockville, md.) Dulbecco's modified Eagle's medium grown to confluence. Cells were infected with HBV AD38 virus particles (Texcell, frederick, USA) at 4000 genome equivalents per cell. After 4 days of virus infection, infected cells were harvested from the flask by trypsinization, washed twice with OptiMEM (Life Technologies, rockville, md.) and resuspended at a density of 0.25E6 cells/ml in DMEM containing 2% FBS and 1% DMSO. Infected cells were seeded onto 384-well collagen-coated plates (Greiner, austria) at a density of 20,000 cells/well containing serial dilutions of the disclosed compound or DMSO (0.5%) in a final volume of 80 μl. Assay plates were incubated for 5 days and QuantiGene was used TM 2.0 nucleic acid quantification kit (Affymetrix, santa Clara, calif.) antiviral activity of test compounds was determined by detecting the presence of HBV DNA in culture supernatants.
Culture supernatants were harvested and treated with lysis buffer containing proteinase K (Affymetrix, santa Clara, calif.). The supernatant was incubated with HBV viral DNA specific probes (Affymetrix, santa Clara, calif.) for 30 minutes at 55 ℃. The DNA was then denatured by adding 0.2M NaOH for 30 min at room temperature, followed by the addition of neutralization buffer (Affymetrix, santa Clara, calif.). The resulting lysed and neutralized supernatant was then added to a capture oligonucleotide coated QuantiGene TM 2.0 384 well plates and incubated overnight at 55 ℃. The HBV specific probe set consists of Capture Expenser oligonucleotide (CE) and blocking probe. After overnight incubation, the wells were incubated with pre-amplicon coupled with alkaline phosphatase, amplicon, and labeled probe sequentially for 1 hour, with a washing step between incubations. After the final wash step, alkaline phosphatase substrate (Luminol APS 5) was added and the resulting luminescence signal was read in EnVision Multilabel Plate Reader (Perkinelmer, santa Clara, calif.). EC50 values were calculated from a fit of the dose-response curve to a four-parameter equation. All EC50 values represent geometric mean of a minimum of four determinations. EC50 values for certain compounds of the present disclosure are reported in the following table.
Table 2: data on compound activity
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Example 58: kinetic solubility
10mM DMSO stock solutions of test compounds were serially diluted into 96-well "DMSO stock dilution plates". Then 2 μl was pipetted from DMSO stock dilution plate into "sample plate" and diluted with 198L of assay medium to yield final concentrations of test compounds in the range of 0.2 to 100 μΜ. The "sample plate" was run on BD Gentest Solubility Scanner.
In order to obtain adequate oral bioavailability in humans and preclinical species, significant water solubility is often required. Absorption from solid crystalline formulations is typically low when the compounds exhibit very low solubility.
Table 3: kinetic solubility data
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All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in this specification are incorporated herein by reference, in their entirety, to the extent not inconsistent with the description of the invention.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, the references provided herein are each incorporated by reference into the present application in their entirety to the same extent as if each reference was individually incorporated by reference. In the event of conflict between the present application and the references provided herein, the present application will control.

Claims (44)

1. A compound of formula II:
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is covered by 1 to 3R 1A Substituted C 1-6 Alkyl, substituted with 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or substituted with 1 to 3 heteroatoms selected from O, 1 to 3R 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1A Independently C 1-2 Haloalkyl or-C (O) NR X R Y ；
Each R 1B C independently halogen, optionally substituted with 1-3-OH 1-6 Alkyl, C 2-4 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl, provided that no more than 1R 1B Is a 5 to 8 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R 1C independently-C (O) NR X R Y Or optionally substituted with 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 12-membered heteroaryl, provided that no more than 1R 1C Is a 5 to 12 membered heteroaryl having 1 to 3 heteroatoms selected from N, O and S;
each R X independently-H or C 1-6 An alkyl group;
each of which isR Y independently-H or C 1-6 An alkyl group;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F independently-H, halogen, C 1-3 Alkyl, -OH or-OC 1-3 Alkyl, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 3 is-H, halogen or C 1-4 An alkyl group;
R 4 is covered by 1 to 5R 4A Substituted phenyl, or substituted with 1 to 4R 4B Substituted pyridinyl; and is also provided with
Each R 1D 、R 4A And R is 4B independently-CN, halogen, optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 Alkyl, -OC 1-4 Alkyl or C 1-4 A haloalkyl group.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R 3 Is halogen or methyl.
3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R 1 Is covered by 1 to 4R 1B Substituted C 3-5 Cycloalkyl, or substituted with 1 to 3 heteroatoms selected from O, 1 to 3R 1C Substituted 3-to 6-membered monocyclic heterocyclyl;
each R 1C independently-C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 8-membered heteroaryl;
each R 1D Independently is optionally-Si (C) 1-4 Alkyl group 3 Substituted C 1-4 An alkyl group;
each R 2A 、R 2B 、R 2C 、R 2D 、R 2E And R is 2F is-H, or R 2C Or R is 2D Can be combined with R 2A Or R is 2B Or with R 2E Or R is 2F Together forming a cyclopropyl group;
R 3 is methyl;
each R 4A independently-CN, halogen or C 1-4 A haloalkyl group; and is also provided with
Each R 4B Independently halogen or C 1-4 A haloalkyl group.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (III):
5. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIa):
6. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIb):
7. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (IV):
8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (V):
9. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (Va):
10. the compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (Vb):
11. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is covered by 1 to 3R 1B Substituted cyclopropyl or cyclobutyl.
12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
Each R 1B Independently halogen, optionally-OH-substituted C 1-3 Alkyl, C 2-4 Alkynyl, -C (O) NR X R Y Or optionally 1 to 3R having 1 to 3 heteroatoms selected from N, O and S 1D Substituted 5-to 6-membered heteroaryl; and
each R 1D Independently is optionally-Si (C) 1-2 Alkyl group 3 Substituted C 1-3 An alkyl group;
R X is C 1-2 An alkyl group; and is also provided with
R Y is-H.
13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 1B Is independently F, -CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein each of said triazolyl and thiadiazolyl is optionally substituted with Me or-CH 2 Si(Me) 3 And (3) substitution.
14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein 2R 1B Optionally F, and 1R 1B is-CH 2 OH、-C≡CH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl, wherein the triazolyl and thiadiazolyl are optionally substituted with Me or-CH 2 Si(Me) 3 And (3) substitution.
15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is cyclopropyl substituted by-C.ident.CH, triazolyl or thiadiazolyl, wherein said triazolyl is optionally substituted by Me or-CH 2 Si(Me) 3 And (3) substitution.
16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is composed of 2 fluorine atoms and 1-CH 2 OH、-C(O)NH 2 -C (O) NHMe, triazolyl or thiadiazolyl substituted cyclobutyl, wherein the triazolyl is optionally substituted with Me.
17. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 The method comprises the following steps:
18. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 The method comprises the following steps:
19. the compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is a group consisting of 1R having 1O heteroatom 1C Substituted 3-to 4-membered monocyclic heterocyclyl.
20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is covered by 1R 1C Substituted oxetanyl.
21. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is covered by 1R 1C Substituted oxetan-3-yl.
22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
Each R 1C independently-C (O) NR X R Y Or 1 to 3C having 1 to 3 heteroatoms selected from N, O and S 1-2 Alkyl substituted 5 to 6 membered heteroaryl;
R X is C 1-2 An alkyl group; and is also provided with
R Y is-H.
23. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 1C independently-C (O) NHMe or triazolyl.
24. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is oxetan-3-yl substituted by C (O) NHMe or triazolyl.
25. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is that
26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Is covered by 1 to 3R 4A Phenyl substituted by radicals, or by 1 to 2R 4B A group-substituted pyridyl group.
27. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Is optionally substituted with 1 to 2R 4A 4-F-phenyl substituted by radicals, or by 1 to 2R 4B Pyridin-4-yl substituted with a group.
28. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
Each R 4A The radicals being independently F, cl, CN or CHF 2 The method comprises the steps of carrying out a first treatment on the surface of the And
each R 4B The radicals being independently F, cl or CHF 2 。
29. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Is optionally substituted with 1 to 2R 4A Group-substituted 4-F-phenyl, wherein each R 4A Independently F, cl, CN or CHF 2 。
30. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Is from 1 to2R 4B Pyridin-4-yl substituted with a group, wherein each R 4B F, cl or CHF independently 2 。
31. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Is that
32. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 Is that
33. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 Is halogen.
34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R 3 Is Cl.
35. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 Is covered by 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently C 1-2 Haloalkyl or-C (O) NR X R Y 。
36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein R 1 Is covered by 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently C 1-2 Haloalkyl or-C (O) NH 2 。
37. According to claim 36 or a pharmaceutically acceptable salt thereof, wherein R 1 Is covered by 1 to 3R 1A Substituted C 1-6 Alkyl, wherein each R 1A Independently CF 3 or-C (O) NH 2 。
38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 Is that
39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein R 1 Is that
40. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is
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41. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is
42. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
43. a pharmaceutical composition comprising a compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
44. Use of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of HBV infection in a human.
HK62020022749.9A 2018-02-26 2019-02-25 Substituted pyrrolizine compounds as hbv replication inhibitors HK40032660B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US62/635,262 2018-02-26

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HK40032660A HK40032660A (en) 2021-03-26
HK40032660B true HK40032660B (en) 2023-09-15

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