CN118055934A - PARG inhibitory compounds - Google Patents

PARG inhibitory compounds Download PDF

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Publication number
CN118055934A
CN118055934A CN202280067788.0A CN202280067788A CN118055934A CN 118055934 A CN118055934 A CN 118055934A CN 202280067788 A CN202280067788 A CN 202280067788A CN 118055934 A CN118055934 A CN 118055934A
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alkyl
alkylene
group
haloalkyl
conh
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U·吕金
A·戈托普洛斯
田进
S·索蒂里奥
L·亚科维诺
A·弗罗伊登曼
O·凯罗勒
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Fox Therapy Inc
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Fox Therapy Inc
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Priority claimed from PCT/EP2022/077470 external-priority patent/WO2023057389A1/en
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Abstract

The present invention relates to compounds of formula (I) or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystalline form, pharmaceutically acceptable salt or prodrug thereof. The invention further relates to compounds of formula (I) of the invention for use in therapy. The compounds of the present invention are particularly useful as PARC inhibitors and in methods of treating proliferative disorders, preferably cancer.

Description

PARG inhibitory compounds
Technical Field
The present invention relates to compounds of formula (I):
Or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof. The invention further relates to compounds of formula (I) of the invention for use in therapy. The compounds of the present invention are particularly useful as PARG inhibitors and in methods of treating proliferative disorders, preferably cancer.
Background
Cancer is a leading cause of death worldwide. Despite improvements in progression free survival and overall survival of cancer patients over the past twenty years, millions of cancer patients still have little treatment options and poor survival outcomes (Jemal et al, j. Natl. Cancer Inst.,2017, volume 109, 1975).
DNA Replication Stress (DRS) is a major source of marker and genomic instability for cancer cells (a) Halazonetis et al, science,2008, volume 319, page 1352; b) Negrini et al, nat.rev.mol.cell biol.,2010, volume 11, page 220). In a broad sense, DRS refers to deregulation of DNA replication and cell cycle progression. DRS can be induced by endogenous or exogenous causes (such as oncogene activation and chemotherapy), respectively (Zeman and Cimprich, nat. Cell biol.,2013, volume 16, page 2). At the replication fork level, DRS causes replication fork stalls, replication body break-away and eventually crashes. Several DNA repair proteins are involved in stability, protection and restarting of replication forks under DRS conditions (a) Costantino et al, science,2014, volume 343, page 88; b) Scully et al, curr. Opin. Genet. Dev.,2021, volume 71, page 154).
Poly (ADP) ribosylation (PARylation) is a transient and reversible post-translational modification that occurs at the site of DNA damage and is defined by the poly (ADP-ribose) polymerase (PARP) protein family (Cohen and Chang, nat. Chem. Biol.,2018, volume 14, page 236). PARylation of the various DNA repair proteins cause their activation. Degradation of Poly (ADP) ribose chains is mediated primarily by poly (ADP-ribose) glycosylase (PARG) proteins. DNA damage dependence PARylation/dePARylation is a fast and dynamic process that needs to be well regulated, as an imbalance between the two processes can lead to DNA damage.
Human PARG encodes a 976 amino acid 111kDa protein. It contains an N-terminal regulatory domain, a catalytic domain and an ADP-ribose binding macrodomain. Five human PARG transcripts have been identified. Full length PARG is mostly nuclear; the smaller subtype is mainly localized to the cytoplasm. PARG acts primarily as an exohydrolase and it releases mono (ADP-ribose) primarily by hydrolyzing the alpha-O-glycosidic ribose-ribose bond in PAR. PARG may also act as an endo-hydrolase. PARG preferentially degrades long and straight PAR chains, while its activity on small and branched PAR chains is significantly reduced (O' Sullivan et al, nat. Commun.,2019, volume 10, page 1182).
Although PARG is the primary cellular PAR degrading enzyme, it cannot act on terminal protein-ribose bonds. Additional hydrolases such as terminal ADP-ribose proteolytic enzyme (TARG 1) and ADP-ribose hydrolase 3 (ARH 3) are also known to catalyze PAR degradation. TARG1 and ARH3 complete the reversion of PARylation by removal of the protein-bound mono (ADP-ribose) moiety (a) Fontana et al Elife,2017, doi:10.7554/eLife.28533; b) Rack et al, genes Dev 2020, volume 34, page 263). TARG1 is located in the nucleus and cytoplasm. ARH3 is found predominantly in the cytoplasm, but may also be found in mitochondria and nuclei (Rack et al, genes dev.,2020, volume 34, page 263).
Genomic aberrations targeting tumor suppressor genes or oncogenes often make cancer cells dependent on specific DNA repair pathways. For example, PARP inhibitors are well known to be particularly effective against tumors harboring mutations in the BRCA1 and BRCA2 genes (a) Bryant et al Nature,2005, volume 434, page 913; b) Farm et al, nature,2005, volume 434, page 917). Targeting synthetic lethal interactions such as the interaction between PARP and BRCA is an attractive new therapeutic approach for cancer treatment.
PARG is involved in DNA replication and various DNA repair mechanisms, including Single Strand Break (SSB) repair and replication fork restart. PARG inhibitors have shown a synthetic lethal phenotype in cells with high levels of DRS, caused by low expression of genes involved in DNA replication and/or replication fork stability (Pillay et al Cancer cell, 2019, volume 35, page 519). In addition, PARG inactivates, depletes or inhibits the sensitivity of cells to radiation and to DNA damaging agents such as alkylating agents (e.g., temozolomide and methyl mesylate) (a) Fujihara et al, curr.cancer Drug Targets,2009, volume 9, page 953; b) Gogola et al, CANCER CELL,2018, volume 33, page 1078; c) Houl et al, nat Commun.,2019, volume 10, page 5654).
In view of the therapeutic potential of PARG inhibitors in cancer treatment, there is an increasing need to develop highly potent and selective PARG inhibitors in addition to those already described in the following documents: (a) James et al ACS chem.biol.,2016, volume 11, page 3179; b) Waszkowycz et al, j.med.chem.,2018, volume 61, page 10767).
Certain compounds useful as PARG inhibitors are further disclosed in documents WO 2016/092326, WO 2016/097749 and WO 2021/055744.
Document US2019/233411 discloses certain Gcn2 inhibitors and their use.
Document WO 2009/050183 discloses certain imidazo [1,2-a ] pyridine derivatives, which are useful for the treatment of diseases mediated by ALK-5 and/or ALK-4 receptors.
Disclosure of Invention
One object of the present invention is to provide compounds which are inhibitors of cellular permeability of PARG. The technical problem of the present invention is solved by the embodiments described herein and characterized by the claims.
Thus, in a first embodiment, the present invention provides a compound of formula (I):
Or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof. It is to be understood that in this specification the term "compound of formula (I)" preferably also includes compounds of formulae (Ia) to (Ibo) unless otherwise indicated.
Another embodiment of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
In another embodiment, the invention relates to a compound of formula (I) of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition of the invention, for use in therapy.
The compounds of formula (I) are useful for the treatment of diseases or disorders in which PARG activity is implicated.
The compounds of formula (I) are useful in methods of treating proliferative disorders. In a preferred embodiment of the invention, the proliferative disorder is cancer, preferably human cancer.
Definition of the definition
The following definitions apply throughout the present specification and claims unless explicitly stated otherwise.
The term "hydrogen" is used herein to refer to protium, deuterium and/or tritium, preferably protium. Thus, the term "non-hydrogen atom" refers to any atom that is not hydrogen (i.e., is not protium, deuterium, or tritium).
The term "hydrocarbyl" refers to a group consisting of carbon and hydrogen atoms.
The term "cycloaliphatic" is used in conjunction with a cyclic group and means that the corresponding cyclic group is non-aromatic.
As used herein, the term "alkyl" refers to a monovalent saturated acyclic (i.e., acyclic) hydrocarbon group that can be straight or branched. Thus, an "alkyl" group does not contain any carbon-carbon double bonds or any carbon-carbon triple bonds. "C 1-5 alkyl" means an alkyl group having 1 to 5 carbon atoms. Preferred exemplary alkyl groups are methyl, ethyl, propyl (e.g., n-propyl or isopropyl) or butyl (e.g., n-butyl, isobutyl, sec-butyl or tert-butyl). Unless otherwise defined, the term "alkyl" preferably refers to a C 1-4 alkyl group, more preferably to a methyl or ethyl group, even more preferably to a methyl group.
As used herein, the term "alkenyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be linear or branched and that contains one or more (e.g., one or two) carbon-carbon double bonds, while it does not contain any carbon-carbon triple bonds. The term "C 2-5 alkenyl" denotes alkenyl groups having 2 to 5 carbon atoms. Preferred exemplary alkenyl groups are ethenyl, propenyl (e.g., prop-1-en-1-yl, prop-1-en-2-yl or prop-2-en-1-yl), butenyl, butadienyl (e.g., but-1, 3-dien-1-yl or but-1, 3-dien-2-yl), pentenyl or pentadienyl (e.g., isoprene). Unless otherwise defined, the term "alkenyl" preferably refers to a C 2-4 alkenyl group.
As used herein, the term "alkynyl" refers to a monovalent unsaturated acyclic hydrocarbon group that may be linear or branched and that contains one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. The term "C 2-5 alkynyl" denotes an alkynyl group having 2 to 5 carbon atoms. Preferred exemplary alkynyl groups are ethynyl, propynyl (e.g., propargyl) or butynyl. Unless otherwise defined, the term "alkynyl" preferably refers to a C 2-4 alkynyl group.
As used herein, the term "alkylene" refers to an alkanediyl, i.e. a divalent saturated acyclic hydrocarbon group, which may be linear or branched. "C 1-5 alkylene" means an alkylene group having 1 to 5 carbon atoms, and the term "C 0-3 alkylene" means that a covalent bond (corresponding to the option "C 0 alkylene") or C 1-3 alkylene is present. Preferred exemplary alkylene groups are methylene (-CH 2 -), ethylene (e.g., -CH 2-CH2 -or-CH (-CH 3) -), propylene (e.g., ,-CH2-CH2-CH2-、-CH(-CH2-CH3)-、-CH2-CH(-CH3)- or-CH (-CH 3)-CH2 -) or butylene (e.g., -CH 2-CH2-CH2-CH2 -). Unless otherwise defined, the term "alkylene" preferably refers to C 1-4 alkylene (including especially straight chain C 1-4 alkylene), more preferably methylene or ethylene, even more preferably methylene.
As used herein, the term "alkenylene" refers to an alkenediyl, i.e., a divalent unsaturated acyclic hydrocarbon group, which may be linear or branched and contains one or more (e.g., one or two) carbon-carbon double bonds, while it does not contain any carbon-carbon triple bonds. "C 2-5 alkenylene" means an alkenylene group having 2 to 5 carbon atoms. Unless otherwise defined, the term "alkenylene" preferably refers to a C 2-4 alkenylene group (including in particular straight-chain C 2-4 alkenylene groups).
As used herein, the term "alkynylene" refers to an alkynediyl, i.e., a divalent unsaturated acyclic hydrocarbon radical, which may be linear or branched and contains one or more (e.g., one or two) carbon-carbon triple bonds and optionally one or more (e.g., one or two) carbon-carbon double bonds. "C 2-5 alkynylene" means an alkynylene group having 2 to 5 carbon atoms. Unless otherwise defined, the term "alkynylene" preferably refers to C 2-4 alkynylene (including in particular straight-chain C 2-4 alkynylene).
As used herein, the term "carbocyclyl" refers to hydrocarbon ring groups, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings), wherein the ring groups may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. Unless otherwise defined, "carbocyclyl" preferably refers to aryl, cycloalkyl, or cycloalkenyl.
As used herein, the term "heterocyclyl" refers to a cyclic group, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings), wherein the cyclic group comprises one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) and/or one or more P ring atoms (if present) may optionally be oxidized, wherein one or more carbocyclic ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring contained in the ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. Unless otherwise defined, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
Preferably, the term "heterocyclyl" refers to a cyclic group, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings), wherein the cyclic group comprises one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the cyclic group may be saturated, partially unsaturated (i.e., unsaturated but not aromatic) or aromatic. For example, each heteroatom-containing ring contained in the ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. Unless otherwise defined, "heterocyclyl" preferably refers to heteroaryl, heterocycloalkyl, or heterocycloalkenyl.
As used herein, the term "aryl" refers to an aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged rings and/or fused ring systems containing at least one aromatic ring (e.g., ring systems consisting of two or three fused rings, wherein at least one of the fused rings is aromatic; or bridged ring systems consisting of two or three rings, wherein at least one of the bridged rings is aromatic). "aryl" may refer, for example, to phenyl, naphthyl, dihydronaphthyl (i.e., 1, 2-dihydronaphthyl), tetrahydronaphthyl (i.e., 1,2,3, 4-tetrahydronaphthyl), indanyl, indenyl (e.g., 1H-indenyl), anthracenyl, phenanthrenyl, 9H-fluorenyl, or azulenyl. Unless otherwise defined, "aryl" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenyl or naphthyl, and most preferably refers to phenyl.
As used herein, the term "arylene" refers to an aryl group as defined above but having two points of attachment, i.e., a divalent aromatic hydrocarbon ring group, including monocyclic aromatic rings as well as bridged and/or fused ring systems containing at least one aromatic ring (e.g., ring systems consisting of two or three fused rings wherein at least one of the fused rings is aromatic, or bridged ring systems consisting of two or three rings wherein at least one of the bridged rings is aromatic). "arylene" may refer, for example, to phenylene (e.g., benzene-1, 2-diyl, benzene-1, 3-diyl, or benzene-1, 4-diyl), naphthylene (e.g., naphthalene-1, 2-diyl, naphthalene-1, 3-diyl, naphthalene-1, 4-diyl, naphthalene-1, 5-diyl, naphthalene-1, 6-diyl, naphthalene-1, 7-diyl, naphthalene-2, 3-diyl, naphthalene-2, 5-diyl, naphthalene-2, 6-diyl, naphthalene-2, 7-diyl, or naphthalene-2, 8-diyl), 1, 2-dihydronaphthylene, 1,2,3, 4-tetrahydronaphthylene, indanyl, indenylene, anthracenylene, phenanthrylene, 9H-fluorenylene, or azulenylene. Unless otherwise defined, "arylene" preferably has 6 to 14 ring atoms, more preferably 6 to 10 ring atoms, even more preferably refers to phenylene or naphthylene, and most preferably refers to phenylene (particularly benzene-1, 4-diyl).
As used herein, the term "heteroaryl" refers to aromatic ring groups, including monocyclic aromatic rings as well as bridged and/or fused ring systems containing at least one aromatic ring (e.g., ring systems consisting of two or three fused rings, wherein at least one of the fused rings is aromatic; or bridged systems consisting of two or three rings, wherein at least one of the bridged rings is aromatic), wherein the aromatic ring groups comprise one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "heteroaryl" may refer, for example, to thienyl (i.e., phenylthio), benzo [ b ] thienyl, naphtho [2,3-b ] thienyl, thianthrenyl, furyl (i.e., furyl), benzofuranyl, isobenzofuranyl, chromanyl, benzopyranyl (e.g., 2H-1-benzopyranyl or 4H-1-benzopyranyl), isochromanyl (e.g., 1H-2-benzopyranyl), chromonyl, xanthenyl, phenoxathianyl, pyrrolyl (e.g., 1H-pyrrolyl), imidazolyl, pyrazolyl, pyridyl (i.e., pyridyl; for example, 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl, indolyl (e.g., 3H-indolyl), isoindolyl, indazolyl, indolizinyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, ryldiazinophenyl, phenanthrolinyl (e.g., [1,10] phenanthrolinyl, [1,7] phenanthrolinyl or [4,7] phenanthrolinyl), phenazinyl, thiazolyl, isothiazolyl, phenothiazinyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl (i.e., furazanyl) or1, 3, 4-oxadiazolyl), thiadiazolyl (e.g., 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl) or [1, 4-dioxazolyl (e.g., 1,4, 5-oxazinyl), pyrazolo [1,5-a ] pyrimidin-3-yl), 1, 2-benzisoxazol-3-yl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzo [ b ] thienyl (i.e., benzothienyl), triazolyl (e.g., 1H-1,2, 3-triazolyl, 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, or 4H-1,2, 4-triazolyl), benzotriazolyl, 1H-tetrazolyl, 2H-tetrazolyl, triazinyl (e.g., 1,2, 3-triazinyl, 1,2, 4-triazinyl, or1, 3, 5-triazinyl), furo [2,3-c ] pyridyl, dihydrofuropyridinyl (e.g., 2, 3-dihydrofuro [2,3-c ] pyridyl, or1, 3-dihydrofuro [3,4-c ] pyridyl), imidazo [ e.g., 1H-1,2, 4-triazolyl, or 4H-1,2, 4-triazolyl), benzotriazolyl (e.g., 1,2,3, 4-triazolyl), imidazo [1, 3-c ] pyridyl, or1, 3-dioxa-yl), imidazo [1, 3, 5-triazinyl, or1, 3-triazinyl (e.g., 1,3, 5-triazinyl), furano [2,3-c ] pyridyl, or1, 3-naphthyridinyl. Unless otherwise defined, the term "heteroaryl" preferably refers to a 5-to 14-membered (more preferably, 5-to 10-membered) monocyclic or fused ring system containing one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroaryl" refers to a 5-or 6-membered monocyclic ring comprising one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
As used herein, the term "heteroaryl" refers to a heteroaryl group as defined above but having two points of attachment, i.e., a divalent aromatic ring group, including monocyclic aromatic rings and bridged and/or fused ring systems containing at least one aromatic ring (e.g., ring systems consisting of two or three fused rings, wherein at least one of the fused rings is aromatic, or bridged ring systems consisting of two or three rings, wherein at least one of the bridged rings is aromatic), wherein the aromatic ring group comprises one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more of the carbocyclic ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the aromatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "heteroarylene" may, for example, refer to a thienyl (i.e., a thiophenylene; for example, thiophene-2, 3-diyl, thiophene-2, 4-diyl, or thiophene-2, 5-diyl), benzo [ b ] thiophenylene, naphtho [2,3-b ] thiophenylene, thianthrenylene, furanylene (i.e., furanylene; for example furan-2, 3-diyl, furan-2, 4-diyl or furan-2, 5-diyl), benzofuranylene, isobenzofuranylene, chromanylene, benzopyranylene, isobenzopyranylene, chromonylene, xanthenylene, phenoxathioylene, pyrrolylene, imidazolylene, pyrazolylene, pyridylene (i.e., pyridinylene), pyrazinylene, pyrimidinylene, pyridazinylene, indolylene, isoindolylene, indazolyl, indolylene, purinylene, quinolinylene, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, cinnolinyl, pteridinyl, carbazolylene, β -carbolinylene, phenanthridinylene, acridinylene, rylenediazinophenyl, phenanthroline, phenazinyl, thiazolylene (e.g., thiazole-2, 4-diyl, thiazole-3, 5-diyl or thiazole-4, 5-diyl), isothiazolylene (e.g., isothiazole-3, 4-diyl, isothiazole-3, 5-diyl or isothiazole-4, 5-diyl), phenothiazinyl, oxazolylene (e.g., oxazole-2, 4-diyl, oxazole-2, 5-diyl or oxazol-4, 5-diyl), isoxazolylene (e.g., isoxazole-3, 4-diyl, isoxazole-3, 5-diyl, or isoxazole-4, 5-diyl), oxadiazolylene (e.g., 1,2, 4-oxadiazole-3, 5-diyl, 1,2, 5-oxadiazole-3, 4-diyl, or 1,3, 4-oxadiazole-2, 5-diyl), thiadiazolylene (e.g., 1,2, 4-thiadiazole-3, 5-diyl, 1,2, 5-thiadiazole-3, 4-diyl, or 1,3, 4-thiadiazole-2, 5-diyl), phenoxazinylene, pyrazolo [1,5-a ] pyrimidinylene, 1, 2-benzisoxazole, benzothiazolylene, benzothiadiazolylene, benzoxazolylene, benzisoxazinyl, benzisoxazolylene, benzothiadiazole, benzothiophene (i.e), benzothienyl), triazolylene (e.g., 1H-1,2, 3-triazolylene, 2H-1,2, 3-triazolylene, 1H-1,2, 4-triazolylene or 4H-1,2, 4-triazolylene), benzotriazolylene, 1H-tetrazolylene, 2H-tetrazolylene, triazinylene (e.g., 1,2, 3-triazinylene, 1,2, 4-triazinylene or 1,3, 5-triazinylene), furo [2,3-c ] pyridylene, dihydrofuropyriylene (e.g., 2, 3-dihydrofuro [2,3-c ] pyridylene or 1, 3-dihydrofuro [3,4-c ] pyridylene), imidazopyridylene (e.g., imidazo [1,2-a ] pyridylene or imidazo [3,2-a ] pyridylene), quinazolinylene, thienopyrimidinylene, tetrahydrothienopyrimidinylene (e.g., 4,5,6, 7-tetrahydrothieno [3,2-c ] pyridylene), dibenzofuranylene, 1, 3-benzodioxolylene, benzodioxanylene (e.g., 1, 3-benzodioxanylene or 1, 4-benzodioxanylene), or coumarinylene. Unless otherwise defined, the term "heteroarylene" preferably refers to a divalent 5-to 14-membered (more preferably, 5-to 10-membered) monocyclic or fused ring system containing one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; even more preferably, "heteroarylene" refers to a divalent 5-or 6-membered monocyclic ring comprising one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized. "heteroarylene" includes any of the particular heteroarylene groups described herein, may be attached through two carbon ring atoms, particularly through those two carbon ring atoms that have the greatest distance from each other (in terms of the number of ring atoms separating them by the shortest possible attachment) within one single ring or within the entire ring system of the corresponding heteroarylene group.
As used herein, the term "cycloalkyl" refers to saturated hydrocarbon ring groups, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; e.g., fused ring systems consisting of two or three fused rings). "cycloalkyl" may refer to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, decalinyl (i.e., decalinyl), or adamantyl. Unless otherwise defined, "cycloalkyl" preferably refers to C 3-11 cycloalkyl, and more preferably to C 3-7 cycloalkyl. Particularly preferred "cycloalkyl" is a monocyclic saturated hydrocarbon ring (e.g., cyclopropyl or cyclohexyl) having 3 to 7 ring members.
As used herein, the term "cycloalkylene" refers to a cycloalkyl group as defined above but having two points of attachment, i.e., a divalent saturated hydrocarbon ring group, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; e.g., fused ring systems consisting of two or three fused rings). "cycloalkylene" may refer, for example, to cyclopropylene (e.g., cyclopropane-1, 1-diyl or cyclopropane-1, 2-diyl), cyclobutylene (e.g., cyclobutane-1, 1-diyl, cyclobutane-1, 2-diyl or cyclobutane-1, 3-diyl), cyclopentylene (e.g., cyclopentane-1, 1-diyl, cyclopentane-1, 2-diyl or cyclopentane-1, 3-diyl), cyclohexylene (e.g., cyclohexane-1, 1-diyl, cyclohexane-1, 2-diyl, cyclohexane-1, 3-diyl or cyclohexane-1, 4-diyl), cycloheptylene, decalin (i.e., decalin) or adamantylene. Unless otherwise defined, "cycloalkylene" preferably refers to C 3-11 cycloalkylene, and more preferably to C 3-7 cycloalkylene. Particularly preferred "cycloalkylene" is a divalent monocyclic saturated hydrocarbon ring (e.g., cyclopropylene or cyclohexylene) having 3 to 7 ring members.
As used herein, the term "heterocycloalkyl" refers to saturated ring groups, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; for example, fused ring systems consisting of two or three fused rings), wherein the ring groups contain one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) and/or one or more P ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "Heterocyclyl" may refer, for example, to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepinyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxazepinyl, thiiranyl, thietanyl, tetrahydrothienyl (i.e., thiamyl), 1, 3-dithianyl, thialkyl, 1-dioxathiapanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl. Unless otherwise defined, "heterocycloalkyl" preferably refers to a 3-to 11-membered saturated ring group that is a single ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl" refers to a 5-or 7-membered saturated monocyclic group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
Preferably, the term "heterocycloalkyl" refers to saturated ring groups, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; for example, fused ring systems consisting of two or three fused rings), wherein the ring groups contain one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "Heterocyclyl" may refer, for example, to aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, azepanyl, diazepinyl (e.g., 1, 4-diazepinyl), oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, morpholinyl (e.g., morpholin-4-yl), thiomorpholinyl (e.g., thiomorpholin-4-yl), oxazepanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxazepinyl, thiiranyl, thietanyl, tetrahydrothienyl (i.e., thiamyl), 1, 3-dithianyl, thialkyl, 1-dioxathiapanyl, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo [2.2.1] hept-5-yl. Unless otherwise defined, "heterocycloalkyl" preferably refers to a 3-to 11-membered saturated ring group that is a single ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkyl" refers to a 5-or 7-membered saturated monocyclic group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
As used herein, the term "heterocycloalkylene" refers to a heterocycloalkyl group as defined above but having two points of attachment, i.e., a divalent saturated ring group, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; e.g., fused ring systems consisting of two or three fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) and/or one or more P ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "heterocycloalkylene" may refer, for example, to an aziridinyl, azetidinyl, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidylene, piperazinylene, azepanylene, diazepanyl (e.g., 1, 4-diazepanyl), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxaazepanylene, oxiranylene, oxetanyl, tetrahydrofuranylene, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxacycloheptylene, thiocyclopropyl, thiocyclobutylene, tetrahydrothiophenylene (i.e., thiocyclopentyl), 1, 3-dithiolanyl, thioanyl, 1-dioxathiaalkyl, thiocycloheptylene, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-bicyclo [ 2.2-5 ] heptylene. Unless otherwise defined, "heterocycloalkylene" preferably refers to a divalent 3-to 11-membered saturated ring group that is a single ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkylene" refers to a divalent 5-or 7-membered saturated monocyclic group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
Preferably, the term "heterocycloalkylene" refers to a heterocycloalkyl group as defined above but having two points of attachment, i.e., a divalent saturated ring group, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; e.g., fused ring systems consisting of two or three fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, and further wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group). For example, each heteroatom-containing ring contained in the saturated ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "heterocycloalkylene" may refer, for example, to an aziridinyl, azetidinyl, pyrrolidinylene, imidazolidinylene, pyrazolidinylene, piperidylene, piperazinylene, azepanylene, diazepanyl (e.g., 1, 4-diazepanyl), oxazolidinylene, isoxazolidinylene, thiazolidinylene, isothiazolidinylene, morpholinylene, thiomorpholinylene, oxaazepanylene, oxiranylene, oxetanyl, tetrahydrofuranylene, 1, 3-dioxolanyl, tetrahydropyranyl, 1, 4-dioxanyl, oxacycloheptylene, thiocyclopropyl, thiocyclobutylene, tetrahydrothiophenylene (i.e., thiocyclopentyl), 1, 3-dithiolanyl, thioanyl, 1-dioxathiaalkyl, thiocycloheptylene, decahydroquinolinyl, decahydroisoquinolinyl, or 2-oxa-5-aza-bicyclo [ 2.2-5 ] heptenyl. Unless otherwise defined, "heterocycloalkylene" preferably refers to a divalent 3-to 11-membered saturated ring group that is a single ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized; more preferably, "heterocycloalkylene" refers to a divalent 5-or 7-membered saturated monocyclic group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, and wherein one or more carbon ring atoms are optionally oxidized.
As used herein, the term "N-heterocycloalkyl" refers to a heterocycloalkyl group as defined above, wherein said heterocycloalkyl group includes at least one nitrogen atom that serves as a point of attachment for said heterocycloalkyl group.
As used herein, the term "cycloalkenyl" refers to unsaturated cycloaliphatic (non-aromatic) hydrocarbon ring groups, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; e.g., fused ring systems consisting of two or three fused rings), wherein the hydrocarbon ring groups comprise one or more (e.g., one or two) carbon-carbon double bonds and do not comprise any carbon-carbon triple bonds. "cycloalkenyl" may refer to, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl. Unless otherwise defined, "cycloalkenyl" preferably refers to C 3-11 cycloalkenyl, and more preferably to C 3-7 cycloalkenyl. Particularly preferred "cycloalkenyl" is a monocyclic unsaturated alicyclic hydrocarbon ring having 3 to 7 ring members and containing one or more (e.g., one or two; preferably one) carbon-carbon double bonds.
As used herein, the term "cycloalkenyl" refers to cycloalkenyl groups as defined above but having two points of attachment, i.e., divalent unsaturated cycloaliphatic (non-aromatic) hydrocarbon ring groups, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may be composed of, for example, two or three rings; e.g., fused ring systems composed of two or three fused rings), wherein the hydrocarbon ring groups contain one or more (e.g., one or two) carbon-carbon double bonds and do not contain any carbon-carbon triple bonds.
As used herein, the term "heterocycloalkenyl" refers to an unsaturated cycloaliphatic (non-aromatic) ring radical, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; for example, fused ring systems consisting of two or three fused rings), wherein the ring radical contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) and/or one or more P ring atoms (if present) may optionally be oxidized, wherein one or more of the carbocyclic ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the ring radical contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated cycloaliphatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "heterocycloalkenyl" may, for example, refer to an imidazolinyl group (e.g., 2-imidazolinyl (i.e., 4, 5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), a tetrahydropyridinyl group (e.g., 1,2,3, 6-tetrahydropyridinyl), a dihydropyridinyl group (e.g., 1, 2-dihydropyridinyl, or 2, 3-dihydropyridinyl), a pyranyl group (e.g., 2H-pyranyl or 4H-pyranyl), a thiopyranyl group (e.g., 2H-thiopyranyl or 4H-thiopyranyl), a dihydropyranyl, a dihydrofuranyl, a dihydropyrazolyl, a dihydropyrazinyl, a dihydroisoindolyl, an octahydroquinolinyl group (e.g., 1,2,3, 4a,5,6, 7-octahydroquinolinyl), or an octahydroisoquinolinyl group (e.g., 1,2,3,4,5,6,7, 8-octahydroisoquinolinyl group). Unless otherwise defined, "heterocycloalkenyl" preferably refers to a 3-to 11-membered unsaturated cycloaliphatic ring group that is a single ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms; more preferably, "heterocycloalkenyl" refers to a 5-to 7-membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms.
Preferably, the term "heterocycloalkenyl" refers to an unsaturated cycloaliphatic (non-aromatic) ring radical, including monocyclic as well as bridged, spiro, and/or fused ring systems (which may consist of, for example, two or three rings; for example, fused ring systems consisting of two or three fused rings), wherein the ring radical contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the ring radical contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated cycloaliphatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring. "heterocycloalkenyl" may, for example, refer to an imidazolinyl group (e.g., 2-imidazolinyl (i.e., 4, 5-dihydro-1H-imidazolyl), 3-imidazolinyl, or 4-imidazolinyl), a tetrahydropyridinyl group (e.g., 1,2,3, 6-tetrahydropyridinyl), a dihydropyridinyl group (e.g., 1, 2-dihydropyridinyl, or2, 3-dihydropyridinyl), a pyranyl group (e.g., 2H-pyranyl or 4H-pyranyl), a thiopyranyl group (e.g., 2H-thiopyranyl or 4H-thiopyranyl), a dihydropyranyl, a dihydrofuranyl, a dihydropyrazolyl, a dihydropyrazinyl, a dihydroisoindolyl, an octahydroquinolinyl group (e.g., 1,2,3, 4a,5,6, 7-octahydroquinolinyl), or an octahydroisoquinolinyl group (e.g., 1,2,3,4,5,6,7, 8-octahydroisoquinolinyl group). Unless otherwise defined, "heterocycloalkenyl" preferably refers to a 3-to 11-membered unsaturated cycloaliphatic ring group that is a single ring or a fused ring system (e.g., a fused ring system consisting of two fused rings), wherein the ring group contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms; more preferably, "heterocycloalkenyl" refers to a 5-to 7-membered monocyclic unsaturated non-aromatic ring group containing one or more (e.g., one, two, or three) ring heteroatoms independently selected from O, S and N, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) are optionally oxidized, wherein one or more carbon ring atoms are optionally oxidized, and wherein the ring group contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms.
As used herein, the term "heterocycloalkenylene" refers to a heterocycloalkenyl group as defined above but having two points of attachment, i.e., a divalent unsaturated cycloaliphatic (non-aromatic) ring radical, including monocyclic as well as bridged rings, spiro and/or fused ring systems (which may consist of, for example, two or three rings; for example, fused ring systems consisting of two or three fused rings), wherein the ring radical contains one or more (e.g., one, two, three or four) ring heteroatoms independently selected from O, S, N, P and Si, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) and/or one or more P ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the ring radical contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated cycloaliphatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring.
Preferably, the term "heterocycloalkenylene" refers to a heterocycloalkenyl group as defined above but having two points of attachment, i.e., a divalent unsaturated cycloaliphatic (non-aromatic) ring radical, including monocyclic as well as bridged rings, spiro rings, and/or fused ring systems (which may consist of, for example, two or three rings; for example, fused ring systems consisting of two or three fused rings), wherein the ring radical contains one or more (e.g., one, two, three, or four) ring heteroatoms independently selected from O, S and N, and the remaining ring atoms are carbon atoms, wherein one or more S ring atoms (if present) and/or one or more N ring atoms (if present) may optionally be oxidized, wherein one or more carbon ring atoms may optionally be oxidized (i.e., to form an oxo group), and further wherein the ring radical contains at least one double bond between adjacent ring atoms and does not contain any triple bond between adjacent ring atoms. For example, each heteroatom-containing ring contained in the unsaturated cycloaliphatic ring group may contain one or two O atoms and/or one or two S atoms (which may optionally be oxidized) and/or one, two, three, or four N atoms (which may optionally be oxidized), provided that the total number of heteroatoms in the corresponding heteroatom-containing ring is 1 to 4 and that at least one carbon ring atom (which may optionally be oxidized) is present in the corresponding heteroatom-containing ring.
As used herein, the term "halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), or iodine (-I). As will be appreciated by those skilled in the art, the terms "halogen" and "halo" may be used interchangeably.
As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (preferably 1 to 6, more preferably 1 to 3) halogen atoms independently selected from fluorine, chlorine, bromine and iodine, and preferably all fluorine atoms. It will be appreciated that the maximum number of halogen atoms is limited by the number of available attachment sites and therefore depends on the number of carbon atoms contained in the alkyl portion of the haloalkyl group. "haloalkyl" may for example refer to -CF3、-CHF2、-CH2F、-CF2-CH3、-CH2-CF3、-CH2-CHF2、-CH2-CF2-CH3-CH2-CF2-CF3 or-CH (CF 3)2. A particularly preferred "haloalkyl" group is-CF 3.
The terms "bond" and "covalent bond" are used synonymously herein unless explicitly indicated otherwise or contradicted by context.
As used herein, the terms "optional," "optionally," and "may" mean that the indicated feature may or may not be present. Whenever the terms "optional", "optionally" or "may" are used, the invention especially relates to both possibilities, i.e. the presence or absence of corresponding features. For example, the expression "X is optionally substituted with Y" (or "X may be substituted with Y") means that X is substituted with Y or unsubstituted. Likewise, if the components of the composition are indicated as "optional", the invention particularly relates to both possibilities, i.e. the presence of the corresponding component in the composition (comprised in the composition) or the absence of the corresponding component.
In this specification, various groups are referred to as "optionally substituted". Typically, these groups may bear one or more substituents, for example one, two, three or four substituents. It will be appreciated that the maximum number of substituents is limited by the number of available attachment sites on the substituted moiety. Unless otherwise defined, an "optionally substituted" group referred to in this specification preferably carries no more than two substituents, and in particular may carry only one substituent. Furthermore, unless otherwise defined, preferably no optional substituents are present, i.e. the corresponding groups are unsubstituted.
Those skilled in the art will appreciate that substituents contained in compounds of the invention may be attached to the remainder of the corresponding compound via a plurality of different positions of the corresponding particular substituent. Preferred attachment positions for each particular substituent are as shown in the examples unless otherwise defined.
As used herein, the terms "a," "an," and "the" are used interchangeably with "one or more" and "at least one," unless otherwise specifically indicated or contradicted by context. Thus, for example, a composition comprising "a" compound of formula (I) may be interpreted to mean a composition comprising "one or more" compounds of formula (I).
It should be understood that wherever a numerical range is provided/disclosed herein, all values and subranges encompassed by the corresponding numerical range are meant to be encompassed within the scope of the present invention. Accordingly, the present invention specifically and individually relates to each value falling within the numerical ranges disclosed herein, as well as each subrange encompassed by the numerical ranges disclosed herein.
As used herein, the term "about" preferably refers to ± 10% of the indicated value, more preferably to ± 5% of the indicated value, in particular to the indicated precise value. If the term "about" is used in conjunction with the endpoints of a range, it preferably refers to the range from-10% of the lower endpoint to the +10% of the upper endpoint, more preferably refers to the range from-5% of the lower endpoint to +5% of the upper endpoint, and even more preferably refers to the range defined by the precise values of the lower endpoint and the upper endpoint.
As used herein, the term "comprising" (or "including" or "containing") has the meaning of "containing, especially" unless explicitly indicated otherwise or contradicted by context, i.e. "contains among other optional elements. In addition, the term also includes the narrower meaning "consisting essentially of. For example, the term "a includes B and C" having the meaning of "a contains, especially B and C", wherein a may contain additional optional elements (e.g., it will also encompass "a contains B, C and D"), but the term also includes the meaning of "a consists essentially of B and C" and the meaning of "a consists of B and C" (i.e., a contains no other components in addition to B and C).
Detailed Description
The present invention is described in detail below. It is to be understood that the present invention is directed in particular to each combination of features and embodiments described herein, including any combination of general and/or preferred features/embodiments.
In a first embodiment, the present invention relates to compounds of formula (I):
or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof.
R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl, (C 1-2) haloalkyl, - (C 1-2 alkylene) -OH and- (C 1-2 alkylene) -O- (C 1-2 alkyl), preferably selected from chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl, (C 1-2) haloalkyl, - (C 1-2 alkylene) -OH and- (C 1-2 alkylene) -O- (C 1-2 alkyl). Preferably, R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl, preferably from chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl. More preferably, R 1 is selected from cyano, (C 1-2) alkyl and (C 1-2) haloalkyl. Preferably, the (C 1-2) alkyl group as discussed herein is methyl. Preferably, the (C 1-2) haloalkyl group as discussed herein is a fluoromethyl group. Thus, preferably R 1 is selected from cyano, methyl and fluoromethyl. More preferably, R 1 is cyano. However, in another preferred embodiment, R 1 is methyl, and in a particularly preferred further embodiment, wherein R 1 is methyl and R 1 is CD 3. In yet another preferred embodiment, R 1 is fluoromethyl.
R 2 and R 3 are each independently (C 1-2) alkyl or (C 1-2) haloalkyl, preferably methyl, or R 2 and R 3 together with the carbon atoms to which they are attached form cyclopropyl. Preferably, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl.
W is selected from -NHS(O)y-、-S(O)yNH-、-NHS(O)(NH)-、-NHS(O)(NCH3)-、-S(O)(NH)-NH-、-S(O)(NCH3)-NH-, wherein y is 1 or 2. Preferably y is 2. Thus, in a preferred embodiment, W is selected from the group consisting of-NHS (O) 2-、-S(O)2 NH-, -NHS (O) (NH) -and-S (O) (NH) -NH-. More preferably, W is selected from the group consisting of-NHS (O) 2 -and-S (O) 2 NH-, even more preferably W is-NHS (O) 2 -. Preferably, as understood herein, the left side of W as defined herein is attached to a carbon atom bearing R 1、R2 and R 3, and the right side of W as defined herein is attached to a ring system of formula (I). In a preferred embodiment, W is-NHS (O) 2 -or-NHS (O) (NCH 3) -. In a preferred embodiment, W is-NHS (O) (NCH 3) -.
X 1 and X 3 are independently selected from N, CH, C (C 1-2 alkyl), CCl and CF, preferably are independently selected from N, CH and CF. Preferably, X 1 is CF or CH and X 3 is CH, more preferably, X 1 and X 3 are each CH. However, in another preferred embodiment, X 1 is CF and X 3 is CH.
X 2 is N or C-Y C2-RC2, preferably X 2 is C-Y C2-RC2.
Y C2 is selected from the group consisting of covalent bond, C 1-5 alkylene, C 2-5 alkynylene, cycloalkylene, cycloalkenylene, heterocycloalkylene and heterocycloalkenylene, wherein each of said alkylene, said alkenylene and said alkynylene is optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, SH, S (C 1-5 alkyl), -S (C 1-5 haloalkyl), NH 1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), - (N-heterocycloalkyl), -CO (C 1-5 alkyl), CONH 2 alkyl), CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C 1-5 alkyl), N (C 1-5 alkyl) -CO- (C 1-5 alkyl), NHC 1-5 alkyl), CONH 2 alkyl (C 1-5 alkyl), preferably selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from the group consisting of-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-and SO 2 -, and further wherein said cycloalkylene, said heterocycloalkylene and said heterocycloalkylene are each optionally substituted by one or more groups independently selected from the group consisting of halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 15 alkyl), -S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl), N (C 1-5 haloalkyl), N (C4357 alkyl), -N (C 1-5 haloalkyl), N- (C3443 haloalkyl), O (C 1-5 alkyl) 3 haloalkyl), N- (C3443 haloalkyl) 3 alkyl NHCO- (C alkyl), N (C alkyl) -CO- (C alkyl), NHCONH alkyl, NHCON (C alkyl), N (C alkyl) CONH- (C alkyl) and N (C alkyl) CON (C alkyl), - (C alkylene) -CN, - (C alkylene) OH, - (C alkylene) O (C alkyl), - (C alkylene) -O (C haloalkyl), - (C alkylene) SH, - (C alkylene) S (C alkyl), - (C alkylene) -S (C haloalkyl), - (C alkylene) NH (C alkyl), - (C alkylene) -NH (C haloalkyl), - (C alkylene) N (C alkyl), - (C alkylene) N (C alkyl) (C haloalkyl), - (C alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH 2、-(C1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2、-(C1-5 alkylene) NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) N- (C 1-5 alkyl) and- (C 1-5 alkylene) N (C 1-5 alkyl) CONH (C 1-5 alkyl), preferably selected from the group consisting of C 1-5 alkyl, and 393 alkyl (393, 3O 2 alkyl, 3C 393 alkyl, 3, and 3 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl). Preferably, Y c2 is selected from the group consisting of covalent bond, C 1-5 alkylene, C 2-5 alkenylene, C 2-5 alkynylene, cycloalkylene and heterocycloalkylene, wherein each of said alkylene, said alkenylene and said alkynylene is optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, SH, S (C 1-5 alkyl), -S (C 1-5 haloalkyl), NH 1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), - (N-heterocycloalkyl), -CO (C 1-5 alkyl), CONH 2 alkyl), CON (C 1-5 alkyl), -CO- (N- 1-5 heterocycloalkyl), NHCO- (C 1-5 alkyl), N (C 1-5 alkyl) -CO- (C 1-5 alkyl), nhalkyl), nh3932 alkyl (C 1-5 alkyl) preferably selected from the group consisting of C 1-5 alkyl, N (C 1-5 alkyl) and CONH 1-5 alkyl CN, OH, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units contained in the alkylene, the alkenylene or the alkynylene are each optionally replaced with a group independently selected from-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-and SO 2 -, and further wherein the cycloalkylene and the heterocycloalkylene are each optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 15 alkyl), -S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl), -N- (C 1-5 alkyl), -C3775 alkyl (C37 alkyl), C37 alkyl N (C alkyl) -CO- (C alkyl), NHCONH alkyl), NHCON (C alkyl), N (C alkyl) CONH- (C alkyl) and N (C alkyl) CON (C alkyl), - (C alkylene) -CN, - (C alkylene) OH, - (C alkylene) O (C alkyl), - (C alkylene) -O (C haloalkyl), - (C alkylene) SH, - (C alkylene) S (C alkyl), - (C alkylene) -S (C haloalkyl), - (C alkylene) NH (C alkyl), - (C alkylene) -NH (C haloalkyl), - (C alkylene) N (C alkyl), - (C alkylene) N (C haloalkyl), - (C alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH 2、-(C1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2、-(C1-5 alkylene) NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) N- (C 1-5 alkyl) and- (C 1-5 alkylene) N (C 1-5 alkyl) CONH (C 1-5 alkyl), preferably selected from the group consisting of C 1-5 alkyl, and 393 alkyl (393, 3O 2 alkyl, 3C 393 alkyl, 3, and 3 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl). More preferably Y C2 is selected from the group consisting of a covalent bond, a C 1-5 alkylene, a C 2-5 alkenylene, and a C 2-5 alkynylene, wherein each of said alkylene, said alkenylene, and said alkynylene is optionally substituted with one or more groups, the one or more groups are independently selected from halogen, CN, OH, O (C 2-5 alkyl), -O (C 2-5 haloalkyl), C 2-5 haloalkyl, SH, S (C 2-5 alkyl), -S (C 2-5 haloalkyl), NH 2-5 alkyl), -NH (C 2-5 haloalkyl), N (C 2-5 alkyl), N (C 2-5 haloalkyl) (C 2-5 alkyl), -N-heterocycloalkyl), -CO (C 2-5 alkyl), CONH 2-5 alkyl), CON (C 2-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C 2-5 alkyl), N (C 2-5 alkyl) -CO- (C 2-5 alkyl), NHCONH 2-5 alkyl), NHCON (C 2-5 alkyl), N (C 2-5 alkyl) CONH- (C 2-5 alkyl) and N (C 2-5 alkyl) CON (C 2-5 alkyl), preferably selected from halogen, O (C 2-5 alkyl) preferably selected from halogen, O (C 2-5 alkyl) and N 2-5 alkyl (C 2-5 alkyl) SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units contained in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-, and SO 2 -. More preferably, Y c2 is selected from the group consisting of covalent bonds, - (C 1-3 alkylene) -, -CO- (C 1-3 alkylene) -, (C 1-3 alkylene) -CO-, -CONH- (C 1-3 alkylene) -, - (C 1-3 alkylene) -CONH-, -NHCO- (C 1-3 alkylene) -, - (C 1-3 alkylene) -NHCO-, -NH- (C 1-3 alkylene) -, - (C 1-3 alkylene) -NH-, -N (C 1-5 alkyl) -, -O- (C 1-3 alkylene) -, - (C 1-3 alkylene) -O-, SO 2-(C1-3 alkylene) -, - (C 1-3 alkylene) SO 2 -, -CONH-, -NHCO-, -NH-, -O-, -CO-, and SO 2-.C1-3 alkylene, herein preferably being a-CH 2 -group.
R C2 is selected from the group consisting of hydrogen, halogen, -OH, -NH 2、-SH、-CN、C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. Preferably, R c2 is selected from hydrogen, halogen, -OH, -NH 2、-SH、-CN、C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. More preferably, R c2 is selected from hydrogen, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R c2 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R c2 is selected from heterocycloalkyl, aryl, and heteroaryl. The alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl), -CO- (C 1-5 alkyl), -nhcon3932 alkyl), -nh3932 alkyl), -N (C 1-5 alkyl), -con2 alkyl) (C 1-5 alkyl), -con2 alkyl) -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)) and-P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl) -, -O (C 1-5 haloalkyl) -, C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -CO (1-5 alkyl), -CONH 2 alkyl) and-C 1-5 alkyl (C 1-5 alkyl). The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl), -N-heterocycloalkyl), -CO (C8 alkyl), -CO (C 1-5 alkyl), -COO (C 2、-CONH(C1-5 alkyl), -COO (C3275 alkyl) -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO-C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 2、-N(C1-5 alkyl), -N (C 2、-N(C1-5 alkyl) CON (C 2、-N(C1-5 alkyl), -OCONH 2、-N(C1-5 alkyl), -OCON (C 2、-N(C1-5 alkyl), -NHCOO (C 2、-N(C1-5 alkyl), -N (C 2、-N(C1-5 alkyl) COO- (C 2、-N(C1-5 alkyl), -P (O) (O (C 2、-N(C1-5 alkyl)), -P (O) (C 2、-N(C1-5 alkyl)), -P (O (C 2、-N(C1-5 alkyl), -C 2、-N(C1-5 alkyl, - (C 2、-N(C1-5 alkylene), -C 2、-N(C1-5 alkylene, - (C 2、-N(C1-5 alkyl), -C 2、-N(C1-5 alkylene) - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)), (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (O) (NH) (C 1-5 alkyl), S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), SH, S (C 1-5 alkyl), S (O) (C 1-5 alkyl), S (O) and S (C 1-5 alkyl) are described herein as examples, -n=s (O) (C alkyl), -S (C haloalkyl), NH alkyl), -NH (C haloalkyl), N (C alkyl), N (C haloalkyl) (C alkyl), -N (heterocycloalkyl), -CO (C alkyl), COO (C alkyl), CONH alkyl), CON (C alkyl), -CO- (N-heterocycloalkyl), NHCO- (C alkyl) N (C alkyl) -CO- (C alkyl), NHCONH alkyl), NHCON (C alkyl), N (C alkyl) CONH- (C alkyl), N (C alkyl) CON (C alkyl), -OCONH alkyl), -OCON (C alkyl), NHCOO (C alkyl), N (C alkyl) COO- (C alkyl), -P (O) (C alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 15 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, -C 1-5 alkylene) OH, -C 1-5 alkylene) O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) SH, -C 1-5 alkylene) S (C 15 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) S (O) (C 1-5 alkyl), -C 1-5 alkylene) S (O) 2(C1-5 alkyl), -C 1-5 alkylene) S (O) (NH) (C 1-5 alkyl), -C 1-5 alkylene) S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 15 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) N (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) (C 1-5 haloalkyl) - (C 1-5 alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2、-(C1-5 alkylene) NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -OH, C2 alkyl, -C 1-5 alkyl, -O (393) alkyl, -C 1-5 S (1-5) alkyl, -O (393) 2, S (393) alkyl) -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2 alkyl), -CONH 1-5 alkyl, and-C 1-5 alkyl -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl), -C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -P (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycle), - (C 1-5 alkylene), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (1-5 SH), -S (1-5 alkyl) - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl) are more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -C 1-5 haloalkyl -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Thus, preferably, -Y C2-RC2 is selected from the group consisting of-O-C 1-12 alkyl, -NH-C 1-12 alkyl, -N (C 1-5 alkyl) -C 1-12 alkyl, -O-C 2-12 alkenyl, -NH-C 2-12 alkenyl, -N (C 1-5 alkyl) -C 2-12 alkenyl, -O-C 2-12 alkynyl, -NH-C 2-12 alkynyl, -N (C 1-5 alkyl) -C 2-12 alkynyl, (C 0-3 alkylene) -cycloalkyl, -CO- (C 0-3 alkylene) cycloalkyl, (C 0-3 alkylene) -CO-cycloalkyl, -CONH- (C 0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-3 alkylene) cycloalkyl, (C 0-3 alkylene) -NHCO-cycloalkyl, -NH- (C 0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -NH-cycloalkyl, -O- (C 0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl -CO-cycloalkyl, -SO 2 -cycloalkyl, (C 0-3 alkylene) -cycloalkenyl, -CO- (C 0-3 alkylene) cycloalkenyl, (C 0-3 alkylene) -CO-cycloalkenyl, -CONH- (C 0-3 alkylene) cycloalkenyl, - (C 0-3 alkylene) -CONH-cycloalkenyl, -NHCO- (C 0-3 alkylene) cycloalkenyl, (C 0-3 alkylene) -NHCO-cycloalkenyl, -NH- (C 0-3 alkylene) cycloalkenyl, - (C 0-3 alkylene) -NH-cycloalkenyl, -O- (C 0-3 alkylene) cycloalkenyl, - (C 0-3 alkylene) -O-cycloalkenyl, -SO 2-(C0-3 alkylene) cycloalkenyl, - (C 0-3 alkylene) -SO 2 -cycloalkenyl, -CONH-cycloalkenyl, -NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, -SO 2 -cycloalkenyl, - (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C62 alkylene) -CONH-heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl -NHCO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -O-heterocycloalkyl, -SO 2-(C0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, -CO- (C 0-3 alkylene) heterocycloalkenyl, - (C 0-3 alkylene) -CO-heterocycloalkenyl, -CONH- (C 0-3-(C0-3 alkylene) -CONH-heterocycloalkenyl, -NHCO- (C 0-3-(C0-3 alkylene) -NHCO-heterocycloalkenyl, -NH- (C 0-3-(C0-3 alkylene) -NH-heterocycloalkenyl, -O- (C5495 alkylene) heterocycloalkenyl, - (C 0-3 alkylene) -O-heterocycloalkenyl, -SO 2-(C0-3 alkylene, -C 0-3 alkylene) -SO- 2 -heterocycloalkenyl -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO 2 -heterocycloalkenyl, (C 0-3 alkylene) aryl, -CO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CO- (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) -CO- 0-3 heteroaryl - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) heteroaryl, (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and-SO 2 -heteroaryl, preferably-Y C2-RC2 is selected from the group consisting of-O-C 1-12 alkyl, -NH-C 1-12 alkyl, -N (C 1-5 alkyl) -C 1-12 alkyl, -O-C 2-12 alkenyl, -NH-C 2-12 alkenyl, -N (C 1-5 alkyl) -C 1-5 alkenyl, -O- 1-5 alkynyl, -NH-C 1-5 alkynyl, -N (C 1-5 alkyl) -C2 alkynyl, (C 1-5 alkylene) -C 1-5 cycloalkyl, (C 1-5 cycloalkyl) and-CO 3938-heteroaryl -CONH- (C 0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-3 alkylene) cycloalkyl, (C 0-3 alkylene) -NHCO-cycloalkyl, -NH- (C 0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -NH-cycloalkyl, -O- (C 0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) -SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO 2 -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, (C 0-3 alkylene) aryl, -CO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -CO-aryl, -SO 2, -SO-aryl - (C 0-3 alkylene) heteroaryl, -CO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) heteroaryl, (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and-SO 2-heteroaryl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -C26 haloalkyl, -S (C 1-5 alkyl), -S (S) haloalkyl, -S (6593) alkyl, -S (C6236 haloalkyl, -S (1-5) -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -S (O) (NH) (C2 alkyl), -S (O) (C 1-5 alkyl) N (C 1-5 alkyl), -S (C 1-5 alkyl) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)) and-P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -C2 alkyl, -OH, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O 1-5 haloalkyl, -O 1-5 (C 1-5 alkyl) -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CO (C 1-5 haloalkyl), -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 2、-CONH(C1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl), -CO- (C 2、-CONH(C1-5 alkyl), -nh3932 alkyl) -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -OCONH 2、-OCONH-(C1-5 alkyl), -OCON (C 2、-OCONH-(C1-5 alkyl), -NHCOO (C 2、-OCONH-(C1-5 alkyl), -N (C 2、-OCONH-(C1-5 alkyl) COO- (C 2、-OCONH-(C1-5 alkyl), -P (O) (C 2、-OCONH-(C1-5 alkyl)) (O (C 2、-OCONH-(C1-5 alkyl)), -P (O) (O (C 2、-OCONH-(C1-5 alkyl)) (C 2、-OCONH-(C1-5 alkyl), -C 2、-OCONH-(C1-5 alkylene) -CN, - (C 2、-OCONH-(C1-5 alkylene) -OH, - (C 2、-OCONH-(C1-5 alkylene) -O (C 2、-OCONH-(C1-5 alkyl), -C 2、-OCONH-(C1-5 alkylene) -O (C 2、-OCONH-(C1-5 haloalkyl), -SH, - (C 2、-OCONH-(C1-5 alkylene) -S (C 2、-OCONH-(C1-5 alkyl), -C 2、-OCONH-(C1-5 alkylene), -S (C 2、-OCONH-(C1-5 haloalkyl), -C 2、-OCONH-(C1-5 alkylene - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2 alkylene) -N (C 1-5 alkyl), (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), -C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), -C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -N (1-5 alkyl), -N=S (O) (C 1-5 alkyl), -C 1-5 haloalkyl, -NH (1-5 alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 2、-CONH(C1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl) -CO- (C 2、-CONH(C1-5 alkyl), -NHCONH 2、-CONH(C1-5 alkyl), -NHCON (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl) CONH- (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl) CON (C 2、-CONH(C1-5 alkyl), -OCONH 2、-CONH(C1-5 alkyl), -OCON (C 2、-CONH(C1-5 alkyl), -NHCOO (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl) cooalkyl), -cooalkyl (C 2、-CONH(C1-5 alkyl) (O 2、-CONH(C1-5 alkyl), -O 2、-CONH(C1-5 alkyl (C 2、-CONH(C1-5 alkyl) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (W-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkyl) -N- (C 1-5 alkyl), (C 1-5 alkyl) -CO- (C 1-5 alkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), C 1-5 alkyl-O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) 1-5 alkyl), and, -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCONH 1-5 (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 1-5 alkyl), -CONH- (C 1-5 alkyl), -N (C 1-5 alkyl), -CONH (C 1-5 alkyl), -C 1-5 alkyl -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl), -C 1-5 alkylene) -S (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycle), - (C 1-5 alkylene), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S 1-5 haloalkyl - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl) are more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -C 1-5 haloalkyl -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
More preferably, -Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) heterocycloalkyl, (C 0-3 alkylene) -O-cycloalkyl, (C 0-3 alkylene) -O-heterocycloalkyl, -SO 2-(C0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, -CO- (C 0-3 alkylene) heterocycloalkenyl- (C 0-3 alkylene) -CO- 0-3 -alkylene - (C 0-3 alkylene) -CONH-heterocyclenyl, -NHCO- (C 0-3 alkylene) heterocyclenyl, - (C 0-3 alkylene) -NHCO-heterocyclenyl, -NH- (C 0-3 alkylene) heterocyclenyl, - (C 0-3 alkylene) -NH-heterocyclenyl, -O- (C 0-3 alkylene) heterocyclenyl, (C 0-3 alkylene) -O-heterocyclenyl, -SO 2-(C0-3 alkylene) heterocyclenyl, - (C 0-3 alkylene) -SO 2 -heterocyclenyl, -CONH-heterocyclenyl, -NHCO-heterocyclenyl, -NH-heterocyclenyl, -O-heterocyclenyl, -CO-heterocyclenyl, -SO 2 -heterocyclenyl, - (C 0-3 alkylene) aryl, -CO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C3443 alkylene) -O- (C 0-3 alkylene) aryl, -NH- (C 0-3 alkylene) aryl - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O- 2 heteroaryl and-SO 2 heteroaryl, preferably-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) heterocycloalkyl- (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl-NHCO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) heterocycloalkyl (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) aryl, -CO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NHCO-aryl, - (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) heteroaryl, - (C 2-(C0-3 alkylene) -O-heteroaryl, -SO 0-3 heteroaryl - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 alkyl), -N (C35 haloalkyl), -N (C4632 alkyl), -N (C438 alkyl), -N (C4335 alkyl), -N (C 1-5 alkyl) -CO (C 1-5 haloalkyl), -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) CONH- (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) CON (C 2、-NHCONH-(C1-5 alkyl), -OCONH 2、-NHCONH-(C1-5 alkyl), -OCON (C 2、-NHCONH-(C1-5 alkyl), -NHCOO (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) COO- (C 2、-NHCONH-(C1-5 alkyl), -P (O) (C 2、-NHCONH-(C1-5 alkyl)), -P (C 2、-NHCONH-(C1-5 alkyl), -P (C 2、-NHCONH-(C1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)), (C 1-5 alkyl) -P (O) (C 1-5 alkyl), (C 1-5 alkyl)) - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N- (1-5 alkyl), - (C 1-5 alkylene) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) 1-5 alkyl), and, -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), CO (C 1-5 alkyl), -COO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl), -CO- (C2 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl), -CONH 2 alkyl -OCON (C 1-5 alkyl) (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl, -C 1-5 alkylene) -S (C 1-5 alkyl) (NH), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (W-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CON3932 alkylene) -CON (CON3932H) and (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -N=S (O) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C2 haloalkyl), -N (C 1-5 alkyl), -N (1-5 haloalkyl), -N (1-5 alkyl), -N (1-5 heterocycloalkyl), -CO (C 1-5 alkyl), -CON 2 alkyl), -CON (1-5 alkyl) -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)); -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), and, - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C2 alkyl) are more preferably selected from the group consisting of (C 1-5 alkyl), halogen, -CN, - 1-5 alkyl, and- 1-5 alkyl C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, -C 1-5 alkylene, -O (C 1-5 alkyl), -C 1-5 alkylene, -O (C 1-5 haloalkyl), -SH-S (C 1-5 alkyl), -S (C 1-5 haloalkyl), - - (C 1-5 alkylene) -SH- (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl) -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene) -NH (C 1-5 haloalkyl), -C 1-5 alkylene-N (C 1-5 alkyl), -C 1-5 alkylene-N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
More preferably, -Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -SO 2 -heterocycloalkenyl, - (C 0-3 alkylene) aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl and-SO 2 -heteroaryl, preferably-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene, -NHH-aryl, -CONH-heteroaryl -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)), (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH (C4632 alkyl), -N (C5342 alkyl), -N (C5352 alkyl), N (C 1-5 alkyl) - (N-heterocycloalkyl), -CO (C 1-5 alkyl), -CO (C 1-5 haloalkyl), -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (W-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COOalkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) (O2 alkyl), -O 1-5 alkyl (C393 2 alkyl) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycle), - (C 1-5 alkylene), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C2 alkyl) COO- (C2 alkyl), preferably selected from the group consisting of C 1-5, C 1-5 alkyl, C 1-5, and (1-5 alkyl), preferably halogen, -C 1-5 O (1-5, 393 2 alkyl) -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), N (C 1-5 alkyl) - (N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -OCONH 2、-OCONH-(C1-5 alkyl), -OCON (C 1-5 alkyl) (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -S (1-5 haloalkyl), -P (O) (O 1-5 alkyl), -P (O 1-5 alkylene) -S (C 1-5 alkyl), -S 1-5 alkylene - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkyl) -N (C 1-5 alkyl), (C 1-5 alkylene) -N (C 1-5 alkyl), (CO) CO 2 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl) - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -N=S (O) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C2 haloalkyl), -N (C 1-5 alkyl), -N (1-5 haloalkyl), -N (1-5 alkyl), -N (1-5 heterocycloalkyl), -CO (C 1-5 alkyl), -CON 2 alkyl), -CON (1-5 alkyl) -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)); -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), and, - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C2 alkyl) are more preferably selected from the group consisting of (C 1-5 alkyl), halogen, -CN, - 1-5 alkyl, and- 1-5 alkyl C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, -C 1-5 alkylene, -O (C 1-5 alkyl), -C 1-5 alkylene, -O (C 1-5 haloalkyl), -SH-S (C 1-5 alkyl), -S (C 1-5 haloalkyl), - - (C 1-5 alkylene) -SH- (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl) -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene) -NH (C 1-5 haloalkyl), -C 1-5 alkylene-N (C 1-5 alkyl), -C 1-5 alkylene-N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Even more preferably, -Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, - (C 0-3 alkylene) aryl and- (C 0-3 alkylene) heteroaryl, preferably-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) aryl and- (C 0-3 alkylene) heteroaryl, wherein said heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -n=s (C 1-5 alkyl), -C8 alkyl), -C 1-5 haloalkyl, -C8235 alkyl, -C7257 haloalkyl, -NH (C8232 alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CO (C 1-5 haloalkyl), -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -och 1-5 alkyl), -oc2 alkyl, -OCON (C 1-5 alkyl), -C 1-5 alkyl -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl), -C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -P (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO- 1-5 cycloalkyl, - (C 1-5 alkylene) -CONH 2 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkyl) -CONH (C 1-5 alkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C2 alkyl), -COO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C2 alkyl), -N 1-5 alkyl), -C 1-5 alkyl), -CO- (C 1-5 alkyl) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S- (C 1-5 alkyl), -S 1-5 haloalkyl - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkyl) - (N-heterocycle alkylene), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2 alkyl), -NH (C 1-5 haloalkyl), -N (1-5 haloalkyl), -N 1-5 alkyl, N (C 1-5 haloalkyl) - (N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 haloalkylene, - (C 1-5 alkyl) -O (SH) and (1-5 alkyl) - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -N 1-5 alkyl - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2 alkyl) and-CONH 2 alkyl (C 1-5 alkyl).
Even more preferably, -Y C2-RC2 is selected from heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, more preferably heterocycloalkyl and heteroaryl, even more preferably heterocycloalkyl, wherein said heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C4293 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 97alkyl), -NH (C 1-5 haloalkyl), -N (C3432 alkyl), -N (C3483 haloalkyl), -N (C5342 alkyl) and-C5342 alkyl -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) -N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N- (1-5 alkyl), - (C 1-5 alkylene) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) 1-5 alkyl), and, -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), a-CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), and-OCONH 1-5 alkyl -OCON (C 1-5 alkyl) (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl, -C 1-5 alkylene) -S (C 1-5 alkyl) (NH), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (W-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CON3932 alkylene) -CON (CON3932H) and (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -N=S (O) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C2 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -N (1-5 heterocycloalkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CON 2 alkyl), -CON (1-5 alkyl) -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)); -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), and, - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) are preferably selected from the group consisting of (C 1-5 alkyl), halogen, -CN, - 1-5 alkyl, and- 1-5 alkyl C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, -C 1-5 alkylene, -O (C 1-5 alkyl), -C 1-5 alkylene, -O (C 1-5 haloalkyl), -SH-S (C 1-5 alkyl), -S (C 1-5 haloalkyl), - - (C 1-5 alkylene) -SH- (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl) -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene) -NH (C 1-5 haloalkyl), -C 1-5 alkylene-N (C 1-5 alkyl), -C 1-5 alkylene-N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 haloalkyl), -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
In one embodiment ，-YC2-RC2Is a heterocycloalkenyl group ，Wherein the heterocycloalkenyl is optionally substituted with one or more groups ，The one or more groups are independently selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-CO(C1-5Haloalkyl )、-CO-Cycloalkyl radicals 、-COO(C1-5Alkyl group )、-COO(C1-5Haloalkyl )、-COO-Cycloalkyl radicals 、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-OCONH2、-OCONH-(C1-5Alkyl group )、-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-NHCOO(C1-5Alkyl group )、-N(C1-5Alkyl group )COO-(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-CN、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-S(O)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)2(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(NH)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Haloalkyl )、-(C1-5Alkylene group )-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Haloalkyl )、-(C1-5Alkylene group )-CO-Cycloalkyl radicals 、-(C1-5Alkylene group )-CONH2、-(C1-5Alkylene group )-CONH(C1-5Alkyl group )、-(C1-5Alkylene group )-CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-NHCO-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCONH2、-(C1-5Alkylene group )-NHCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH2、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-OCONH2、-(C1-5Alkylene group )-OCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCOO(C1-5Alkyl group )And -(C1-5Alkylene group )-N(C1-5Alkyl group )COO-(C1-5Alkyl group )，Preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-COO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-OCONH2、-OCONH-(C1-5Alkyl group )、-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-NHCOO(C1-5Alkyl group )、-N(C1-5Alkyl group )COO-(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-CN、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-S(O)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)2(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(NH)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Haloalkyl )、-(C1-5Alkylene group )-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Alkyl group )、-(C1-5Alkylene group )-CONH2、-(C1-5Alkylene group )-CONH(C1-5Alkyl group )、-(C1-5Alkylene group )-CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-NHCO-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCONH2、-(C1-5Alkylene group )-NHCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH2、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-OCONH2、-(C1-5Alkylene group )-OCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCOO(C1-5Alkyl group )And -(C1-5Alkylene group )-N(C1-5Alkyl group )COO-(C1-5Alkyl group )，Preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-CN、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-S(O)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)2(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(NH)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Haloalkyl )、-(C1-5Alkylene group )-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Alkyl group )、-(C1-5Alkylene group )-CONH2、-(C1-5Alkylene group )-CONH(C1-5Alkyl group )、-(C1-5Alkylene group )-CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-NHCO-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCONH2、-(C1-5Alkylene group )-NHCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH2、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )And -(C1-5Alkylene group )-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )，More preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )And -CON(C1-5Alkyl group )(C1-5Alkyl group )，More preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )And -CON(C1-5Alkyl group )(C1-5Alkyl group )。
Preferably, if-Y C2-RC2 is aryl, then-Y C2-RC2 is phenyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C2 alkyl), -CO (C 1-5 haloalkyl), -COO (C 1-5 alkyl), -COO (C393 alkyl), -COO 2 alkyl) -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 2、-N(C1-5 alkyl), -N (C 2、-N(C1-5 alkyl) CON (C 2、-N(C1-5 alkyl), -OCONH 2、-N(C1-5 alkyl), -OCON (C 2、-N(C1-5 alkyl), -NHCOO (C 2、-N(C1-5 alkyl), -N (C 2、-N(C1-5 alkyl) COO- (C 2、-N(C1-5 alkyl), -P (O) (O (C 2、-N(C1-5 alkyl)), -P (O) (C 2、-N(C1-5 alkyl)), -P (O (C 2、-N(C1-5 alkyl), -CN (C 2、-N(C1-5 alkyl), -C 2、-N(C1-5 alkylene, - (C 2、-N(C1-5 alkyl), -alkylene, - (C 2、-N(C1-5 alkyl) - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)), (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C2 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (S 1-5 alkyl) (S 1-5 alkyl), (S 1-5 alkyl) (S 1-5 alkyl) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -nhconc 1-5 alkyl (C 1-5 alkyl), -N (C 1-5 alkyl), -CONH 2 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl), -on (C 1-5 alkyl) -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (1-5 alkyl), -C 1-5 alkylene) -S (O) 1-5 alkyl), -S (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (1-5 alkyl) - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -N=S (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl), -CO- (C 1-5 alkyl), -CON 2 alkyl), -CON (C 1-5 alkyl), -CON 2 alkyl) -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, -C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O 2(C1-5 alkyl), -C 1-5 alkylene) -S (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CON3932 alkylene) -CON (CON3932H) and (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkyl) -O (C 1-5 alkyl), (C 1-5 alkyl) -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene), -S (C 1-5 alkyl), -S (C 1-5 alkylene), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -C 1-5 alkylene), -NH (C 1-5 alkyl), -NH (C 1-5 alkylene), -N (C 1-5 alkyl), -C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C2 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl) (C2 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O 1-5 alkyl, -O 1-5 haloalkyl, -O 1-5 alkyl -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Preferably, if-Y C2-RC2 is heteroaryl, -Y C2-RC2 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or indazolyl, wherein heteroaryl may be optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 alkyl), -N (C 1-5 alkyl), -N (C 1-5 alkyl), -C3775 alkyl -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), and-N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), and-P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkyl) - (W-heterocycle alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) are preferably selected from the group consisting of (C 1-5 alkyl), halogen, -CN, - 1-5 alkyl, and- 1-5 alkyl C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, -C 1-5 alkylene, -O (C 1-5 alkyl), -C 1-5 alkylene, -O (C 1-5 haloalkyl), -SH-S (C 1-5 alkyl), -S (C 1-5 haloalkyl), - - (C 1-5 alkylene) -SH- (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl) -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene) -NH (C 1-5 haloalkyl), -C 1-5 alkylene-N (C 1-5 alkyl), -C 1-5 alkylene-N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Preferably, if-Y C2-RC2 is heterocycloalkyl, -Y C2-RC2 is morpholinyl, 1-dioxothiomorpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 6-oxo-1, 6-dihydropyridinyl or piperazinyl, wherein heterocycloalkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 42 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5) alkyl), -C538 haloalkyl, -C4393 alkyl, C538 haloalkyl), -CO (C4393 alkyl) -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) -N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N- (1-5 alkyl), - (C 1-5 alkylene) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) 1-5 alkyl), and, -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), a-CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), and-OCONH 1-5 alkyl -OCON (C 1-5 alkyl) (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl, -C 1-5 alkylene) -S (C 1-5 alkyl) (NH), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CON3932 alkylene) -CON (CON3932H) and (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -N=S (O) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C2 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -N (1-5 heterocycloalkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CON 2 alkyl), -CON (1-5 alkyl) -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)); -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), and, - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 1-5 alkyl) -N (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) are preferably selected from the group consisting of (C 1-5 alkyl), halogen, -CN, - 1-5 alkyl, and- 1-5 alkyl C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, -C 1-5 alkylene, -O (C 1-5 alkyl), -C 1-5 alkylene, -O (C 1-5 haloalkyl), -SH-S (C 1-5 alkyl), -S (C 1-5 haloalkyl), - - (C 1-5 alkylene) -SH- (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl) -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene) -NH (C 1-5 haloalkyl), -C 1-5 alkylene-N (C 1-5 alkyl), -C 1-5 alkylene-N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). More preferably, -Y C2-RC2 is piperazinyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CO (C 1-5 haloalkyl), -COO (C 1-5 alkyl), -COO (C 1-5 alkyl), -COO (C393 alkyl) -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (W-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 2、-N(C1-5 alkyl), -N (C 2、-N(C1-5 alkyl) CON (C 2、-N(C1-5 alkyl), -OCONH 2、-N(C1-5 alkyl), -OCON (C 2、-N(C1-5 alkyl), -NHCOO (C 2、-N(C1-5 alkyl), -N (C 2、-N(C1-5 alkyl) COO- (C 2、-N(C1-5 alkyl), -P (O) (O (C 2、-N(C1-5 alkyl)), -P (O) (C 2、-N(C1-5 alkyl)), -P (O (C 2、-N(C1-5 alkyl), -CN (C 2、-N(C1-5 alkyl), -C 2、-N(C1-5 alkylene, - (C 2、-N(C1-5 alkyl), -alkylene, - (C 2、-N(C1-5 alkyl) - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)), (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C2 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (S 1-5 alkyl) (S 1-5 alkyl), (S 1-5 alkyl) (S 1-5 alkyl) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -nhconc 1-5 alkyl (C 1-5 alkyl), -N (C 1-5 alkyl), -CONH 2 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl), -on (C 1-5 alkyl) -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (1-5 alkyl), -C 1-5 alkylene) -S (O) 1-5 alkyl), -S (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (1-5 alkyl) - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -N=S (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl), -CO- (C 1-5 alkyl), -CON 2 alkyl), -CON (C 1-5 alkyl), -CON 2 alkyl) -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, -C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O 2(C1-5 alkyl), -C 1-5 alkylene) -S (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CON3932 alkylene) -CON (CON3932H) and (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkyl) -O (C 1-5 alkyl), (C 1-5 alkyl) -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene), -S (C 1-5 alkyl), -S (C 1-5 alkylene), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -C 1-5 alkylene), -NH (C 1-5 alkyl), -NH (C 1-5 alkylene), -N (C 1-5 alkyl), -C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C2 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl) (C2 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O 1-5 alkyl, -O 1-5 haloalkyl, -O 1-5 alkyl -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl). Even more preferably, -Y C2-RC2 is piperazinyl (preferably N-piperazinyl) optionally substituted (preferably N-substituted) with-CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). Most preferably, -Y C2-RC2 is piperazinyl (preferably N-piperazinyl) substituted (preferably N-substituted, preferably at an N atom different from the N atom attached to the ring system as shown in formula (I)) by-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably by-CON (CH 3)2).
Preferably, if-Y C2-RC2 is heterocycloalkenyl, then-Y C2-RC2 is oxacyclohexenyl or azacyclohexenyl, wherein heterocycloalkenyl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 15 alkyl), S (O) (C 15 alkyl), S (O) 2(C15 alkyl), S (O) (NH) (C 15 alkyl), S (O) (N (C 15 alkyl)) (C 15 alkyl), -n=s (O) (C 15 alkyl) (C 15 alkyl), -S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), -NH (C2 haloalkyl), N (C 2、NH(C1-5 alkyl) (C 2、NH(C1-5 haloalkyl), -N-heterocycloalkyl), -CO (C 2、NH(C1-5 alkyl), -CO (C 2、NH(C1-5 haloalkyl), -COO 2 alkyl, -393 2 alkyl, -COO 2 alkyl, -COO (393 2 alkyl), and- 2、NH(C1-5 alkyl -CO- (N-heterocycloalkyl), NHCO- (C 1-5 alkyl), N (C 1-5 alkyl) -CO- (C 1-5 alkyl), NHCONH 1-5 alkyl), NHCON (C 1-5 alkyl), N (C 1-5 alkyl) CONH- (C 1-5 alkyl), N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), NHCOO (C 1-5 alkyl), N (C 1-5 alkyl) COO- (C 1-5 alkyl) -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl))), -P (O) (C 1-5 alkylene) -CN, - (C 1-5 alkylene) OH, - (C 1-5 alkylene) O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) SH, - (C 1-5 alkylene) S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) S (O) (C 15 alkyl), - (C 1-5 alkylene) S (O) 2(C15 alkyl), - (C 1-5 alkylene) S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) N (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl), - (C 1-5 alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2 CONH 2 alkylene), - (C 1-5 CONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CON (C 1-5 alkyl) N- (C 1-5 alkyl), - (C alkylene) N (C alkyl) CON (C alkyl), - (C alkylene) -OCONH- (C alkyl), - (C alkylene) -OCON (C alkyl), - (C alkylene) NHCOO (C alkyl) and- (C alkylene) N (C alkyl) COO- (C alkyl), preferably selected from halogen, CN, OH, C alkyl, C haloalkyl, O (C alkyl), -O (C haloalkyl), SH, S (C alkyl), S (O) (NH) (C alkyl), S (O) (C alkyl)) (C alkyl), -n=s (O) (C alkyl), -S (C haloalkyl), NH alkyl), -NH (C haloalkyl), N (C alkyl), N (C haloalkyl) (C alkyl), S (C haloalkyl) (C alkyl), - (N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), -CONH 2、CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C2 alkyl), -P (O) (C 1-5 alkyl), -P (C 1-5 alkyl)), -P (1-5 alkyl) (O (C 1-5 alkyl)), -P (O (C 1-5 alkyl), -N (C 1-5 alkyl), -CN- (C 1-5 alkyl), -CN (C 1-5 alkyl) - (C 1-5 alkylene) O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) SH, - (C 1-5 alkylene) S (C 15 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) S (O) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (1-5 alkyl), - (C 1-5 alkylene) NH (C 1-5 alkylene) - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) N (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl), - (C 1-5 alkylene) (W-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2 alkylene) CONH- (C 1-5 alkyl), - (C 1-5 alkyl) CONH- (C 1-5 alkyl), (C 1-5 alkylene) CON (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl-O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl) -S (O) (C 1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl), a, -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 1-5 alkyl), -CONH (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -O (C 1-5 alkyl)) -C 1-5 alkyl - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), (1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2 alkyl), -NH (C 1-5 alkyl), -N (1-5 alkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene), -NH (C 1-5 haloalkyl), -N (C 1-5 alkylene) -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl), and-CON (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -C 1-5 haloalkyl), -CO (C 1-5 alkyl), and-CON (C 1-5 alkyl). More preferably, -Y C2-RC2 is azacyclohexenyl optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 15 alkyl), S (O) (C 15 alkyl), S (O) 2(C15 alkyl), S (O) (NH) (C 15 alkyl), S (O) (N (C 15 alkyl)) (C 15 alkyl), -n=s (O) (C 15 alkyl) (C 15 alkyl), -S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C2 haloalkyl) (C 1-5 alkyl), -CO (C2 haloalkyl), -CO-cycloalkyl, COO (C 1-5 alkyl), -COO (C 1-5 alkyl), C393 alkyl NHCO- (C 1-5 alkyl), N (C 1-5 alkyl) -CO- (C 1-5 alkyl), NHCONH 1-5 alkyl), NHCON (C 1-5 alkyl), N (C 1-5 alkyl) CONH- (C 1-5 alkyl), N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), NHCOO (C 1-5 alkyl), N (C 1-5 alkyl) COO- (C 1-5 alkyl) -P (O) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl))), -P (O) (C 1-5 alkylene) -CN, - (C 1-5 alkylene) OH, - (C 1-5 alkylene) O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) SH, - (C 1-5 alkylene) S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) S (O) (C 15 alkyl), - (C 1-5 alkylene) S (O) 2(C15 alkyl), - (C 1-5 alkylene) S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) N (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl), - (C 1-5 alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2 CONH 2 alkylene), - (C 1-5 CONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CON (C 1-5 alkyl) N- (C 1-5 alkyl), - (C alkylene) N (C alkyl) CON (C alkyl), - (C alkylene) -OCONH- (C alkyl), - (C alkylene) -OCON (C alkyl), - (C alkylene) NHCOO (C alkyl) and- (C alkylene) N (C alkyl) COO- (C alkyl), preferably selected from halogen, CN, OH, C alkyl, C haloalkyl, O (C alkyl), -O (C haloalkyl), SH, S (C alkyl), S (O) (NH) (C alkyl), S (O) (C alkyl)) (C alkyl), -n=s (O) (C alkyl), -S (C haloalkyl), NH alkyl), -NH (C haloalkyl), N (C alkyl), N (C haloalkyl) (C alkyl), S (C haloalkyl) (C alkyl), - (N-heterocycloalkyl), -CO (C 1-5 alkyl), -COO (C 1-5 alkyl), -CONH 2、CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -OCONH 1-5 alkyl), -OCON (C 1-5 alkyl), -NHCOO (C 1-5 alkyl), -N (C 1-5 alkyl) COO- (C2 alkyl), -P (O) (C 1-5 alkyl), -P (C 1-5 alkyl)), -P (1-5 alkyl) (O (C 1-5 alkyl)), -P (O (C 1-5 alkyl), -N (C 1-5 alkyl), -CN- (C 1-5 alkyl), -CN (C 1-5 alkyl) - (C 1-5 alkylene) O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) SH, - (C 1-5 alkylene) S (C 15 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) S (O) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) S (O) (1-5 alkyl), - (C 1-5 alkylene) NH (C 1-5 alkylene) - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) N (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl), - (C 1-5 alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2 alkylene) CONH- (C 1-5 alkyl), - (C 1-5 alkyl) CONH- (C 1-5 alkyl), (C 1-5 alkylene) CON (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) N (C 1-5 alkyl) COO- (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl-O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl) -S (O) (C 1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl), a, -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 1-5 alkyl), -CONH (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (C 1-5 alkyl), -O (C 1-5 alkyl)) -C 1-5 alkyl - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), (1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2 alkyl), -NH (C 1-5 alkyl), -N (1-5 alkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene), -NH (C 1-5 haloalkyl), -N (C 1-5 alkylene) -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl), and-CON (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -C 1-5 haloalkyl), -CO (C 1-5 alkyl), and-CON (C 1-5 alkyl). Even more preferably, -Y C2-RC2 is an azepinyl group substituted (preferably N-substituted) with-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably with-CON (CH 3)2 preferably, the azepinyl group is referred to herein as 1,2,3, 6-tetrahydropyridinyl.
In another preferred embodiment, if-Y C2-RC2 is heterocycloalkyl, then-Y C2-RC2 is 2-oxaspiro [3.5] non-6-en-7-yl, 2-oxaspiro [3.5] non-7-yl, 2-oxa-8-azaspiro [4.5] dec-8-yl, 9-oxa-3-azaspiro [5.5] undec-3-yl, 2-oxa-6-azaspiro [3.4] oct-6-yl, 1-oxa-7-azaspiro [3.5] non-7-yl, 1-oxa-8-azaspiro [4.5] dec-8-yl, 6-oxa-2-azaspiro [3.3] hept-2-yl, 2, 8-diazaspiro [4.5] dec-8-yl, 7-oxa-3-azabicyclo [3.3.0] oct-3-yl, 8-oxa-3-azabicyclo [4.3.0] non-3-yl, 1-oxa-3-azaspiro [3.5] non-3-yl, 1-oxa-8-oxa-azaspiro [3.5] non-azol-3.5 ] non-yl, 1-oxa-8-yl, 1-oxa-8-yl, 2-oxa-azaspiro [3.5] non-yl, 3-oxa-3-yl.
In a specific embodiment, -Y C2-RC2 is selected from:
preferably-Y c2-Rc2 is/>
In a specific embodiment, -Y C2-RC2 is selected from:
in a specific embodiment, -Y C2-RC2 is selected from:
x 4 is N or C-R C4.
R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) cycloalkenyl, -O- (C 0-3 alkylene) -cycloalkenyl, -CO- (C 0-3 alkylene) -cycloalkenyl, - (C2 alkylene) -heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, -O- (C 0-3 alkylene) -heterocycloalkenyl, -C 0-3 alkylene) -heterocycloalkylene, - (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) cycloalkyl, - (C 0-3 alkylene) cycloalkenyl, -O- (C 0-3 alkylene) -cycloalkenyl, -CO- (C 0-3 alkylene) -cycloalkenyl, - (C 0-3 alkylene) -heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkylene, - (C 0-3 alkylene) -heterocycloalkenyl, -O- (C 0-3 alkylene) -heterocycloalkenyl, - (C 0-3 alkylene) -O- (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -heteroaryl, -O- (C 0-3 alkylene) -heteroaryl and-CO- (C 0-3 alkylene) -heteroaryl, preferably selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), -CO (C 1-6 alkyl), C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -S (C 1-6 haloalkyl), -NH (C 1-6 haloalkyl), -N (C 1-6 haloalkyl) 2、-CO(C1-6 haloalkyl), -C 2、-CO(C1-6 alkylene, -O- (C 2、-CO(C1-6 alkylene) cycloalkyl, -CO- (C 2、-CO(C1-6 alkylene) -cycloalkyl, - (C 2、-CO(C1-6 alkylene) -heterocycloalkyl, -O- (C 2、-CO(C1-6 alkylene) -heterocycloalkyl, -CO- (C 2、-CO(C1-6 alkylene) -heterocycloalkyl, -C- (C 2、-CO(C1-6 alkylene) -heterocycloalkyl, -C393 (C 2、-CO(C1-6 alkylene) -aryl, -O 2、-CO(C1-6 alkylene, -aryl -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -heteroaryl, -O- (C 0-3 alkylene) -heteroaryl and-CO- (C 0-3 alkylene) -heteroaryl. The alkyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C2 alkyl) (2、-NHCONH-(C1-5 alkyl), -N (C2 alkyl) CONH 2 alkyl) (2、-NHCONH-(C1-5 alkyl), and-CONH 2、-NHCONH-(C1-5 alkyl (C 2、-NHCONH-(C1-5 alkyl), preferably selected from halogen, -C 2、-NHCONH-(C1-5 alkyl, -CN (C 2、-NHCONH-(C1-5 alkyl) -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably said alkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -N- (C 1-5 alkyl), -CO- (1-5 alkyl) -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl) and-N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (1-5 alkyl), -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -nhcon2 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl), and N (1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl) is preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S 1-5 haloalkyl, -NH (1-5) alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Preferably, R C4 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), C 1-6 haloalkyl, - (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -cycloalkenyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, - (C 0-3 alkylene) -aryl and- (C 0-3 alkylene) -heteroaryl, preferably selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), C 1-6 haloalkyl, - (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl and- (C 0-3 alkylene) -heteroaryl. Said alkyl or alkynyl (preferably said alkyl) is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCON (C 2、-NHCONH-(C1-5 alkyl), -nhconc 2、-NHCONH-(C1-5 alkyl), -N (C2 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl), -CONH 2 alkyl) and preferably selected from halogen (C 2、-NHCONH-(C1-5 alkyl) -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -O (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl). The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (1-5 alkyl), -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -nhcon2 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl), and N (1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl) is preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 haloalkyl), -S 1-5 haloalkyl), -C 1-5 alkyl (NH), (1-5 alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Further preferably, R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, and C 1-6 haloalkyl, more preferably, R C4 is selected from the group consisting of hydrogen, halogen, C 1-2 alkyl, and C 2-3 alkynyl, even more preferably, R C4 is selected from the group consisting of hydrogen, halogen, and C 1-2 alkyl, even more preferably, R C4 is hydrogen or halogen.
In another preferred embodiment, R C4 is selected from the group consisting of- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -cycloalkenyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, - (C 0-3 alkylene) -aryl and- (C 0-3 alkylene) -heteroaryl, preferably selected from the group consisting of- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl and- (C 0-3 alkylene) -heteroaryl. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (1-5 alkyl), -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -nhcon2 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl), and N (1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl) is preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S 1-5 haloalkyl, -NH (1-5) alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl). More preferably, R C4 is selected from the group consisting of- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl and- (C 0-3 alkylene) -heteroaryl, preferably from the group consisting of cycloalkyl, heterocycloalkyl and heteroaryl. The cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -NH (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl). Even more preferably, R C4 is selected from heterocycloalkyl and heteroaryl. The heterocycloalkyl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -NH (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
In a further preferred embodiment of the present invention, R C4 is selected from the group consisting of-CH 2 -cycloalkyl, -CH 2 -cycloalkenyl, -CH 2 -heterocycloalkyl-CH 2 -heterocyclenyl, -CH 2 -aryl and-CH 2 -heteroaryl, preferably selected from the group consisting of-CH 2 -cycloalkyl, -CH 2 -heterocycloalkyl, -CH 2 -aryl and-CH 2 -heteroaryl. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (1-5 alkyl), -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -nhcon2 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl), and N (1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl) is preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S 1-5 haloalkyl, -NH (1-5) alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl). More preferably, R C4 is selected from the group consisting of-CH 2 -heterocycloalkyl and-CH 2 -heteroaryl. The heterocycloalkyl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
If R C4 is heteroaryl, R C4 is preferably imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or indazolyl, wherein heteroaryl may optionally be substituted with one or more groups independently halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C5243 alkyl), -N (C 1-5 alkyl), -N (C3443 alkyl), -N (C 1-5 alkyl), -N (C3443 alkyl), -N (C 1-5 alkyl) C (C4635 alkyl) -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl) and-N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl), - (C 1-5 alkylene) -N-heterocycloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (1-5 haloalkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl) - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
If R C4 is heterocycloalkyl, then R C4 is preferably morpholinyl, 1-dioxothiomorpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 6-oxo-1, 6-dihydropyridinyl or piperazinyl, wherein heterocycloalkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -C 1-5 alkyl), -CO- (C 1-5 haloalkyl), -NHC 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -C 1-5 alkyl) -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl) and-N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl), - (C 1-5 alkylene) -N-heterocycloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (1-5 haloalkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl, preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl). More preferably, R C4 is piperazinyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCO- (C 1-5 alkyl), -NHCON (C 1-5 alkyl), and-NHCON (C 1-5 alkyl), -CON 2 alkyl - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkyl), (C 1-5 alkylene) -CON (C 1-5 alkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) are preferably selected from the group consisting of halogen, -CN, -OH, C2 alkyl, C2 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (1-5 haloalkyl), -NH 2 alkyl), -NH 2 haloalkyl, -C 1-5 alkyl) (C 1-5 alkyl), -N (1-5 alkyl) (C 1-5 alkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). Even more preferably, R C4 is piperazinyl (preferably N-piperazinyl) optionally substituted (preferably N-substituted) with-CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). Most preferably, R C4 is piperazinyl (preferably N-piperazinyl) substituted (preferably N-substituted, preferably at an N atom different from the N atom attached to the ring system as shown in formula (I)) by-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably by-CON (CH 3)2).
If R C4 is heterocycloalkenyl, then R C4 is oxacyclohexenyl or azacyclohexenyl, preferably R C4 is azacyclohexenyl, wherein heterocycloalkenyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C32alkyl), -N (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -CON 2、-NHCONH-(C1-5 alkyl), -CONH (C 2、-NHCONH-(C1-5 alkyl) -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl) and-N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl), - (C 1-5 alkylene) -N-heterocycloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (1-5 haloalkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl, preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
In another embodiment, wherein R C4 is heterocycloalkyl, R C4 is preferably 2-oxaspiro [3.5] non-6-en-7-yl, 2-oxaspiro [3.5] non-7-yl, 2-oxa-8-azaspiro [4.5] dec-8-yl, 9-oxa-3-azaspiro [5.5] undec-3-yl, 2-oxa-6-azaspiro [3.4] oct-6-yl, 1-oxa-7-azaspiro [3.5] non-7-yl, 1-oxa-8-azaspiro [4.5] dec-8-yl, 6-oxa-2-azaspiro [3.3] hept-2-yl 2, 8-diazaspiro [4.5] dec-8-yl, 7-oxa-3-azabicyclo [3.3.0] oct-3-yl, 8-oxa-3-azabicyclo [4.3.0] non-3-yl, 2-oxa-6-azaspiro [3.5] non-6-yl, 7-oxo-3, 6, 8-triazabicyclo [4.3.0] non-3-yl, 3-pyrrol-o [3,4-c ] pyrazol-2-yl, 3, 6-diazabicyclo [3.1.1] hept-3-yl or 2, 7-diazaspiro [3.5] non-7-yl.
Preferably, if X 2 comprises cycloalkyl, heterocycloalkyl, aryl or heteroaryl, then X 4 is C-R C4, wherein R C4 is selected from hydrogen, halogen, C 1-6 alkyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl) and C 1-6 haloalkyl. More preferably, if X 2 comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then X 4 is C-R C4, wherein R C4 is selected from hydrogen and halogen.
Further preferably, if X 4 comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then X 2 does not comprise any of the groups cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
Further preferably, if X 2 comprises cycloalkyl, heterocycloalkyl, aryl or heteroaryl and X 4 comprises cycloalkyl, heterocycloalkyl, aryl or heteroaryl, then R C4 and-Y C2-RC2 together comprise no more than 12 non-hydrogen atoms, preferably no more than 10 non-hydrogen atoms.
X 5 is N or C-R C5. Preferably, no more than one of X 4 and X 5 is N. In certain preferred embodiments, X 4 is N and X 5 is C-R C5, preferably X 4 is N and X 5 is CH. In certain preferred embodiments, X 4 is C-R C4 and X 5 is N, preferably X 4 is CH and X 5 is N. In certain preferred embodiments, X 4 is C-R C4 and X 5 is C-R C5. In certain preferred embodiments X 4 is CH and X 5 is CH.
R C5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) C 1-6 alkyl, and C 1-6 haloalkyl. Preferably, R C5 is selected from hydrogen, halogen, C 1-3 alkyl, -O (C 1-3 alkyl), -S (C 1-3 alkyl), -NH (C 1-3 alkyl) and C 1-3 haloalkyl. More preferably, R C5 is selected from hydrogen, halogen, C 1-3 alkyl, and C 1-3 haloalkyl.
R 4 is Y R5-RR5.
Y R5 is selected from the group consisting of covalent bond, C 1-4 alkylene, C 2-4 alkenylene and C 2-4 alkynylene, wherein each of said alkylene, said alkenylene and said alkynylene is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 2(C1-5 alkyl), -S (C 1-5 haloalkyl), -SO (C 1-5 haloalkyl), -SO 2(C1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl) and-N (C 1-5 haloalkyl) (C2 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -S (C 1-5 alkyl), -SO 2 alkyl), -SO 1-5 haloalkyl, -SO 2 haloalkyl) and-NH 1-5 haloalkyl -N (C 1-5 alkyl) (C 1-5 alkyl) and-N (C 1-5 haloalkyl) (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH (C 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl) and-N (C 1-5 haloalkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units comprised in the alkylene, the alkenylene or the alkynylene are each optionally substituted with a group independently selected from-O-, NH-, N (C 1-5 alkyl) -, CO-, -COO S-, -SO-and SO 2 -, preferably selected from-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-and SO 2 -. Preferably, Y R5 is selected from the group consisting of covalent bonds, C 1-2 alkylene, -CO- (C 1-2 alkylene) -, - (C 1-2 alkylene) -CO-, -CONH- (C 1-2 alkylene) -, - (C 1-2 alkylene) -CONH-, -NHCO- (C 1-2 alkylene) -, - (C 1-2 alkylene) -NHCO-, -NH- (C 1-2 alkylene) -, - (C 1-2 alkylene) -NH-, -O- (C 1-2 alkylene) -, - (C 1-2 alkylene) -O-, SO 2-(C1-2 alkylene) -, - (C 1-2 alkylene) SO 2-、-CONH-、CON(C1-5 alkyl) -, -NHCO-, -N (C 1-5 alkyl) CO-, -NH-, -O-, -CO-, -COO and-SO 2-.C1-2 alkylene, preferably being a-CH 2 -group herein.
R R5 is selected from the group consisting of C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl, preferably from the group consisting of C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Preferably, R R5 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. More preferably, R R5 is selected from heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R R5 is selected from aryl and heteroaryl. Most preferably, R R5 is heteroaryl. The alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), NH 21、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl). Said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 2(C1-5 alkyl), -S (C 1-5 haloalkyl), -SO (C 1-5 haloalkyl), -SO 2(C1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -C2 alkyl, -C2 haloalkyl, -O (C2 alkyl), -O (C 1-5 alkyl), -NH 6532 haloalkyl), -S (1-5 haloalkyl), -NH 2 haloalkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Preferably, Y R5 is selected from the group consisting of covalent bonds, C 1-2 alkylene, -CO- (C 1-2 alkylene) -, - (C 1-2 alkylene) -CO-, -CONH- (C 1-2 alkylene) -, - (C 1-2 alkylene) -CONH-, -NHCO- (C 1-2 alkylene) -, - (C 1-2 alkylene) -NHCO-, -NH- (C 1-2 alkylene) -, - (C 1-2 alkylene) -NH-, -O- (C 1-2 alkylene) -, - (C 1-2 alkylene) -O-, SO 2-(C1-2 alkylene) -, - (C 1-2 alkylene) SO 2 -, -CONH-, -NHCO-, -NH-, -O-, -CO-, and SO 2 -. Therefore, preferably, the method comprises, preferably, R 4 is selected from the group consisting of- (C 0-2 alkylene) -cycloalkyl, -CO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CO-cycloalkyl, -CONH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NHCO-cycloalkyl, -NH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NH-cycloalkyl, -O- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -O-cycloalkyl, SO 2-(C0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, - (C 0-2 alkylene) -cycloalkenyl, -CO- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -CO-cycloalkenyl, -CONH- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -CONH-cycloalkenyl, -NHCO- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -NHCO-cycloalkenyl, -NH- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -NH-cycloalkenyl, -O- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -O-cycloalkenyl, SO 2-(C0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) SO 2 -cycloalkenyl, -CONH-cycloalkenyl, -NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, SO 2 -cycloalkenyl, - (C 0-2 alkylene) -heterocycloalkyl, -CO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NH-heterocycloalkyl, -C 0-2 alkylene-NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -O-heterocycloalkyl, SO 2-(C0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO 2 -heterocycloalkyl, - (C 0-2 alkylene) -heterocycloalkenyl, -CO- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -CO-heterocycloalkenyl, -CONH- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -CONH-heterocycloalkenyl, -NHCO- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -NHCO-heterocycloalkenyl, -NH- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -NH-heterocycloalkenyl, -O- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -O-heterocycloalkenyl, SO 2-(C0-2 alkylene, - (C 0-2 alkylene) -SO 2 -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, SO 2 -heterocycloalkenyl, - (C 0-2 alkylene) -aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, -CONH- (C 0-2 alkylene) -CONH-aryl, -C 0-2 alkylene) -heteroaryl - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, SO 2-(C0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and SO 2 -heteroaryl, preferably selected from the group consisting of- (C 0-2 alkylene) -cycloalkyl, -CO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CO-cycloalkyl, -CONH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NHCO-cycloalkyl, -NH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NH-cycloalkyl, -O- (C 0-2 alkylene) -cycloalkyl, - (C3443 alkylene) -O-62 alkylene) -O-cycloalkyl, SO 2-(C0-2 -cycloalkyl, - (C 0-2 alkylene) SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO 2 -cycloalkyl, - (C 0-2 alkylene) -heterocycloalkyl, -CO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NH-heterocycloalkyl, -O- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -O-heterocycloalkyl, SO 2-(C0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO 2 -heterocycloalkyl, - (C 0-2 alkylene) -aryl -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-heteroaryl, -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO- 0-2 alkylene) -NHCO -NH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, SO 2-(C0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and SO 2 -heteroaryl. The cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 2(C1-5 alkyl), -S (C 2(C1-5 haloalkyl), -SO 2(C1-5 haloalkyl), -NH 2(C1-5 alkyl), -NH (C 2(C1-5 haloalkyl), -N (C 2(C1-5 alkyl), -N (C 2(C1-5 haloalkyl) (C 2(C1-5 alkyl), -CONH 2 alkyl), and-CON (C 2(C1-5 alkyl), preferably selected from halogen, CN, OH, C 2(C1-5 alkyl, C2 haloalkyl, O (C 2(C1-5 alkyl), O (C 2(C1-5 haloalkyl), S (C 2(C1-5 haloalkyl), NH 2(C1-5 alkyl), NH (C 2(C1-5 haloalkyl), N 2(C1-5 alkyl (C 2(C1-5 haloalkyl) CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl). More preferably, the process is carried out, R 4 is selected from the group consisting of- (C 0-2 alkylene) -aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-heteroaryl, -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, SO 2-(C0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and SO 2 -heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 42 alkyl), -S (C 1-5 haloalkyl), -SO (C 1-5 haloalkyl), -SO 35haloalkyl), -C4326 haloalkyl), -N (528) alkyl, -NH (65343 haloalkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), O (C 15 haloalkyl), SH, S (C 15 alkyl), S (C 15 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 15 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl).
In certain embodiments, R 4 is selected from the group consisting of- (C 0-2 alkylene) -CO-cycloalkyl, preferably-CO-cyclohexyl, and- (C 0-2 alkylene) -CO-aryl, preferably-CO-phenyl.
In certain embodiments, R 4 is selected from-COO- (C 1-5 alkyl) or-CONH- (C 1-5 alkyl).
In a specific embodiment, R 4 is selected from:
Preferably, Y R5 is a covalent bond. Thus, R 4 is preferably selected from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl, more preferably from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. More preferably, R 4 is selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl. More preferably, R 4 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. Even more preferably, R 4 is selected from aryl and heteroaryl. Most preferably, R 4 is heteroaryl. The alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). Said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 2(C1-5 alkyl), -S (C 1-5 haloalkyl), -SO (C 1-5 haloalkyl), -SO 2(C1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C2 alkyl, -C2 haloalkyl, -O (C2 alkyl), -O (C 1-5 haloalkyl), -S (1-5 haloalkyl), -NH 2 haloalkyl), -NH (1-5 haloalkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
Preferably, R 4 is a five-membered heteroaryl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 2(C1-5 alkyl), -S (C 1-5 haloalkyl), -SO (C 1-5 haloalkyl), -SO 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2 alkyl) and-CON (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -S (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (1-5 haloalkyl), -N (C 1-5 alkyl), -N 1-5 haloalkyl), -C 1-5 haloalkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). The five membered heteroaryl group is preferably selected from imidazolyl, isoxazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl or 1,3, 4-thiadiazolyl. More preferably, the five membered heteroaryl is 1,2, 4-thiadiazolyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 2(C1-5 alkyl), -S (C 1-5 haloalkyl), -SO (C 1-5 haloalkyl), -SO 2(C1-5 haloalkyl), -NH 2(C1-5 alkyl), -NH (C 2(C1-5 haloalkyl), -N (C 2(C1-5 alkyl), -N (C 2(C1-5 haloalkyl) (C 2(C1-5 alkyl), -CONH 2 alkyl) and-CON (C 2(C1-5 alkyl), preferably selected from halogen, -CN, -OH, C2 alkyl, -C 2(C1-5 haloalkyl, -O (C 2(C1-5 alkyl), -NH 2(C1-5 alkyl), preferably selected from the group consisting of C 2(C1-5 alkyl, -NH 2(C1-5 alkyl, -C 2(C1-5 alkyl, preferably, N (C 2(C1-5 alkyl) C 1-5 haloalkyl, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), more preferably optionally substituted with C 1-5 alkyl, C 1-5 haloalkyl, even more preferably optionally substituted with C 1-5 haloalkyl, preferably selected from-CH 2F、-CHF2 and CF 3, most preferably optionally substituted with-CHF 2.
In a specific embodiment, R 4 is
Preferably, the present invention relates to compounds of formula (I) wherein W is-NHS (O) 2 -. Thus, in another embodiment, the invention relates to a compound of formula (Ia):
R 1、R2、R3、R4、X1、X2、X3、X4 and X 5 in the compound of formula (Ia) are as defined above for the compound of formula (I).
In a preferred embodiment, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus, preferably, the compound of formula (Ia) is a compound of formula (Ib):
R 1、R4、X1、X2、X3、X4 and X 5 in the compound of formula (Ib) are as defined above for the compound of formula (I).
R 1 is selected from the group consisting of hydrogen, chlorine, fluorine, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl (C 1-2) haloalkyl, - (C 1-2 alkylene) -OH and- (C 1-2 alkylene) -O- (C 1-2 alkyl). Preferably, R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl. More preferably, R 1 is selected from cyano, (C 1-2) haloalkyl and (C 1-2) alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R 1 is cyano. Thus, in a preferred embodiment, the compound of formula (Ib) is a compound of formula (Ic):
R 4、X1、X2、X3、X4 and X 5 in the compound of formula (Ic) are as defined above for the compound of formula (I).
Also encompassed within the scope of the invention are compounds of formula (I) or compounds of formula (Ia) or compounds of formula (Ib) wherein R 1 is methyl. In certain preferred embodiments of the present invention, R 1 is methyl. Also encompassed within the scope of the invention are compounds of formula (I) or compounds of formula (Ia) or compounds of formula (Ib) wherein R 1 is fluoromethyl. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
Preferably, within the scope of the present invention, X 1 and X 3 are each CH. Thus, preferably, the compound of formula (I) of the present invention is a compound of formula (Id):
W, R 1、R2、R3、R4、X2、X4 and X 5 in the compound of formula (Id) are as defined above for the compound of formula (I).
Preferably, the present invention relates to compounds of formula (I) wherein W is-NHS (O) 2 -. Thus, in another embodiment, the compound of formula (Id) of the present invention is a compound of formula (Ie):
R 1、R2、R3、R4、X2、X4 and X 5 in the compound of formula (Ie) are as defined above for the compound of formula (I).
In a preferred embodiment, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus, preferably, the compound of formula (Ie) of the present invention is a compound of formula (If):
r 1、R4、X2、X4 and X 5 in the compounds of formula (If) are as defined above for the compounds of formula (I) of the invention.
Within the scope of the present invention, R 1 is preferably selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl. More preferably, R 1 is selected from cyano, (C 1-2) haloalkyl and (C 1-2) alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R 1 is cyano.
Thus, preferably, the compound of formula (If) of the present invention is a compound of formula (ig):
R 4、X2、X4 and X 5 in the compounds of formula (Ig) are as defined above for the compounds of formula (I) of the invention.
Within the scope of the present invention, compounds of formula (Id) or compounds of formula (Ie) or compounds of formula (If) wherein R 1 is methyl are also encompassed within the present invention. In certain preferred embodiments of the present invention, R 1 is methyl. Also encompassed within the scope of the invention are compounds of formula (Id) or compounds of formula (Ie) or compounds of formula (If) wherein R 1 is fluoromethyl. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
As contemplated by the present invention, X 4 is N or C-R C4 and X 5 is N or C-R C5. Furthermore, as defined above, preferably no more than one of X 4 and X 5 is N. In certain embodiments of the invention, X 5 is N. Thus, if X 5 is N, preferably X 4 is C-R C4. Thus, in certain preferred embodiments the compound of formula (I) is a compound of formula (Ih):
W, R C4、R1、R2、RS、R4、X1、X2 and X 3 in the compound of formula (Ih) are as defined above for the compound of formula (I).
Preferably, within the scope of the present invention, W is-NHS (O) 2 -. Thus, preferably, the compound of formula (I) or the compound of formula (Ia) or the compound of formula (Ih) is a compound of formula (Ii):
r C4、R1、R2、R3、R4、X1、X2 and X 3 in the compound of formula (Ii) are as defined above for the compound of formula (I).
In a preferred embodiment, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus, preferably, the compound of formula (Ii) of the present invention is a compound of formula (Ij):
R C4、R1、R4、X1、X2 and X 3 in the compound of formula (Ij) are as defined above for the compound of formula (I).
Within the scope of the present invention, preferably R 1 is hydrogen, chlorine, fluorine, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl. More preferably, R 1 is selected from cyano, (C 1-2) haloalkyl and (C 1-2) alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R 1 is cyano.
Thus, it is preferred within the scope of the present invention that the compound of formula (I) or the compound of formula (Ib) or the compound of formula (Ic) or the compound of formula (Ih) or the compound of formula (Ii) or the compound of formula (Ij) of the present invention is a compound of formula (Ik):
R C4、R4、X1、X2 and X 3 in the compound of formula (Ik) are as defined above for the compound of formula (I).
In one embodiment of the compounds of formula (I) of the present invention, X 1 and X 3 are each CH. Thus, preferably, the compound of formula (I) of the present invention is a compound of formula (IL):
W, R C4、R1、R2、R3、R4 and X 2 in the compound of formula (IL) are as defined above for the compound of formula (I).
Preferably, within the scope of the present invention, W is-NHS (O) 2 -. Thus, preferably, the compound of formula (IL) of the present invention is a compound of formula (Im):
R C4、R1、R2、R3、R4 and X 2 in the compound of formula (IL) are as defined above for the compound of formula (I).
Preferably, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus, preferably, the compound of formula (Im) of the present invention is a compound of formula (In):
R C4、R1、R4 and X 2 In the compound of formula (In) are as defined above for the compound of formula (I).
Within the scope of the present invention, preferably R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl. More preferably, R 1 is selected from cyano, (C 1-2) haloalkyl and (C 1-2) alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R 1 is cyano.
Accordingly, it is preferable within the scope of the present invention that the compound of formula (In) is a compound of formula (Io):
r C4、R4 and X 2 in the compound of formula (Io) are as defined above for the compound of formula (I).
Within the scope of the present invention, compounds of formula (IL) or compounds of formula (Im) or compounds of formula (In) wherein R 1 is methyl are also encompassed within the present invention. In certain preferred embodiments of the present invention, R 1 is methyl. Alternatively, within the scope of the present invention, compounds of formula (IL) or compounds of formula (Im) or compounds of formula (In) wherein R 1 is fluoromethyl are also encompassed within the present invention. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
In one embodiment of the compounds of formula (I) of the present invention R 4 is selected from aryl and heteroaryl. Most preferably, R 4 is heteroaryl. The aryl or heteroaryl groups are optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH2, -CONH (C 1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). Preferably, R 4 is a five-membered heteroaryl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). The five membered heteroaryl group is preferably selected from imidazolyl, isoxazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl or 1,3, 4-thiadiazolyl. More preferably, the five membered heteroaryl is 1,2, 4-thiadiazolyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably optionally substituted with C 1-5 alkyl, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), more preferably optionally substituted with C 1-5 alkyl, C 1-5 haloalkyl, even more preferably optionally substituted with C 1-5 haloalkyl, preferably selected from CHF 2F,-CHF2 and most preferably substituted with CHF 2.
Thus, in a preferred embodiment, the compound of formula (I) is a compound of formula (Ip):
W, R 1、R2、R3、X1、X2、X3、X4 and X 5 in the compound of formula (Ip) are as defined above for the compound of formula (I).
Preferably W is-NHS (O) 2 -. Thus, within the scope of the present invention, the compound of formula (Ip) is a compound of formula (Iq):
R 1、R2、R3、X1、X2、X3、X4 and X 5 in the compound of formula (Io) are as defined above for the compound of formula (I).
In another preferred embodiment, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus, in a preferred embodiment, the compound of formula (Iq) according to the invention is a compound according to formula (Ir):
R 1、X1、X2、X3、X4 and X 5 in the compound of formula (Ir) are as defined above for the compound of formula (I).
Further preferably, R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl. Preferably, R 1 is selected from cyano, (C 1-2) haloalkyl and (C 1-2) alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R 1 is cyano.
Thus, it Is preferred within the scope of the present invention that the compound of formula (Ir) Is a compound of formula (Is):
x 1、X2、X3、X4 and X 5 in the compound of formula (Ir) are as defined above for the compound of formula (I).
It should be noted that compounds of formula (Ip) or compounds of formula (Iq) or compounds of formula (Ir) wherein R 1 is methyl are also encompassed within the scope of the present invention. In certain preferred embodiments of the present invention, R 1 is methyl. It should also be noted that alternatively a compound of formula (Ip) or a compound of formula (Iq) or a compound of formula (Ir) wherein R 1 is fluoromethyl is also contemplated within the scope of the invention. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
Further preferred within the scope of the present invention are embodiments wherein X 1 and X 3 are each CH.
Thus, the compounds of formula (Ip) of the present invention are also directed to embodiments wherein the compound of formula (Ip) is a compound of formula (It):
W, R 1、R2、R3、X2、X4 and X 5 in the compound of formula (It) are as defined above for the compound of formula (I).
Preferably, W is-NHS (O) 2 -. Thus, further within the scope of the present invention, the compounds of formula (Iq) of the present invention are also embodiments wherein the compound of formula (Iq) is a compound of formula (Iu),
R 1、R2、R3、X2、X4 and X 5 in the compound of formula (Iu) are as defined above for the compound of formula (I).
Preferably in the compounds of formula (Iu) R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl.
Thus, as further covered by the present invention, the compounds of formula (Ir) of the present invention are also directed to embodiments wherein the compound of formula (Ir) is a compound of formula (Iv),
R 1、X2、X4 and X 5 in the compound of formula (Iv) are as defined above for the compound of formula (I).
Since R 1 Is preferably cyano, the compounds of formula (Is) of the invention are also directed to embodiments wherein the compounds of formula (Is) are or are of formula (Iw)
X 2、X4 and X 5 in the compound of formula (Iw) are as defined above for the compound of formula (I).
Also encompassed within the scope of the invention are compounds of formula (It) or compounds of formula (Iu) or compounds of formula (Iv) wherein R 1 is methyl. In certain preferred embodiments of the present invention, R 1 is methyl. Alternatively, it is also within the scope of the present invention for the compound of formula (It) or the compound of formula (Iu) or the compound of formula (Iv) wherein R 1 is fluoromethyl. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
As contemplated by the present invention, X 4 is N or C-R C4 and X 5 is N or C-R C5. Furthermore, as defined above, preferably no more than one of X 4 and X 5 is N. In certain embodiments of the invention, X 5 is N. Thus, if X 5 is N, preferably X 4 is C-R C4. Thus, in certain preferred embodiments the compound of formula (It) is a compound of formula (Ix):
W, R C4、R1、R2、R3 and X 2 in the compound of formula (Ix) are as defined above for the compound of formula (I).
Further correspondingly, since preferably within the scope of the present invention W is-NHS (O) 2 -, the compound of formula (Iu) is in certain preferred embodiments a compound of formula (Iy):
R C4、R1、R2、R3 and X 2 in the compound of formula (Iy) are as defined above for the compound of formula (I).
Preferably R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus further accordingly, in certain preferred embodiments the compound of formula (Iv) is a compound of formula (Iz):
R C4、R1 and X 2 in the compound of formula (Iz) are as defined above for the compound of formula (I).
Within the scope of the present invention, preferably R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl. More preferably, R 1 is selected from cyano, (C 1-2) haloalkyl and (C 1-2) alkyl, preferably cyano, fluoromethyl and methyl. More preferably, R 1 is cyano. Thus, further correspondingly, in certain preferred embodiments the compound of formula (Iw) is a compound of formula (Iaa):
R C4, and X 2 in the compound of formula (Iaa) are as defined above for the compound of formula (I).
It should be noted, however, that compounds of formula (Ix) or compounds of formula (Iy) or compounds of formula (Iz) wherein R 1 is methyl are also encompassed within the scope of the present invention. In certain preferred embodiments of the present invention, R 1 is methyl. It should also be noted that alternatively a compound of formula (Ix) or a compound of formula (Iy) or a compound of formula (Iz) wherein R 1 is fluoromethyl is also contemplated within the scope of the present invention. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
Preferably X 2 is C-Y C2-RC2 within the scope of the present invention. Most preferably, -Y C2-RC2 is piperazinyl (preferably N-piperazinyl) substituted (preferably N-substituted, preferably at an N atom different from the N atom attached to the ring system as shown in formula (I)) by-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably by-CON (CH 3)2).
Thus, preferably, the compounds of formula (I) of the present invention are compounds of formula (Iab):
W, R 1、R2、R3、R4、X1、X3、X4 and X 5 in the compounds of formula (Iab) are as defined for the compounds of formula (I) of the invention.
Preferably W is-NHS (O) 2 -. Thus, preferably the compound of formula (Ia) or the compound of formula (Iab) of the present invention is a compound of formula (Iac):
R 1、R2、R3、R4、X1、X3、X4 and X 5 in the compounds of formula (Iac) are as defined for the compounds of formula (I) of the invention.
Preferably, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus further correspondingly, it is preferred that the compound of formula (Iac) or the compound of formula (Ib) of the invention is a compound of formula (Iad):
R 1、R4、X1、X3、X4 and X 5 in the compounds of formula (Iad) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, preferably, R 1 is cyano, and thus preferably the compound of formula (Ic) of the invention or the compound of formula (Iad) of the invention is a compound of formula (Iae):
R 4、X1、X3、X4 and X 5 in the compounds of formula (Iae) are as defined for the compounds of formula (I) of the invention.
It should be noted, however, that compounds of formula (Iab) or compounds of formula (Iac) or compounds of formula (Iad) wherein R 1 is methyl are also contemplated within the scope of the present invention. In certain preferred embodiments of the present invention, R 1 is methyl. Alternatively, it should be noted that compounds of formula (Iab) or compounds of formula (Iac) or compounds of formula (Iad) wherein R 1 is fluoromethyl are also contemplated within the scope of the invention. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
Further preferred within the scope of the present invention are embodiments wherein X 1 and X 3 are each CH.
Accordingly, the compound of formula (Iac) of the present invention is accordingly preferably a compound of formula (Iag):
W, R 1、R2、R3、R4、X4 and X 5 in the compounds of formula (Iaf) are as defined for the compounds of formula (I) according to the invention.
Preferably W is-NHS (O) 2 -. Further correspondingly, the compound of formula (Iad) or the compound of formula (Iaf) of the invention as defined herein is preferably a compound of formula (Iag):
R 1、R2、R3、R4、X4 and X 5 in the compounds of formula (Iag) are as defined for the compounds of formula (I) of the invention.
Preferably, R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Further correspondingly, the compound of formula (Iae) or the compound of formula (Iag) of the present invention is preferably a compound of formula (Iah):
R 1、R4、X4 and X 5 in the compounds of formula (Iah) are as defined for the compounds of formula (I) of the invention.
Preferably, R 1 is cyano. Accordingly, further correspondingly, the compound of formula (Iaf) of the invention or the compound of formula (Iah) of the invention is preferably a compound of formula (Iai):
R 4、X4 and X 5 in the compounds of formula (Iai) are as defined for the compounds of formula (I) of the invention.
Also encompassed within the scope of the invention are compounds of formula (Iaf) or compounds of formula (Iag) or compounds of formula (Iah) wherein R 1 is methyl. In certain preferred embodiments of the present invention, R 1 is methyl. Alternatively, it is also within the scope of the present invention for the compound of formula (Iaf) or the compound of formula (Iag) or the compound of formula (Iah) wherein R 1 is fluoromethyl. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
As further contemplated by the present invention, X 4 is N or C-R C4 and X 5 is N or C-R C5. Furthermore, as defined above, preferably no more than one of X 4 and X 5 is N. In certain embodiments of the invention, X 5 is N. Thus, if X 5 is N, preferably X 4 is C-R C4.
Accordingly, the compounds of formula (Iab) according to the invention are therefore preferably compounds of formula (Iaj):
W, R C4、R1、R2、R3、R4、X1 and X 3 in the compounds of formula (Iaj) are as defined for the compounds of formula (I) according to the invention.
W is preferably-NHS (O) 2 -. Thus further correspondingly, the compound of formula (Iac) or the compound of formula (Iaj) of the invention is preferably a compound of formula (Iak):
r C4、R1、R2、R3、R4、X1 and X 3 in the compounds of formula (Iak) are as defined for the compounds of formula (I) of the invention.
As disclosed herein, preferably R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl. Thus further correspondingly, the compound of formula (Iad) or the compound of formula (Iak) of the invention is preferably a compound of formula (IaL):
R C4、R1、R4、X1 and X 3 in the compounds of formula (IaL) are as defined for the compounds of formula (I) of the invention.
Further preferably R 1 is cyano. Thus further correspondingly, the compound of formula (Iae) or the compound of formula (IaL) of the present invention is preferably a compound of formula (Iam):
R C4、R4、X1 and X 3 in the compounds of formula (Iam) are as defined for the compounds of formula (I) according to the invention.
Also encompassed within the scope of the invention are compounds of formula (Iaj) or compounds of formula (Iak) or compounds of formula (IaL) wherein R 1 is methyl. In certain preferred embodiments of the present invention, R 1 is methyl. Furthermore, it is also within the scope of the present invention for the compound of formula (Iaj) or the compound of formula (Iak) or the compound of formula (IaL) to be wherein R 1 is fluoromethyl. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
Further correspondingly, the compound of formula (Iaf) of the present invention is preferably a compound of formula (Ian):
W, R 1、R2、R3、R4 and R C4 in the compounds of formula (Ian) are as defined for the compounds of formula (I) of the invention. Further correspondingly, the compound of formula (Iag) of the present invention is preferably a compound of formula (Iao):
R 1、R2、R3、R4 and R C4 in the compounds of formula (Iao) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, the compound of formula (Iah) of the present invention is preferably a compound of formula (Iap):
R 1、R4 and R C4 in the compounds of formula (Iap) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, the compound of formula (Iai) of the present invention is preferably a compound of formula (Iag):
R 4 and R C4 in the compounds of formula (Iaq) are as defined for the compounds of formula (I) of the invention.
As further contemplated by the present invention, X 4 is N or C-R C4 and X 5 is N or C-R C5. Furthermore, as defined above, preferably no more than one of X 4 and X 5 is N. In certain embodiments of the invention, X 4 is N. Thus, if X 4 is N, preferably X 5 is C-R C5.
Accordingly, in certain preferred embodiments of the present invention, the compound of formula (I) of the present invention is a compound of formula (Iar):
W, R 1、R2、R3、R4、X1、X2、X3 and R C5 in the compounds of formula (Iar) are as defined for the compounds of formula (I) according to the invention.
Further correspondingly, since W is preferably-NHS (O) 2 -, in certain preferred embodiments of the invention, the compound of formula (Ia) of the invention is a compound of formula (Ias):
R 1、R2、R3、R4、X1、X2、X3 and R C5 in the compounds of formula (Iar) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, since preferably R 2 and R 3 form together with the carbon atom to which they are attached a cyclopropyl group, in certain preferred embodiments of the invention, the compounds of formula (Ib) of the invention are compounds of formula (Iat):
R 1、R4、X1、X2、X3 and R C5 in the compounds of formula (Iat) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, since preferably R 1 is cyano, in certain preferred embodiments of the invention, the compound of formula (Ic) of the invention is a compound of formula (Iau):
R 4、X1、X2、X3 and R C5 in the compounds of formula (Iau) are as defined for the compounds of formula (I) of the invention.
However, it is also within the scope of the present invention for the compound of formula (Iar) or the compound of formula (Ias) or the compound of formula (Iat) wherein R 1 is methyl. In certain preferred embodiments of the present invention, R 1 is methyl. Furthermore, it is also within the scope of the present invention for the compound of formula (Iar) or the compound of formula (Ias) or the compound of formula (Iat) wherein R 1 is fluoromethyl. In certain preferred embodiments of the present invention, R 1 is fluoromethyl.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (Id) of the present invention is a compound of formula (Iav):
W, R 1、R2、R3、R4、X2 and R C5 in the compounds of formula (Iav) are as defined for the compounds of formula (I) according to the invention.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (Ie) of the present invention is a compound of formula (Iaw):
r 1、R2、R3、R4、X2 and R C5 in the compounds of formula (Iaw) are as defined for the compounds of formula (I) of the invention.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (If) of the present invention is a compound of formula (Iax):
R 1、R4、X2 and R C5 in the compounds of formula (Iax) are as defined for the compounds of formula (I) of the invention.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (Ig) of the present invention is a compound of formula (Iay):
r 4、X2 and R C5 in the compounds of formula (Iay) are as defined for the compounds of formula (I) of the invention.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (Ip) of the present invention is a compound of formula (Iaz):
W, R 1、R2、R3、X1、X2、X3 and R C5 in the compounds of formula (Iaz) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, since preferably W is-NHS (O) 2 -, in certain preferred embodiments of the invention, the compound of formula (Iq) of the invention is a compound of formula (Iba):
R 1、R2、R3、X1、X2、X3 and R C5 in the compounds of formula (Iba) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, since preferably R 2 and R 3 form together with the carbon atom to which they are attached a cyclopropyl group, in certain preferred embodiments of the invention, the compounds of formula (Ir) according to the invention are compounds of formula (Ibb):
R 1、X2 and R C5 in the compounds of formula (Ibb) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, since preferably R 1 Is cyano, in certain preferred embodiments of the invention, the compounds of formula (Is) of the invention are compounds of formula (Ibc):
further preferred within the scope of the present invention are embodiments wherein X 1 and X 3 are each CH. Thus, in certain preferred embodiments, the compound of formula (It) is a compound of formula (Ibd):
W, R 1、R2、R3、X2 and R C5 in the compounds of formula (Ibd) are as defined for the compounds of formula (I) of the invention.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (Iu) of the present invention is a compound of formula (Ibe):
R 1、R2、R3、X2 and R C5 in the compounds of formula (Ibe) are as defined for the compounds of formula (I) of the invention.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (Iv) of the present invention is a compound of formula (Ibf):
R 1、X2 and R C5 in the compounds of formula (Ibf) are as defined for the compounds of formula (I) of the invention.
Further accordingly, in certain preferred embodiments of the present invention, the compound of formula (Iw) of the present invention is a compound of formula (Ibg):
X 2 and R C5 in the compounds of formula (Ibf) are as defined for the compounds of formula (I) of the invention.
In certain embodiments of the present invention, preferably X 2 is C-Y C2-RC2. Most preferably, -Y C2-RC2 is piperazinyl (preferably N-piperazinyl) substituted (preferably N-substituted, preferably at an N atom different from the N atom attached to the ring system as shown in formula (I)) by-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably by-CON (CH 3)2).
Accordingly, in certain preferred embodiments of the present invention, the compound of formula (Iab) is a compound of formula (Ibh):
W, R 1、R2、R3、R4、X1、X3 and R c5 in the compounds of formula (Ibh) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, in certain preferred embodiments of the invention the compound of formula (Iac) is a compound of formula (Ibi):
R 1、R2、R3、R4、X1、X3 and R C5 in the compounds of formula (Ibi) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, in certain preferred embodiments of the present invention the compound of formula (Iad) is a compound of formula (Ibj):
R 1、R4、X1、X3 and R C5 in the compounds of formula (Ibi) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, in certain preferred embodiments of the invention the compound of formula (Iae) is a compound of formula (Ibk):
R 4、X1、X3 and R C5 in the compounds of formula (Ibi) are as defined for the compounds of formula (I) of the invention.
Further preferred within the scope of the present invention are embodiments wherein X 1 and X 3 are each CH. Thus, in certain preferred embodiments, the compound of formula (Iaf) is a compound of formula (IbL):
W, R 1、R2、R3、R4 and R C5 in the compounds of formula (IbL) are as defined for the compounds of formula (I) of the invention. Further correspondingly, in certain preferred embodiments of the invention the compound of formula (Iag) is a compound of formula (Ibm):
R 1、R2、R3、R4 and R C5 in the compounds of formula (Ibm) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, in certain preferred embodiments of the invention the compound of formula (Iah) is a compound of formula (Ibn):
R 1、R4 and R C5 in the compounds of formula (Ibn) are as defined for the compounds of formula (I) of the invention.
Further correspondingly, in certain preferred embodiments of the present invention the compound of formula (Iai) is a compound of formula (Ibo):
R 4 and R C5 in the compounds of formula (Ibn) are as defined for the compounds of formula (I) of the invention.
In certain embodiments of the invention, X 1 is CF and X 3 is CH. Thus, the compound of formula (I) is a compound of formula (Ibp):
w, R 1、R2、R3、R4、X2、X4 and X 5 in the compound of formula (Ibp) are as defined above for the compound of formula (I).
Further correspondingly, since preferably W is-NHS (O) 2 -, in certain preferred embodiments of the invention, the compound of formula (Ibp) of the present invention is a compound of formula (Ibq):
R 1、R2、R3、R4、X2、X4 and X 5 in the compound of formula (Ibq) are as defined above for the compound of formula (I).
Further correspondingly, since preferably R 2 and R 3 form together with the carbon atom to which they are attached a cyclopropyl group, in certain preferred embodiments of the invention, the compounds of formula (Ibq) of the invention are compounds of formula (Ibr):
R 1、R4、X2、X4 and X 5 in the compound of formula (Ibr) are as defined above for the compound of formula (I).
Further, since preferably R 1 is cyano, in certain preferred embodiments of the invention, the compounds of formula (Ibr) of the present invention are compounds of formula (Ibs):
R 4、X2、X4 and X 5 in the compounds of formula (Ibs) are as defined above for the compounds of formula (I).
It should be noted, however, that compounds of formula (Ibp), (Ibq) or (Ibr) wherein R 1 is methyl or fluoromethyl are also contemplated within the scope of the present invention.
In certain embodiments of the present invention, preferably X 2 is C-Y C2-RC2. Most preferably, -Y C2-RC2 is piperazinyl (preferably N-piperazinyl) substituted (preferably N-substituted, preferably at an N atom different from the N atom attached to the ring system as shown in formula (I)) by-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably by-CON (CH 3) 2.
Accordingly, in certain embodiments of the invention the compound of formula (Ibp) is a compound of formula (Ibt):
W, R 1、R2、R3、R4、X4 and X 5 in the compound of formula (Ibt) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Ibq) is a compound of formula (Ibu):
r 1、R2、R3、R4、X4 and X 5 in the compound of formula (Ibu) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Ibr) is a compound of formula (Ibv).
R 1、R4、X4 and X 5 in the compound of formula (Ibv) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Ibs) is a compound of formula (Ibw).
R 4、X4 and X 5 in the compound of formula (Ibt) are as defined above for the compound of formula (I).
It should be noted, however, that compounds of formula (Ibt), (Ibu) or (Ibv) wherein R 1 is methyl or fluoromethyl are also contemplated within the scope of the invention.
In certain preferred embodiments, X 4 is C-R C4 and X 5 is C-R C5. Thus, the compound of formula (I) is in certain embodiments a compound of formula (Ibx):
W, R 1、R2、R3、R4、RC4、RC5、X1、X2 and X 3 in the compound of formula (Ibx) are as defined above for the compound of formula (I).
Further correspondingly, since preferably W is-NHS (O) 2 -, in certain preferred embodiments of the invention, the compound of formula (Ibx) of the invention is a compound of formula (Iby):
R 1、R2、R3、R4、RC4、RC5、X1、X2 and X 3 in the compound of formula (Iby) are as defined above for the compound of formula (I).
Further correspondingly, since preferably R 2 and R 3 form together with the carbon atom to which they are attached a cyclopropyl group, in certain preferred embodiments of the invention, the compounds of formula (Iby) of the invention are compounds of formula (Ibz):
R 1、R4、RC4、RC5、X1、X2 and X 3 in the compound of formula (Ibz) are as defined above for the compound of formula (I).
Further correspondingly, since preferably R 1 is cyano, in certain preferred embodiments of the invention, the compound of formula (Ibz) of the invention is a compound of formula (Ica):
R 4、RC4、RC5、X1、X2 and X 3 in the compound of formula (Ica) are as defined above for the compound of formula (I).
It should be noted, however, that compounds of formula (Ibx), (Iby) or (Ibz) wherein R 1 is methyl or fluoromethyl are also contemplated within the scope of the invention.
In certain preferred embodiments X 1 is CH and X 3 is CH.
Accordingly, in certain embodiments of the invention the compound of formula (Ibx) is a compound of formula (Icb):
W, R 1、R2、R3、R4、RC4、RC5 and X 2 in the compound of formula (Icb) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Iby) is a compound of formula (Icc):
R 1、R2、R3、R4、RC4、RC5 and X 2 in the compound of formula (Icc) are as defined above for the compound of formula (I). Further correspondingly, in certain embodiments of the invention the compound of formula (Ibz) is a compound of formula (Icd):
R 1、R4、RC4、RC5 and X 2 in the compound of formula (Icd) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Ica) is a compound of formula (Ice):
R 4、RC4、RC5 and X 2 in the compound of formula (Ice) are as defined above for the compound of formula (I).
In certain preferred embodiments X 4 is CH and X 5 is CH.
Accordingly, in certain embodiments of the present invention the compound of formula (Icb) is a compound of formula (Icf):
W, R 1、R2、R3、R4 and X 2 in the compound of formula (Icf) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Icc) is a compound of formula (Icg):
r 1、R2、R3、R4 and X 2 in the compound of formula (Icg) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Icd) is a compound of formula (Ich):
R 1、R4 and X 2 in the compound of formula (ICh) are as defined above for the compound of formula (I).
Further correspondingly, in certain embodiments of the invention the compound of formula (Icd) is a compound of formula (Ici):
r 4 and X 2 in the compound of formula (Ici) are as defined above for the compound of formula (I).
Preferred compounds of formula (I) are selected from the following compounds:
or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof.
Further preferred compounds of formula (I) are selected from:
Or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystal form, pharmaceutically acceptable salt or prodrug thereof. /(I)
Further preferred compounds of formula (I) are selected from:
further preferred compounds of formula (I) are selected from:
further preferred compounds of formula (I) are selected from:
Further preferred compounds of formula (I) are selected from
Further preferred compounds of formula (I) arePreferably
Particularly preferred are exemplary compounds as described below, namely compounds 1 to 299. Preferably, the compound of formula (I) is selected from:
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
The invention also relates to each of the intermediates described further below in the examples section of this specification, including any of these intermediates in non-salt form or in salt (e.g., pharmaceutically acceptable salt) form of the corresponding compound. Such intermediates are particularly useful in the synthesis of compounds of formula (I).
The scope of the present invention encompasses all pharmaceutically acceptable salt forms of the compounds of formula (I), which may be formed, for example, by protonation of an atom carrying a lone pair of electrons susceptible to protonation, such as an amino group, with an inorganic or organic acid, or as salts of an acid group, such as a carboxylic acid group, with a physiologically acceptable cation. Exemplary base addition salts include, for example: alkali metal salts such as sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; zinc salts; an ammonium salt; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine salts, meglumine salts, ethylenediamine salts, or choline salts; aralkylamine salts such as N, N-dibenzylethylenediamine salt, benzathine salt, phenethylbenzylamine salt; heterocyclic aromatic amine salts such as pyridinium, picolinium, quinolinium or isoquinolinium salts; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt; and basic amino acid salts such as arginine, lysine or histidine salts. Exemplary acid addition salts include, for example: inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate (such as sulfate or bisulfate), nitrate, phosphate (such as phosphate, hydrogen phosphate or dihydrogen phosphate), carbonate, bicarbonate, perchlorate, borate or thiocyanate; organic acid salts such as acetate, propionate, butyrate, valerate, caproate, heptanoate, caprylate, cyclopentanepropionate, caprate, undecanoate, oleate, stearate, lactate, maleate, oxalate, fumarate, tartrate, malate, citrate, succinate, adipate, gluconate, glycolate, nicotinate, benzoate, salicylate, ascorbate, pamoate, camphorite, glucoheptanoate, or pivalate; sulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate (isethionate), benzenesulfonate, p-toluenesulfonate (tosylate), 2-naphthalenesulfonate, 3-benzenesulfonate or camphorsulfonate; glycerophosphate; and acidic amino acid salts such as aspartate or glutamate. Preferred pharmaceutically acceptable salts of the compounds of formula (I) include hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate and phosphate. Particularly preferred pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride salts. Thus, it is preferred that the compound of formula (I) (including any of the specific compounds of formula (I) described herein) be in the form of the hydrochloride, hydrobromide, mesylate, sulfate, tartrate, fumarate, acetate, citrate or phosphate salt, and it is particularly preferred that the compound of formula (I) be in the form of the hydrochloride salt.
The present invention also relates specifically to compounds of formula (I) in non-salt form, including any of the specific compounds of formula (I) described herein.
Furthermore, the scope of the present invention encompasses compounds of formula (I) in any solvated form, including, for example, solvates with water (i.e., as a hydrate) or with organic solvents such as methanol, ethanol, isopropanol, acetic acid, ethyl acetate, ethanolamine, DMSO, or acetonitrile. All physical forms of the compounds of formula (I), including any amorphous or crystalline forms (i.e. polymorphs), are also encompassed within the scope of the present invention. It is to be understood that such solvates and physical forms of pharmaceutically acceptable salts of the compounds of formula (I) are also encompassed within the present invention.
Furthermore, the compounds of formula (I) may exist in the form of different isomers, in particular stereoisomers (including, for example, geometric isomers (or cis/trans isomers), enantiomers and diastereomers) or tautomers (including, in particular, proton-mobile tautomers such as keto/enol tautomers or thioketone/thiol tautomers). All such isomers of the compounds of formula (I) are considered as part of the present invention, either in mixture or in pure or substantially pure form. As regards stereoisomers, the invention covers isolated optical isomers of the compounds according to the invention as well as any mixtures thereof (including in particular racemic mixtures/racemates). The racemates may be resolved by physical means, such as fractional crystallization, separation or crystallization of diastereoisomeric derivatives, or separation by chiral column chromatography. The individual optical isomers can also be obtained from the racemates by salt formation with an optically active acid followed by crystallization. The invention also encompasses any tautomer of the compound of formula (I). It is understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein explicitly show only one of the possible tautomeric forms. The formulae and chemical names provided herein are intended to encompass any tautomeric form of the corresponding compounds, and are not limited to only the specific tautomeric form depicted in the drawings or identified by the compound name.
The scope of the present invention also encompasses compounds of formula (I) wherein one or more atoms are replaced by a specific isotope of the corresponding atom. For example, the present invention encompasses compounds of formula (I) wherein one or more hydrogen atoms (or e.g., all hydrogen atoms) are replaced with deuterium atoms (i.e., 2 H; also referred to as "D"). Thus, the present invention also encompasses deuterium enriched compounds of formula (I). Naturally occurring hydrogen is an isotopic mixture comprising about 99.98mol-% hydrogen-1 (1 H) and about 0.0156mol-% deuterium (2 H or D). Deuterium levels at one or more hydrogen positions in the compound of formula (I) may be increased using deuteration techniques known in the art. For example, the compounds of formula (I) or reactants or precursors for synthesizing the compounds of formula (I) may be subjected to an H/D exchange reaction by using, for example, heavy water (D 2 O). Additional suitable deuteration techniques are described in: atzrodt J et al, bioorg Med Chem, volume 20, 18, pages 5658-5667, 2012; william JS et al Journal of Labelled Compounds and Radiopharmaceuticals, volume 53, pages 11-12, pages 635-644, 2010; modvig A et al, J Org Chem, volume 79, pages 5861-5868, 2014. The deuterium content can be determined, for example, using mass spectrometry or NMR spectrometry. Unless otherwise specifically indicated, it is preferred that the compound of formula (I) is not enriched in deuterium. Thus, the presence of a naturally occurring hydrogen atom or 1 H hydrogen atom in the compound of formula (I) is preferred.
The invention also encompasses compounds of formula (I) wherein one or more atoms are replaced by positron emitting isotopes of the corresponding atoms, such as 18F、11C、13N、15O、76Br、77Br、120 I and/or 124 I. Such compounds may be used as tracers, tracers or imaging probes in Positron Emission Tomography (PET). Thus, the invention includes (I) a compound of formula (I) wherein one or more fluorine atoms (or e.g., all fluorine atoms) are replaced with 18 F atoms, (ii) a compound of formula (I) wherein one or more carbon atoms (or e.g., all carbon atoms) are replaced with 11 C atoms, (iii) a compound of formula (I) wherein one or more nitrogen atoms (or e.g., all nitrogen atoms) are replaced with 13 N atoms, (iv) a compound of formula (I) wherein one or more oxygen atoms (or e.g., all oxygen atoms) are replaced with 15 O atoms, (v) a compound of formula (I) wherein one or more bromine atoms (or e.g., all bromine atoms) are replaced with 76 Br atoms, (vi) a compound of formula (I) wherein one or more bromine atoms (or e.g., all bromine atoms) are replaced with 77 Br atoms, (vii) a compound of formula (I) wherein one or more iodine atoms (or e.g., all iodine atoms) are replaced with 120 I atoms, and (viii) a compound of formula (I) wherein one or more bromine atoms (or more iodine atoms) are replaced with 124 atoms. Generally, it is preferred that none of the atoms in the compound of formula (I) be replaced by a specific isotope.
The invention also encompasses prodrugs of compounds of formula (I). As preferably understood herein, the term "prodrug" of a compound of formula (I) refers to a derivative of a compound of formula (I) that is metabolized to the compound of formula (I) upon administration to a subject. The prodrug of the compound of formula (I) may comprise a modification of the-OH, -NH 2 or-COOH group, which if present in the compound of formula (I) may preferably be hydrolysed to the-OH, -NH 2 or-COOH group, respectively, for example, after administration to a subject. For example, as known to the skilled person, such prodrugs may preferably comprise compounds of formula (I) comprising a derivative of an-OH moiety, wherein the-OH moiety is converted to an-OR X moiety, wherein R x preferably comprises a moiety selected from-CO-, -CH 2-O-CO,-CH2 -O-CO-O-and-CH (CH 3) -O-COO-, more preferably wherein R x is selected from-CO-R y、-CH2-O-CO-Ry、-CH2-O-CO-O-Ry and-CH (CH 3)-O-COO-Ry, wherein R y is preferably carbocyclyl, heterocyclyl, C 1-5 alkyl, -NH- (C 1-5 alkyl) OR-S- (C 1-5 alkyl), wherein the alkyl is optionally substituted with a group selected from: halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 1-5 alkyl), and-CON (C 1-5 alkyl), and wherein the carbocyclyl and heterocyclyl are each optionally substituted with a group selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl). Further, for example, such prodrugs may preferably comprise compounds of formula (I) comprising a derivative of the-NH 2 moiety, wherein the-NH 2 moiety is converted to the-NHCOO-R y moiety, wherein R y is as defined above, as known to the skilled person. Furthermore, for example, such prodrugs may preferably comprise compounds of formula (I) comprising a derivative of a-COOH moiety, wherein the-COOH group is converted to a-COOR y moiety, wherein R y is as defined above, as known to the skilled person. Additional examples of groups from which prodrugs can be derived are known to the skilled artisan.
Pharmaceutical composition
The compounds provided herein may be administered as the compounds themselves or may be formulated as pharmaceuticals. The drug/pharmaceutical composition may optionally comprise one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, antioxidants and/or solubilizers.
The pharmaceutical composition may comprise one or more solubilizing agents, such as polyethylene glycol, including polyethylene glycols having a molecular weight in the range of about 200Da to about 5000Da (e.g., PEG200, PEG300, PEG400, or PEG 600), ethylene glycol, propylene glycol, glycerin, nonionic surfactants, tyloxapol, polysorbate 80, polyethylene glycol-15-hydroxystearate (e.g.,HS15, CAS 70142-34-6), phospholipids, lecithins, dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, hydroxyethyl-gamma-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, dihydroxypropyl-beta-cyclodextrin, sulfobutyl ether-gamma-cyclodextrin, glucosyl-alpha-cyclodextrin, glucosyl-beta-cyclodextrin, diglucosyl-beta-cyclodextrin, maltosyl-alpha-cyclodextrin, maltosyl-beta-cyclodextrin, maltosyl-gamma-cyclodextrin, maltotriosyl-beta-cyclodextrin, methyl-beta-cyclodextrin, carboxyalkyl sulfide, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, vinyl acetate copolymer, sodium lauryl sulfate, or any combination thereof.
The pharmaceutical composition may further comprise one or more preservatives, in particular one or more antimicrobial preservatives such as benzyl alcohol, chlorobutanol, 2-ethoxyethanol, m-cresol, chlorocresol (e.g. 2-chloro-3-methyl-phenol or 4-chloro-3-methyl-phenol), benzalkonium chloride, isooctylphenoxyethylbenzyl dimethyl ammonium chloride, benzoic acid (or a pharmaceutically acceptable salt thereof), sorbic acid (or a pharmaceutically acceptable salt thereof), chlorhexidine, sodium ethylmercuric thiolate, or any combination thereof.
Pharmaceutical compositions may be formulated by techniques known to those skilled in the art, such as those described in "Remington: THE SCIENCE AND PRACTICE of Pharmacy ", pharmaceutical Press,22 edition". The pharmaceutical compositions may be formulated for oral, parenteral such as intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol or vaginal administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, troches, lozenges, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicinal chewing gums, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersions and powders and granules for reconstitution. Emulsions are preferred dosage forms for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and oval shaped dosage forms. Dosage forms for nasal administration may be administered by inhalation and insufflation, for example by a metered dose inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches and transdermal delivery systems.
The compounds of formula (I) or the above pharmaceutical compositions comprising the compounds of formula (I) may be administered to a subject by any convenient route of administration, whether systemic/peripheral or at the site of desired action, including but not limited to one or more of the following: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical (e.g., transdermal, intranasal, ocular, buccal, and sublingual), parenteral (e.g., using injection techniques or infusion techniques, and including, for example, administration by injection, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid, or intrasternal, by, e.g., a drug-eluting implant, e.g., subcutaneously or intramuscularly), pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through the mouth or nose), gastrointestinal, intrauterine, intraocular, subcutaneous, ocular (including intravitreal or intracameral), rectal, or vaginal.
If the compound or pharmaceutical composition is administered parenterally, examples of such administration include one or more of the following: the compound or pharmaceutical composition is administered intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricular, intraurethral, intrasternally, intracardiac, intracranial, intramuscular, or subcutaneously, and/or by using infusion techniques. For parenteral administration, the compounds are preferably used in the form of sterile aqueous solutions which may contain other substances, for example, sufficient salts or glucose to render the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably at a pH of 3-9) if desired. The preparation of a suitable parenteral formulation under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
The compounds or pharmaceutical compositions may also be administered orally in the form of tablets, capsules, ovals, elixirs, solutions or suspensions, which may contain flavoring or coloring agents for immediate release, delayed release, modified release, sustained release, pulsed release or controlled release applications.
Tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium carboxymethyl starch, croscarmellose sodium and certain complex silicates, and granulating binders such as polyvinylpyrrolidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glyceryl behenate, and talc may be included. Solid compositions of a similar type may also be used as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, emulsifying and/or suspending agents, as well as diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
For oral administration, the compound or pharmaceutical composition is preferably administered by oral ingestion, particularly by swallowing. Thus, the compound or pharmaceutical composition may be administered orally into the gastrointestinal tract, which may also be referred to as "oral-gastrointestinal" administration.
Alternatively, the compound or pharmaceutical composition may be administered in the form of a suppository or pessary, or may be topically applied in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of the present invention may also be administered transdermally or transdermally, for example, by the use of a skin patch.
The compound or pharmaceutical composition may also be administered via a slow release system. Suitable examples of sustained-release compositions include semipermeable polymer matrices in the form of shaped articles, e.g., films, or microcapsules. Sustained release matrices include, for example, polylactide, copolymers of L-glutamic acid and gamma-ethyl-L-glutamic acid, poly (hydroxyethyl 2-methacrylate), ethylene-vinyl acetate or poly-D- (-) -3-hydroxybutyric acid. Sustained release pharmaceutical compositions also include liposome encapsulated compounds. The invention therefore also relates to liposomes containing the compounds of the invention.
The compound or pharmaceutical composition may also be administered by the pulmonary, rectal or ocular route. For ophthalmic use, they may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or preferably as solutions in isotonic, pH adjusted sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, they may be formulated in ointments such as petrolatum.
It is also envisaged to prepare dry powder formulations of the compounds of formula (I) for pulmonary administration, in particular inhalation. Such dry powders may be prepared by spray drying under conditions that produce a substantially amorphous glassy or substantially crystalline bioactive powder. Thus, dry powders of the compounds of the present invention may be prepared according to an emulsion/spray-drying process.
For topical application to the skin, the compounds or pharmaceutical compositions may be formulated as suitable ointments containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid paraffin, white vaseline, polyethylene glycol, emulsifying wax and water. Alternatively, they may be formulated as suitable lotions or creams suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, 2-octyldodecanol, benzyl alcohol and water.
Accordingly, the present invention relates to a compound or pharmaceutical composition provided herein, wherein the corresponding compound or pharmaceutical composition is administered by any one of the following routes: an oral route; topical routes including percutaneous, intranasal, ocular, buccal or sublingual routes; parenteral routes using injection or infusion techniques include subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intra-articular, subarachnoid, intrasternal, intraventricular, intraurethral or intracranial routes; pulmonary routes, including by inhalation or insufflation therapy; gastrointestinal routes; an intrauterine route; an intraocular route; subcutaneous route; ocular pathways, including by intravitreal or intracameral pathways; a rectal route; or the vaginal route. The preferred route of administration is oral or parenteral. For each of the compounds or pharmaceutical compositions provided herein, oral administration (particularly by oral ingestion) of the corresponding compound or pharmaceutical composition is particularly preferred.
Typically, the physician will determine the actual dosage that is most appropriate for the individual subject. The particular dosage level and frequency of administration for any particular individual subject may vary and will depend upon a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual subject undergoing therapy.
The recommended, but non-limiting, dosage of the compounds of the invention for oral administration to humans (about 70kg body weight) may be from 0.05mg to 2000mg, preferably from 0.1mg to 1000mg, of active ingredient per unit dose. The unit dose may be administered, for example, 1 to 3 times per day. The unit dose may also be administered 1 to 7 times per week, for example no more than once per day. It will be appreciated that conventional changes in dosages may be required depending on the age and weight of the patient/subject and the severity of the condition to be treated. The precise dosage and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.
Therapeutic use
In one embodiment, the present invention relates to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in therapy.
The present invention provides compounds that act as PARG inhibitors. Accordingly, the present invention provides a method of inhibiting PARG enzyme activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.
The invention also provides methods of selectively inhibiting PARG enzyme activity relative to PARP1 or ARH3 enzyme activity in vitro or in vivo. The method comprises the step of contacting the cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.
In another embodiment, the present invention relates to a compound of formula (I) as disclosed herein for use in a method of treating a disease or disorder in which PARG activity is implicated in a subject or patient in need of such treatment. The method of treatment comprises administering to the subject/patient a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition. In other words, in one embodiment the present invention relates to a compound of formula (I) as disclosed herein for use in the treatment of a disease or disorder in which PARG activity is involved.
In another embodiment, the invention relates to a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof. Accordingly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in inhibiting cell proliferation in vitro or in vivo.
Thus, in another embodiment, the invention relates to a method of treating a proliferative disorder in a subject or patient in need of such treatment. The method of treating a proliferative disorder in a subject or patient in need thereof comprises administering to said subject/patient a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition. Preferably, as disclosed herein, the proliferative disorder is cancer. Accordingly, the present invention relates to a method of treating cancer in a subject or patient in need thereof. The method of treating cancer in a subject or patient in need thereof comprises administering to the subject/patient a therapeutically effective amount of the compound of formula (I) as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition. In a specific embodiment, the cancer is a human cancer.
In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a proliferative disorder. Preferably, as disclosed herein, the proliferative disorder is cancer. Accordingly, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in the treatment of cancer. In a specific embodiment, the cancer is a human cancer.
In another embodiment, the present invention relates to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a medicament for the treatment of a proliferative disorder. In a preferred embodiment, the proliferative disorder is cancer, more preferably human cancer. Thus, preferably the present invention relates to a compound of formula (I) as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a medicament for use in the treatment of cancer, preferably in the treatment of human cancer.
In another embodiment, the present invention relates to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a medicament for inhibiting PARG enzyme activity. Preferably, the inhibition of PARG enzyme activity is a selective inhibition of PARG enzyme activity relative to PARP1 or ARH3 enzyme activity. The present invention therefore relates to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a medicament for selectively inhibiting PARG enzyme activity relative to PARP1 or ARH3 enzyme activity.
The present invention also provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the manufacture of a medicament for the treatment of a disease or disorder in which PARG activity is implicated as defined herein.
As understood herein, the term "proliferative disorder" is used interchangeably herein and refers to undesired or uncontrolled excessive or abnormal cell proliferation of cells, such as tumor growth or proliferation growth, whether in vitro or in vivo. Examples of proliferative disorders include, but are not limited to, premalignant and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancers, leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Any type of cell may be treated, including but not limited to lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.
The antiproliferative effect of the compounds of formula (I) of the present invention has particular application in the treatment of human cancers (due to their inhibition of PARG enzyme activity). Anticancer effects may be produced by one or more mechanisms including, but not limited to, modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (diffusion of a tumor from its origin), inhibition of invasion (diffusion of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).
Antiproliferative treatment using a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate thereof as defined above may be applied as monotherapy or may include conventional surgery or radiation therapy or chemotherapy in addition to the compounds of the invention. Such chemotherapies may include one or more of the following classes of antineoplastic agents: -
(I) Other antiproliferative/antineoplastic agents for medical oncology and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotics (e.g. vinca alkaloids such as vincristine, vinblastine amide and vinorelbine, and taxanes such as paclitaxel and taxotere and polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecins);
(ii) Cytostatic agents such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide, and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5 oc-reductase inhibitors such as finasteride;
(iii) Antiinvasive agents [ e.g. c-Src kinase family inhibitors such as 4- (6-chloro-2, 3-methylenedioxyanilino) -7- [2- (4-methylpiperazin-1-yl) ethoxy ] -5-tetrahydropyran-4-yloxy quinazoline (AZD 0530; international patent application WO 01/94341), N- (2-chloro-6-methylphenyl) -2- {6- [4- (2-hydroxyethyl) piperazin-1-yl ] -2-methylpyridin-4-ylamino } thiazole 5-carboxamide (dasatinib, BMS-354825; J.Med. Chem.,2004, volume 47, pages 6658-6661) and bosutinib (SKI-606) metalloproteinase inhibitors such as Marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase ];
(iv) Inhibitors of growth factor function: such inhibitors include, for example, growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB 2 antibody trastuzumab [ Herceptin TM ], anti-EGFR antibody panitumumab, anti-erbB 1 antibody cetuximab [ Erbitux, C225], and any growth factor or growth factor receptor antibodies disclosed by stew et al (CRITICAL REVIEWS IN oncology/haematology,2005, volume 54, pages 11-29); such inhibitors also include tyrosine kinase inhibitors, e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, ZD 1839), N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) -quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib), inhibitors of the hepatocyte growth factor family, inhibitors of the insulin growth factor family, inhibitors of the platelet derived growth factor family such as imatinib and/or nilotinib (AMN 107), serine/threonine kinase inhibitors (e.g., CI 1033, erbB2 tyrosine kinase inhibitors, such as farnesyl transferase inhibitors, e.g., sorafenib (BAY 43-9006), tipifanib (R1 15777) and lonafil (SCH 66336)), cell signaling inhibitors through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g. AZD1 152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX 39459) and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors;
(v) Anti-angiogenic agents such as those inhibiting the action of vascular endothelial growth factor, [ e.g. anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM) and e.g. VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD 6474), vandetanib (PTK 787), sunitinib (SU 1 1248), axitinib (AG-0137636), pazopanib (GW 786034) and 4- (4-fluoro-2-methylindol-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylpropoxy) quinazoline (AZD 2171; example 240 in WO 00/47212), compounds such as those disclosed in international patent applications W097/22596, WO 97/30035, WO 97/32856 and WO 98/13354, and compounds acting by other mechanisms such as lenalidomide, inhibitors of integrin ανβ3 function and angiostatin) ].
(Vi) Vascular damaging agents such as combretastatin A4 and the compounds disclosed in International patent applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) Endothelin receptor antagonists such as ziprasidtan (ZD 4054) or atrasentan;
(viii) Antisense therapies, e.g., those targeting the above targets, such as the anti-ras antisense ISIS2503;
(ix) Gene therapy methods, including, for example, methods of replacing aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods of increasing patient tolerance to chemotherapy or radiation therapy such as multi-drug resistant gene therapy; and
(X) Immunotherapeutic methods, including, for example, ex vivo and in vivo methods of increasing the immunogenicity of a patient's tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, methods of reducing T cell anergy, methods of using transfected immune cells such as cytokine-transfected dendritic cells, methods of using cytokine-transfected tumor cell lines and methods of using anti-idiotype antibodies.
In a specific embodiment, the antiproliferative treatment as defined above may comprise conventional surgery or radiation therapy or chemotherapy in addition to the compounds of formula (I) of the present invention. Such combination therapy may be achieved by simultaneous, sequential or separate administration of the components of the therapy. Such combination products employ the compounds of the invention in the dosage ranges described above and other pharmaceutically active agents in their approved dosage ranges.
The invention also relates to a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in combination with another anti-tumour agent in the treatment of cancer (e.g. cancer involving solid tumours). The antineoplastic agent is preferably selected from the antineoplastic agents listed above.
As understood herein, the term "combination" refers to simultaneous, separate or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. When administered sequentially or separately, the delay in administration of the second component should not be such as to negate the beneficial effects of the combination.
Examples
The following examples are given for the purpose of illustration only and should not be construed as limiting the scope of the invention as defined by the appended claims.
Synthesis of Compound of formula (I)
The synthesis of embodiments A, B and C of compounds of formula (I) according to the present invention is preferably performed according to the general synthetic sequence shown in schemes 1-3.
In addition to the routes described below, other routes may be used to synthesize the target compounds, according to common general knowledge of a person skilled in the art of organic synthesis. Thus, the transformation sequences illustrated in the schemes below are not limiting, and suitable synthetic steps from the various schemes may be combined to form additional synthetic sequences. Furthermore, modification of any substituent may be effected before and/or after the illustrated transformations. These modifications may be, for example, the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallization, metal-catalyzed coupling reactions, substitution or other reactions known to those skilled in the art. These transformations include those that introduce functional groups that allow further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art (see, e.g., greene's Protective Groups in Organic Synthesis; editions: P.G.M.Wuts, 5 th edition, wiley 2014). Specific examples are described in the following paragraphs. Furthermore, two or more successive steps may be performed without post-treatment between the steps, such as a "one-pot" reaction, as is well known to those skilled in the art. Those skilled in the art will also appreciate that the reaction may produce by-products which, when appropriate, may be used to prepare compounds of formula (I) using similar methods as noted in the general schemes below.
Scheme 1
Scheme 1 shows a preferred synthetic method for compounds of formula a. As will be appreciated by those skilled in the art, this scheme also extends to compounds of formula (I) wherein X 4 is N and X 5 is C-R C5, for example, by palladium-catalyzed cross-coupling reactions after C-H functionalization of compound a to C-R C5 by bromination at the C-H position (see, e.g., kim et al, KR 2012078530).
In a first step, ethyl 2-chloroacetate 1 is reacted with ethyl formate 2 under basic conditions to provide (Z) -2-chloro-3-ethoxy-3-oxoprop-1-en-1-ol potassium 3. The reaction is preferably carried out in a solvent such as t-butyl methyl ether, diisopropyl ether, diethyl ether, 1, 2-dimethoxyethane, dioxane, DMF, DME, THF or a mixture of toluene, diethyl ether and EtOH in the presence of a base such as sodium ethoxide, sodium methoxide, potassium tert-butoxide or sodium tert-butoxide. (see, e.g., a) Stephen et al, US2017/369489; b) Murar et al, eu.j.med.chem.,2017, 126, 754). The reaction is carried out at a temperature in the range of-78 ℃ to room temperature. The reaction is preferably completed after 1 hour to 24 hours.
In a second step, a compound of formula 4, wherein X 1 and X 3 are as defined for the compound of formula (I), is reacted with (Z) -2-chloro-3-ethoxy-3-oxoprop-1-en-1-ol potassium 3 to give a compound of formula 5. The cyclization may be carried out under acidic conditions (see e.g., xi et al, WO 2019/99311). The use of sulfuric acid in EtOH as described herein is preferred. The reaction is preferably carried out at 70℃to 100℃for 5 hours to 24 hours.
In a third step, in several synthetic steps, a compound of formula 5, wherein X 1 and X 3 are as defined for the compound of formula (I), is converted into a compound of formula 6, wherein X 1、X3 and R 4 are as defined for the compound of formula (I). If R 4 is a 2- (difluoromethyl) -1,3, 4-thiadiazole group, then the compound of formula 5 is reacted with hydrazine hydrate to produce a hydrazide. The formation of the hydrazide may be performed under neutral conditions (see, e.g., dong et al, J.Med. Chem.,2020, volume 63, page 3028). The formation of the hydrazide is preferably carried out in EtOH and the reaction is preferably carried out under heating or microwave conditions at 50 ℃ to 100 ℃ for 1 hour to 24 hours. The hydrazide is then reacted with ethyl 2, 2-difluoroacetate to produce the dihydrazide. The reaction may be carried out under basic conditions, preferably the use of DBU as described herein in EtOH, THF or DMF. The reaction is preferably carried out in a microwave oven or in an oil bath at room temperature to 100 ℃ for 0.5 to 24 hours. Finally, the dihydrazide is cyclized to a compound of formula 6 by treatment with an oxygen/sulfur exchange reagent, wherein R 4 is a 2- (difluoromethyl) -1,3, 4-thiadiazole group (see, e.g., brunet et al, WO 2020/127974). Preferably, the use of the lawson reagent described herein in toluene or THF. The reaction is preferably carried out at 50℃to 130℃for 0.5 hours to 24 hours.
In a fourth step, a compound of formula 6, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with benzyl mercaptan to give a compound of formula 7. The coupling reaction may be carried out by palladium-catalyzed C-S cross-coupling reactions (see, e.g., jiang, buchwald, 'Metal-Catalyzed Cross-Coupling Reactions', 2 nd edition: de Meijere, DIEDERICH, editions: wiley-VCH: weinheim, germany, 2004). Preferred is the use of tris (dibenzylideneacetone) dipalladium (0), (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphane) and N-ethyl-N-isopropyl-propan-2-amine as described herein in dioxane. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 80-100 ℃ for 1-48 hours.
In a fifth step, a compound of formula 7, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with a chlorinating reagent to give the sulfonyl chloride of formula 8. The formation of the sulfonyl chloride may be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI 2, etc. in MeCN with equal amounts of acetic acid and water (see, e.g., sutton et al, WO 2021/055744). Preferably, the DCDMH described herein is used in MeCN with equal amounts of acetic acid and water. The reaction is preferably carried out under an argon atmosphere at0 ℃ to room temperature for 05 hours to 5 hours.
In a sixth step, a compound of formula 8, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with an amine of formula 9, wherein R 1、R2 and R 3 are as defined for the compound of formula (I), to give a compound of formula 10. The reaction may be carried out under alkaline conditions (see, e.g., sutton et al, WO 2021/055744). Preferably, trimethylamine, pyridine and the like described herein are used in DCM, THF or DMF. The reaction is preferably carried out under an argon atmosphere at 0 ℃ to room temperature for 0.5 to 24 hours.
In a final step, the compound of formula 10, wherein X 1、X3、R1、R2、R3 and R 4 are as defined for the compound of formula (I), is coupled with various amines to give the compound of formula a, wherein X 2 is as defined for the compound of formula (I). The coupling reaction may be carried out by palladium-catalyzed C-N cross-coupling reactions (see, e.g., a) Jiang, buchwald, 'Metal-Catalyzed Cross-Coupling Reactions', 2 nd edition: de Meijere, DIEDERICH, edit: wiley-VCH: weinheim, germany,2004; b) Sutton et al, WO 2021/055744). Preference is given to the use of cesium carbonate and Pd-PEPSI-IHept Cl as described herein in dioxane. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 80-120 ℃ for 1-48 hours. Preference is also given to the use of cesium carbonate RuPhos-Pd-G3, ruphos as described herein in dioxane or palladium acetate, ruphos, sodium tert-butoxide in THF. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 70-130 ℃ for 1-24 hours.
Scheme 2
Scheme 2 shows a preferred synthetic method for compounds of formula B. As will be appreciated by those skilled in the art, compounds of formula (I) wherein X 4 is C-R c4 and X 5 is N may be obtained by functionalization of the C-1 position in compound 20, for example via palladium catalyzed cross-coupling reactions.
In a first step, the cyano group of the compound of formula 11, wherein X 1 and X 3 are as defined for the compound of formula (I), is reduced to give the compound of formula 12. The reaction is preferably carried out in THF in the presence of a reducing agent such as BH 3.THF、BH3.Me2S、PtO2/H2, sodium tetrahydroborate, etc. (see, e.g., long et al, WO 2018/71535). The reaction is carried out at a temperature in the range of 20 ℃ to 40 ℃. The reaction is preferably completed after 0.5 to 24 hours.
In a second step, a compound of formula 12, wherein X 1 and X 3 are as defined for the compound of formula (I), is reacted with ethyl 2-chloro-2-oxoacetate 13 under basic conditions to give a compound of formula 14. The acylation is preferably carried out in a solvent such as DCM, dioxane or THF in the presence of a base such as trimethylamine or N-ethyl-N-isopropyl-2-amine (see, e.g., blaquiere et al, WO 2015/25025). The reaction is carried out at a temperature in the range of-5 ℃ to room temperature. The reaction is preferably completed after 1 hour to 24 hours.
In a third step, the compound of formula 14, wherein X 1 and X 3 are as defined for the compound of formula (I), is converted to the compound of formula 15. The cyclization is preferably carried out in 1, 2-dichloroethane, toluene or in the absence of solvents in the presence of dehydrating agents such as trichlorophosphates, phosphorus pentoxide and trichlorophosphates, pyridine and trifluoroacetic anhydride and the like. The reaction is carried out at a temperature in the range of 70 ℃ to 140 ℃. The reaction is preferably completed after 1 hour to 24 hours.
In a fourth step, the compound of formula 15, wherein X 1 and X 3 are as defined for the compound of formula (I), is converted into the compound of formula 16 by several synthetic steps. If R 4 is 2- (difluoromethyl) -1,3, 4-thiadiazole, then reacting the compound of formula 15 with hydrazine hydrate to produce a hydrazide. The formation of the hydrazide may be performed under neutral conditions (see, e.g., dong et al, J.Med. Chem.,2020, volume 63, page 3028). The formation of the hydrazide is preferably carried out in EtOH and the reaction is preferably carried out under heating or microwave conditions at 50 ℃ to 100 ℃ for 1 hour to 24 hours. The hydrazide is then reacted with ethyl 2, 2-difluoroacetate to produce the dihydrazide. The reaction may be carried out under basic conditions, preferably the use of DBU as described herein in EtOH, THF or DMF. The reaction is preferably carried out in a microwave oven or in an oil bath at room temperature to 100 ℃ for 0.5 to 24 hours. Finally, the dihydrazide is cyclized to a compound of formula 16 by treatment with an oxygen/sulfur exchange reagent, wherein R 4 is a 2- (difluoromethyl) -1,3, 4-thiadiazole group (see, e.g., brunet et al, WO 2020/127974). Preferably, the use of the lawson reagent described herein in toluene or THF. The reaction is preferably carried out at 50℃to 130℃for 0.5 hours to 24 hours.
In a fifth step, a compound of formula 16, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with benzyl mercaptan to give a compound of formula 17. The coupling reaction may be carried out by palladium-catalyzed C-S cross-coupling reactions (see, e.g., jiang, buchwald, 'Metal-Catalyzed Cross-Coupling Reactions', 2 nd edition: de Meijere, DIEDERICH, editions: wiley-VCH: weinheim, germany, 2004). Preferred is the use of tris (dibenzylideneacetone) dipalladium (0), (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphane) and N-ethyl-N-isopropyl-propan-2-amine as described herein in dioxane. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 80-100 ℃ for 1-48 hours.
In a sixth step, a compound of formula 17, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with an iodide reagent to give a compound of formula 18. The iodination may be performed by treatment with NIS, I 2, etc. in MeCN, THF, dioxane, DMF, etc. (see, e.g., bentley et al; WO 2011/138266). The use of NIS in MeCN as described herein is preferred. The reaction is preferably carried out under an argon atmosphere at0 ℃ to room temperature for 0.5 to 5 hours.
In a seventh step, a compound of formula 18, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with a chlorinating reagent to give the sulfonyl chloride of formula 19. The formation of the sulfonyl chloride may be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI 2, etc. in MeCN with equal amounts of acetic acid and water (see, e.g., sutton et al, WO 2021/055744). Preferably, the DCDMH described herein is used in MeCN with equal amounts of acetic acid and water. The reaction is preferably carried out under an argon atmosphere at 0 ℃ to room temperature for 0.5 to 5 hours.
In an eighth step, a compound of formula 19 wherein X 1、X3 and R 4 are as defined for the compound of formula (I) is reacted with an amine of formula 20 wherein R 1、R2 and R 3 are as defined for the compound of formula (I) to give a compound of formula 21. The reaction may be carried out under alkaline conditions (see, e.g., sutton et al, WO 2021/055744). Preferably, trimethylamine, pyridine and the like described herein are used in DCM, THF or DMF. The reaction is preferably carried out under an argon atmosphere at 0 ℃ to room temperature for 0.5 to 24 hours.
In a ninth step, the iodide of the compound of formula 21, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is removed by hydrogenation to give the compound of formula 22. The reaction is preferably carried out in THF, meOH, etOH, dioxane or DMF in the presence of a hydrogenation catalyst such as Pd/C, pd (OH) 2, raney nickel, ptO 2, etc., under a hydrogen atmosphere (see, e.g., aissaoui et al, U.S. Pat. No. 5,110,514). The reaction is carried out at a temperature in the range of 20 ° -80 °. The reaction is preferably completed after 0.5 to 24 hours.
In a final step, the compound of formula 22, wherein X 1、X3、R1、R2、R3 and R 4 are as defined for the compound of formula (I), is coupled with various amines to give the compound of formula B, wherein X 2 is as defined for the compound of formula (I). The coupling reaction may be carried out by palladium-catalyzed C-N cross-coupling reactions (see, e.g., a) Jiang, buchwald, 'Metal-Catalyzed Cross-Coupling Reactions', 2 nd edition: de Meijere, DIEDERICH, edit: wiley-VCH: weinheim, germany,2004; b) Sutton et al, WO 2021/055744). Preference is given to the use of cesium carbonate and Pd-PEPSI-IHept Cl as described herein in dioxane. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 80-120 ℃ for 1-48 hours. Preference is also given to the use of cesium carbonate RuPhos-Pd-G3, ruphos as described herein in dioxane or palladium acetate, ruphos, sodium tert-butoxide in THF. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 70-130 ℃ for 1-24 hours.
Scheme 3
Scheme 3 shows a preferred synthetic method for compounds of formula C. As will be appreciated by those skilled in the art, compounds of formula (I) wherein X 4 is C-R c4 may be obtained by functionalization of the C-1 position of compound 33, for example via a palladium catalyzed cross-coupling reaction. As will be appreciated by those skilled in the art, compounds of formula (I) wherein X 5 is C-R c5 are obtainable by bromination of the C-H position by functionalization of the CH position at X 5 (see, for example, yao et al, org. Lett., volume 22, page 4511, 2020), followed by a palladium catalyzed cross-coupling reaction.
In a first step, a compound of formula 23, wherein X 1 and X 3 are as defined for the compound of formula (I), is reacted with 4, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane 24 to give a compound of formula 25. The coupling reaction is catalyzed by palladium catalysts, for example by Pd (0) catalysts such as tetrakis (triphenylphosphine) palladium (0) [ Pd (PPh 3)4 ], tris (dibenzylideneacetone) dipalladium (0) [ Pd 2(dba)3 ], or by Pd (II) catalysts such as bis (triphenylphosphine) -palladium (II) Pd (PPh 3)2C12), palladium (II) acetate and triphenylphosphine or by [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride.
In a second step, a compound of formula 25, wherein X 1 and X 3 are as defined for the compound of formula (I), is reacted with 3-methoxy-3-oxopropionic acid 26 to give a compound of formula 27. The cyclization is preferably carried out in a solvent such as 1, 2-dimethoxyethane, dioxane, DMF, DME, THF or MeCN in the presence of N-iodo-succinimide and sodium acetate (see, for example, tang et al adv. Synth. Catalysis,2016, volume 358, page 2878). The reaction is carried out in a microwave oven or in an oil bath at a temperature of 80-100 ℃. The reaction is preferably completed after 1 to 36 hours.
In a third step, the compound of formula 27, wherein X 1 and X 3 are as defined for the compound of formula (I), is converted to the compound of formula 28 by several synthetic steps. If R 4 is 2- (difluoromethyl) 1,3, 4-thiadiazole, then reacting the compound of formula 27 with hydrazine hydrate to produce a hydrazide. The formation of the hydrazide may be performed under neutral conditions (see, e.g., dong et al, J.Med. Chem.,2020, volume 63, page 3028). The formation of the hydrazide is preferably carried out in EtOH and the reaction is preferably carried out under heating or microwave conditions at 50 ℃ to 100 ℃ for 1 hour to 24 hours. The hydrazide is then reacted with ethyl 2, 2-difluoroacetate to produce the dihydrazide. The reaction may be carried out under basic conditions, preferably the use of DBU as described herein in EtOH, THF or DMF. The reaction is preferably carried out in a microwave oven or in an oil bath at room temperature to 100 ℃ for 0.5 to 24 hours. Finally, the dihydrazide is cyclized to the compound of formula 28 by treatment with an oxygen/sulfur exchange reagent, wherein R 4 is a 2- (difluoromethyl) -1,3, 4-thiadiazole group (see, e.g., brunet et al, WO 2020/127974). Preferably, the use of the lawson reagent described herein in toluene or THF. The reaction is preferably carried out at 50℃to 130℃for 0.5 hours to 24 hours.
In a fourth step, a compound of formula 28, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with benzyl mercaptan to give a compound of formula 29. The coupling reaction may be carried out by palladium-catalyzed C-S cross-coupling reactions (see, e.g., jiang, buchwald, 'Metal-Catalyzed Cross-Coupling Reactions', 2 nd edition: de Meijere, DIEDERICH, editions: wiley-VCH: weinheim, germany, 2004). Preferred is the use of tris (dibenzylideneacetone) dipalladium (0), (9, 9-dimethyl-9H-xanthene-4, 5-diyl) bis (diphenylphosphane) and N-ethyl-N-isopropyl-propan-2-amine as described herein in dioxane. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 80-100 ℃ for 1-48 hours.
In a fifth step, a compound of formula 29, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with an iodide reagent to give a compound of formula 30. The iodination may be performed by treatment with NIS, I 2, etc. in MeCN, THF, dioxane, DMF, etc. (see, e.g., bentley et al; WO 2011/138266). The use of NIS in MeCN as described herein is preferred. The reaction is preferably carried out under an argon atmosphere at0 ℃ to room temperature for 0.5 to 5 hours.
In a sixth step, a compound of formula 30, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is reacted with a chlorinating reagent to give the sulfonyl chloride of formula 31. The formation of the sulfonyl chloride may be carried out by treatment with NCS, sulfonyl chloride, DCDMH, CI 2, etc. in MeCN with equal amounts of acetic acid and water (see, e.g., sutton et al, WO 2021/055744). Preferably, the DCDMH described herein is used in MeCN with equal amounts of acetic acid and water. The reaction is preferably carried out under an argon atmosphere at 0 ℃ to room temperature for 0.5 to 5 hours.
In a seventh step, a compound of formula 31 wherein X 1、X3 and R 4 are as defined for the compound of formula (I) is reacted with an amine of formula 32 wherein R 1、R2 and R 3 are as defined for the compound of formula (I) to give a compound of formula 33. The reaction may be carried out under alkaline conditions (see, e.g., sutton et al, WO 2021/055744). Preferably, trimethylamine, pyridine and the like described herein are used in DCM, THF or DMF. The reaction is preferably carried out under an argon atmosphere at 0 ℃ to room temperature for 0.5 to 24 hours.
In an eighth step, iodide of the compound of formula 33, wherein X 1、X3 and R 4 are as defined for the compound of formula (I), is removed by hydrogenation to give the compound of formula 34. The reaction is preferably carried out in THF, meOH, etOH, dioxane or DMF in the presence of a hydrogenation catalyst such as Pd/C, pd (OH) 2, raney nickel, ptO 2, etc., under a hydrogen atmosphere (see, e.g., aissaoui et al, USS 2011/105514). The reaction is carried out at a temperature in the range of 20 ° -80 °. The reaction is preferably completed after 0.5 to 24 hours.
In a final step, the compound of formula 34, wherein X 1、X3、R1、R2、R3 and R 4 are as defined for the compound of formula (I), is coupled with various amines to give a compound of formula (C), wherein X 2 is as defined for the compound of formula (I): this coupling reaction may be carried out by a palladium-catalyzed C-N cross-coupling reaction (see, for example: a) Jiang, buchwald, 'Metal-Catalyzed Cross-Coupling Reactions', 2 nd edition: de Meijere, DIEDERICH, editions: wiley-VCH: weinheim, germany,2004; b) Sutton et al, WO 2021/055744). Preference is given to the use of cesium carbonate and Pd-PEPSI-IHept Cl as described herein in dioxane. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 80-120 ℃ for 1-48 hours. Preference is also given to the use of cesium carbonate RuPhos-Pd-G3, ruphos as described herein in dioxane or palladium acetate, ruphos, sodium tert-butoxide in THF. The reaction is preferably carried out in a microwave oven or in an oil bath under an argon atmosphere at 70-130 ℃ for 1-24 hours.
Preparation example
General considerations
Abbreviations used in the following description are: acOH (acetic acid); aq. (aqueous); ar (argon); atm (atmosphere); BH 3 THF (borane tetrahydrofuran complex); br. (broad, 1 H NMR signal); b OC2 O (di-tert-butyl dicarbonate); (Cataxium APdG 3 (methanesulfonic acid [ (bis (1-adamantyl) -N-butylphosphine) -2- (2 '-amino-1, 1' -biphenyl) ] palladium (II)), (CDCl 3 (deuterated chloroform), cHex (cyclohexane), CMPB (cyanomethylene trimethyl phosphorane); C S2CO3 (cesium carbonate), cul (copper iodide)), DABCO ((1, 4-diazabicyclo [2.2.2] octane)); (DAST (diethylaminosulfur trifluoride)), DBU (1, 8-diazabicyclo (5.4.0) undec-7-ene), DCE (dichloroethane), d (bimodal, 1 H NMR signal), DCM (dichloromethane), DIBAL-H (diisobutylaluminum hydride), DIPEA or DIEA (diisopropylethylamine), DMAP (4-N-dimethylaminopyridine), DME (1, 2-dimethoxyethane), DAST (DAST-1, 8-diazabicyclo (5.4.0)) undec-7-ene), DMEDA (dimethyl ethylenediamine); DMF (N-dimethylformamide); DMSO (dimethyl sulfoxide); DPPA (diphenyl azide phosphate); dtbbpy (bis (1, 1-dimethylethyl) -2,2' -bipyridine); ES (electrospray); etOAc or EA (ethyl acetate); etOH (ethanol); h (hours); FA (formic acid); HATU (1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridinium 3-oxide hexafluorophosphate); HFIP (hexafluoroisopropanol); 1 H NMR (proton nuclear magnetic resonance spectroscopy); HPLC (high performance liquid chromatography), iPrOH (isopropanol); k 3PO4 (tripotassium phosphate); ir [ dF (CF 3)(dtbbpy)PF6 ((4, 4 '-di-tert-butyl-2, 2' -bipyridine) bis [3, 5-difluoro-2- [ 5-trifluoromethyl-2-pyridinyl-kN) phenyl-kC ] iridium (III)); liOH (lithium hydroxide); m (multiple peaks, 1 H NMR signal); mCPBA (m-chloroperoxybenzoic acid), meCN (acetonitrile), meOH (methanol); min (min); mnO 2 (manganese (IV) oxide); MS (mass spectrometry); MTBE (methyl tert-butyl ether); naBH 4 (sodium borohydride); naHCO 3 (sodium bicarbonate); na 2S2O3 (sodium thiosulfate); NCS (N-chlorosuccinimide); NH 3 (ammonia); NH 4 Cl (ammonium fluoride); niCl 2 (nickel dichloride); NIS (N-iodosuccinimide); NMP (N-methylpyrrolidone); NMR (nuclear magnetic resonance); pd/C (palladium on carbon); pd 2dba3 (tris (dibenzylideneacetone) dipalladium); pd (dppf) Cl 2 (1, 1-bis (diphenylphosphino) ferrocene palladium dichloride); pd (Ph 3)2Cl2 (bis (triphenylphosphine) palladium (II)) PE (petroleum ether), pd-PEPSI-IPentCl o-methylpyridine ([ 1, 3-bis [2, 6-bis (1-ethylpropyl) phenyl ] -4, 5-dichloro-imidazol-2-ylidene ] -dichloro- (2-methylpyridin-1-ium-1-yl) palladium, pd (OH) 2 (palladium hydroxide), pd (Ph 3)4 (palladium-tetrakis (triphenylphosphine)); phl (OAc) 2 ((diacetoxyiodide) benzene), P (tBu) 3 (tri-tert-butylphosphine), py (pyridine), q (quartet, 1H NMR signal), quin (penta, 1H signal), rac (racemization), RT (retention time), s (unimodal, 1 H NMR signal), sat (saturation), t (triplet, 1 H NMR signal), TBAF (tetrabutylammonium fluoride), tert-BuBrettPhos, [ (2-t-butyl-2-tert-butylphosphine) 3 '-di-tert-butyl-3' -2-tert-propylphosphine (3 ', 3' -2-tert-butylphosphine) benzene, 6 '-di-tert-butylphosphine) benzene (tri-tert-butylphosphine) Pv (1, 6' -n-butylphosphine). 4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II)) TBDMSCl or TBSCl (t-butyldimethylsilyl chloride); tBuOH (t-butanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran); TLC (thin layer chromatography); TMSCHN 2 (trimethylsilyl diazomethane); TMSCN (trimethylsilyl cyanide); TMSOTf (trimethylsilyl triflate); TTMSS (trimethylsilane); UPLC (ultra high performance liquid chromatography), UV (ultraviolet light), wt-%; xantphos (4, 5-bis (diphenylphosphine) -9, 9-dimethylxanthene); xantphos Pd G4 (methanesulfonic acid [9, 9-dimethyl-4, 5-bis (diphenylphosphine) xanthene ] (2 '-methylamino-1, 1' -biphenyl-2-yl) palladium (II)).
General procedure: all starting materials and solvents were obtained from commercial sources or prepared according to literature references. Commercially available reagents and anhydrous solvents were used as supplied directly without further purification. Unless otherwise indicated, all reactions were stirred. The organic solution was dried conventionally over anhydrous sodium sulfate. Column chromatography was performed on a pre-packed silica (100 mesh-1000 mesh, 40 μm-63 μm) column using the amounts shown. All air-sensitive and moisture-sensitive reactions were carried out in oven-dried (120 ℃) glassware under an inert atmosphere of nitrogen or argon. Compound names were generated using CHEMDRAW PRIME (PERKIN ELMER). In some cases, the names of commonly accepted commercially available reagents are used instead of the names generated by ChemDraw.
Reversed phase HPLC conditions for LCMS analysis of final compound:
Method 1: SHIMADZU LCMS-2020Kinetex EVO C18 2.1 X130 mm,5 μm, 50deg.C; mobile phase: a:0.0375% TFA in water (v/v); b: meCN solution (v/v) of 0.01875% TFA; the flow rate was maintained at 1.5mL/min; elution was performed with mobile phase for 1.55 min, using UV detection at 220nm and 254 nm. Gradient information from 95% A-5% B to 5%A-95% B, 0 min-0.80 min; 0.80 min-1.20 min, kept at 5%A-95% b;1.20 min-1.21 min, recovering to 95% A-5% B,1.21 min-1.55 min, and maintaining at 95% A-5% B.
Method 2: SHIMADZU LCMS-2020Kinetex EVO C18 2.1 X130 mm,5 μm,40 ℃; mobile phase: a:0.025% NH 3-H2 O aqueous solution (v/v), B: meCN; the flow rate was maintained at 1.5mL/min; elution was performed with mobile phase for 1.55 min, using UV detection at 220nm and 254 nm. Gradient information from 95% A-5% B to 5%A-95% B, 0 min-0.80 min; 0.80 min-1.20 min, kept at 5%A-95% b;1.20 min-1.21 min, recovering to 95% A-5% B,1.21 min-1.55 min, and maintaining at 95% A-5% B.
Method 3: SHIMADZU LCMS-2020Kinetex EVO C18 2.1 X130 mm,5 μm, 50deg.C; mobile phase: a:0.0375% TFA in water (v/v); b: meCN solution (v/v) of 0.01875% TFA; the flow rate was maintained at 2.0mL/min; elution was performed with mobile phase for 0.80 min, using UV detection at 220nm and 254 nm. Gradient information from 95% A-5% B to 5%A-95% B, 0 min-0.80 min; 0.80 min-1.20 min, kept at 5%A-95% b;1.20 min-1.21 min, recovering to 95% A-5% B,1.21 min-1.55 min, and maintaining at 95% A-5% B.
Method 4: SHIMADZU LCMS-2020EVO C18.1X120 mm,2.6 μm, 50deg.C; mobile phase: a:0.0375% TFA in water (v/v); b: meCN solution (v/v) of 0.01875% TFA; the flow rate was maintained at 2.0mL/min; elution with mobile phase was performed for 1.00 min, using UV detection at 220nm and 254 nm. Gradient information from 95% A-5% B to 5%A-95% B, 0.01 min-0.60 min; 0.61 min to 0.78 min, kept at 5%A-95% b; and (3) recovering from the solution to 95% A-5% B in 0.78-0.79 min and maintaining at 95% A-5% B in 0.79-0.80 min.
Method 5: SHIMADZU LCMS-2020Kinetex EVO C18 2.1 X130 mm,5 μm, 50deg.C; mobile phase: a:0.0375% TFA in water (v/v); b: meCN solution (v/v) of 0.01875% TFA; the flow rate was maintained at 2.0mL/min; elution was performed with mobile phase for 0.80 min, using UV detection at 220nm and 254 nm. Gradient information from 95% A-5% B to 5%A-95% B, 0 min-0.80 min; 0.80 min-1.20 min, kept at 5%A-95% b;1.20 min-1.21 min, recovering to 95% A-5% B,1.21 min-1.55 min, and maintaining at 95% A-5% B.
1 H NMR spectrum:
1 H NMR spectra were obtained on a Bruker AVANCE III spectrometer using the residual non-deuterated solvent as reference at 400 MHz. 1 H NMR signals are specified with their multiplicity/combined multiplicity as is evident from the spectra; possible higher order effects are not considered. The chemical shift (δ) of the signal is expressed in ppm (parts per million).
Salt stoichiometry:
in this context, in particular in the experimental section, for the synthesis of the intermediates and examples of the invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of the salt form obtained by the corresponding preparation and/or purification method is in most cases unknown. Unless otherwise indicated, a suffix of a chemical name or structural formula such as "hydrochloride", "trifluoroacetate", "sodium salt" or "xHO", "xCF 3COOH", "xNa+" is to be understood as not being of stoichiometric specification, but only as salt form. This applies analogously to the case in which synthetic intermediates or example compounds or their salts have been obtained as solvates by the described preparation and/or purification processes, such as hydrates having (if defined) an unknown stoichiometric composition.
Preparation of intermediate 1.1
(Z) -2-chloro-3-ethoxy-3-oxoprop-1-en-1-ol potassium salt
A solution of ethyl 2-chloroacetate (10 g,81.60mmol,8.70 mL) and ethyl formate (6.04 g,81.60mmol,6.56 mL) in Tetrahydrofuran (THF) (150 mL) was stirred at-10℃for 20min, then t-BuOK (11.90 g,106.08 mmol) was added in portions such that the temperature of the mixture remained below 0℃to 5 ℃. The reaction was warmed to 20 ℃ for 16 hours. The reaction mixture was filtered to give a solid which was triturated with EtOAc (50 mL) at 20 ℃ for 5 hours, filtered and the solid dried in vacuo to give (Z) -2-chloro-3-ethoxy-3-oxoprop-1-en-1-ol potassium (12 g,63.61mmol,77.95% yield) as a yellow solid.
1H NMR(400MHz,DMSO-d6)δ8.88-8.24(m,1H),4.16(q,J＝7.2Hz,2H),1.24(t,J＝7.2Hz,3H)。
Preparation of intermediate 1.2
6-Bromo-8-chloroimidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a solution of 5-bromo-3-chloro-pyridin-2-amine (2 g,9.64 mmol) and potassium (Z) -2-chloro-3-ethoxy-3-oxoprop-1-en-1-ol (7.27 g,38.56 mmol) in EtOH (100 mL) was added H 2SO4 (2.84 g,28.92mmol,1.54 mL) at 20deg.C. The reaction mixture was heated to 90 ℃ for 16 hours. The reaction mixture was cooled to 20 ℃. EtOH was removed under reduced pressure, water (50 mL) was added, and the mixture was extracted with EtAOc (3 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over Na 2SO4, filtered and concentrated to give a residue which was chromatographed on flash silica gel40g Silica flash column, eluent 0-30% ethyl acetate/petroleum ether, gradient 80 mL/min) to give the product 6-bromo-8-chloroimidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester (1.7 g,5.21mmol,54.03% yield) as a white solid.
RT 0.888 min (method) 1);m/z 304.9(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):δ9.24(s,1H),8.301(s,1H),8.05-8.04(m,1H),4.40-4.35(m,2H),1.35(t,J＝7.2Hz,3H).
Preparation of intermediate 1.3
6-Bromo-8-chloroimidazo [1,2-a ] pyridine-3-carbohydrazide
To a solution of ethyl 6-bromo-8-chloroimidazo [1,2-a ] pyridine-3-carboxylate (1.7 g,5.21mmol,93% purity) in EtOH (20 mL) at 20deg.C was added NH 2NH2*H2 O (3.26 g,63.76mmol,3.16mL,98% purity). The mixture was refluxed for 2 hours and then cooled to 20 ℃. The precipitated solid was isolated to give the product 6-bromo-8-chloroimidazo [1,2-a ] pyridine-3-carbohydrazide (1.5 g,4.97mmol,95.49% yield) as a white solid.
RT 0.487 min (method) 1);m/z 290.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):10.68-9.40(m,2H),8.32(s,1H),7.92(d,J＝1.6Hz,1H),4.83-4.27(m,2H).
Preparation of intermediate 1.4
6-Bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,2-a ] pyridine-3-carbohydrazide
To a mixture of 6-bromo-8-chloroimidazo [1,2-a ] pyridine-3-carbohydrazide (1.3 g,4.31 mmol) and ethyl 2, 2-difluoroacetate (5.35 g,43.11 mmol) in EtOH (110 mL) was added 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) (1.31 g,8.62 mmol) at 20deg.C. The mixture was refluxed for 16 hours, then cooled to 20 ℃ and finally concentrated to give a residue which was purified by flash chromatography on silica gel20gSilica flash column, eluent 90% ethyl acetate/petroleum ether, gradient 80 mL/min) to give the product 6-bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,2-a ] pyridine-3-carbohydrazide (0.85 g,2.17 mmol) as a white solid.
RT 0.770 min (method) 1);m/z 368.9(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):11.03-10.93(m,2H),9.49(s,1H),8.48(s,1H),8.03(s,1H),6.48(t,J＝52.8Hz,1H).
Preparation of intermediate 1.5
2- (6-Bromo-8-chloroimidazo [1,2-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a solution of 6-bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,2-a ] pyridin-3-carbohydrazide (200.00 mg,511.52 μmol) in toluene (4 mL) was added the Lawson reagent (227.58 mg,562.67 μmol. The mixture was stirred at 110℃for 2 hours. The mixture was cooled to 20℃and concentrated to give a residue which was triturated with MeOH (5 mL) for 30 minutes and the filter cake was collected after filtration to give the product 2- (6-bromo-8-chloro-imidazo [1,2-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (140 mg,382.95 μmol,74.87% yield) as a white solid.
1H NMR(DMSO-d6,400MHz):7.54-7.84(t,J＝53.2Hz,1H),8.08(d,J＝1.6Hz,1H),8.64(s,1H),9.61(d,J＝1.6Hz,1H).
Preparation of intermediate 1.6
2- (6- (Benzylthio) -8-chloroimidazo [1,2-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
A mixture of 2- (6-bromo-8-chloro-imidazo [1,2-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (100 mg, 273.53. Mu. Mol), xantphos (31.65 mg, 54.71. Mu. Mol), N-Diisopropylethylamine (DIPEA) (70.70 mg, 547.07. Mu. Mol) and Pd 2(dba)3 (tris (dibenzylideneacetone) dipalladium (0)) (25.05 mg, 27.35. Mu. Mol) in dioxane (2 mL) was stirred at 20 ℃. N 2 was bubbled through the mixture for 5 minutes, and finally phenyl methyl mercaptan (33.97 mg, 273.53. Mu. Mol, 32.05. Mu.L) was added. The mixture was heated to 65 ℃ and stirred for 16 hours. The reaction mixture was cooled to 20 ℃ and concentrated to give a residue which was purified by flash silica gel chromatography20gSilica flash column, eluent 0-30% ethyl acetate/petroleum ether, gradient 30 mL/min) afforded the product 2- (6-benzylsulfonyl-8-chloroimidazo [1,2-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (80 mg,193.70 μmol,70.81% yield) as a yellow solid.
RT 1.012 min (method 1); m/z 408.9 (M+H) +(ESI+).
Preparation of intermediate 1.7
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonyl chloride
To a mixture of 2- (6-benzylsulfonyl-8-chloroimidazo [1,2-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (20 mg, 48.91. Mu. Mol), acOH (5.29 mg, 88.05. Mu. Mol, 5.04. Mu.L) and H 2 O (881.21. Mu.g, 48.91. Mu. Mol) in MeCN (0.5 mL) was added 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (17.35 mg, 88.05. Mu. Mol) at 0 ℃. The mixture was stirred at 0℃for 0.5 h. THF (3 mL) was added and the solution was dried over Na 2SO4, filtered and concentrated to give the product 8-chloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] imidazo [1,2-a ] pyridine-6-sulfonyl chloride (18 mg,46.73 μmol,95.53% yield) as a white solid which was used in the next step without further purification.
Preparation of example 1
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 1-aminocyclopropane-1-carbonitrile (5.79 mg, 48.81. Mu. Mol, HCl) in pyridine (294.00 mg,3.72 mmol) was added dropwise over 1 minute a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonyl chloride (18.00 mg, 46.71. Mu. Mol) in THF (0.3 mL) at 0deg.C. The mixture was stirred at 20℃for 16 hours. The reaction mixture was concentrated to give a residue which was purified by preparative HPLC (column: phenomenex C18 75 x 30mm x 3 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:30% -60%,7 min) to give 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (4.34 mg,10.07 μmol,20.64% yield) as a grey solid.
RT 0.882 min (method) 1);m/z 430.9(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.95(s,1H),8.76(s,1H),8.25(s,1H),7.87(s,1H),7.71(t,J＝52.8Hz,1H),1.23(s,2H),1.15(s,2H).
Example 2 preparation
4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
A mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (30 mg, 69.63. Mu. Mol), N-dimethylpiperazine-1-carboxamide (13.14 mg, 83.56. Mu. Mol), pd-PEPSI-IHeptCl (6.77 mg, 6.96. Mu. Mol) and CS 2CO3 (68.06 mg, 208.89. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with N 2 (3 times) and then stirred at 100℃for 12 hours under an atmosphere of N 2. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (column: phenomenex Synergi C18:150:25 mm:10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:30% -60%,10 min) to give the product 4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (15.36 mg,39.7% yield, 99.29% purity) as an off-white solid.
RT 0.882 min (method) 1);m/z 552.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.75(s,1H),9.57(br,1H),8.65(s,1H),7.71(t,J＝53.2,1H),7.01(s,1H),3.66-3.65(m,4H),3.38-3.36(m,4H),2.81(s,6H),1.45-1.37(m,4H).
Example 3 preparation
(R) -N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (2-methylmorpholino) imidazo [1,2-a ] pyridine-6-sulfonamide
A mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] imidazo [1,2-a ] pyridine-6-sulfonamide (10 mg, 23.21. Mu. Mol), (R) -2-methylmorpholine (2.82 mg, 27.85. Mu. Mol), pd-PEPSI-IHept Cl (2.26 mg, 2.32. Mu. Mol) and Cs 2CO3 (22.69 mg, 69.63. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with N 2 (3 times) and then stirred at 100℃for 12 hours under an atmosphere of N 2. The mixture was filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: phenomenex Synergi C, 150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:32% -62%,10 min) to give the product (R) -N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (2-methylmorpholino) imidazo [1,2-a ] pyridine-6-sulfonamide (3.22 mg,28.00% yield) as a yellow solid.
RT 0.870 (method) 1);m/z 496.0(M+H)+(ES+);1H NMR(400MHz,DMSO-d6)δ9.71(d,J＝1.2Hz,1H),8.62(s,1H),8.30(s,1H),7.55-7.85(t,J＝53.2Hz,1H),6.98(d,J＝1.2Hz,1H),4.18-4.32(m,2H),3.98(dd,J＝11.2,1.6Hz,1H),3.74-3.85(m,2H),2.92(m,1H)2.61-2.67(m,1H),1.35 -1.41(m,2H),1.26 -1.33(m,2H),1.20(d,J＝6.4Hz,3H).
Preparation of intermediate 4.1
(5-Bromo-3-chloropyridin-2-yl) methylamines
To a mixture of 5-bromo-3-chloropyridine carbonitrile (2.0 g,9.20 mmol) in THF (10 mL) was added BH 3 THF (1M, 11.04 mL) over 5 minutes with ice water cooling. The mixture was stirred at 0 ℃ for 30 minutes, then warmed to 20 ℃ and stirred at that temperature for an additional 30 minutes. The mixture was cooled to 0 ℃ and quenched by dropwise addition of MeOH (10 mL) over 5 minutes. The mixture was heated to 70 ℃ and stirred at that temperature for 30 minutes. The reaction was concentrated in vacuo to give the crude product (2.2 g) as a light brown solid. The crude product was dissolved in HCl (aq, 2M,20 mL), washed with DCM (20 mL;2 times), and finally the aqueous phase concentrated in vacuo to give the product (5-bromo-3-chloro-2-pyridinyl) methylamine (1.5 g,4.07mmol,44.26% yield, 70% purity, HCl salt) as a light brown solid.
RT 0.18 min (method 2);m/z 222.9(M+H)+(ESI+),1H NMR(400MHz,DMSO-d6)δ＝8.78(d,J＝2.0Hz,1H),8.69(br,3H),8.47(d,J＝2.0Hz,1H),4.24(d,J＝6.2Hz,2H).
Preparation of intermediate 4.2
2- (((5-Bromo-3-chloropyridin-2-yl) methyl) amino) -2-oxoacetic acid ethyl ester
DIPEA (2.25 g,17.45 mmol) was added to a mixture of (5-bromo-3-chloro-2-pyridinyl) methylamine (1.5 g,5.82mmol, HCl salt) in DCM (30 mL) under ice-water cooling. Then, ethyl 2-chloro-2-oxoacetate (952.77 mg,6.98 mmol) was added over 5 minutes, and the mixture was stirred at 0℃for 30 minutes. The mixture was warmed to 20 ℃ and stirred at that temperature for 30 minutes. The mixture was quenched with aqueous NaHCO 3 (50 mL) and extracted with DCM (50 mL). The organic phase was separated, dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: etoac=10:1 to 1:1) to give the product ethyl 2- (((5-bromo-3-chloropyridin-2-yl) methyl) amino) -2-oxoacetate (1300 mg,3.64mmol,62.57% yield, 65.6% purity) as a white solid. RT 0.61 min (method 1); m/z 322.8 (M+H) +(ESI+). The product was used in the next step without further purification.
Preparation of intermediate 4.3
6-Bromo-8-chloroimidazo [1,5-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of ethyl 2- (((5-bromo-3-chloropyridin-2-yl) methyl) amino) -2-oxoacetate (1300 mg,4.04 mmol) in POCl 3 (15 mL) was added phosphorus pentoxide (2.87 g,20.21 mmol) with ice water cooling. The mixture was heated to 110 ℃ and stirred at that temperature for 5 hours. The mixture was cooled to 25 ℃ and concentrated in vacuo to give a residue. The residue was dissolved in EtOAc (50 mL) and washed with water (30 mL) and aqueous NaHCO 3 (30 mL). And then finally concentrated in vacuo to give a residue. The residue was purified by silica gel column chromatography (PE: etoac=10:1 to 3:1) to give the product ethyl 6-bromo-8-chloroimidazo [1,5-a ] pyridine-3-carboxylate (900 mg,2.97mmol,73.34% yield) as a white solid.
RT 0.718 min (method 1), M/z 304.8 (M+H) +(ESI+),1 H NMR (400 MHz, chloroform-d) delta=9.47 (s, 1H), 7.77 (s, 1H), 7.20 (s, 1H), 4.65-4.42 (M, 2H), 1.57-1.42 (M, 3H)
Preparation of intermediate 4.4
6-Bromo-8-chloroimidazo [1,5-a ] pyridine-3-carbohydrazide
To a mixture of ethyl 6-bromo-8-chloroimidazo [1,5-a ] pyridine-3-carboxylate (900 mg,2.97 mmol) in EtOH (20 mL) was added NH 2NH2H2 O (1.48 g,29.65mmol, 98%). The mixture was heated to 80 ℃ and stirred at that temperature for 2 hours. The reaction was cooled to 25 ℃ and precipitated solids were isolated. The crude product was triturated with EtOH (5 mL) to give 6-bromo-8-chloroimidazo [1,5-a ] pyridine-3-carbohydrazide (650 mg,2.25mmol,75.72% yield) as a white solid.
RT 0.56 min (method) 1);m/z 290.8(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ＝10.02(s,1H),9.50(s,1H),7.72(s,1H),7.51(s,1H),4.58(d,J＝4.0Hz,2H).
Preparation of intermediate 4.5
6-Bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,5-a ] pyridine-3-carbohydrazide
To a mixture of 6-bromo-8-chloroimidazo [1,5-a ] pyridine-3-carbohydrazide (650 mg,2.25 mmol) in EtOH (20 mL) was added ethyl 2, 2-difluoroacetate (3.10 g,22.45 mmol) and DBU (683.58 mg,4.49 mmol). The mixture was heated to 100 ℃ and stirred at that temperature for 16 hours. The mixture was cooled to 25 ℃ and concentrated in vacuo. The residue was dissolved with DCM (50 mL), washed with aqueous NH 4 Cl (30 mL;2 times) and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (PE/etoac=1:1 to MeOH: etoac=1:10) to give the product 6-bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,5-a ] pyridine-3-carbohydrazide (650 mg,1.56mmol,69.32% yield, 88% purity) as a white solid.
RT 0.62 min (method 1);m/z 368.8(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ＝10.95(br,2H),9.44(s,1H),7.81(s,1H),7.59(s,1H),6.38(t,J＝53.2,1H).
Preparation of intermediate 4.6
2- (6-Bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a mixture of 6-bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,5-a ] pyridine-3-carbohydrazide (550 mg,1.50 mmol) in toluene (20 mL) was added the lawsen reagent (665.80 mg,1.65 mmol) under an atmosphere of N 2. The reaction was heated to 120 ℃ and stirred at that temperature for 2 hours. The reaction was cooled to 25 ℃ and concentrated in vacuo. The residue was triturated with MeOH (10 mL) at 70 ℃ for 1 hour, filtered, the filter cake collected and dried in vacuo to give the product 2- (6-bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (530 mg,1.45mmol,96.88% yield) as a pale yellow solid.
RT 0.806 min (method) 1);m/z 366.8(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ＝9.62(s,1H),8.64(s,1H),8.09(s,1H),7.70(t,J＝53.2,1H).
Preparation of intermediate 4.7
2- (6- (Benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
Pd 2(dba)3 (112.72 mg, 123.09. Mu. Mol), xantphos (71.22 mg, 123.09. Mu. Mol) and DIEA (477.26 mg,3.69 mmol) were added to a mixture of 2- (6-bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (450 mg,1.23 mmol) and phenyl methyl mercaptan (168.17 mg,1.35 mmol) in dioxane (10 mL) degassed with nitrogen under nitrogen for 2 minutes. The mixture was heated to 90 ℃ and stirred at that temperature for 16 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: etoac=20:1 to 5:1) to give the product 2- (6- (benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (250 mg,489.15 μmol,39.74% yield, 80% purity) as a pale yellow solid.
RT 0.99 min (method 1); m/z 409.0 (M+H) +(ESI+);1 H NMR (400 MHz, chloroform) -d)δ＝9.35(s,1H),7.69-7.67(m,1H),7.39-7.28(m,2H),7.25-7.12(m,3H),7.05(t,J＝53.2,1H),7.00(s,1H),6.90(s,1H),4.10(s,2H)
Preparation of intermediate 4.8
2- (6- (Benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a mixture of 2- (6- (benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (130 mg, 317.95. Mu. Mol) in MeCN (5 mL) was added NIS (78.68 mg, 349.74. Mu. Mol) at 0deg.C. The mixture was stirred at 25℃for 5 hours. The reaction mixture was used directly in the next step.
RT 0.99 min (method 1); m/z 535.0 (M+H) +(ESI+
Preparation of intermediate 4.9
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride
A mixture of 2- (6- (benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (170 mg, 317.95. Mu. Mol) in MeCN (5 mL) was cooled to 0deg.C, then H 2 O (5.73 mg, 317.95. Mu. Mol), acOH (38.19 mg, 635.89. Mu. Mol) and 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (125.28 mg, 635.89. Mu. Mol) were added. The mixture was stirred at 0 ℃ for 2 hours. The mixture was diluted with THF (8 mL), dried over Na 2SO4, filtered and concentrated in vacuo to give the crude 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride (160 mg,219.14 μmol,68.92% yield, 70% purity) as a light brown oil.
It should be noted that the formation of the dichloro compound 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (see intermediate 18.2) during this process is not excluded.
Preparation of intermediate 4.10
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1-aminocyclopropane-1-carbonitrile (128.51 mg,1.57mmol, hydrochloride) in pyridine (3 mL) was added a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride (160 mg, 313.05. Mu. Mol) in THF (2 mL) at 0deg.C. The mixture was stirred at 0 ℃ for 1 hour. The reaction was concentrated in vacuo. The residue was dissolved in DCM (20 mL) and washed with brine (20 mL), dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: etoac=10:1 to 3:1) to give the product 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonamide (110 mg,128.43 μmol,41.02% yield, 65% purity) as a yellow solid.
RT 0.966 min (method 1);m/z 556.9(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ＝10.00(s,1H),9.70(br,1H),7.72(t,J＝53.2,1H),7.48(d,J＝1.1Hz,1H),1.54 -1.48(m,2H),1.42-1.35(m,2H)
Example 4 preparation
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonamide (15 mg,26.94 μmol) in THF (5 mL) was added DIPEA (17.41 mg,134.71 μmol) and Pd/C (5 mg,10% purity) at 20 ℃. The mixture was stirred at 20℃under H 2 (15 psi) for 2 hours. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:33% -63%,15 min) to give 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (4.02 mg, 9.23. Mu. Mol,34.25% yield, 98.9% purity, formate) as a pale yellow solid.
RT 0.966 min (method 1); m/z 431.1 (M+H) +(ESI+); h NMR (400 MHz, methanol) -d4)δ＝10.25(s,1H),8.56(br,1H),7.99(s,1H),7.51(s,1H),7.36(t,J＝53.2Hz,1H),1.54-1.50(m,2H),1.50-1.46(m,2H).
Example 5 preparation
4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (70 mg, 162.47. Mu. Mol) in 1, 4-dioxane (1 mL) degassed with nitrogen for 2 min was added N, N-dimethylpiperazine-1-carboxamide (38.31 mg, 243.71. Mu. Mol), CS 2CO3 (105.87 mg, 324.95. Mu. Mol) and Pd-PEPSI-IHept Cl (15.80 mg, 16.25. Mu. Mol). The mixture was stirred at 100℃for 16 hours. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3 μm; mobile phase: A:0.1% TFA in water, B: meCN; B%:48% -68%,7 min) to give 6mg of the product with 80% purity. Thereafter, the product was further purified by preparative HPLC (column: waters Xbridge 150. 25 mM. 5 μm; mobile phase: A:1mM NH 4HCO3 in water, B: meCN; B%:35% -53%,10 min) to give the product 4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.48 mg, 4.39. Mu. Mol,2.70% yield, 97.7% purity) as a pale yellow solid.
RT 0.72 min (method 1); m/z 552.0 (M+H) +(ESI+);1 H NMR (400 MHz, methanol -d4)δ＝9.93(s,1H),7.93(s,1H),7.35(t,J＝53.2,1H),6.79(s,1H),3.61-3.52(m,4H),3.44-3.41(m,4H),2.92(s,6H),1.57-1.50(m,2H),1.49 -1.42(m,2H).
Preparation of intermediate 6.1
1, 8-Dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a mixture of NCS (65.32 mg, 489.15. Mu. Mol,4 eq) in MeCN (2 mL) was added an aqueous solution of HCl (2M, 244.57. Mu.L) and 2- (6-benzylsulfonyl-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -L,3, 4-thiadiazole (50 mg, 122.29. Mu. Mol) at 0deg.C. The mixture was warmed to 20 ℃ and stirred at that temperature for 1 hour. The mixture was diluted with DCM (10 mL) and washed with water (10 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure to give the crude 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (50 mg,94.13 μmol,76.97% yield, 79% purity) as a yellow oil. The crude product was used in the next step without further purification.
Example 6 preparation
1, 8-Dichloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (50 mg,94.13 μmol,79% purity) and DIPEA (24.33 mg,188.26 μmol) in DCM (2 mL) was added 1-aminocyclopropane-1-carbonitrile (15.46 mg,188.26 μmol, HCl salt). The mixture was stirred at 20℃for 1 hour. Pyridine (148.91 mg,1.88mmol, 151.95. Mu.L) was added and the mixture was stirred at 20℃for an additional 16 hours. The mixture was concentrated to give a residue which was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75*30mm*3 μm; mobile phase: A:0.1% aqueous TFA, B: meCN; B%:50% -80%,7 min) to give 1, 8-dichloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg, 21.49. Mu. Mol,66.67% yield) as a yellow solid.
RT 0.87 min (method) 1);m/z 464.9(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ＝9.91(s,1H),9.71(s,1H),7.71(t,J＝53.2,1H),7.50(s,1H),1.60-1.45(m,2H),1.42-1.30(m,2H).
Example 7 preparation
N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
A mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (10.0 mg, 23.21. Mu. Mol), 2-oxa-7-azaspiro [3.5] nonane (4.4 mg, 34.82. Mu. Mol), pd-PEPSI-IHept Cl (2.3 mg, 2.32. Mu. Mol) and CS 2CO3 (22.7 mg, 69.63. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with nitrogen (3 times) and then stirred under nitrogen at 100℃for 12 hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:33% -53%,10 min) to give the product N (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (4.3 mg, 8.24. Mu. Mol) as a yellow solid.
RT 0.877 (methods) 1);m/z 522.1(M+H)+(ES+);1H NMR(400MHz,DMSO-d6)δ9.62(s,1H),8.58(s,1H),8.37(s,1H),7.69(t,J＝53.2Hz,1H),6.97(s,1H),4.39(s,4H),3.55-3.53(m,4H),1.97-2.01(m,4H),1.28-1.24(m,2H),1.22-1.18(m,2H).
Example 8 preparation
N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyrylpiperazin-1-yl) imidazo [1,2-a ] pyridine-6-sulphonamide
A mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (10.0 mg, 23.21. Mu. Mol), 2-methyl-1- (piperazin-1-yl) propan-1-one (4.4 mg, 27.85. Mu. Mol), pd-PEPSI-IHept Cl (2.3 mg, 2.32. Mu. Mol) and CS2CO3 (22.7 mg, 69.63. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with nitrogen (3 times) and then stirred under nitrogen at 100℃for 12 hours. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: phenomenex C18X 30mm X3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:35% -65%,7 min) to give the product N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyrylpiperazin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (2.3 mg, 4.16. Mu. Mol) as a pale yellow solid.
RT 0.867 min (method 1);m/z 551.0(M+H)+(ESI+);1H NMR(400MHz,MeOH-d4)δ＝9.67(s,1H),8.62(s,1H),8.40(s,1H),7.53-7.91(t,J＝53.2Hz,1H),6.99(d,J＝1.2Hz,1H),3.76(d,J＝4.8Hz,2H),3.71(s,2H),3.63(s,2H),3.56(s,2H),2.92-2.99(m,1H),1.23-1.31(m,2H),1.17-1.23(m,2H),1.05(d,J＝6.4Hz,6H).
Preparation of intermediate 9.1
Methyl (2- (N-methyl isobutyramide) ethyl) carbamic acid tert-butyl ester
A mixture of tert-butyl methyl (2- (methylamino) ethyl) carbamate (300.0 mg,1.59 mmol) and Et 3 N (322.5 mg,3.19 mmol) in DCM (3 mL) was degassed and purged with nitrogen (3 times) then 2-methylpropanoyl chloride (186.8 mg,1.75 mmol) was added dropwise at 0deg.C. The mixture was stirred under nitrogen at 20 ℃ for 1 hour, then poured into saturated aqueous NaHCO 3 (10 mL) and extracted with DCM (10 mL,3 times). The combined organic layers were washed with brine (25 ml,2 times), dried over Na 2SO4, filtered and concentrated to give the product tert-butyl methyl (2- (N-methylisobutyramide) ethyl) carbamate (300.0 mg,1.16 mmol) as a yellow oil.
1H NMR(400MHz,DMSO-d6)δ3.36-3.45(m,2H),3.28(t,J＝6.4Hz,3H)2.99(br s,1H)2.74-2.83(m,5H)1.38(s,9H),0.93-1.00(m,6H).
Preparation of intermediate 9.2
N-methyl-N- (2- (methylamino) ethyl) isobutyramide
To a solution of tert-butyl methyl (2- (N-methyl isobutyramide) ethyl) carbamate (300.0 mg,1.16 mmol) in DCM (3 mL) was added a solution of HCl in dioxane (4M, 3 mL). The mixture was stirred at 20℃for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in MeOH (2 mL) and basic resin (2 g) was added. The mixture was stirred at 20℃for 0.5 h. The mixture was filtered and concentrated to give the product N-methyl-N- (2- (methylamino) ethyl) isobutyramide (116 mg,0.73 mmol) as a colorless oil.
1H NMR(400MHz,CDCl3)δ3.70(t,J＝6.0Hz,2H)3.15(s,3H)3.11(t,J＝6.0Hz,2H)2.79-2.87(m,1H)2.69(s,3H)1.12(d,J＝6.8Hz,6H).
Example 9 preparation
N- (2- ((6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridin-8-yl) (methyl) amino) ethyl) -N-methyl isobutyramide
A mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (10.0 mg, 23.21. Mu. Mol), N-methyl-N- (2- (methylamino) ethyl) isobutyramide (4.4 mg, 27.85. Mu. Mol), pd-PEPSI-IHept Cl (2.3 mg, 2.32. Mu. Mol) and CS 2CO3 (22.7 mg, 69.63. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with nitrogen (3 times) and then stirred under nitrogen at 100℃for 12 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: phenomenex C18 75 x 30mm x 3 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:38% -68%,7 min) to give the product N- (2- ((6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridin-8-yl) (methyl) amino) ethyl) -N-methyl isobutyramide (1.4 mg,2.53 μmol) as a yellow solid.
RT 0.898 min (method 1);m/z 553.0(M+H)+(ESI+);1H NMR(400MHz,CDCl3)δ9.85(d,J＝1.6Hz,1H),8.13(s,1H),7.76(s,1H),7.40(d,J＝1.2Hz,1H),7.10(t,J＝53.2Hz,1H),3.68-3.78(m,4H),3.59(s,3H),3.14(s,3H),2.83(m,1H),1.63(s,2H),1.38-1.42(m,2H),1.12-1.16(m,6H).
Preparation of intermediate 10.1
5-Chloro-6-vinylpyridin-3-amine
Pd (dppf) Cl 2 (431.5 mg, 589.67. Mu. Mol) was added to a mixture of2, 5-dibromo-3-chloropyridine (1.60 g,5.90 mmol), 4, 5-tetramethyl-2-vinyl-1, 3, 2-dioxaborolane (1.36 g,8.85 mmol) and Na 2CO3 (1.25 g,11.79 mmol) in dioxane (15 mL) and water (1 mL) under a nitrogen atmosphere. The mixture was stirred at 100℃for 16 hours. Concentrating the mixture in vacuo to give a residue, which is chromatographed on flash silica gel20g Silica flash column, eluent 0-20% DCM/PE gradient 35 mL/min) to give the product 5-bromo-3-chloro-2-vinylpyridine (1.80 g,8.24mmol; resulting from 3 reactions performed in parallel) as a yellow oil.
1H NMR(400MHz,CDCl3)δ8.53(d,J＝2.0Hz,1H),7.84(d,J＝2.0Hz,1H),7.17(dd,J＝16.8,10.8Hz,1H),6.50(dd,J＝17.2,2.0Hz,1H),5.63(dd,J＝10.4,1.6Hz,1H).
Preparation of intermediate 10.2
6-Bromo-8-chloroindolizine-3-carboxylic acid methyl ester
To a solution of 5-bromo-3-chloro-2-vinylpyridine (2.20 g,10.07 mmol) and 3-methoxy-3-oxopropionic acid (2.38 g,20.14 mmol) in MeCN (40 mL) was added NIS (7.93 g,35.24 mmol) and NaOAc (2.48 g,30.21 mmol). The mixture was stirred under nitrogen at 100 ℃ for 16 hours. Concentrating the mixture in vacuo to give a residue, which is chromatographed on flash silica gel20gSilica flash column, eluent 0-10% EtOAc/PE, gradient 35 mL/min) afforded the product, methyl 6-bromo-8-chloroindolizine-3-carboxylate (1.76 g,6.10 mmol), as a yellow oil.
RT 1.053 min (method 1);m/z 289.9(M+H)+(ESI+);1H NMR(400MHz,CDCl3)δ9.48(s,1H),7.42(d,J＝4.8Hz,1H),7.10(d,J＝1.6Hz,1H),6.63(d,J＝4.4Hz,1H),3.85(s,3H).
Preparation of intermediate 10.3
6-Bromo-8-chloroindolizine-3-carbohydrazide
To a solution of methyl 6-bromo-8-chloroindolizine-3-carboxylate (1.76 g,6.10 mmol) in EtOH (20 mL) was added N 2H4H2 O (3.74 g,73.20mmol,98% purity). The mixture was heated to 100 ℃ and stirred for 2 hours. The mixture was cooled to 25 ℃ and filtered. The filter cake was dried in vacuo to give the product 6-bromo-8-chloroindolizine-3-carbohydrazide (1.36 g,4.71 mmol) as a white solid.
RT 0.808 min (method) 1);m/z 289.9(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ9.69-9.78(m,2H),7.90(br,2H),7.60(d,J＝4.4Hz,1H),7.41(d,J＝1.6Hz,1H),6.72(dd,J＝4.4,0.4Hz,1H).
Preparation of intermediate 10.4
6-Bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,2-a ] pyridine-3-carbohydrazide
To a solution of 6-bromo-8-chloroimidazo [1,2-a ] pyridine-3-carbohydrazide (1.36 g,4.71 mmol) and DBU (1.43 g,9.42 mmol) in EtOH (15 mL) was added ethyl 2, 2-difluoroacetate (5.84 g,47.10 mmol). The mixture was stirred at 105℃for 16 hours. Concentrating the mixture in vacuo to give a residue, which is chromatographed on flash silica gel12g Silica flash column, eluent 0-50% EtOAc/PE, gradient 36 mL/min) afforded the product 6-bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,2-a ] pyridine-3-carbohydrazide (3836 mg,1.05 mmol) as a yellow solid.
RT 0.885 min (method 1);m/z 368.0(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.56(s,1H),9.66(s,1H),7.75(d,J＝4.8Hz,1H),7.53(d,J＝1.2Hz,1H),6.80(d,J＝4.00Hz,1H),6.47(t,J＝53.2Hz,1H).
Preparation of intermediate 10.5
2- (6-Bromo-8-chloroindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a solution of 6-bromo-8-chloro-N' - (2, 2-difluoroacetyl) indolizine-3-carbohydrazide (386.0 mg,1.05 mmol) in toluene (5 mL) was added the Lawson reagent (468.5 mg,1.16 mmol). The mixture was stirred at 110℃for 2 hours. Concentrating the mixture in vacuo to give a residue, which is chromatographed on flash silica gel4gSilica flash column, eluent 0-100% EtOAc/PE gradient 10mL/min afforded the product 2- (6-bromo-8-chloroindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (210.0 mg,0.58 mmol) as a yellow solid.
RT 1.086 min (method 1);m/z 365.9(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.51-7.82(m,3H),6.94(d,J＝4.0Hz,1H).
Preparation of intermediate 10.6
2- (6- (Benzylthio) -8-chloroindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
A mixture of 2- (6-bromo-8-chloroindol-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (210.0 mg, 575.98. Mu. Mol), phenyl methyl mercaptan (71.5 mg, 575.98. Mu. Mol), pd2 (dba) 3 (52.7 mg, 57.60. Mu. Mol), DIEA (148.9 mg,1.15 mmol) and Xantphos (66.7 mg, 115.20. Mu. Mol) in dioxane (3 mL) was degassed with nitrogen and heated to 90℃for 2 hours under a nitrogen atmosphere. Concentrating the mixture in vacuo to give a residue, which is chromatographed on flash silica gel4gSilica flash column, eluent 0-50% EtOAc/PE, gradient 10 mL/min) afforded the product 2- (6- (benzylthio) -8-chloroindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (200.0 mg, 490.33. Mu. Mol) as a yellow solid.
RT 1.156 min (method) 1);m/z 408.1(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ7.15-7.84(m,9H),6.87(d,J＝4.52Hz,1H),4.27(s,2H).
Preparation of intermediate 10.7
2- (6- (Benzylsulfinyl) -8-chloro-1-iodoindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a mixture of 2- (6- (benzylthio) -8-chloroindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (150.0 mg, 367.75. Mu. Mol) in MeCN (0.5 mL) was added NIS (182.0 mg, 809.05. Mu. Mol), acOH (22.1 mg, 367.75. Mu. Mol) and H 2 O (6.6 mg, 367.75. Mu. Mol). The mixture was stirred at 20℃for 2 hours. The mixture was concentrated in vacuo to give a residue which was purified by prep HPLC (column: waters Xbridge 150 x 50mM x10 μm; mobile phase: a:1mM aqueous NH 4HCO3, B: meCN; B%:49% -79%,11 min) to give the product 2- (6- (benzylsulfinyl) -8-chloro-1-iodoindol-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (100.0 mg,181.89 μmol) as a yellow solid.
RT 1.054 min (method 1); m/z 550.0 (M+H) +(ESI+).
Preparation of intermediate 10.8
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride
To a mixture of 2- (6- (benzylsulfinyl) -8-chloro-1-iodoindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (20.0 mg, 36.38. Mu. Mol) in MeCN (2 mL) was added H 2 O (0.7 mg, 36.38. Mu. Mol) and AcOH (4.4 mg, 72.76. Mu. Mol) at 0deg.C. The mixture was stirred at 0℃for 10 min. 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (14.3 mg, 72.76. Mu. Mol) was added to the solution, and the mixture was stirred at 0℃for 2 hours. The mixture was diluted with THF (3 mL) and dried over Na 2SO4. After filtration, the filtrate was concentrated in vacuo to give crude 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride (20.0 mg,19.60 μmol) as a light brown oil. The crude product was used in the next step without further purification.
Preparation of intermediate 10.9
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride (20.0 mg, 39.80. Mu. Mol) in pyridine (1 mL) was added a solution of 1-aminocyclopropane-1-carbonitrile (16.1 mg, 196.05. Mu. Mol, HCl salt) in THF (1 mL) at 0℃over 1 minute. The mixture was stirred at 0 ℃ for 1 hour. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in DCM (20 mL) and washed with brine (20 mL). The organic phase was dried over Na 2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% formic acid in water, B: meCN; B%:45% -75% for 10 min) to give the product 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonamide (15.0 mg, 24.13. Mu. Mol,89.4% purity) as a yellow solid.
RT 0.890 min (method 1); m/z 555.7 (M+H) +(ESI+).
Example 10 preparation
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonamide
To a mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonamide (15.0 mg, 26.99. Mu. Mol) in THF (5 mL) at 20deg.C was added DIEA (3.5 mg, 26.99. Mu. Mol) and Pd/C (5.0 mg, 26.99. Mu. Mol,10% purity). The mixture was stirred at 20℃under a hydrogen atmosphere (15 Psi) for 2 hours. The mixture was filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex C1875 x 30mm x 3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:40% -70%,7 min) to give the product 8-chloro-N- (1-cyanocyclopropyl) -3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] indolizine-6-sulfonamide (1.9 mg, 3.75. Mu. Mol, FA salt) as a yellow solid.
RT 0.899 min (method 1);m/z 430.0(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.37(s,2H),7.91(d,J＝4.4Hz,1H),7.68(t,J＝53.2Hz,1H),7.40(d,J＝1.2Hz,1H),6.98(d,J＝4.4Hz,1H),1.22-1.18(m,2H),1.11-1.15(m,2H).
Preparation of intermediate 11.1
6- (Benzylthio) -8-chloroimidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of ethyl 6-bromo-8-chloro-imidazo [1,2-a ] pyridine-3-carboxylate (1.50 g,4.94mmol, intermediate 1.2), phenyl methyl mercaptan (0.61 g,4.94mmol,579.03 μl), DIPEA (1.28 g,9.88mmol,1.72 mL) and Xantphos (0.57 g,988.34 μmol) in dioxane (15 mL) was added Pd 2(dba)3 (0.45 g,494.17 μmol). The mixture was stirred under nitrogen at 90 ℃ for 2 hours. The mixture was cooled to room temperature, quenched with H 2 O (100 mL) and extracted with EtOAc (100 mL2 times). The combined organic layers were washed with brine (100 mL), dried over Na 2SO4, and filtered. Concentrating the filtrate under reduced pressure to obtain residue, and subjecting to flash silica gel chromatography40gSilica flash column, eluent 60-100% etoac/PE, gradient 100 mL/min) gives crude product which is further purified rapidly by reverse phase (solvent for sample dissolution about 10g of sample is dissolved in 10mL MeOH, (column: i.d.95 mm. H365mm Welch Ultimate XB. Mu.m. C18-40 μm;120A; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:5% -90%40 min; 90%10 min; 200 mL/min)). The mixture was concentrated under reduced pressure to remove most of the MeCN, then the resulting mixture was neutralized to ph=8 with NaHCO 3 and extracted with EtOAc (100 ml;2 times). The combined organic layers were washed with brine (100 mL;2 times), dried over Na 2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the product 6-benzylsulfonyl-8-chloro-imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester (1.5 g,4.32 mmol) as a brown solid. (the reaction was run in parallel in two batches and purified together).
1H NMR(DMSO-d6,400MHz):8.99(d,J＝1.6Hz,1H),8.31(s,1H),7.85(d,J＝1.6Hz,1H),7.33-7.18(m,5H),4.41-4.32(m,2H),4.29(s,2H),1.34(t,J＝7.2Hz,3H).
Preparation of intermediate 11.2
8-Chloro-6- (chlorosulfonyl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of ethyl 6-benzylsulfonyl-8-chloro-imidazo [1,2-a ] pyridine-3-carboxylate (200.0 mg, 576.65. Mu. Mol), acOH (58.9 mg, 980.31. Mu. Mol, 56.1. Mu.L) and H 2 O (10.4 mg, 576.65. Mu. Mol, 10.4. Mu.L) in MeCN (2 mL) was added 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (227.2 mg,1.15 mmol) at 0 ℃. The mixture was stirred at 0℃for 0.5 h. The mixture was diluted with THF (15 mL), dried over Na 2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the product ethyl 8-chloro-6-chlorosulfonyl-imidazo [1,2-a ] pyridine-3-carboxylate (150.0 mg,464.18 μmol) as a yellow oil, which was used in the next step without purification.
Example 11 preparation
8-Chloro-6- (N- (1-cyanocyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of 1-aminocyclopropane carbonitrile (55.0 mg, 464.18. Mu. Mol, HCl salt) in pyridine (392.0 mg,4.96mmol,0.4 mL) was added dropwise a solution of ethyl 8-chloro-6-chlorosulfonyl-imidazo [1,2-a ] pyridine-3-carboxylate (150.0 mg, 464.18. Mu. Mol) in THF (1 mL) at 0deg.C. The mixture was stirred at 20℃for 2 hours, then quenched with H 2 O (30 mL) and extracted with EtOAc (20 mL;3 times). The combined organic layers were washed with brine (30 mL), dried over Na 2SO4, filtered and concentrated. The residue was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN;30% -60%,10 min) to give ethyl 8-chloro-6- [ (1-cyanocyclopropyl) sulfamoyl ] imidazo [1,2-a ] pyridine-3-carboxylate (4.1 mg, 9.76. Mu. Mol,99% purity, FA salt) as a pale yellow solid.
RT 0.643 min (method 1);m/z 368.8(M+H)+(ES+);1H NMR(DMSO-d6,400MHz):9.64(d,J＝1.2Hz,1H),8.47(s,1H),8.26(s,1H),7.88(d,J＝1.2Hz,1H),4.51-4.35(m,2H),1.40-1.32(m,5H),1.28-1.18(m,2H).
Example 12 preparation
6- (N- (1-Cyanocyclopropyl) sulfamoyl) -8- (4- (dimethylcarbamoyl) piperazin-1-yl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of ethyl 8-chloro-6- [ (1-cyanocyclopropyl) sulfamoyl ] imidazo [1,2-a ] pyridine-3-carboxylate (10.0 mg, 24.11. Mu. Mol, FA salt) and Cs 2CO3 (23.6 mg, 72.32. Mu. Mol) in dioxane (0.5 mL) was added Pd-PEPSI-IHeptCl (2.4 mg, 2.41. Mu. Mol) in a glove box. The mixture was stirred under argon atmosphere at 100 ℃ for 3 hours. The mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:28% -58%,10 min) to give the product ethyl 6- [ (1-cyanocyclopropyl) sulfamoyl ] -8- [4- (dimethylcarbamoyl) piperazin-1-yl ] imidazo [1,2-a ] pyridine-3-carboxylate (1.6 mg, 2.83. Mu. Mol, FA salt) as an off-white solid.
RT 0.687 min (method 1);m/z 490.1(M+H)+(ES+);1H NMR(DMSO-d6,400MHz):9.33(d,J＝1.2Hz,1H),8.37(s,1H),8.32(s,1H),6.97(d,J＝1.2Hz,1H),4.47-4.32(m,2H),3.63-3.56(m,4H),3.35(br d,J＝4.8Hz,4H),2.80(s,6H),1.37(t,J＝7.2Hz,3H),1.33-1.27(m,2H),1.25-1.18(m,2H).
Preparation of intermediate 13.1
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1-methylcyclopropan-1-amine (37.80 mg, 531.49. Mu. Mol) in pyridine (1 mL) and NMP (N-methyl-2-pyrrolidone) (1 mL) was added a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride (90 mg, 176.09. Mu. Mol) in MeCN (2 mL) at 0deg.C. The reaction was stirred at 0 ℃ for 50 minutes. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL;2 times). The organic phase was collected, dried over Na 2SO4, filtered and concentrated in vacuo to give a residue which was purified by preparative TLC (PE: etoac=3:1) to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (25 mg,45.81 μmol,26.01% yield) as a pale yellow solid.
It should be noted that the formation of the dichloro compound 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide during this process is not excluded.
RT 0.510 min (method 3); m/z 545.8 (M+H) +(ESI+)
Preparation of intermediate 13.2
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (25 mg,45.81 μmol) in tetrahydrofuran (3 mL) was added Pd/C (5 mg,10% purity). The reaction was degassed three times with H 2 (15 Psi) and then the reaction was stirred at 20℃for 3 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg,30.96 μmol,67.59% yield, 65% purity) as a brown solid.
It should be noted that the formation of the dichloro compound 1, 8-dichloro-3- (5- (difluoromethyl) 1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (see intermediate examples 18c and 18 d) also during this process is not excluded.
RT 0.468 min (method 3); m/z 420.0 (M+H) +(ESI+
Example 13 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
Pd-PEPPI-IHept Cl (3.48 mg, 3.57. Mu. Mol) and Cs 2CO3 (23.28 mg, 71.45. Mu. Mol) were added to a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg, 35.73. Mu. Mol) and N, N-dimethylpiperazine-1-carboxamide (11.23 mg, 71.45. Mu. Mol) in degassed 1, 4-dioxane (1 mL) under nitrogen. The mixture was stirred at 100℃for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (EtOAc: PE=2:1) to give 5mg of the crude product, which was further purified by preparative HPLC (column: phenomenex luna C18:150:25 mm x10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:37% -67%,10 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (1.03 mg, 1.85% yield) as a pale yellow solid.
RT 0.435 min (method 3); m/z 541.2 (M+H) +(ESI+);1 H NMR (chloroform -d,400MHz,)9.88(s,1H),7.72(s,1H),7.08(t,J＝53.6Hz,1H),6.66(d,J＝1.1Hz,1H),5.06(s,1H),3.53-3.50(m,4H),3.36-3.34(m,4H),2.91(s,6H),1.39(s,3H),0.95-0.92(m,2H),0.62-0.60(m,2H).
Preparation of intermediate 14.1
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1- (fluoromethyl) cyclopropyl-1-amine (18.43 mg, 146.74. Mu. Mol, HCl salt) in pyridine (1 mL) and THF (1 mL) at 0deg.C was added a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride (50 mg, 97.83. Mu. Mol) in MeCN (2 mL), and the mixture was stirred at 0deg.C for 1 hour. The mixture was quenched with water (10 mL) and extracted with EtOAc (20 mL;2 times). The organic phase was collected, dried over Na 2SO4, filtered and concentrated in vacuo to give a residue which was purified by preparative TLC (PE: etoac=3:1) to give 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonamide (39 mg,52.58 μmol,53.74% yield, 76% purity) as a pale yellow solid.
RT 0.487 min (method 3); m/z 463.9 (M+H) +(ESI+
Preparation of intermediate 14.2
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonamide (35 mg, 62.08. Mu. Mol) in THF (5 mL) was added Pd/C (5 mg,10% purity). The reaction was degassed three times with H 2 (15 Psi) and then the reaction was stirred at 20℃for 3 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the crude product, which was purified by preparative TLC (PE: etoac=1:1) to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg,12.49 μmol,20.12% yield, 54.7% purity) as a brown solid.
RT 0.441 min (method 3); m/z 437.9 (M+H) +(ESI+)
Example 14 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
Pd-PEPSI-IHept Cl (2.22 mg, 2.28. Mu. Mol) and Cs 2CO3 (14.88 mg, 45.68. Mu. Mol) were added to a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg, 22.84. Mu. Mol) and N, N-dimethylpiperazine-1-carboxamide (7.18 mg, 45.68. Mu. Mol) in degassed 1, 4-dioxane (1 mL) under nitrogen and the mixture stirred at 100℃for 1.5 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:36% -66%,10 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.88 mg, 5.16. Mu. Mol,22.57% yield) as a pale yellow solid.
RT 0.417 min (method 3); m/z 559.1 (M+H) +(ESI+);1 H NMR (chloroform -d,400MHz):9.89(s,1H),7.73(s,1H),7.08(t,J＝53.6Hz,1H),6.65(s,1H),5.50(s,1H),4.28(d,J＝48.4Hz,2H),3.53-3.51(m,4H),3.37-3.34(m,4H),2.91(s,6H),1.16-1.15(m,2H),0.88-0.86(m,2H).
Preparation of intermediate 18.1
2- (6- (Benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a mixture of 2- (6- (benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (900 mg,2.20 mmol) in MeCN (10 mL) was added NIS (1.39 g,6.16 mmol) and AcOH (396.54 mg,6.60mmol, 377.66. Mu.L). The reaction mixture was warmed to 25 ℃, stirred 16 and filtered. The filter cake was washed with MeCN (5 mL). The filtrate was then concentrated in vacuo to give the product 2- (6- (benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (850 mg,1.59 mmol) as a yellow solid.
RT 0.607 min (method) 3);m/z 534.8(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):9.33(s,1H),7.67(t,J＝50.8Hz,1H),7.50(s,1H),7.38(d,2H),7.29(t,J＝7.2Hz,2H),7.20(t,J＝7.2Hz,1H),4.34(s,2H)
Preparation of intermediate 18.2
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a mixture of 2- (6- (benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (850.00 mg,1.59 mmol) in MeCN (12 mL) was added AcOH (190.90 mg,3.18mmol,181.81 μl), H 2 O (57.27 mg,3.18mmol,57.27 μl) and 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (626.31 mg,3.18 mmol) at 0 ℃. The mixture was then stirred at 0 ℃ for 1 hour. The mixture was used directly in the next step without further treatment.
RT 0.510 min (method 3); m/z 510.8 (M+H) +(ESI+);
examples 18a and 18b preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 1-methylcyclopropylamine (354.84 mg,4.99 mmol) in THF (10 mL) and H 2 O (5 mL) was added NaHCO 3 (1.40 g,16.63 mmol) and the mixture was cooled to 0deg.C. A mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (850 mg, crude) from the previous step in MeCN (12 mL) is then added dropwise. The resulting reaction mixture was stirred at 0deg.C for 1 hour, quenched with H 2 O (30 mL), and extracted with EtOAc (60 mL;3 times). The combined organic layers were washed with brine (50 mL;3 times), dried over Na 2SO4, filtered and the filtrate concentrated in vacuo. Passing the crude product through flash silica gel chromatography12gSilica flash column, eluent 0-50% etoac/petroleum ether, gradient 30 mL/min) afforded the product as a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (430 mg, crude) as a yellow solid.
RT 0.537 min (method 3); m/z 545.8 (M+H) +(ESI+),m/z 453.9(M+H)+(ESI+);
Examples 18c and 18d preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (430 mg, crude) in THF (5 mL) was added TEA (239.18 mg,2.36mmol,329.00 μl) and Pd/C (787.90 μl,10% purity). The reaction mixture was degassed three times with H 2 (balloon, 15 psi) then stirred at 25 ℃ under an atmosphere of H 2 (balloon, 15 psi) for 3 hours and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18.150X 25mm X10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:55% -70%,10 min) and lyophilized directly to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (80 mg, 175.30. Mu. Mol,92% purity) as a yellow solid, and the product 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (120 mg) as a yellow solid.
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
RT 0.476 min (method) 3);m/z 420.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.11(s,,1H),7.91(s,1H),7.38(s,1H),7.09(t,J＝53.6Hz,1H),5.16(s,1H),1.41(s,3H),0.93-0.90(m,2H),0.65-0.62(m,2H)
1, 8-Dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide RT for 0.509 min (method) 1);m/z 454.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz)10.10(s,1H),7.35(s,1H),7.09(t,J＝53.6Hz,1H),5.17(s,1H),1.41(s,3H),0.96-0.87(m,2H),0.68-0.60(m,2H)
Example 15 preparation
N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (methoxymethyl) piperidinyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg, 69.63. Mu. Mol) and 4- (methoxymethyl) piperidine (17.99 mg, 139.26. Mu. Mol) in dioxane (1 mL) under nitrogen was added Cs 2CO3 (68.06 mg, 208.89. Mu. Mol) and Pd-PEPSI-IPent Cl (6.77 mg, 6.96. Mu. Mol). The reaction mixture was stirred at 100 ℃ for 12 hours, then filtered and the filtrate concentrated in vacuo. The resulting residue was purified by preparative TLC (EtOAc: petroleum ether=1:1) to give an impure product (22 mg) which was further purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:43% -73%,10 min) and lyophilized directly to give the product N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (methoxymethyl) piperidin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (9.02 mg,17.06 μmol,24.49% yield, 99% purity) as a pale yellow solid.
RT 0.458 min (method 3);m/z 524.0(M+H)+(ESI+);1H NMR(CD3OD,400MHz):9.87(s,1H),7.84(s,1H),7.33(t,J＝53.6Hz,1H),6.74(d,J＝1.2Hz,1H),3.87(d,J＝12.4Hz,2H),3.37(s,3H),3.36(s,2H),3.02-2.93(m,2H),1.99 -1.91(m,2H),1.91-1.81(m,1H),1.64-1.55(m,2H),1.55-1.49(m,2H),1.49-1.42(m,2H).
Example 16 preparation
N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-methoxypiperidin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg, 69.63. Mu. Mol) and 4-methoxypiperidine (16.04 mg, 139.26. Mu. Mol) in dioxane (1 mL) was added Cs 2CO3 (68.06 mg, 208.89. Mu. Mol) and Pd-PEPSI-IPent Cl (6.77 mg, 6.96. Mu. Mol). The mixture was degassed three times with N 2, then stirred at 100 ℃ for 12 hours, cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:34% -64%,10.5 min) and lyophilized directly to give the product N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-methoxy-1-piperidinyl) imidazo [1,5-a ] pyridine-6-sulfonamide (11 mg, 21.59. Mu. Mol,31.00% yield, 100% purity) as a yellow solid.
RT 0.434 min (method 3);m/z 510.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.94(s,1H),7.74(s,1H),7.08(t,J＝54.0Hz,1H),6.67(s,1H),5.92-5.61(br,1H),3.64-3.61(m,2H),3.55-3.47(m,1H),3.42(s,3H),3.25-3.14(m,2H),2.15-2.06(m,2H),1.92 -1.81(m,2H),1.73-1.67(m,2H),1.52 -1.49(m,2H).
Example 17 preparation
N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (hydroxymethyl) piperidin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (30.00 mg, 69.63. Mu. Mol) and 4-piperidinylmethanol (16.04 mg, 139.26. Mu. Mol) in dioxane (1 mL) were added Cs 2CO3 (68.06 mg, 208.89. Mu. Mol) and Pd-PEPSI-IPent Cl (6.77 mg, 6.96. Mu. Mol). The mixture was degassed three times with N 2, then stirred at 80 ℃ for 12 hours, cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo. The residue obtained was purified by preparative TLC (petroleum ether: etoac=1:1) to give an impure product, which was then further purified by preparative HPLC (column: phenomenex luna C18.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:33% -63%,10 min) and lyophilized directly to give the product N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (hydroxymethyl) -1-piperidinyl) imidazo [1,5-a ] pyridine-6-sulfonamide (5.8 mg,10.81 μmol,15.53% yield, 95.00% purity) as a yellow solid.
RT 0.404 min (method 3);m/z 510.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.95(s,1H),7.76(s,1H),7.09(t,J＝54.0Hz,1H),6.68(d,J＝1.4Hz,1H),5.62(s,1H),3.89(d,J＝12.4Hz,2H),3.65(d,J＝6.2Hz,2H),3.05-2.92(td,J＝12.0,2.4Hz,2H),1.97(dd,J＝12.8,2.4Hz,2H),1.88-1.78(m,1H),1.75 -1.70(m,2H),1.68 -1.63(m,1H),1.63-1.60(m,2H),1.56-1.52(m,2H).
Example 18 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (hydroxymethyl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg, 23.82. Mu. Mol) and 4-piperidinylmethanol (4.12 mg, 35.73. Mu. Mol) in dioxane (1 mL) were added Cs 2CO3 (23.28 mg, 71.46. Mu. Mol) and Pd-PEPSI-IPent Cl (2.32 mg, 2.38. Mu. Mol). The mixture was degassed three times with N 2, then stirred at 100 ℃ for 30 minutes, cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:35% -65%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (hydroxymethyl) -1-piperidinyl) -N- (1-methylcyclopropyl) -imidazo [1,5-a ] pyridine-6-sulfonamide (6.4 mg, 11.94. Mu. Mol,50.12% yield, 93% purity) as a yellow solid.
RT 0.450 min (method) 3);m/z 499.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.83(s,1H),7.71(s,1H),7.08(t,J＝54.4Hz,1H),6.64(s,1H),5.01(s,1H),3.82(d,J＝12.4Hz,2H),3.64(d,J＝6.0Hz,2H),2.93(t,J＝12.0Hz,2H),2.04-1.96(m,2H),1.81 -1.76(m,1H),1.65-1.58(m,2H),1.39(s,3H),0.95(s,2H),0.64-0.55(m,2H).
Example 19 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (2-hydroxy-prop-2-yl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg, 23.82. Mu. Mol) and 2- (4-piperidinyl) propan-2-ol (5.12 mg, 35.73. Mu. Mol) in dioxane (1 mL) was added Cs 2CO3 (23.28 mg, 71.45. Mu. Mol) and Pd-PEPSI-IPent Cl (2.32 mg, 2.38. Mu. Mol). The mixture was degassed three times with N 2, then stirred at 100 ℃ for 1 hour, cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN;45% -75%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-hydroxy-1-methyl-ethyl) -1-piperidinyl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (1 mg,1.71 μmol,7.16% yield, 97.7% purity, FA salt) as a yellow solid.
RT 0.474 min (method) 3);m/z 527.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.56(s,1H),8.49-8.39(br,1H),8.38-8.33(br,1H),7.94(s,1H),7.66(t,J＝52.4Hz,1H),6.66(s,1H),4.36-4.04(m,1H),3.84(d,J＝12.2Hz,2H),2.83(t,J＝11.2Hz,2H),1.90-1.83(m,2H),1.58-1.49(m,2H),1.49(s,1H),1.15(s,3H),1.10(s,6H),0.72(s,2H),0.44(s,2H)
Example 20 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (methoxymethyl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg, 23.82. Mu. Mol) and 4- (methoxymethyl) piperidine (4.62 mg, 35.73. Mu. Mol) in dioxane (1 mL) was added CS2CO3 (23.28 mg, 71.45. Mu. Mol) and Pd-PEPSI-IPent Cl (2.32 mg, 2.38. Mu. Mol). The mixture was degassed three times with N 2, then stirred at 100 ℃ for 30 minutes, and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:35% -65%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (methoxymethyl) -1-piperidinyl) -N- (1-methylcyclopropyl) -imidazo [1,5-a ] pyridine-6-sulfonamide (4.73 mg, 9.02. Mu. Mol,37.85% yield, 97.7% purity) as a yellow solid.
RT 0.499 min (method) 3);m/z 513.2(M+H)+(ESI+);1H NMR(CDCl3400MHz):9.83(s,1H),7.70(s,1H),7.08(t,J＝54.0Hz,1H),6.63(d,J＝1.2Hz,1H),5.02(s,1H),3.84-3.74(m,2H),3.40(s,3H),3.35(d,J＝6.0Hz,2H),2.98-2.86(m,2H),1.99-1.92(m,2H),1.88(s,1H),1.59-1.58(m,2H),1.38(s,3H),0.97-0.91(m,2H),0.63-0.57(m,2H).
Example 21 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (methoxymethyl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg, 66.04. Mu. Mol) and 4- (methoxymethyl) piperidine (12.80 mg, 99.05. Mu. Mol) in dioxane (1 mL) were added Cs 2CO3 (64.55 mg, 198.11. Mu. Mol) and Pd-PEPSI-IPent Cl (6.42 mg, 6.60. Mu. Mol). The mixture was degassed three times with N 2, then stirred at 100 ℃ for 30 minutes, cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo. The residue obtained was purified by preparative TLC (petroleum ether: etoac=0:1) to give an impure product which was further purified by preparative HPLC (column: phenomenex luna C, 150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:60% -90%,10 min) and lyophilized to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (methoxymethyl) -1-piperidinyl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (5.6 mg,9.44 μmol,14.30% yield, 100% purity, FA salt) as a yellow solid.
RT 0.543 min (method) 3);m/z 547.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.59(d,J＝0.8Hz,1H),8.50(s,1H),8.37(s,1H),7.68(t,J＝53.2Hz,1H),6.80(d,J＝0.8Hz,1H),3.46(s,2H),3.28(s,2H),3.27(s,3H),2.73(t,J＝11.4Hz,2H),1.88-1.81(m,2H),1.80-1.72(m,1H),1.58-1.46(m,2H),1.16(s,3H),0.77-0.69(m,2H),0.49-0.42(m,2H).
Example 22 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-hydroxyethyl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
Cs 2CO3 (28.69 mg, 88.04. Mu. Mol) and Pd-PEPPI-IPent Cl (4.28 mg, 4.40. Mu. Mol) were added to a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 44.02. Mu. Mol) and 1- (4-piperidinyl) ethanol (22.75 mg, 176.08. Mu. Mol) in dioxane (1 mL) under a nitrogen atmosphere. The mixture was stirred at 100 ℃ for 16 hours, then cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by preparative TLC (EtOAc: petroleum ether=3:1) to give an impure product, which was further purified by preparative HPLC (column: phenomenex luna C18.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:43% -73%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-hydroxyethyl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (1.4 mg,2.59 μmol,5.89% yield, 95.82% purity) as a yellow solid.
RT 0.472 min (method) 3);m/z 513.0(M+H)+(ESI+);1H NMR(CD3OD,400MHz):9.79(s,1H),7.83(s,1H),7.33(t,J＝53.6Hz,1H),6.70(s,1H),3.87(d,J＝12.4Hz,2H),3.61(t,J＝6.0Hz,1H),2.96-2.84(m,2H),2.06(d,J＝10.8Hz,1H),1.85(d,J＝12.8Hz,1H),1.66 -1.60(m,1H),1.59-1.48(m,2H),1.26(s,3H),1.23(d,J＝6.4Hz,3H),0.86-0.81(m,2H),0.53-0.48(m,2H).
Example 23 preparation
Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-hydroxyethyl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
Pd-PEPSI-IPent Cl (7.49 mg, 7.70. Mu. Mol) and Cs 2CO3 (75.30 mg, 231.12. Mu. Mol) were added to a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (35 mg, 77.04. Mu. Mol) and 1- (4-piperidinyl) ethanol (19.91 mg, 154.08. Mu. Mol) in dioxane (1 mL) under a nitrogen atmosphere. The mixture was stirred at 100 ℃ for 20 minutes, then cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18.150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:50% -80%,10 min) and lyophilized directly to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-hydroxyethyl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (2.9 mg, 5.14. Mu. Mol,6.67% yield, 97.16% purity) as a yellow solid.
RT 0.493 min (method) 3);m/z 547.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.59(s,1H),8.49(s,1H),7.68(t,J＝52.8Hz,1H),6.79(s,1H),4.45(d,J＝4.4Hz,1H),3.49(d,J＝11.2Hz,2H),3.47-3.42(m,1H),2.69(t,J＝11.2Hz,1H),1.96(d,J＝12.0Hz,1H),1.72(d,J＝11.6Hz,1H),1.63-1.47(m,2H),1.41-1.32(m,1H),1.17(s,3H),1.10(d,J＝6.2Hz,3H),0.76-0.70(m,2H),0.49-0.43(m,2H).
Example 24 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (2-hydroxy-prop-2-yl) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 44.02. Mu. Mol) and 2- (4-piperidinyl) propan-2-ol (9.46 mg, 66.04. Mu. Mol) in dioxane (1 mL) were added Cs 2CO3 (43.03 mg, 132.07. Mu. Mol) and Pd-PEPPI-IPent Cl (4.28 mg, 4.40. Mu. Mol). The mixture was degassed three times with N 2, then stirred at 100 ℃ for 30 minutes, cooled to 20 ℃ and filtered. The filtrate was concentrated in vacuo. The residue obtained was purified by preparative TLC (EtOAc: petroleum ether=1:0) to give an impure product which was further purified by preparative HPLC (column: phenomenex luna C18.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:50% -80%,10 min) and lyophilized directly to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-hydroxy-1-methyl-ethyl) -1-piperidinyl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (3.91 mg,6.18 μmol,14.03% yield, 95.9% purity, FA salt) as a yellow solid.
RT 0.507 min (method) 3);m/z 561.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.59(s,1H),8.52(s,1H),8.39(s,1H),7.07(t,J＝53.2Hz,1H),6.79(s,1H),4.41 -4.02(m,1H),3.52(d,J＝11.4Hz,2H),2.67(t,J＝11.4Hz,2H),1.86(d,J＝12.0Hz,2H),1.67-1.51(m,2H),1.47-1.36(m,1H),1.17(s,3H),1.11(s,6H),0.79-0.68(m,2H),0.52-0.40(m,2H)
Example 25a preparation
1, 8-Dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1- (fluoromethyl) cyclopropylamine (179.54 mg,1.43mmol, HCl salt) in water (3 mL) and THF (3 mL) was added NaHCO 3 (240.23 mg,2.86mmol, 111.22. Mu.L) and then a solution of 1, 8-dichloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] imidazo [1,5-a ] pyridine-6-sulfonyl chloride (400 mg, 953.19. Mu. Mol) in THF (3 mL) was added dropwise at 0deg.C. The resulting mixture was stirred at 0deg.C for 20 min, quenched with H 2 O (25 mL), and extracted with EtOAc (30 mL;2 times). The combined organic layers were washed with brine (50 mL;2 times), dried over Na 2SO4, filtered and the filtrate concentrated in vacuo to give a residue which was chromatographed on flash silica gel20gSilica flash column, eluent 0-50% etoac/petroleum ether; gradient 30 mL/min) to give the product 1, 8-dichloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] imidazo [1,5-a ] pyridine-6-sulfonamide (180 mg,343.01 μmol,35.99% yield, 90% purity) as a yellow solid.
RT 0.52 min (method 1);m/z 471.8&173.8(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.80(s,1H),9.03(s,1H),7.71(t,J＝53.2Hz,1H),7.48(s,1H),4.25(d,J＝52.8Hz,2H),0.91 -0.89(m,2H),0.83 -0.77(m,2H).
Example 25 preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a mixture of 1, 8-dichloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg, 105.87. Mu. Mol) in dioxane (2 mL) was added Cs 2CO3 (68.99 mg, 211.73. Mu. Mol), N-dimethylpiperazine-1-carboxamide (33.29 mg, 211.73. Mu. Mol) and Pd-PEPSI-IPent Cl (9.11 mg, 10.59. Mu. Mol). The reaction mixture was degassed three times with N 2, stirred at 100 ℃ for 1 hour and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18.150X 25mm X10 μm; mobile phase: A:0.221% NH 3.H2 O in water, B: meCN; B%:43% -73%,10 min) and lyophilized directly to give the product 4- [ 1-chloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -6- [ [1 (fluoromethyl) cyclopropyl ] sulfamoyl ] imidazo [1,5-a ] pyridin-8-yl ] -N, N-dimethyl-piperazine-1-carboxamide (12.4 mg, 20.49. Mu. Mol,19.36% yield, 98% purity) as a yellow solid.
RT 0.494 min (method 2);m/z 593.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.90(s,1H),7.07(t,J＝54.0Hz,1H),6.73(s,1H),5.46(s,1H),4.27(d,J＝48.4Hz,2H),3.55-3.51(m,4H),3.22-3.16(m,4H),2.90(s,6H),1.15-1.14(m,2H),0.89-0.87(m,2H)
Example 26 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (80 mg, 182.71. Mu. Mol) in t-BuOH (2 mL) and H 2 O (0.2 mL) was added tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (169.49 mg, 548.14. Mu. Mol) and K 3PO4 (46.54 mg, 219.25. Mu. Mol). The mixture was degassed and purged with N 2 (3 times) then cataCXium A-Pd-G3 (13.31 mg, 18.27. Mu. Mol) was added. The mixture was stirred under an atmosphere of N 2 at 60 ℃ for 16 hours. The reaction mixture was extracted with EtOAc (10 ml,3 times). The combined organic layers were washed with brine (30 mL) and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=2/1) and preparative HPLC (column: phenomenex Synergi C18150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:40% -70%,10 min) and lyophilized directly to give the product tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (23.85 mg,37.12 μmol,20.32% yield, 94% purity) as a yellow solid.
RT 0.516 min (method) 3);m/z 585.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.14(s,1H),7.86(s,1H),7.20(s,1H),7.09(t,J＝56.0Hz,1H),6.36(s,1H),5.49(s,1H),4.29(d,J＝48.0Hz,2H),4.20-4.18(m,2H),3.73(t,J＝8.0Hz,2H),2.63-2.57(m,2H),1.53(s,9H),1.18-1.13(m,2H),0.91-0.88(m,2H).
Example 27 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
A solution of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (20 mg, 34.21. Mu. Mol) in HCI/dioxane (4M, 1 mL) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo to give the crude product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (25 mg, crude, HCl salt) as a yellow solid. The crude product (5 mg) was purified by preparative HPLC (column: phenomenex luna C, 150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:11% -41%,10 min) and then lyophilized to give the product with a purity of 85%. This material was further purified by preparative HPLC (column: phenomenex luna C18.150.25 mm.10 μm; mobile phase: A:0.1% aqueous trifluoroacetic acid, B: meCN; B%:11% -44%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (3.06 mg, 4.86. Mu. Mol,56.34% yield, TFA salt) as a yellow solid.
RT 0.343 min (method 3);m/z 485.2(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.86(s,1H),8.93(s,1H),8.92-8.90(m,1H),8.11(s,1H),7.69(t,J＝52.0Hz,1H),7.32(d,J＝0.8Hz,1H),6.49(s,1H),4.24(d,J＝40.0Hz,2H),3.89(s,2H),3.43(t,J＝8.0Hz,2H),2.80 -2.72(m,2H),0.90-0.85(m,2H),0.84-0.74(m,2H).
Example 28 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide
To a solution of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 41.28. Mu. Mol, HCl salt) in THF (0.5 mL) and H 2 O (0.25 mL) at 0deg.C were added K 2CO3 (17.11 mg, 123.83. Mu. Mol) and dimethylcarbamoyl chloride (6.66 mg, 61.92. Mu. Mol, 5.69. Mu. L). The mixture was stirred at 25 ℃ for 1 hour, then diluted with water (15 mL) and extracted with EtOAc (15 mL,3 times). The organic layer was washed with brine (20 mL), dried over Na 2SO4, filtered and concentrated in vacuo to give 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide (23 mg,39.30 μmol,90.26% yield, 90% purity) as a yellow solid. 7mg of the crude product was further purified by preparative HPLC (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:35% -65%,10 min) and lyophilized directly to give 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide (3.81 mg, 6.51. Mu. Mol,54.4% yield, 95% purity) as a yellow solid.
RT 0.458 min (method 3);m/z 556.3(M+H)+(ESI+),1H NMR(CDCl3,400MHz):10.14(s,1H),7.88(s,1H),7.22(s,1H),7.09(t,J＝52.0Hz,1H),6.38(s,1H),5.54(s,1H),4.29(d,J＝48.0Hz,1H),4.08-4.06(m,2H),3.55(t,J＝8.0Hz,2H),2.92(s,6H),2.70-2.68(m,2H),1.17-1.13(m,2H),0.90-0.87(m,2H).
Example 29 preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide
To a mixture of 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide (16 mg,28.80 μmol) in MeCN (0.5 mL) was added 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (5.67 mg,28.80 μmol) at 0 ℃. The mixture was stirred at 20 ℃ for 16 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:45% -75%,10 min) and lyophilized directly to give the product 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridin 1 (2H) -carboxamide (2.77 mg, 4.51. Mu. Mol,15.65% yield, 96% purity) as a yellow solid.
RT 0.479 min (method 3);m/z 590.3(M+H)+(ESI+),1H NMR(CDCl3,400MHz):10.13(d,J＝1.2Hz,1H),7.12(d,J＝1.2Hz,1H),7.09(t,J＝52.0Hz,1H),5.89(s,1H),5.54(s,1H),4.29(d,J＝48.0Hz,2H),4.02-3.99(m,2H),3.56(t,J＝8.0Hz,2H),2.91(s,6H),2.62-2.53(m,2H),1.17-1.13(m,2H),0.90(t,J＝8.0Hz,2H).
Example 30 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylic acid tert-butyl ester
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (100 mg, 238.18. Mu. Mol) in dioxane (2 mL) was added piperazine-1-carboxylic acid tert-butyl ester (106.09 mg, 476.35. Mu. Mol), cs 2CO3 (155.21 mg, 476.35. Mu. Mol) and Pd-PEPSI-IPentCl o-methylpyridine (20.49 mg, 23.82. Mu. Mol), and the reaction mixture was degassed with N 2 (3 times). The mixture was stirred at 100 ℃ for 1 hour, then filtered and the filtrate concentrated in vacuo. The resulting residue was purified by preparative TLC (petroleum ether: etoac=0/1) to give the product tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] 181-piperidin-8-yl) piperazine-1-carboxylate (130 mg,182.57 μmol,76.65% yield, 80% purity) as a yellow solid.
RT 0.653 min (method 3);m/z 514.0(M+H)+(ES+);1H NMR(CDCl3,400MHz):9.88(s,1H),7.71(s,1H),7.08(t,J＝53.6Hz,1H),6.65(s,1H),5.04(s,1H),3.72-3.70(m,4H),3.31-3.29(m,4H),1.52(s,9H),1.39(s,3H),0.95-0.90(m,2H),0.62-0.59(m,2H).
Example 31 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
A mixture of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylate (50 mg, 87.77. Mu. Mol) in HCl/dioxane (4M, 2 mL) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:11% -41%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (12.90 mg, 26.38. Mu. Mol,30.05% yield, 96% purity, FA salt) as a yellow solid.
RT 0.360 min (method 3);m/z 470.1(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.58(s,1H),8.43(s,1H),8.25(s,1H),7.99(s,1H),7.67(t,J＝53.2Hz,1H),6.67(s,1H),3.26(s,4H),3.01(s,4H),1.15(s,3H),0.73-0.71(m,2H),0.50-0.38(m,2H).
Example 32 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyrylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulphonamide
To a mixture of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,63.89 μmol, FA salt) in THF (2 mL) and H 2 O (1 mL) at 0 ℃ was added NaHCO 3 (aqueous solution, 53.67mg,638.94 μmol,24.85 μl) and isobutyryl chloride (13.62 mg,127.79 μmol,13.35 μl), and the mixture was stirred at 0 ℃ for 15 minutes. The mixture was poured into water (7 mL) and extracted with EtOAc (12 mL;2 times). The combined organic layers were dried over Na 2SO4, filtered and concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:41% -71%,10 min)) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyrylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (5.98 mg,10.97 μmol,17.17% yield, 96.39% purity) as a yellow solid.
RT 0.498 min (method) 3),m/z 540.2(M+H)+(ESI+),1H NMR(CDCl3,400MHz)9.90(s,1H),7.73(s,1H),7.08(t,J＝53.6Hz,1H),6.66(s,1H),5.08(s,1H),3.91-3.81(m,4H),4.00-3.65(m,2H),3.65-3.32(m,2H),2.88-2.85(m,1H),1.40(s,3H),1.20(d,J＝6.8Hz,6H),0.95-0.92(m,2H),0.65-0.55(m,2H).
Example 33 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg, 119.09. Mu. Mol) and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridin-1 (2H) -carboxylate (110.47 mg, 357.26. Mu. Mol) in t-BuOH (1 mL) and H 2 O (0.1 mL) was added K 3PO4 (30.33 mg, 142.91. Mu. Mol). The mixture was degassed with N 2 (3 times). cataCXium A-Pd-G3 (8.6 mg, 11.91. Mu. Mol) was then added. The mixture was stirred at 60 ℃ for 16 hours, cooled to room temperature and dissolved in MeOH (1 mL). The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:60% -90%,10 min) and then lyophilized to give the product, tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (35.21 mg, 60.27. Mu. Mol,50.61% yield, 97% purity), as a yellow solid.
RT 0.567 min (method 3);m/z 567.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.13(s,1H),7.85(s,1H),7.21(s,1H),7.09(t,J＝53.6Hz,1H),6.35(s,1H),5.13(s,1H),4.21-4.19(m,2H),3.73(t,J＝5.2Hz,2H),2.63-2.61(m,2H),1.53(s,9H),1.39(s,3H),0.92(t,J＝6.0Hz,2H),0.62(t,J＝6.4Hz,2H).
Example 34 preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
To a solution of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (140 mg, 247.06. Mu. Mol) in MeCN (1.5 mL) was added NCS (49.49 mg, 370.60. Mu. Mol) and the mixture stirred at 20 ℃ for 16H. The reaction was quenched with NaHCO 3 (10 mL). The resulting mixture was then extracted with EtOAc (30 mL;3 times). The combined organic layers were washed with brine (20 mL;3 times), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure to give 36mg of crude product. 15mg of this crude product was purified by preparative HPLC (column: phenomenex luna C, 150, 25mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:65% -95%,10 min) and lyophilized to give the product tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (4.28 mg, 6.79. Mu. Mol,6.6% yield, 95.3% purity) as a yellow solid.
RT 0.598 min (method 3);m/z 601.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.12(d,J＝1.4Hz,1H),7.11(d,J＝1.2Hz,1H),7.09(t,J＝53.6Hz,1H),5.88(s,1H),5.15(s,1H),4.16-4.14(m,2H),3.75(t,J＝5.2Hz,2H),2.58-2.39(m,2H),1.53(s,9H),1.39(s,3H),0.92(t,J＝6.4Hz,2H),0.62(t,J＝6.8Hz,2H).
Example 35 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (35 mg, 58.23. Mu. Mol) in HCl/dioxane (4M, 0.2 mL) was stirred at 20℃for 1 hour. The mixture was concentrated to give 35mg of crude product. 10mg of this crude product was purified by preparative HPLC (column: phenomenex luna C, 150, 25mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:15% -45%,10 min) and lyophilized to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (3.1 mg, 5.44. Mu. Mol,32.7% yield, 96% purity, FA salt) as a yellow solid.
RT 0.376 min (method 3);m/z 501.3(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.83(d,J＝1.6Hz,1H),8.73-8.42(m,1H),8.25(s,1H),7.69(t,J＝53.6Hz,1H),7.12(d,J＝1.2Hz,1H),5.92(s,1H),3.52-3.50(m,2H),3.11(t,J＝5.6Hz,2H),2.34(s,2H),1.19(s,3H),0.73(t,J＝6.4Hz,2H),0.49-0.46(m,J,2H).
Example 36 preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide
To a solution of 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 36.56. Mu. Mol, FA salt) in THF (0.6 mL) and H 2 O (0.3 mL) were added K 2CO3 (16.55 mg, 119.77. Mu. Mol) and dimethylcarbamoyl chloride (6.44 mg, 59.88. Mu. Mol, 5.50. Mu.L). The mixture was stirred at 0deg.C for 1 hour, diluted with H 2 O (5 mL) and extracted with EtOAc (5 mL,3 times). The organic layer was washed with brine (5 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:48% -78%,10 min) and lyophilized to give the product 4- (1-chloro-3- (5- (difluoromethyl) -l,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide (5.38 mg, 9.31. Mu. Mol,25.46% yield, 99% purity) as a yellow solid.
RT 0.498 min (method) 3);m/z 572.4(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):10.12(d,J＝0.8Hz,1H),7.12(d,J＝0.8Hz,1H),7.09(t,J＝53.6Hz,1H),5.88(s,1H),5.19(s,1H),4.01-3.99(m,2H),3.57(t,J＝5.2Hz,2H),2.91(s,6H),2.57-2.54(m,2H),1.39(s,3H),0.92(t,J＝6.0Hz,2H),0.62(t,J＝5.6Hz,2H).
Example 37 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (200 mg,0.423 mmol) in 1, 4-dioxane (4 mL) was added 2-oxa-7-azaspiro [3.5] nonane (162 mg,1.27 mmol), cs 2CO3 (414 mg,1.27 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (36 mg,0.0423 mmol). The reaction mixture was degassed with N 2 (3 times) and stirred at 90 ℃ for 1 hour. It was then filtered and the filtrate concentrated in vacuo. The resulting residue was purified by preparative TLC (petroleum: etoac=3/1) to give crude product (32 mg) which was further triturated with MeOH (2 mL) at 20 ℃ for 10 min to give the product 1-chloro-3- (5- (difluoromethyl) -l,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (25.55 mg,44.9 μmol,10.61% yield, 100% purity) as a yellow solid.
RT 0.515 min (method) 3);m/z 563.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz,)9.87(s,1H),7.07(t,J＝53.6Hz,1H),6.69(s,1H),5.58(s,1H),4.53(s,4H),4.26(d,J＝48.4Hz,2H),3.29-2.94(m,4H),2.17(m,4H),1.17-1.13(m,2H),0.89-0.86(m,2H).
Example 38 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (40 mg, 88.05. Mu. Mol) in dioxane (1 mL) was added 2-oxa-7-azaspiro [3.5] nonane (22.40 mg, 176.09. Mu. Mol), cs 2CO3 (86.06 mg, 264.14. Mu. Mol) and Pd-PEPPPSI-IPentCl o-methylpyridine (7.58 mg, 8.80. Mu. Mol). The reaction mixture was degassed with N 2 (3 times) and the mixture was stirred at 90 ℃ for 1 hour. It was then filtered and the filtrate concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: etoac=0:1) and lyophilized to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (15.58 mg,27.55 μmol,31.29% yield, 96.39% purity) as a yellow solid.
RT 0.509 min (method 3);m/z 545.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.87(s,1H),7.68(t,J＝53.2Hz,1H),6.70(s,1H),5.09(s,1H),4.54(s,4H),3.10-3.05(m,4H),2.25-2.10(m,4H),1.39(s,3H),0.94-0.91(m,2H),0.66-0.59(m,2H).
Example 39 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
A mixture of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (40 mg, 70.59. Mu. Mol) in HCl/dioxane (4M, 1.5 mL) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (45 mg, crude, HCl salt) as a yellow solid.
RT 0.351 min (method) 3);m/z 467.1(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.88(s,1H),9.27(d,J＝0.8Hz,1H),8.58(s,1H),8.13(s,1H),7.69(t,J＝53.2Hz,1H),7.38(d,J＝0.8Hz,1H),6.49(s,1H),3.92-3.87(m,2H),3.45-3.35(m,2H),2.85-2.72(m,2H),1.18(s,3H),0.74-0.72(m,2H),0.49-0.45(m,2H).
Example 40 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-5, 6-dihydropyridine-1 (2H) -carboxamide
To a mixture of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (45 mg, 96.46. Mu. Mol, HCl salt) in THF (2 mL) and H 2 O (1 mL) at 0deg.C was added K 2CO3 (39.99 mg, 289.37. Mu. Mol) and dimethylcarbamoyl chloride (15.56 mg, 144.69. Mu. Mol, 13.30. Mu.L). The mixture was stirred at 0deg.C for 15 min, poured into water (10 mL), and extracted with EtOAc (15 mL;2 times). The combined organic layers were then dried over Na 2SO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: phenomenex luna C, 150, 25mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:40% -70%,10 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethyl-5, 6-dihydropyridine 1 (2H) -carboxamide (12.1 mg, 22.06. Mu. Mol,22.87% yield, 98% purity) as a yellow solid.
RT 0.494 min (method 3);m/z 538.1(M+H)+(ESI+),1H NMR(CDCl3,400MHz):10.13(s,1H),7.87(s,1H),7.22(d,J＝1.2Hz,1H),7.09(t,J＝53.2Hz,1H),6.38(s,1H),5.09(s,1H),4.10-3.95(m,2H),3.65-3.45(m,2H),2.92(s,6H),2.70-2.58(m,2H),1.39(s,3H),0.93-0.91(m,2H),0.68-0.58(m,2H).
The following general procedure applies to the synthesis of the compounds described below.
General procedure 1 (Buchwald coupling): to a solution of the chlorine compound (1.00 eq) in1, 4-dioxane (500 mg/mL) was added the amine substrate (1 to 3eq, free base or salt) and Cs 2CO3 (2 to 4 eq). The mixture was degassed with N 2 (3 times) or placed in a glove box. Pd-PEPSI-IPentCl o-methylpyridine (0.05 to 0.1 eq) was then added. The mixture was stirred under N 2 at 80 ℃ to 100 ℃ for 1 to 16 hours outside the glove box. The reaction mixture was then cooled to room temperature, diluted with H 2 O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 2 (Boc cleavage): TFA (1/5 to 1/3 of the DCM volume) or HCl/dioxane (4N, 1/5 to 1/3 of the DCM volume) was added to a solution of the Boc-protected compound in DCM (0.1 g/mL) at 0deg.C, and the mixture was stirred at 0deg.C for 2 to 16 hours. The mixture was then concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 3 (bromination and iodination): to a mixture of substrate (1 eq) in CHCl 3 (0.01 to 0.1 g/mL) or MeCN (0.01 to 0.1 g/mL) was added dropwise a solution of NBS (0.8 to 1.1 eq) or NIS (0.8 to 1.1 eq) in CHCl 3 (0.01 to 0.1 g/mL) or MeCN (0.01 to 0.1 g/mL) at 0 ℃. The mixture was stirred at room temperature for 0.5 hours and concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 4 (amine transesterification): to a mixture of the ester substrate (1 eq) in EtOH (10 to 100 mg/mL) and H 2 O (1/10 to 1/3 of EtOH volume) was added the amine substrate (1 to 10eq, free base or HCl salt). The mixture is stirred at 20 ℃ to 100 ℃ for 2 hours to 20 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 5 (amide formation using peptide coupling agents): to a solution of the acid substrate (1 eq) in DMF (20 to 100 mg/mL) was added HATU (1 to 2 eq) and DIEA (1.5 to 2 eq). The mixture was stirred at 20 ℃ for 30 minutes and amine substrate (1.2 to 1.5eq, free base or HCl salt) was added. The reaction was stirred at 20 ℃ for 1 to 16 hours, then diluted with ice/H 2 O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous Na 2SO4, filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 6 (Suzuki coupling using Xantphos Pd G4): to a solution of bromide or iodide substrate (1 eq), borate or boric acid substrate (1 to 4 eq) and Cs 2CO3 (2 to 4 eq) in dioxane (10 to 100 mg/mL) and H 2 O (1/10 to 1/5 of the volume of dioxane) was added Xantphos Pd G4 (0.1 to 0.2 eq). The reaction mixture was degassed and purged with N 2 (3 times), stirred at 80 ℃ to 100 ℃ for 2 hours to 16 hours and concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
Alternatively, after stirring at 80 ℃ to 100 ℃ for 2 hours to 16 hours, the reaction mixture was cooled to room temperature, diluted with H 2 O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 7 (hydrogenation): pd/C (m=1/10 to 1/5mg substrate mass, 10% purity) was added to a solution of olefinic substrate (1 eq) in THF (2.5 to 50 g/mL) under N 2. The suspension was degassed under vacuum and purged with H 2 (3 times). The mixture was stirred at 20 ℃ to 50 ℃ under an atmosphere of H 2 (15 psi) for 2 hours to 16 hours, then filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 8 (Sonogashira coupling 1): to a solution of bromide or iodide substrate (1 eq) in DMF or dioxane or DMF/MeOH (1 to 100 mg/mL) was added CuI (0.05 to 0.3 eq), K 2CO3 (2 to 4 eq) or TEA (1/2 to 1V of solvent) and Pd (PPh 3)2Cl2 or Pd (dppf) Cl 2 (0.05 to 0.3 eq.) the reaction mixture was degassed and purged with N 2 (3 times) then alkyne substrate (1 to 3 eq) was added to the mixture, the reaction mixture was stirred at 80 ℃ to 150 ℃ for 0.5 to 16 hours under an atmosphere of N 2, then poured into water and extracted with EtOAc (3 times), the combined organic layers were dried over Na 2SO4, filtered and concentrated under reduced pressure the resulting residue was purified by reverse phase preparative HPLC (reverse phase) or preparative or column chromatography of SiO 2 to give the corresponding product.
General procedure 9 (saponification): to a mixture of the ester substrate (1 eq) in MeOH (10 to 200 mg/mL) and H 2 O (1/3 to 1/1 of MeOH volume) was added LiOH or LiOH H 2 O (2 to 10 eq). The mixture was stirred at 20 ℃ to 80 ℃ for 1 hour to 16 hours. Post-processing procedure 1: the pH of the reaction mixture was adjusted to 1 to 6 by adding aqueous hydrochloric acid (1N), followed by extraction with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na 2SO4, filtered and concentrated under reduced pressure to give the crude product which was used in the next step without further purification. Post-treatment 2: the pH of the reaction mixture was adjusted to 1 to 6 by adding aqueous hydrochloric acid (1N). The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 10 (Sonogashira coupling 2): p (t-Bu) 3 (0.2 eq,10% w/w in hexane), TEA or DABCO (2 eq) and allyl (chloro) palladium (0.1 eq) were added to a solution of MeCN (50 mg/mL) of bromide or iodide substrate (1 eq). The reaction mixture was degassed and purged with N 2 (3 times) and then alkyne substrate (2 eq) was added to the mixture. The reaction mixture was stirred at room temperature for 1 to 16 hours under an atmosphere of N 2 and concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
Alternatively, after stirring, the reaction mixture was diluted with H 2 O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 11 (TBS lysis): KF (2 eq) was added to a solution of TBS protected compound in MeOH (0.5 g/mL). The mixture was stirred at room temperature for 1 to 16 hours and then concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 12 (amide formation using acid chloride): to a solution of the amine substrate (1 eq) in THF (20 to 100 mg/mL) was added NaHCO 3 (saturated solution, 20 to 100 mg/mL) or TEA (1.5 to 2 eq). The mixture was stirred at 0 ℃ for 2 minutes, and acid chloride (1.2 to 1.5 eq) was added to the mixture. The reaction was stirred at 20 ℃ for 0.5 to 1 hour, then diluted with ice-H 2 O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2SO4, filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
General procedure 13 (Stille coupling): to a solution of tin substrate (1 eq) in dioxane (v=15 mg/mL) was added halogenated substrate (1.5 eq), K 2CO3 (2 eq) and Pd (dppf) Cl 2 (0.1 eq). The reaction mixture was degassed and purged with N 2 (3 times). The reaction mixture was stirred at 80 ℃ under an atmosphere of N 2 for 16 hours, then poured into water and extracted with EtOAc. The combined organic layers were dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue obtained is purified by reverse phase prep HPLC (reverse phase)
General procedure 14 (ester formation): a solution of the acid substrate (1 eq), DMAP (0.5 eq) and DCC (2 eq) in DCM (20 to 100 mg/mL) was stirred at room temperature for 1 to 3 hours and the alcohol substrate (1 to 2 eq) was added. The mixture was stirred at room temperature for 1 to 16 hours. The resulting mixture was diluted with ice/H 2 O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over anhydrous Na 2SO4, filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by reverse phase prep HPLC (reverse phase) or prep TLC or SiO 2 column chromatography (normal phase) to give the corresponding product.
Example 41.A preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a mixture of 1-methylcyclopropylamine (78.20 mg,726.90 μmol, HCl salt) in NaHCO 3 (saturated aqueous solution, 3 mL) was added dropwise a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonyl chloride (140 mg,363.45 μmol) in THF (1.5 mL) at 0 ℃. The mixture was stirred at 15℃for 2 hours. The reaction mixture was quenched with H 2 O (30 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (30 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. Subjecting the residue to flash chromatography on silica gel4gSilica flash column, eluent 20-40% ethyl acetate/petroleum, 75 mL/min) afforded the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (50 mg,119.09 μmol,32.77% yield) as a white solid.
RT 0.809 minutes (method) 1);m/z 420.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.99(d,J＝1.2Hz,1H),8.81(s,1H),8.58(s,1H),7.94(d,J＝1.2Hz,1H),7.73(t,J＝53.2Hz,1H),1.17-1.20(m,3H),0.67-0.76(m,2H),0.45-0.53(m,2H).
Example 41 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of N, N-dimethylpiperazine-1-carboxamide (14.98 mg, 95.27. Mu. Mol) in dioxane (0.5 mL) was added 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (20 mg, 47.64. Mu. Mol), cs 2CO3 (31.04 mg, 95.27. Mu. Mol) and Pd-PEPPI-IPentCl o-methylpyridine (2.05 mg, 2.38. Mu. Mol) in a glove box. The mixture was stirred under argon at 100 ℃ outside the glove box for 2 hours, cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:32% -62%,7 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (3.05 mg, 5.42. Mu. Mol,11.37% yield, 96% purity) as a pale yellow solid.
RT 0.896 min (method 1);m/z 541.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.67(s,1H),8.63(s,1H),8.32-8.50(m,1H),7.71(t,J＝53.2Hz,1H),7.02(s,1H),3.64(br,4H),3.35-3.37(m,4H),2.81(s,6H),1.14(s,3H),0.66-0.77(m,2H),0.39-0.52(m,2H).
Example 42 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (30 mg, 69.63. Mu. Mol) in dioxane (0.5 mL) was added 2-oxa-7-azaspiro [3.5] nonane (25.19 mg, 104.45. Mu. Mol, TFA salt), cs 2CO3 (68.06 mg, 208.89. Mu. Mol). In a glove box, pd-PEPSI-IPentCl o-methylpyridine (3.00 mg, 3.48. Mu. Mol) was added. The mixture was then stirred at 100 ℃ under argon outside the glove box for 1 hour, cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column Phenomenex Synergi C18150 x 25mm x10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:31% -61%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (7.35 mg,13.67 μmol,19.64% yield, 94.99% purity) as a pale yellow solid.
RT 0.918 min (method) 1);m/z 511.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz)9.88(d,J＝1.6Hz,1H),8.18(s,1H),6.95-7.24(m,2H),5.06(s,1H),4.54(s,4H),3.49-3.60(m,4H),2.11-2.21(m,4H),1.35(s,3H),0.87-0.95(m,2H),0.55-0.62(m,2H).
Preparation of intermediate 43.1
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonyl bromide
Three batches were run in parallel and mixed for post-treatment.
To a mixture of 2- (6- (benzylthio) -8-chloroimidazo [1,2-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (1 g,2.45 mmol), acOH (293.74 mg,4.89mmol,279.75 μl), H 2 O (88.12 mg,4.89mmol,88.12 μl) in MeCN (10 mL) was added 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (2.80 g,9.78 mmol) at 0 ℃ and the mixture was stirred at 0 ℃ for 0.5 hours. The 3 batches were combined. The resulting mixture was quenched with ice/water (90 mL) and extracted with DCM (90 mL,3 times). The combined organic layers were washed with brine (50 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate (10% dcm additive) =5/1 to 1/1) to give the product 8-chloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] imidazo [1,2-a ] pyridine-6-sulfonyl bromide (3.15 g,7.33mmol, 99.73%) as a yellow solid.
RT 0.770 min (method 1); m/z 430.7 (M+H) +(ESI+)
Preparation of Compound 43
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
Three batches were run in parallel and mixed for post-treatment.
To a mixture of 1- (fluoromethyl) cyclopropan-1-amine (705.83 mg,5.62mmol, HCl salt) in saturated NaHCO 3 (7 mL) was added a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,2-a ] pyridine-6-sulfonyl bromide (1.05 g,2.44 mmol) in THF (5 mL) and the mixture stirred at 15℃for 1h. The 3 batches were combined. The resulting mixture was diluted with H 2 O (60 mL) and extracted with EtOAc (60 mL,2 times). The combined organic layers were then washed with brine (30 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was subjected to column chromatography (SiO 2, petroleum ether/ethyl acetate=5/1 to 2/1) to give 1.7g of an impure product. 50mg of the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (17.49 mg, 39.95. Mu. Mol,8.06% yield) was purified by preparative HPLC (column: phenomenex luna C18.150X 25mm X10. Mu.m; mobile phase: A:0.225% aqueous formic acid; B: meCN; B%:41% -61%,10 min) and lyophilized directly.
RT 0.784 min (method 1);m/z 438.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.97(d,J＝1.6Hz,1H),9.08-8.90(m,1H),8.79(s,1H),7.94(d,J＝1.6Hz,1H),7.71(t,J＝53.2Hz,1H),4.24(d,J＝48.4Hz,1H),0.92-0.84(m,2H),0.83-0.76(m,2H).
Example 44 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of N, N-dimethylpiperazine-1-carboxamide (14.36 mg, 91.36. Mu. Mol) in dioxane (0.5 mL) was added 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (20 mg, 45.68. Mu. Mol), cs 2CO3 (29.77 mg, 91.36. Mu. Mol) and Pd-PEPPI-IPentCl o-methylpyridine (1.97 mg, 2.28. Mu. Mol) in a glove box. The mixture was stirred at 100 ℃ under argon outside the glove box for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:29% -59%,7 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (5.73 mg, 10.16. Mu. Mol,22.23% yield, 99% purity) as a pale yellow solid.
RT 0.887 min (method 1);m/z 559.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.65(s,1H),8.67-8.82(m,1H),8.62(s,1H),7.71(t,J＝53.2Hz,1H),7.02(s,1H),4.23(d,J＝48.8Hz,2H),3.63(br,4H),3.36(br,4H),2.81(s,6H),0.81-0.88(m,2H),0.74-0.81(m,2H).
Example 45 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- ((dimethyl (oxo) -l 6-sulfa-nylidene) amino) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (15 mg, 35.73. Mu. Mol) in dioxane was added dimethyl (piperidin-4-ylimino) -lambda 6 -sulphone (13.35 mg, 53.59. Mu. Mol,2HCl salt), pd-PEPPI-IPentCl o-methylpyridine (1.74 mg, 1.79. Mu. Mol) and Cs 2CO3 (46.56 mg, 142.91. Mu. Mol) in a glove box. The mixture was stirred at 100 ℃ under argon outside the glove box for 2 hours, cooled to room temperature, diluted with H 2 O (30 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (30 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex Synergi C, 150 x 25mm x10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:29% -59%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- ((dimethyl (oxo) -l 6-sulfanylideneamino) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (6.53 mg,11.67 μmol,32.66% yield, 100% purity) as a yellow solid.
RT 0.904 min (method 1);m/z 560.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.61(d,J＝1.2Hz,1H),8.58(s,1H),8.39(s,1H),7.69(t,J＝53.2Hz,1H),6.97(s,1H),4.11-4.23(m,2H),3.44-3.52(m,1H),3.30(s,6H),3.15-3.23(m,2H),1.81-1.96(m,2H),1.56-1.71(m,2H),1.13(s,3H),0.68-0.74(m,2H),0.41-0.46(m,2H).
Example 46 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (6- (hydroxymethyl) -3-azabicyclo [3.1.1] hept-3-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (50 mg, 119.09. Mu. Mol) in dioxane (0.6 mL) was added (3-azabicyclo [3.1.1] hept-6-yl) methanol (29.23 mg, 178.64. Mu. Mol, HCl salt), pd-PEP-IPentCl o-methylpyridine (5.79 mg, 5.95. Mu. Mol) and Cs 2CO3 (116.40 mg, 357.27. Mu. Mol) in a glove box. The mixture was stirred at 100 ℃ under argon outside the glove box for 2 hours. The reaction mixture was cooled to room temperature, diluted with H 2 O (30 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (30 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex Synergi C18.150.25 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:29% -59%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (6- (hydroxymethyl) -3-azabicyclo [3.1.1] hept-3-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (6.53 mg, 11.67. Mu. Mol,32.66% yield, 100% purity) as a yellow solid
RT 1.010 min (method) 1);m/z 511.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.45-9.52(m,1H),8.52-8.57(m,1H),8.30-8.43(m,1H),7.54-7.87(m,1H),6.61-6.67(m,1H),4.18-4.24(m,1H),3.96-4.13(m,3H),3.67-3.71(m,1H),3.39-3.43(m,1H),2.35-2.45(m,3H),1.82-2.08(m,1H),1.38-1.51(m,1H),1.16(d,J＝2.4Hz,3H),0.69-0.76(m,2H),0.41-0.47(m,2H).
Example 47 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (30 mg, 68.52. Mu. Mol) in dioxane (0.5 mL) were added 2-oxa-7-azaspiro [3.5] nonane (24.79 mg, 102.78. Mu. Mol, TFA salt) and Cs 2CO3 (66.97 mg, 205.55. Mu. Mol). In the glove box, pd-PEPPI-IPentCl o-methylpyridine (2.95 mg, 3.43. Mu. Mol) was added. The mixture was stirred at 100 ℃ under argon outside the glove box for 1 hour, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column Phenomenex luna C18150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:38% -68%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (4.9 mg,9.27 μmol,13.53% yield, 100% purity) as a yellow solid.
RT 0.855 min (method 1);m/z 529.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.88(d,J＝1.6Hz,1H),8.18(s,1H),6.93-7.24(m,2H),5.46(s,1H),4.54(s,4H),4.25(d,J＝48.8Hz,2H),3.51-3.61(m,4H),2.10-2.18(m,4H),1.09-1.18(m,2H),0.83-0.88(m,2H)
Preparation of Compound 48
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylthio) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 4- (methylthio) piperidine (53.92 mg, 321.54. Mu. Mol, HCl salt) in dioxane (1 mL) were added 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (90 mg, 214.36. Mu. Mol) and Cs 2CO3 (209.53 mg, 643.08. Mu. Mol). In the glove box, pd-PEPPI-IPentCl o-methylpyridine (9.22 mg, 10.72. Mu. Mol) was added. The mixture was stirred at 100 ℃ under Ar 2 outside the glove box for 2 hours, then cooled to room temperature, diluted with H 2 O (30 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (30 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:51% -81%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylthio) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (25 mg, 48.07. Mu. Mol,22.42% yield, 98.95% purity) as a yellow solid
RT 0.634 min (method) 3);m/z 515.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz)9.87(d,J＝1.6Hz,1H),8.17(s,1H),6.95-7.24(m,2H),5.05(s,1H),4.18-4.28(m,2H),3.10-3.20(m,2H),2.79-2.92(m,1H),2.15-2.25(m,5H),1.85-1.98(m,2H),1.36(s,3H),0.87-0.95(m,2H),0.56-0.62(m,2H)
Example 49 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (S-methylsulfanylimino) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a mixture of 3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- (1-methylcyclopropyl) -8- (4-methylsulfanyl-1-piperidinyl) imidazo [1,2-a ] pyridine-6-sulfonamide (20 mg,38.86 μmol) in EtOH (0.5 mL) was added Phl (OAc) 2 (50.07 mg,155.45 μmol) and ammonium carbamate (6.07 mg,77.73 μmol). The mixture was stirred at 20 ℃ for 16 hours, then diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over Na 2SO4 and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:24% -54%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (S-methylsulfonyliminopiperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (12.51 mg, 22.93. Mu. Mol,58.99% yield, 100% purity) as a yellow solid.
RT 0.780 min (method) 1);m/z 546.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz)9.92(d,J＝1.2Hz,1H),8.19(s,1H),6.96-7.26(m,2H),5.30(s,1H),4.61(t,J＝12.4Hz,2H),3.14-3.30(m,1H),2.94-3.06(m,5H),2.33-2.50(m,2H),2.08-2.22(m,2H),1.37(s,3H),0.89-0.99(m,2H),0.56-0.65(m,2H)
Example 50 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylsulfonyl) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylthio) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (20 mg,38.86 μmol) in DCM (0.5 mL) was added m-CPBA (15.39 mg,75.78 μmol,85% purity), and the mixture stirred at 0 ℃ for 1 hour. The reaction mixture was diluted with NaS 2O3 (saturated aqueous solution, 20 mL) and extracted with EtOAc (20 mL, 2X). The combined organic layers were washed with brine (20 ml,2 times), dried over anqueous Na 2SO4 and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: waters Xbridge 150X 25mM X5 μm; mobile phase: A:10mM NH 4HCO3 in water, B: meCN; B%:37% -67%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylsulfonyl) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (2.13 mg, 3.78. Mu. Mol,9.73% yield, 97% purity) as a pale yellow solid.
RT 0.679 min (method 3);m/z 547.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz)9.93(d,J＝1.6Hz,1H),8.20(s,1H),6.96-7.26(m,2H),5.09(s,1H),4.53-4.65(m,2H),3.07-3.18(m,1H),2.96-3.06(m,2H),2.93(s,3H),2.35-2.46(m,2H),2.11-2.26(m,2H),1.39(s,3H),0.90-0.97(m,2H),0.57-0.65(m,2H).
Example 51 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylsulfinyl) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylthio) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (30 mg,58.29 μmol) in DCM (0.5 mL) was added m-CPBA (11.24 mg,55.38 μmol,85% purity), and the mixture stirred at 0 ℃ for 1 hour. The reaction mixture was quenched with Na2S2O3 (saturated aqueous solution, 20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na 2SO4 and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm x10 um; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:33% -63%,10 min) and lyophilized to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (4- (methylsulfinyl) piperidin-1-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (5.96 mg,11.10 μmol,19.04% yield, 98.822% purity) as a yellow solid.
RT 0.679 min (method 1);m/z 531.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz)8.89(d,J＝1.2Hz,1H),8.17(s,1H),7.23-6.96(m,2H),5.34(s,1H),4.52-4.44(m,2H),3.13-3.06(m,1H),2.86-2.84(m,2H),2.64(s,3H),2.34-2.33(m,1H),2.10-2.02(m,3H),1.36(s,3H),0.93-0.90(m,2H),0.60-0.57(m,2H)
The compounds listed in the following table were prepared according to the corresponding general procedure or, when illustrated in a similar manner to the relevant examples, starting from the corresponding intermediates or examples. It should be noted that the skilled person is able to select the correct intermediates and reaction conditions to obtain any of the compounds listed in the following table (or any other table in the present application relating to the synthesis of compounds by reference to any general procedure).
Compound 55 appears to include two isomers according to the following structure:
Example 70a preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
A mixture of tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (220.94 mg, 714.53. Mu. Mol), 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (200 mg, 476.35. Mu. Mol), cataCXium A-Pd-G 3 and K 3PO4 in N-BuOH (5 mL) was degassed, purged with N 2 (3 times) and stirred at 60℃for 16 hours under an atmosphere of N 2. The mixture was cooled to 20 ℃, poured into water (20 mL) and filtered. The resulting solid was triturated with pe:ea=3:1 for 10 minutes at 20 ℃. After filtration, the solid was dried in vacuo to give 170mg of crude product. 10mg of this crude product was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:54% -84%,7 min) and lyophilized directly to give the product tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (6.05 mg, 10.68. Mu. Mol,38.08% yield, 100% purity) as a yellow solid.
RT 0.991 min (method) 1);m/z 567.2(M+H)+(ES+);1H NMR(CDCl3,400MHz)10.22(d,J＝1.6Hz,1H),8.28(s,1H),7.67(d,J＝1.6Hz,1H),6.95-7.25(m,2H),5.13(s,1H),4.20-4.30(m,2H),3.75(t,J＝5.6Hz,2H),2.70-2.80(m,2H),1.52(s,9H),1.37(s,3H),0.86-0.95(m,2H),0.58-0.64(m,2H)
Example 70 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,2-a ] pyridine-6-sulfonamide hydrochloride
To a solution of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -3, 6-dihydropyridine-1 (2H) -carboxylate (150 mg,264.72 μmol) in DCM (2 mL) was added HCl/dioxane (4 m,2 mL) and the mixture stirred at 20 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure to give 90mg of crude product. 15mg of this crude product was purified by preparative HPLC (column: phenomenex luna C18150 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:10% -40%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,2-a ] pyridine-6-sulfonamide hydrochloride (3.69 mg, 7.91. Mu. Mol,18.94% yield, 100% purity, HCl salt) as a yellow solid
RT 0.767 min (method) 1);m/z 467.1(M+H)+(ES+);1H NMR(CDCl3,400MHz)10.23(d,J＝1.6Hz,1H),8.27(s,1H),7.70(d,J＝1.6Hz,1H),6.98-7.27(m,2H),5.09-5.21(m,1H),3.72-3.78(m,2H),3.27(t,J＝5.6Hz,2H),2.69-2.78(m,2H),1.38(s,3H),0.90-0.94(m,2H),0.59-0.65(m,2H).
Example 71 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide
To a solution of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,2-a ] pyridine-6-sulfonamide (20 mg, 42.87. Mu. Mol) in THF (0.5 mL) were added DIEA (11.08 mg, 85.74. Mu. Mol, 14.93. Mu. L) and dimethylcarbamoyl chloride (3.69 mg, 34.30. Mu. Mol, 3.15. Mu. L) and the mixture was stirred at 0℃for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:44% -74%,7 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethyl-3, 6-dihydropyridine-1 (2H) -carboxamide (3.82 mg, 7.11. Mu. Mol,16.57% yield) as a white solid.
RT 0.620 min (method) 3);m/z 538.2(M+H)+(ES+);1H NMR(DMSO-d6,400MHz)9.99(d,J＝1.6Hz,1H),8.75(s,1H),8.45-8.55(m,1H),7.56-7.87(m,2H),7.40(s,1H),4.00(d,J＝1.6Hz,2H),3.42-3.46(m,2H),2.81(s,6H),2.70-2.80(m,3H),1.14(s,3H),0.68-0.75(m,2H),0.43-0.50(m,2H)
Example 72 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-hydroxy-3-methylbut-1-yn-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (30 mg, 71.45. Mu. Mol) in DMF (1 mL) was added K 2CO3(39.50mg,285.81μmol)、Pd(dppf)Cl2 (5.23 mg, 7.15. Mu. Mol) and CuI (1.36 mg, 7.15. Mu. Mol). The reaction mixture was degassed and purged with N 2 (3 times), followed by the addition of 2-methylbutan-3-yn-2-ol (6.61 mg,78.60 μmol,7.68 μl). The reaction mixture was then stirred under an atmosphere of N 2 at 100 ℃ for 2 hours, followed by concentration under reduced pressure. The resulting residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: phenomenex Synergi C18:150:25:10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:34% -64%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-hydroxy-3-methylbut-1-yn-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (7.42 mg, 15.87. Mu. Mol,22.21% yield, 100% purity) as an off-white solid.
RT 0.980 min (method 1);m/z 468.1(M+H)+(ES+);1H NMR(400MHz,DMSO-d6)9.99(d,J＝1.6Hz,1H),8.75(s,1H),8.37-8.62(m,1H),7.53-7.86(m,2H),5.73(s,1H),1.55(s,6H),1.15(s,3H),0.67-0.74(m,2H),0.41-0.49(m,2H).
Example 73 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-hydroxy-3-methylbutyl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
Pd/C (5 mg,10% purity) was added to a solution of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-hydroxy-3-methylbut-1-yn-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (10 mg, 21.39. Mu. Mol) in EtOH (1 mL) under N 2. Vacuum degassing the suspension; purged with H 2 (3 times) and stirred at 20 ℃ for 2 hours under H 2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: waters Xbridge 150X 25mm X5 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:16% -46%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-hydroxy-3-methylbutyl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (0.89 mg, 1.89. Mu. Mol,8.82% yield, 100% purity) as a pale yellow solid.
RT 0.889 min (method 1);m/z 472.0(M+H)+(ES+);1H NMR(400MHz,CDCl3)10.16(d,J＝1.6Hz,1H),8.27(s,1H),7.63(s,1H),7.105(t,J＝53.2Hz,1H),5.13(s,1H),3.20-3.30(m,2H),1.97-2.03(m,2H),1.36(s,9H),0.86-0.92(m,2H),0.55-0.63(m,2H).
Example 74 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (50 mg, 114.20. Mu. Mol) in MeOH (2 mL) under N 2 was added Pd/C (25 mg, 114.20. Mu. Mol,10% purity), DIEA (44.28 mg, 342.59. Mu. Mol, 59.67. Mu. L). The suspension was degassed under vacuum, purged with H 2 (3 times) and stirred at 20℃for 24 hours under H 2 (15 psi). The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex luna C, 150, 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid; B: meCN; B%:29% -59%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (1.31 mg,3.25 μmol,2.84% yield, 100% purity) as a yellow solid.
RT 0.557 min (method) 3);m/z 403.9(M+H)+(ES+);1H NMR(DMSO-d6,400MHz):10.03(s,1H),8.92(br,1H),8.75(s,1H),8.05(d,J＝9.2Hz,1H),7.85-7.56(m,2H),4.235(d,J＝48.8Hz,2H),0.76-0.85(m,4H).
Preparation of intermediate 75.1
8-Chloro-6- (chlorosulfonyl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of ethyl 6- (benzylthio) -8-chloroimidazo [1,2-a ] pyridine-3-carboxylate (500 mg,1.44 mmol), acOH (329.80. Mu.L, 5.77 mmol), H 2 O (103.89. Mu.L, 5.77 mmol) in MeCN (5 mL) was added sulfuryl dichloride (504.46. Mu.L, 5.05 mmol) at 0deg.C. The mixture was stirred at 0 ℃ for 0.5H, then diluted with DCM (30 mL), washed with ice H 2 O (30 mL), brine (30 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure at 20 ℃ to give the product ethyl 8-chloro-6- (chlorosulfonyl) imidazo [1,2-a ] pyridine-3-carboxylate (450 mg,1.39mmol,96.59% yield) as a yellow oil. The crude product was used directly in the next step without purification.
RT 0.724 min (method 1); m/z 322.7 (M+H) + (ESI+)
Example 75 preparation
8-Chloro-6- (N- (1-cyanocyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of 1-aminocyclopropane-1-carbonitrile (165.11 mg,1.39mmol, HCl salt) in pyridine (561.99 μl,6.96 mmol) was added dropwise a solution of ethyl 8-chloro-6- (chlorosulfonyl) imidazo [1,2-a ] pyridine-3-carboxylate (450 mg,1.39 mmol) in THF (5 mL) at 0deg.C. The mixture was stirred at 20 ℃ for 16 hours, then cooled to room temperature, quenched with H 2 O (30 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (30 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel12gSilica flash column, eluent 30% -60% ethyl acetate/petroleum ether, 75 mL/min) was purified and concentrated to give the product 8-chloro-6- (N- (1-cyanocyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester (0.3 g,813.46 μmol,58.42% yield) as a white solid.
RT 0.834 min (method) 1);m/z 369.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.71(d,J＝1.6Hz,1H),9.67-9.39(m,1H),8.51(s,1H),7.95(d,J＝1.6Hz,1H),4.48-4.39(m,2H),1.54-1.46(m,2H),1.44-4.34(m,5H).
Example 76 preparation
Ethyl 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate.
To a solution of 1-methylcyclopropan-1-amine (1.20 g,11.14mmol, HCl salt) in NaHCO 3 (saturated aqueous solution, 30 mL) was added dropwise a solution of ethyl 8-chloro-6- (chlorosulfonyl) imidazo [1,2-a ] pyridine-3-carboxylate (1.8 g,5.57 mmol) in THF (15 mL) at 0deg.C. The mixture was stirred at 15 ℃ for 2 hours, then quenched with H 2 O (50 mL) and extracted with EtOAc (50 mL,3 times). The combined organic layers were washed with brine (50 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. Subjecting the residue to flash chromatography on silica gel40gSilica flash column, eluent 25% -40% ethyl acetate/petroleum ether, 100 mL/min) was purified and concentrated to give the product 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester (0.6 g,1.68mmol,30.10% yield) as a white solid.
1H NMR(DMSO-d6,400MHz):9.62(d,J＝1.6Hz,1H),8.52(s,1H),8.46(s,1H),7.85-7.95(m,1H),4.41(q,7.2Hz,2H),1.38(t,J＝7.2Hz,3H),1.16(s,3H),0.65-0.74(m,2H),0.40-0.52(m,2H).
Preparation of intermediate 77.1
8-Chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid
To a solution of ethyl 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate (400 mg,1.12 mmol) in MeOH (2 mL) and H 2 O (2 mL) was added LiOH (160.63 mg,6.71 mmol) in one portion. The reaction mixture was stirred at 60 ℃ for 2 hours. The reaction mixture was acidified to ph=4 with 1M aqueous hydrochloric acid. The white precipitate was filtered, collected and dried under reduced pressure to give the product 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid (280 mg,679.28 μmol,60.76% yield, 80% purity) as a yellow solid.
RT 0.559 min (method 1);m/z 330.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.66(s,1H),8.50(s,1H),8.40(s,1H),7.88(s,1H),1.15(s,3H),0.64-0.73(m,2H),0.41-0.50(m,2H).
Example 77 preparation
8-Chloro-N-isobutyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxamide
To a mixture of 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid (40 mg, 121.30. Mu. Mol) in DMF (1 mL) was added HATU (55.35 mg, 145.56. Mu. Mol) and DIPEA (31.35 mg, 242.60. Mu. Mol). The mixture was stirred at 15℃for 10 minutes. 2-methylpropan-1-amine (17.74 mg, 242.60. Mu. Mol) was then added, and the mixture was stirred at 15℃for 16 hours. The reaction mixture was cooled to room temperature, quenched with H 2 O (30 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (30 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO 2, petroleum ether: etoac=0:1) to give the product 8-chloro-N-isobutyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxamide (45 mg,116.92 μmol,96.39% yield) as a white solid.
1H NMR(DMSO-d6,400MHz):9.96(d,J＝1.2Hz,1H),8.78(t,J＝5.2Hz,1H),8.53(s,1H),8.44(s,1H),7.80(s,1H),3.15(t,J＝6.4Hz,2H),1.76-1.93(m,1H),1.14(s,3H),0.93(d,J＝6.4Hz,6H),0.68(s,2H),0.41-0.53(m,2H).
Example 78 preparation
N-isobutyl-6- (N- (1-methylcyclopropyl) sulfamoyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-3-carboxamide
To a solution of 2-oxa-7-azaspiro [3.5] nonane (13.22 mg, 103.93. Mu. Mol) in dioxane (0.5 mL) was added 8-chloro-N-isobutyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxamide (20 mg, 51.96. Mu. Mol), cs 2CO3 (33.86 mg, 103.93. Mu. Mol) and Pd-PEPPI-IPentCl o-methylpyridine (2.24 mg, 2.60. Mu. Mol) in a glove box. Outside the glove box, the mixture was stirred under argon at 90 ℃ for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:31% -61%,7 min) and lyophilized directly to give the product N-isobutyl-6- (N- (1-methylcyclopropyl) sulfamoyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-3-carboxamide (0.53 mg, 1.10. Mu. Mol,2.12% yield, 99% purity) as an off-white solid.
RT 0.867 min (method 1);M/z 476.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.58(s,1H),8.65(t,J＝5.6Hz,1H),8.36(s,1H),8.25(s,1H),6.85(s,1H),4.39(s,4H),3.47-3.51(m,4H),3.08-3.15(m,2H),1.94-2.00(m,4H),1.79-1.90(m,1H),1.09(s,3H),0.92(d,J＝6.8Hz,6H),0.61-0.71(m,2H),0.37-0.45(m,2H).
Example 79 preparation
6- (N- (1-methylcyclopropyl) sulfamoyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-3-carboxylic acid methyl ester
A mixture of 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid methyl ester (30 mg, 87.26. Mu. Mol), 2-oxa-7-azaspiro [3.5] nonane (31.57 mg, 130.90. Mu. Mol, TFA salt), cs 2CO3 (85.30 mg, 261.79. Mu. Mol), pd-PEPSI-IPentCl o-methylpyridine (3.75 mg, 4.36. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with N 2 (3 times). The reaction mixture was stirred under an atmosphere of N 2 at 100 ℃ for 12 hours, then cooled to room temperature, diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (30 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative TLC (SiO 2, petroleum ether/etoac=2/1) to give the product methyl 6- (N- (1-methylcyclopropyl) sulfamoyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,2-a ] pyridine-3-carboxylate (16 mg,36.82 μmol,42.20% yield) as a yellow solid.
RT 0.834 min (method 1); m/z 435.2 (m+h) +(ESI+);1H NMR(CDCl3, 400 MHz) 9.43 (d, J =
1.6Hz,1H),8.20(s,1H),6.84(d,J＝1.6Hz,1H),4.88(s,1H),4.45(s,4H),3.90(s,3H),3.38-3.46(m,4H),2.01-2.13(m,4H),1.24(s,3H),0.73-0.81(m,2H),0.45-0.51(m,2H)
Example 80 preparation
8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a solution of N, N-dimethylpiperazine-1-carboxamide (131.81 mg, 838.43. Mu. Mol) in dioxane (1 mL) was added ethyl 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate (100 mg, 279.48. Mu. Mol), pd-PEPSI-IPentCl o-methylpyridine (12.03 mg, 13.97. Mu. Mol), cs 2CO3 (182.12 mg, 558.95. Mu. Mol) in a glove box. Outside the glove box, the mixture was stirred at 100 ℃ under Ar 2 for 2 hours. The mixture was quenched with cold water (50 mL) and extracted with EtOAc (50 mL,3 times). The combined organic layers were washed with brine (20 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO 2, DCM/meoh=15/1) to give the product ethyl 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate (100 mg,188.06 μmol,67.29% yield, 90% purity) as a brown oil.
RT 0.845 min (method 1);m/z 479.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.54(s,1H),8.26(s,1H),6.91(s,1H),5.02(s,1H),3.47-3.42(q,2H),3.61-3.60(m,4H),3.53-3.52(m,4H),2.89(s,6H),1.44(t,3H),1.31(s,3H),0.87-0.85(m,2H),0.57-0.54(m,2H).
Preparation of intermediate 81.1
8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid.
To a solution of ethyl 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate (10 mg, 18.81. Mu. Mol) in MeOH (0.1 mL), H 2 O (0.02 mL) was added LiOH H 2 O (2.37 mg, 56.42. Mu. Mol). The mixture was stirred at 20℃for 3 hours. Then, the pH of the reaction was adjusted to 1-2 with 1M aqueous hydrochloric acid and the solution was extracted with EtOAc (10 mL,3 times). The combined organic layers were washed with brine (20 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex C1875 x 30mm x 3 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:20% -50%,7 min) and lyophilized directly to give the product 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid (3.45 mg,7.66 μmol,40.72% yield, 100% purity) as a yellow solid.
RT 0.794 min (method) 1);m/z 451.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.64(s,1H),8.24-8.20(m,1H),8.23(s,1H),8.04(s,1H),6.84(s,1H),3.56-3.55(m,4H),3.30-3.33(m,4H),2.79(s,6H),1.10(s,3H),0.69-0.66(m,2H),0.43-0.40(m,2H).
Example 81 preparation
8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid methyl ester
To a solution of 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid (10 mg, 22.20. Mu. Mol) in MeOH (0.15 mL) and toluene (0.5 mL) was added TMSCN 2 (2M, 22.20. Mu.L). The mixture was stirred at 20 ℃ for 2 hours and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex C18 x 75 x 30mm x 3 μm; mobile phase: a:0.225% aqueous formic acid solution, B: meCN; B%:28% -58%,7 min) and lyophilized directly to give the product methyl 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate (5.36 mg,11.54 μmol,51.98% yield, 100% purity) as a yellow gum.
RT 0.856 min (method) 1);m/z 465.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.52(s,1H),8.26(s,1H),6.93(s,1H),5.17(s,1H),3.97(s,3H),3.61-3.59(m,4H),3.52-3.51(m,4H),2.88(s,6H),1.31(s,3H),0.86-0.83(m,2H),0.56-0.53(m,2H).
Example 82 preparation
8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) -N- (oxetan-3-yl) imidazo [1,2-a ] pyridine-3-carboxamide
To a mixture of 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid (20 mg, 44.39. Mu. Mol), oxetan-3-amine (3.89 mg, 53.27. Mu. Mol) in DMF (0.5 mL) was added DIEA (8.61 mg, 66.59. Mu. Mol, 11.60. Mu. L) and HATU (25.32 mg, 66.59. Mu. Mol). The mixture was stirred at 20℃for 1 hour. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL,3 times). The combined organic layers were washed with brine (20 mL), dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting mixture was purified by preparative HPLC (column: phenomenex Synergi C, 150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:20% -50%,10 min) and lyophilized directly to give the product 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) -N- (oxetan-3-yl) imidazo [1,2-a ] pyridine-3-carboxamide (5.89 mg,11.32 μmol,25.50% yield, 97.180% purity) as a pale yellow solid.
RT 0.770 min (method) 1);m/z 506.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.56(d,J＝1.6Hz,1H),9.29(d,J＝6.8Hz,1H),8.43(s,1H),8.27(s,1H),6.89(d,J＝1.6Hz,1H),5.01-5.12(m,1H),4.81(t,J＝6.8Hz,2H),4.62(t,J＝6.48Hz,2H),3.53-3.60(m,4H),3.30-3.34(m,4H),2.79(s,6H),1.09(s,3H),0.61-0.71(m,2H),0.36-0.46(m,2H)
The compounds listed in the following table were prepared according to the corresponding general procedure or, when illustrated in a similar manner to the relevant examples, starting from the corresponding intermediates or examples.
Preparation of intermediate 96.1
6-Amino-5-bromo-pyridine-3-sulfonyl chloride
2 Batches were run in parallel and pooled for processing.
A solution of 3-bromopyridin-2-amine (10 g,57.80 mmol) in chlorosulfonic acid (67.35 g,578.00mmol,38.49 mL) was stirred at 140℃for 1 hour. The reaction mixture was cooled to 0 ℃ and poured into ice water (500 mL). The resulting mixture (two batches were combined together) was filtered. The solid was collected, dried under reduced pressure and triturated with petroleum ether: etOAc (1:1, 100 mL) at 20deg.C for 2 hours. The mixture was then filtered and the solid collected, followed by drying under reduced pressure. The crude compound was triturated with HCl/dioxane (4 n,110 ml) at 20 ℃ for 1 hour and filtered to give the product 6-amino-5-bromo-pyridine-3-sulfonyl chloride (26.5 g,97.11mmol,72.91% yield, 99.5% purity) as a white solid.
RT 0.817 min (method) 1);m/z 272.9(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):8.25(d,J＝1.6Hz.1H),8.12(d,J＝1.6Hz.1H).
Preparation of intermediate 96.2
6-Amino-5-bromo-N- (1-methylcyclopropyl) pyridine-3-sulfonamide
2 Batches were run in parallel and pooled for processing.
To a mixture of 6-amino-5-bromo-pyridine-3-sulfonyl chloride (12.9 g,47.51 mmol) in DCM (130 mL) was added TEA (14.42 g,142.53mmol,19.84 mL) in portions at 0deg.C followed by 1-methylcyclopropan-1-amine (5.62 g,52.26mmol, HCl salt). The reaction mixture was stirred at 15 ℃ for 1 hour and concentrated under reduced pressure. The residue (from 2 batches) was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=5/1 to 4/5) to give the product 6-amino-5-bromo-N- (1-methylcyclopropyl) pyridine-3-sulfonamide (22 g,68.19mmol,71.76% yield, 94.9% purity) as a white solid.
RT 0.735 min (method) 1);m/z 305.9(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):8.27(d,J＝2.0Hz.1H),7.92(d,J＝2.0Hz.1H),7.85(s,1H),7.16(br,2H),1.09(s,3H),0.62(t,J＝4.8Hz.2H),0.40(t,J＝5.2Hz,2H).
Preparation of intermediate 96.3
8-Bromo-N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
A mixture of 6-amino-5-bromo-N- (1-methylcyclopropyl) pyridine-3-sulfonamide (12 g,39.19 mmol) in 2-chloroacetaldehyde/H 2 O (260.27 g,1.33mol,213.34mL,40% purity) was stirred at 100deg.C for 1 hour. The resulting mixture was cooled to room temperature and diluted with H 2 O (300 mL). The mixture was extracted with EtOAc (200 ml,3 times). The combined organic layers were washed with brine (400 mL), dried over anhydrous Na 2SO4, filtered and dried under reduced pressure. The residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=5/1 to 4/5) to give the product 8-bromo-N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (12.9 g,39.07mmol,99.68% yield, 100% purity) as a white solid.
RT 0.628 min (method) 1);m/z 329.9(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.25(d,J＝1.6Hz,1H),8.32(s,1H),8.25(d,J＝1.2Hz,1H),7.77(d,J＝1.2Hz,1H),7.73(d,J＝1.6Hz,1H),1.13(s,3H),0.67(t,J＝4.8Hz.2H),0.44(t,J＝5.2Hz,2H).
Preparation of intermediate 96.4
N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
To a solution of N, N-dimethylpiperazine-1-carboxamide (476.11 mg,3.03 mmol) in dioxane (5 mL) was added 8-bromo-N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (0.5 g,1.51 mmol), cs 2CO3 (986.73 mg,3.03 mmol) and Pd-PEPSI-IPentCl (65.15 mg, 75.71. Mu. Mol) in a glove box. Then, outside the glove box, the mixture was stirred under argon at 100 ℃ for 2 hours. The reaction mixture was cooled to room temperature, quenched with H 2 O (50 mL) and extracted with EtOAc (50 mL;3 times). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel12gSilica flash column, eluent 60% -100% ethyl acetate/petroleum, 75 mL/min) to give the product N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (0.3 g,738.00 μmol,48.74% yield) as a brown solid.
RT 0.716 min (method) 1);m/z 407.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):8.76(s,1H),8.16(s,1H),8.10(d,J＝1.2Hz,1H),7.61(d,J＝1.2Hz,1H),6.66(s,1H),3.60-3.56(m,4H),3.32-3.28(m,4H),2.80(s,6H),1.11(s,3H),0.71-0.65(m,2H),0.37-0.44(m,2H).
Preparation of intermediate 96.5
4- (3-Iodo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (2.75 g,6.77 mmol) in MeCN (30 mL) was added a solution of NIS (1.67 g,7.44 mmol) in MeCN (20 mL) at 0deg.C. The reaction mixture was stirred at 15 ℃ for 0.5 hours and concentrated under reduced pressure. The residue obtained was purified by preparative HPLC (column Phenomenex luna C, 150, 40mm 15 μm; mobile phase: a:0.225% formic acid in water; B: meCN; B%:37% -67%,10 min) to give an impure product which was passed through a flash silica column @24gSilica flash column, eluent 50% -100% ethyl acetate/petroleum ether gradient, 45 mL/min) to give the product 4- (3-iodo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.1 g,3.94mmol,58.31% yield, 100% purity) as an off-white solid.
RT 0.673 min (method 1);m/z 533.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.44(d,J＝1.2Hz,1H),7.72(s,1H),6.72(s,1H),5.04(s,1H),3.70-3.55(m,4H),3.54-3.45(m,4H),2.89(s,6H),1.32(s,3H),0.85(t,J＝6.4Hz,2H),0.56(t,J＝6.4Hz,2H)
Preparation of intermediate 96.6
4- (3-Bromo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
Intermediate 96.2 was prepared according to general procedure 3 and obtained in 29.86% yield.
RT 0.759 min (method 1);m/z 487.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):8.33(s,1H),8.21(s,1H),7.82(s,1H),6.79(s,1H),3.62(s,4H),3.33(s,4H),2.80(s,6H),1.12(s,3H),0.61 -0.72(m,2H),0.39-0.47(m,2H).
Preparation of intermediate 96.7
(3-Bromo-8- (4- (dimethylcarbamoyl) piperazin-1-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a mixture of 4- (3-bromo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (100 mg,206.02 μmol) in DCM (1.5 mL) was added Boc 2 O (67.44 mg,309.03 μmol,70.99 μmol) and DMAP (5.03 mg,41.20 μmol) in sequence. The reaction mixture was stirred at 20 ℃ for 2 hours and concentrated under reduced pressure. The resulting residue was purified by preparative TLC (SiO 2, PE: ea=0:1) to give tert-butyl ((3-bromo-8- (4- (dimethylcarbamoyl) piperazin-1-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (71 mg,119.43 μmol,57.97% yield, 98.49% purity) as a colorless oil.
RT 0.811 min (method 1);m/z 585.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.51(s,1H),7.64(s,1H),6.79(s,1H),3.70-3.60(m,4H),3.60-3.50(m,4H),2.89(s,6H),1.59(s,3H),1.41(s,9H),1.12-0.94(m,4H).
Preparation of intermediate 96.8
(8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -3- (5-methylpyridin-2-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a solution of tert-butyl ((3-bromo-8- (4- (dimethylcarbamoyl) piperazin-1-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (12 mg,20.49 μmol) in dioxane (1 mL) was added successively 2- (dibutyl (pentyl) stannyl) -5-methylpyridine (23.50 mg,61.48 μmol), K 2CO3 (5.67 mg,40.99 μmol) and Pd (PPh 3)4 (2.37 mg,2.05 μmol) the reaction mixture was degassed, purged with N 2 (3 times) and stirred at 80 ℃ for 16 hours, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, the resulting residue was purified by preparative HPLC (column: phenomenex luna C: 150 mm; mobile phase: 0.225% aqueous formic acid, B: meCN; B%:58% -88% for 10 minutes) to give the product ((4- (dimethyl-piperazin 1-6-yl) imidazo [1, 2.05 μmol) sulfonyl ] 1-methyl) carbamate as a solid ((3-cyclopropyl) having a purity of 20.96% and a dry purity of (1.37 mg,2.05 μmol).
RT 1.003 min (method) 1);m/z 598.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.28(d,J＝1.2Hz,1H),8.51(s,1H),8.07(s,1H),7.65(d,J＝8Hz,1H),7.58(dd,J＝2.0Hz,J＝8Hz,1H),6.93(d,J＝1.2Hz,1H),3.65-3.50(m,8H),2.90(s,6H),2.40(s,3H),1.64(s,3H),1.34(s,9H),1.25-1.24(m,2H),1.10-0.95(m,2H).
Example 96 preparation
N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (5-methylpyridin-2-yl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
To a solution of tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (5-methylpyridin-2-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (12 mg, 20.08. Mu. Mol) in DCM (3 mL) was added TFA (1.54 g,13.51 mmol). The reaction mixture was stirred at 15 ℃ for 1 hour and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:35% -65%,9 min) to give the product N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (5-methylpyridin-2-yl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (1.63 mg,3.26 μmol,16.24% yield, 99.55% purity) as an off-white solid.
RT 0.692 min (method 1);m/z 498.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.18(d,J＝1.6Hz,1H),8.56(s,1H),8.05(s,1H),7.65(d,J＝8.0Hz,1H),7.60(dd,J＝1.6Hz,J＝8.4Hz,1H),6.81(d,J＝1.2Hz,1H),5.0(s,1H),3.65-3.55(m,4H),3.55-3.48(m,4H),2.90(s,6H),2.40(s,3H),1.33(s,3H),0.91(t,J＝6Hz,2H),0.56(t,J＝6Hz,2H).
Example 97 preparation
N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (6-methylpyridin-3-yl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
To a solution of 4- (3-bromo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (15 mg, 30.90. Mu. Mol), (6-methyl-3-pyridinyl) boronic acid (8.46 mg, 61.81. Mu. Mol) and Cs 2CO3 (20.14 mg, 61.81. Mu. Mol) in dioxane (1.5 mL) and H 2 O (0.3 mL) was added Xanthos Pd G4 (5.95 mg, 6.18. Mu. Mol). The reaction mixture was degassed and purged with N 2 (3 times), stirred at 80 ℃ for 16 hours, then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid; B: meCN; B%:19% -49%;10 min) to give the product N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (6-methylpyridin-3-yl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (6.93 mg, 13.79. Mu. Mol,44.62% yield, 99.01% purity) as a white solid.
RT 0.722 min (method 1);m/z 498.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.69(s,1H),8.42(s,1H),7.75(d,J＝8.0Hz,1H),7.71(s,1H),7.37(d,J＝8.0,1H),6.68(s,1H),4.97(s,1H),3.75-3.60(m,4H),3.58-3.48(m,4H),2.90(s,6H),2.69(s,3H),1.30(s,3H),0.82(t,J＝6.0Hz,2H),0.53(t,J＝6.4Hz,2H).
Example 98 preparation
4- (3-Ethyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
Pd/C (2 mg,10% purity) was added to a solution of N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3-vinylimidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (5 mg, 11.56. Mu. Mol) in THF (2 mL) under N 2. The suspension was degassed under vacuum and purged with H 2 (3 times). The mixture was stirred at 20℃under H 2 (15 psi) for 3 hours, then filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid; B: meCN; B%:18% -48%,10 min) to give the product 4- (3-ethyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.98 mg, 6.86. Mu. Mol,59.32% yield, 100% purity) as an off-white solid.
RT 0.663 min (method) 1);m/z 435.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.22(d,J＝1.2Hz,1H),7.42(s,1H),6.61(d,J＝1.2Hz,1H),5.08(s,1H),3.70-3.60(m,4H),3.60-3.47(m,4H),2.95-2.80(s,8H),1.42(t,J＝7.6Hz,3H),1.29(s,3H),0.83(t,J＝5.6Hz,2H),0.52(t,J＝5.2Hz,2H).
Example 99 preparation
N, N-dimethyl-4- (3- (3-methylbut-1-yn-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
To a solution of 4- (3-bromo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (15 mg,30.90 μmol) in DMF (1.5 mL) was added CuI (588.54 μg,3.09 μmol), K 2CO3 (17.08 mg,123.61 μmol) and Pd (PPh 3)2Cl2 (2.17 mg,3.09 μmol). The reaction mixture was degassed and purged with N 2 (3 times), then 3-methylbutan-1-yne (2.32 mg,33.99 μmol,3.48 μmol) was added to the mixture by syringe, the reaction mixture was stirred at 110 ℃ for 16 hours under an atmosphere of N 2, then poured into water (5 mL) and extracted with EtOAc (5 mL,3 times), the combined organic layers were dried over Na 2SO4, filtered and concentrated under reduced pressure to give a residue by HPLC (prepared by a column of 563 μm 6257); the mobile phase A is 0.225% formic acid aqueous solution, B is MeCN, B is 48% -78%,7 min) to obtain the product N, N-dimethyl-4- (3- (3-methylbutan-1-yn-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (3.35 mg,7.09 mu mol,22.94% yield, 100% purity) as an off-white solid.
RT 0.849 min (method 1);m/z 473.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.50(d,J＝1.6Hz,1H),7.73(s,1H),6.67(d,J＝1.6Hz,1H),4.93(s,1H),3.70-3.58(m,4H),3.58-3.45(m,4H),3.00-2.92(m,1H),2.89(s,6H),1.36(d,J＝6.8Hz,6H),1.32(s,3H),0.86(t,J＝6.0Hz,2H),0.55(t,J＝5.2Hz,2H).
Preparation of intermediate 100.1
N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- ((trimethylsilyl) ethynyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
To a solution of 4- (3-iodo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (15 mg,28.17 μmol) in DMF (2 mL) was added CuI (1.61 mg,8.45 μmol), DIPEA (5.46 mg,42.26 μmol,7.36 μmol) and Pd (PPh 3)4 (1.63 mg,1.41 μmol). The reaction mixture was degassed and purged with N 2 (3 times), then ethynyl trimethylsilane (3.32 mg,33.81 μmol,4.68 μl) was added to the mixture by syringe, the mixture was stirred at 80 ℃ for 4 hours at N 2, then poured into water (10 mL) and extracted with EtOAc (10 mL,3 times), the combined organic layers were dried over Na 2SO4, filtered and concentrated under reduced pressure, the residue was prepared by HPLC (34 mm, 34 m); the mobile phase A was 0.225% formic acid in water, B: meCN; B%:54% -84%,10 min) was purified to give the product N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- ((trimethylsilyl) ethynyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (12 mg, 20.29. Mu. Mol,72.02% yield, 85% purity) as a brown solid.
RT 0.938 min (method 1);m/z 503.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.52(d,J＝1.2Hz,1H),7.84(s,1H),6.73(s,1H),4.96(s,1H),3.70-3.58(m,4H),3.58-3.45(m,4H),2.89(s,6H),1.32(s,3H),0.90-0.80(m,2H),0.60-0.50(m,2H),0.08(s,9H).
Preparation of example 100
4- (3-Ethynyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- ((trimethylsilyl) ethynyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (6 mg,11.94 μmol) in MeOH (0.5 mL) was added K 2CO3 (4.95 mg,35.81 μmol). The reaction mixture was stirred at 20 ℃ for 2 hours and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: waters Xbridge 150X 25mM X5 μm; mobile phase: A:10mM aqueous NH 4HCO3; B: meCN; B%:32% -62%;8 min) to give the product 4- (3-ethynyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (0.65 mg, 1.51. Mu. Mol,12.65% yield, 100% purity) as an off-white gum.
RT 0.814 min (method 1);m/z 431.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.56(d,J＝1.2Hz,1H),7.86(s,1H),6.72(s,1H),4.98(s,1H),3.85(s,1H),3.70-3.60(m,4H),3.58-3.45(m,4H),2.89(s,6H),1.32(s,3H),0.85(t,J＝5.6Hz,2H),0.56(t,J＝6.0Hz,2H).
Example 101 preparation
N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (prop-1-yn-1-yl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
To a solution of 4- (3-iodo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (20 mg, 37.57. Mu. Mol) in dioxane (2 mL) was added CuI (715.44. Mu.g, 3.76. Mu. Mol), TEA (727.00 mg,7.18 mmol) and Pd 2(dba)3 (3.44 mg, 3.76. Mu. Mol). The reaction mixture was degassed and purged with N 2 (3 times). Then, prop-1-yne (1M in THF, 45.08. Mu.L) was added. The reaction mixture was stirred at 20 ℃ for 16 hours under N 2, poured into water (10 mL) and extracted with EA (10 mL,3 times). The combined organic layers were dried over Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex luna C18150 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid; B: meCN; B%:42% -72%;10 min) to give the product N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (prop-1-yn-1-yl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (15 mg,33.74 μmol,89.82% yield, 100% purity) as a white solid.
RT 0.825 min (method) 1);m/z 445.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.54(d,J＝1.2Hz,1H),7.73(s,1H),6.67(d,J＝1.2Hz,1H),5.01(s,1H),3.70-3.55(m,4H),3.55-3.45(m,4H),2.89(s,6H),2.24(s,3H),1.31(s,3H),0.84(t,J＝6.0Hz,2H),0.55(t,J＝6.4Hz,2H).
Example 102 preparation
N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3-propylimidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
Pd/C (4 mg,10% purity) was added to a solution of N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (prop-1-yn-1-yl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (8 mg, 18.00. Mu. Mol) in THF (2 mL) under N 2. The suspension was degassed under vacuum and purged with H 2 (3 times). The mixture was stirred at 20℃under H 2 (15 psi) for 3 hours, then filtered and the filtrate concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column Phenomenex luna C18150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid; B: meCN; B%:25% -55%;10 min) to give the product N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3-propylimidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (4.05 mg,9.03 μmol,50.17% yield, 100% purity) as an off-white solid.
RT 0.746 min (method 1);m/z 449.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.23(s,1H),7.42(s,1H),6.60(s,1H),5.00(s,1H),3.70-3.55(m,4H),3.55-3.45(m,4H),2.89(s,6H),2.84(t,J＝7.2Hz,2H),1.90-1.75(m,2H),1.29(s,3H),1.06(t,J＝7.6Hz,3H),0.84(t,J＝6.0Hz,2H),0.52(t,J＝6.4Hz,2H).
Preparation of example 103
N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (trifluoromethyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide
To a solution of 4- (3-iodo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (6 mg,11.27 μmol) in DMF (1 mL) was added diphenyl (trifluoromethyl) sulfonium; triflate (6.84 mg, 16.90. Mu. Mol) and copper (1.43 mg, 22.54. Mu. Mol). The reaction mixture was stirred at 60 ℃ for 2 hours under N 2, then filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid; B: meCN; B%:41% -71%;10 min) to give the product N, N-dimethyl-4- (6- (N- (1-methylcyclopropyl) sulfamoyl) -3- (trifluoromethyl) imidazo [1,2-a ] pyridin-8-yl) piperazine-1-carboxamide (1.55 mg, 3.27. Mu. Mol,28.99% yield, 100% purity) as a yellow gum.
RT 0.908 min (method) 1);m/z 475.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):8.44(s,1H),7.96(s,1H),6.80(s,1H),5.00(s,1H),3.70-3.60(m,4H),3.60-3.45(m,4H),2.90(s,6H),1.33(s,3H),0.84(t,J＝6.0Hz,2H),0.57(t,J＝6.0Hz,2H).
The compounds listed in the following table were prepared according to the corresponding general procedure or, when illustrated in a similar manner to the relevant examples, starting from the corresponding intermediates or examples.
Alternative preparation of intermediate 10.7
2- (6- (Benzylthio) -8-chloro-1-iodoindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a solution of 2- (6- (benzylthio) -8-chloroindol-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (700 mg,172 mmol) in ACN (10 mL) was added NIS (470 mg,1.89 mmol). The mixture was stirred at 50 ℃ for 2 hours and concentrated in vacuo. The crude product was triturated with MeOH (10 mL) at 20 ℃ for 5 minutes and the precipitate was filtered. The filter cake was dried in vacuo to give the product 2- (6- (benzylthio) -8-chloro-1-iodoindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (700 mg,1.31mmol,76.41% yield) as a yellow solid.
RT 0.812 min (method 3); m/z 533.8 (M+H) +(ESI+).
Preparation of intermediate 113.1
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl chloride
To a solution of 2- (6- (benzylthio) -8-chloro-1-iodoindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (250 mg, 468.35. Mu. Mol), acOH (112.50 mg,1.87mmol, 107.15. Mu.L) and H 2 O (33.75 mg,1.87mmol, 33.75. Mu.L) in ACN (3 mL) at 0deg.C was added 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (276.82 mg,1.41 mmol). The reaction was stirred at 0 ℃ for 15min to give a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl chloride which was used directly as such in the next step.
Preparation of intermediate 113.2
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonamide and 1, 8-dichloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonamide
To a solution of Py (1 mL) and MeCN (3 mL) in 1-aminocyclopropane carbonitrile hydrochloride (165.96 mg,1.40 mmol) was added dropwise a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl chloride at 0 ℃. The mixture was warmed to 20 ℃, stirred for 1 hour and poured into HCl solution (1 n,30 ml). The aqueous phase was extracted with ethyl acetate (10 ml,2 times). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel4gSilica flash column, eluent 0-25% ethyl acetate/petroleum ether gradient, 12 mL/min) to give the product 8-chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonamide and 1, 8-dichloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonamide (130 mg, crude) as yellow solid.
RT 0.890 min (method 1); m/z 555.9 and 463.9 (M+H) +(ESI+).
Preparation of examples 113 and 114
4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide and 4- (1-chloro-6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide
In a glove box, a mixture of 8-chloro-N- (1-cyanocyclopropyl) -3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -1-iodo-indolizine-6-sulfonamide and 1, 8-dichloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonamide (100 mg, crude), N-dimethylpiperazine-1-carboxamide (31.12 mg, 197.93. Mu. Mol), cs 2CO3 (117.25 mg, 359.88. Mu. Mol) and Pd-PEPPSI-IPentCl o-methylpyridine (17.50 mg, 17.99. Mu. Mol) in dioxane (1 mL) was degassed and purged with Ar 2 (3 times). Then, the mixture was stirred under an argon atmosphere at 80 ℃ for 26 hours outside the glove box. The mixture was filtered and the mother liquor was concentrated in vacuo. The resulting residue was purified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=1:1) to afford two impure products.
The impure product 1 was repurified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=0:1) and lyophilized directly to give the product 4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.3 mg,4.12 μmol,2.29% yield, 98.511% purity) as a yellow solid.
RT 0.585 min (method 3);m/z 551.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.97(s,1H),9.32(br,1H),7.84(d,J＝4.4Hz,1H),7.52-7.79(m,1H),6.96(d,J＝4.8Hz,1H),6.79(s,1H),3.36-3.38(m,4H),3.22(s,4H),2.80(s,6H),1.44-1.49(m,2H),1.35-1.40(m,2H)
The impure product 2 was purified by preparative HPLC (column: phenomenex luna C18.150X 25mM X10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:42% -72%,10 min) followed by preparative HPLC (column: waters Xbridge 150X 10 μm; mobile phase: A:1mM NH 4HCO3 aqueous solution, B: meCN; B%:35% -65%,11 min) and freeze-dried directly to give the product 4- (1-chloro-6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (1.73 mg, 2.96. Mu. Mol,1.64% yield, 99.99% purity) as a yellow solid.
RT 0.587 min (method 3);m/z 585.0(M+H)+(ESI+);iH NMR(DMSO-d6,400MHz):9.98(s,1H),9.06-9.19(m,1H),7.90(s,1H),7.46-7.74(m,1H),6.91(s,1H),3.41(s,4H),3.08-3.12(m,4H),2.82(s,6H),1.44-1.46(m,2H),1.39-1.41(m,2H).
Example 115 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) indolizine-6-sulfonamide
To a solution of 1-methylcyclopropylamine (30.05 mg, 279.35. Mu. Mol, HCl salt) in NMP (0.5 mL) and pyridine (0.5 mL) was added a crude mixture (95 mg, crude) of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl chloride at 0 ℃. The reaction was stirred at 20 ℃ for 2 hours and concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18150 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:61% -91%,10 min) and lyophilized directly to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) indolizine-6-sulfonamide (25 mg,45.89 μmol,24.64% yield) as a brown solid.
RT 0.668 min (method) 3);m/z 544.8(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.19(d,J＝1.2Hz,1H),8.45(s,1H),8.18(s,1H),7.82 -7.66(m,1H),7.43(d,J＝1.2Hz,1H),,1.18 -1.16(m,3H),0.73 -0.68(m,2H),0.48 -0.43(m,2H).
Example 116 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) indolizine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-N- (1-methylcyclopropyl) indolizine-6-sulfonamide (23 mg,42.22 μmol) in MeOH (0.5 mL) was added Pd/C (5 mg,10% purity). The mixture was degassed, purged with H 2 (3 times), and stirred at 20 ℃ for 16 hours under H 2 (15 Psi). The mixture was filtered to remove insoluble material and the filtrate concentrated in vacuo to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) indolizine-6-sulfonamide (10 mg,23.87 μmol,56.55% yield) as a grey solid.
RT 0.625 min (method 3); m/z 418.9 (M+H) +(ESI+).
Example 117 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide
In a glove box, a mixture of N, N-dimethylpiperazine-1-carboxamide (7.51 mg, 47.75. Mu. Mol), 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) indolizine-6-sulfonamide (10 mg, 23.87. Mu. Mol), cs 2CO3 (15.56 mg, 47.75. Mu. Mol) and Pd-PEPSI-IPentCl o-methylpyridine (1 mg, 1.03. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with argon (3 times). Then, outside the glove box, the mixture was stirred at 100 ℃ for 16 hours under an argon atmosphere and concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex Luna C18100 x 30mm x 5 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:40% -70%,8 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide (1.28 mg,2.32 μmol,9.74% yield, 98% purity) as a yellow solid.
RT 0.575 min (method) 3);m/z 540.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):9.89(s,1H),8.27(s,1H),7.81(d,J＝4.8Hz,1H),7.79-7.50(m,1H),6.93(d,J＝4.4Hz,1H),6.79(s,1H),3.39-3.35(m,4H),3.19(brs,4H),2.80(s,6H),1.13(s,3H),0.70(s,2H),0.43(d,J＝1.6Hz,2H).
Example 118 preparation
1, 8-Dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide
To a solution of 1- (fluoromethyl) cyclopropylamine (45.26 mg, 360.47. Mu. Mol, HCl salt) in pyridine (1 mL) and NMP (0.5 mL) was added a crude mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodoindolizine-6-sulfonyl chloride and 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl chloride (95 mg, crude) at 0deg.C. The mixture was stirred at 20 ℃ for 2 hours and concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18150 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:57% -58%,10 min) and lyophilized directly to give the product 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (25 mg,53.04 μmol,28.48% yield) as a brown solid.
RT 0.633 min (method 3);m/z 472.8(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.18(d,J＝1.2Hz,1H),8.85(s,1H),8.19(s,1H),7.83-7.53(m,1H),7.45(d,J＝1.2Hz,1H),4.32-4.16(m,2H),0.88-0.84(m,2H),0.81-0.77(m,2H).
Example 119 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide
In a glove box, a mixture of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (25 mg, 53.04. Mu. Mol), N-dimethylpiperazine-1-carboxamide (16.68 mg, 106.09. Mu. Mol), cs 2CO3 (34.57 mg, 106.09. Mu. Mol) and Pd-pep psi-IPentCl o-methylpyridine (1 mg, 1.03. Mu. Mol) in dioxane (0.5 mL) was degassed and purged with argon (3 times). Then, the mixture was stirred under an argon atmosphere at 100 ℃ for 16 hours outside the glove box. The mixture was concentrated in vacuo. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: phenomenex Luna C18.30 mm 5 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:37% -67%,8 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide (0.91 mg,1.53 μmol,2.88% yield, 93.47% purity) as a yellow solid.
RT 0.563 min (method 3);m/z 558.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):9.86(s,1H),8.66(s,1H),7.81(d,J＝4.8Hz,1H),7.79-7.51(m,1H),6.93(d,J＝4.8Hz,1H),6.79(d,J＝1.2Hz,1H),4.39-4.08(m,2H),3.37(t,J＝5.2Hz,4H),3.19(t,J＝4.8Hz,4H),2.80(s,6H),0.81(d,J＝4.4Hz,2H),0.76(d,J＝4.4Hz,2H)
Example 120 preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide
Pd-PSI-IPentCl o-picoline (4.13 mg, 4.24. Mu. Mol) and Cs 2CO3 (27.65 mg, 84.87. Mu. Mol) were added to a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (20 mg, 42.44. Mu. Mol) and N, N-dimethylpiperazine-1-carboxamide (6.67 mg, 42.44. Mu. Mol) in dioxane (0.5 mL) under N 2. The mixture was stirred at 80 ℃ for 5 hours and concentrated in vacuo. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative TLC (SiO 2, petroleum ether/ethyl acetate=0:1) and lyophilized directly to give the product 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-8-yl) -N, N-dimethylpiperazine-1-carboxamide (3.48 mg,5.74 μmol,13.52% yield, 97.595% purity) as a yellow solid.
RT 0.492 min (0.8 min method) 3);m/z 592.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz,):10.11(d,J＝1.2Hz,1H),7.33(s,1H),7.20-6.93(m,1H),6.82(d,J＝0.8Hz,1H),5.46(s,1H),4.34-4.20(m,2H),3.83-2.96(m,8H),2.90(s,6H),1.18-1.12(m,2H),0.88-0.83(m,2H).
Preparation of intermediate 121.1
1-Bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl bromide
To a solution of 2- (6- (benzylthio) -8-chloro-1-iodoindolizin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (400 mg, 749.37. Mu. Mol), acOH (90.00 mg,1.50mmol, 85.71. Mu.L) and water (27.01 mg,1.50mmol, 27.01. Mu.L) in ACN (4 mL) at 0deg.C was added 1, 3-dibromo-5, 5-dimethylimidazolidine-2, 4-dione (428.52 mg,1.50 mmol). The mixture was stirred at 0deg.C for 2 hours and then poured into water (20 mL). The aqueous phase was extracted with DCM (10 mL,2 times). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo at 20 ℃. The residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=1/0 to 20/1) to give the product 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl bromide (260 mg,512.26 μmol,68.36% yield) as a brown solid.
Example 121 preparation
1-Bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide
To a solution of 1- (fluoromethyl) cyclopropylamine (50.21 mg, 399.87. Mu. Mol, HCl salt), naHCO 3(215.17mg,2.56mmol,99.62μL)、H2 O (2 mL) in THF (2 mL) at 0deg.C was added 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) indolizine-6-sulfonyl bromide (260 mg, 512.26. Mu. Mol). The mixture was stirred at 0deg.C for 2 hours and then poured into water (20 mL). The aqueous phase was extracted with EtOAc (10 ml,2 times). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=1/0 to 10/1) to give the product 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (100 mg,193.89 μmol,37.85% yield) as a yellow solid.
1H NMR(DMSO-d6,400MHz):10.09(d,J＝1.2Hz,1H),8.83(s,1H),8.14(s,1H),7.78-7.49(m,1H),7.41(d,J＝1.2Hz,1H),4.30(d,J＝48.4),0.84-0.74(m,4H)
Example 122 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methyl-3- (methylamino) but-1-yn-1-yl) indolizine-6-sulfonamide
A mixture of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (10 mg, 19.39. Mu. Mol), allylic (chloro) palladium (354.74. Mu.g, 1.94. Mu. Mol), P (t-Bu) 3 (7.85 mg, 3.88. Mu. Mol, 9.10. Mu.L, 10% w/w in hexane) and TEA (3.92 mg, 38.78. Mu. Mol, 5.40. Mu.L) in ACN (0.2 mL) was degassed and purged with N 2 (3 times). N, 2-dimethylbut-3-yn-2-amine (3.77 mg, 38.78. Mu. Mol, 3.23. Mu.L) was then added to the mixture via syringe. The mixture was stirred at 20℃for 1 hour. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex Luna C18.150.25 mm.10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:18% -48%,10 min) and lyophilized directly to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methyl-3- (methylamino) but-1-yn-1-yl) indolizine-6-sulfonamide (3.06 mg, 5.29. Mu. Mol,27.30% yield, 100% purity, FA salt) as a white solid.
RT 0.409 min (method 4);m/z 554.0(M+Na)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.10(d,J＝1.2Hz,1H),8.86(br s,1H),8.20(s,1H),8.07(s,1H),7.82-7.54(m,1H),7.44(d,J＝1.2Hz,1H),4.39-4.12(m,2H),2.39(s,3H),1.37(s,6H),0.91-0.84(m,2H),0.83-0.77(m,2H).
Preparation of intermediate 123.1
1- (3- ((Tert-butyldimethylsilyl) oxy) prop-1-yn-1-yl) -8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide
A mixture of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (70 mg, 135.72. Mu. Mol), cuI (2.58 mg, 13.57. Mu. Mol), TEA (363.50 mg,3.59mmol,0.5 mL) and Pd [ P (t-Bu) 3]2Cl2 (10.02 mg, 13.57. Mu. Mol) in DMF (1 mL) was degassed and purged with N 2 (3 times). T-butyldimethyl (prop-2-yn-1-yloxy) silane (46.23 mg, 271.45. Mu. Mol, 55.04. Mu.L) was then added to the mixture via syringe. The mixture was stirred under an atmosphere of N 2 at 100deg.C for 16 hours and then poured into water (30 mL). The aqueous phase was extracted with EtOAc (10 ml,2 times). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=3:1) and lyophilized directly to give the product 1- (3- ((tert-butyldimethylsilyl) oxy) prop-1-yn-1-yl) -8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (10 mg,16.52 μmol,12.18% yield) as a yellow solid.
RT 0.593 min (method 4); m/z 605.1 (M+H) + (ESI+).
Example 123 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-hydroxypropyl-1-yn-1-yl) indolizine-6-sulfonamide
To a solution of 1- (3- ((tert-butyldimethylsilyl) oxy) prop-1-yn-1-yl) -8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (10 mg, 16.52. Mu. Mol) in MeOH (0.2 mL) was added KF (1.92 mg, 33.05. Mu. Mol). The mixture was stirred at 20 ℃ for 4 hours and then concentrated in vacuo. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: waters Xbridge 150X 25mM X10 μm; mobile phase: A:10mM aqueous NH 4HCO3, B: meCN; B%:25% -55%,8 min) and lyophilized directly to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-hydroxypro-1-yn-1-yl) indolizine-6-sulfonamide (1.27 mg, 2.59. Mu. Mol,15.66% yield, 100% purity) as a yellow solid.
RT 0.438 min (method 4);m/z 513.0(M+Na)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.09(d,J＝1.2Hz,1H),8.85(br,1H),8.11(s,1H),7.67(t,J＝53.2Hz,1H),7.46(d,J＝1.2Hz,1H),5.33(t,J＝6.0Hz,1H),4.36(d,J＝6.0Hz,2H),4.31-4.18(d,J＝48.4Hz,2H),0.89-0.86(m,2H),0.81-0.78(m,2H).
Preparation of intermediate 124.1
3- ((8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) methylene) azetidine-1-carboxylic acid tert-butyl ester
A solution of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (60 mg, 116.33. Mu. Mol), 3- ((4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene) azetidine-1-carboxylic acid tert-butyl ester (41.21 mg, 139.60. Mu. Mol) and Pd (dppf) Cl 2(8.47mg,11.63μmol)、K3PO4 (1.5M in water, 155.11. Mu.L) in t-BuOH (1 mL) was degassed, purged with N 2 (3 times) and stirred at 60℃for 4 hours under an atmosphere of N 2. To the mixture was further added 3- ((4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene) azetidine-1-carboxylic acid tert-butyl ester (41.21 mg, 139.60. Mu. Mol), K 3PO4 (1.5M aqueous solution, 100. Mu.L) and Pd (dppf) Cl 2 (8.47 mg, 11.63. Mu. Mol) and the reaction was stirred at 60℃for another 4 hours. To the mixture was again added 3- ((4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) methylene) azetidine-1-carboxylic acid tert-butyl ester (41.21 mg, 139.60. Mu. Mol) and Pd (dppf) Cl 2 (8.47 mg, 11.63. Mu. Mol) and the reaction was stirred at 60℃for an additional 4 hours. The mixture was poured into water (10 mL) and the aqueous layer was extracted with EtOAc (5 mL,2 times). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=3:2) to give the product 3- ((8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) methylene) azetidine-1-carboxylic acid tert-butyl ester (17 mg,28.14 μmol,24.19% yield) as a yellow solid.
RT 0.538 min (method 4); m/z 503.9 (M-Boc+H) + (ESI).
Preparation of intermediate 124.2
3- ((8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester
Pd/C (10 mg,10% purity) was added to a solution of tert-butyl 3- ((8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) methylene) azetidine-1-carboxylate (20 mg, 33.11. Mu. Mol) in MeOH (1 mL) under an atmosphere of N 2. The suspension was degassed and purged with H 2 (3 times) and then stirred at 20 ℃ for 2 hours. The mixture was filtered and the filtrate concentrated in vacuo to give the product tert-butyl 3- ((8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) methyl) azetidine-1-carboxylate (5 mg,8.25 μmol,24.92% yield) as a yellow solid.
RT 0.529 min (method 4); m/z 506.2 (M-BocH) + (ESI+).
Example 124 preparation
1- (Azetidin-3-ylmethyl) -8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide
To a solution of 3- ((8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (15 mg, 24.75. Mu. Mol) and 2, 6-lutidine (21.22 mg, 197.99. Mu. Mol, 23.06. Mu. L) in DCM (0.5 mL) was added dropwise TMSOTF (33.00 mg, 148.50. Mu. Mol, 26.83. Mu. L) at 0 ℃. The mixture was stirred at 20 ℃ for 1.5 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:13% -43%,8 min) and lyophilized directly to give the product 1- (azetidin-3-ylmethyl) -8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (0.6 mg,1.14 μmol,4.61% yield, 96.24% purity, FA salt) as a yellow solid.
RT 0.366 min (method) 4);m/z 506.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.08(d,J＝1.2Hz,1H),8.40(s,1H),7.86-7.78(m,1H),7.75(s,1H),7.34(d,J＝1.2Hz,1H),4.35-4.15(m,2H),3.85-3.81(m,2H),3.61-3.57(m,2H),3.13-3.05(m,2H),2.60(s,1H),0.88-0.82(m,2H),0.82-0.76(m,2H).
Example 125 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-isobutyiindolizine-6-sulfonamide
To a mixture of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (20 mg, 38.78. Mu. Mol), pd 2(dba)3 (3.55 mg, 3.88. Mu. Mol) and XPhos (3.70 mg, 7.76. Mu. Mol) in DMA (1 mL) was added isobutylzinc (II) bromide (0.5M, 310.22. Mu.L) under N 2. The mixture was then stirred under an atmosphere of N 2 at 80℃for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was flash distilled in reverse phase20G flash column Welch Ultimate XB-C18 20-40 μm;120A, mobile phase: a:0.1% formic acid aqueous solution, B: meCN; b%:5% -95%,40 mL/min). The resulting impure product was then purified by preparative HPLC (column: phenomenex luna C luna C, 150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:65% -95%,58 min) and lyophilized directly to give another impure product which was further purified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=3:1) to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-isobutyiindolizine-6-sulfonamide (1.58 mg,3.04 μmol,7.84% yield, 94.8% purity) as a white solid.
RT 0.596 min (method 4);m/z 492.9(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.10(s,1H),8.80(s,1H),7.81(s,1H),7.67(t,J＝53.2Hz,1H),7.32(s,1H),4.26(t,J＝48.8Hz,1H),2.93(d,J＝6.8Hz,2H),1.95-1.99(m,1H),0.96(d,J＝6.4Hz,6H),0.87(t,J＝4.8Hz,2H),0.81(t,J＝4.0Hz,2H).
Example 126 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide
Pd/C (5 mg,10% purity) and DIPEA (5.01 mg, 38.78. Mu. Mol, 6.75. Mu.L) were added to a solution of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (20 mg, 38.78. Mu. Mol) in MeOH (0.5 mL) under an atmosphere of N 2. The suspension was degassed and purged 3 times with H 2, then the reaction was stirred at 30 ℃ for 2 hours, filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C, 150, 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:40% -70%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (960.00 μg,2.37 μmol,6.11% yield, 99.29% purity) as a white solid.
RT 0.558 min (method) 3);m/z 402.9(M+H)+(ESI+);1H NMR(CDCl3,400MHz,):10.39(s,1H),7.65(d,J＝9.2Hz,1H),7.48(d,J＝4.8Hz,1H),7.34(dd,J＝9.6,1.6Hz,1H),7.20-6.93(m,1H),6.77(d,J＝4.4Hz,1H),5.47(s,1H),4.29(d,J＝48.4Hz,2H),1.16-1.10(m,2H),0.88-0.83(m,2H)
Example 127 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-isobutyiindolizine-6-sulfonamide
Pd/C (5 mg,10% purity) and DIPEA (2.62 mg, 20.29. Mu. Mol, 3.53. Mu.L) were added to a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-isobutyiindolizine-6-sulfonamide (10 mg, 20.29. Mu. Mol) in MeOH (1 mL) under an atmosphere of N 2. The suspension was degassed and purged with H 2 (3 times). Then, the mixture was stirred at 30 ℃ for 1 hour, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC (column: phenomenex luna C, 150, 25mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:70% -100%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-isobutyiindolizine-6-sulfonamide (960.00. Mu.g, 1.91. Mu. Mol,9.43% yield, 91.39% purity) as a yellow solid.
RT 0.470 min (method 3);m/z 458.9(M+H)+(ESI+);1H NMR(CDCl3,400MHz,):10.33(s,1H),7.58(d,J＝9.2Hz,1H),7.29(s,1H),7.25(d,J＝9.2Hz,1H),7.05(t,J＝53.2Hz,1H),5.43(s,1H),4.29(d,J＝48.0Hz,2H),2.67(d,J＝6.8Hz,2H),2.00-1.92(m,1H),1.16-1.11(m,2H),0.98(d,J＝6.4Hz,6H),0.91-0.86(m,2H).
Preparation of intermediate 128.1
4- (8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
A mixture of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) indolizine-6-sulfonamide (30 mg, 58.17. Mu. Mol), tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridin-1 (2H) -carboxylate (25.18 mg, 81.43. Mu. Mol), pd (dppf) Cl 2(4.26mg,5.82μmol)、K2CO3 (16.08 mg, 116.33. Mu. Mol) and H 2 O (0.025 mL) in dioxane (0.5 mL) was degassed and purged with N 2 (3 times). The mixture was then stirred under an atmosphere of N 2 at 80℃for 2 hours and poured into water (10 mL). The aqueous phase was extracted with EtOAc (5 ml,2 times). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=2:1) to give the product tert-butyl 4- (8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (12.75 mg,20.63 μmol,35.46% yield) as a yellow solid.
RT 0.656 min (method 3);m/z 561.9(M-56+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.34(d,J＝1.6Hz,1H),7.34(d,J＝1.2Hz,1H),7.31(s,1H),7.08-6.92(m,1H),5.75(br s,1H),5.46(s,1H),4.33(t,J＝48.4Hz,2H),4.11-4.08(m,2H),3.68(t,J＝5.6Hz,2H),2.51-2.47(m,2H),1.52(s,9H),1.14(br d,J＝4.0Hz,2H),0.90 -0.87(m,2H).
Example 128 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (1, 2,3, 6-tetrahydropyridin-4-yl) indolizine-6-sulfonamide
To a solution of tert-butyl 4- (8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) indol-1-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (10.00 mg,16.18 μmol) in DCM (0.5 mL) was added TFA (1.5 mL). The mixture was stirred at 20 ℃ for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column: welch Ultimate C18.150.25 mm 5 μm; mobile phase: A:0.225% aqueous TFA, B: meCN; B%:21% -51%,10 min) and lyophilized directly to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (1, 2,3, 6-tetrahydropyridin-4-yl) indolizine-6-sulfonamide (1.6 mg, 3.09. Mu. Mol,19.09% yield, 99.99% purity, TFA salt) as a white solid.
RT 0.390 min (method 4);m/z 518.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz,):10.13(d,J＝1.2Hz,1H),8.89(d,J＝3.2Hz,1H),8.84(s,1H),7.82-7.80(m,1H),7.80-7.52(m,1H),7.43(d,J＝1.2Hz,1H),5.80(br,1H),4.27(d,J＝48.4Hz,2H),3.79(d,J＝1.2Hz,2H),3.44-3.35(m,2H),2.69-2.61(m,2H),0.95-0.75(m,4H).
Example 129 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (40 mg, 95.27. Mu. Mol) in dioxane (1 mL) was added 2-oxa-7-azaspiro [3.5] nonane (24.23 mg, 190.54. Mu. Mol), cs 2CO3 (93.12 mg, 285.81. Mu. Mol) and Pd-PEPPI-IPentCl o-methylpyridine (8.20 mg, 9.53. Mu. Mol). The reaction mixture was degassed with N 2 (3 times) and the mixture was stirred at 90 ℃ for 1 hour. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative TLC (ethyl acetate) to give the impure product which was further triturated with MeOH (1 mL) to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (9.89 mg,19.15 μmol,20.10% yield, 98.86% purity) as a yellow solid.
RT 0.473 min (method 4);m/z 511.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.84(s,1H),7.70(s,1H),7.08(t,J＝53.6Hz,1H),6.63(d,J＝1.2Hz,1H),5.06(s,1H),4.54(s,4H),3.26-3.23(m,4H),2.16-2.13(m,4H),1.39(s,3H),0.94-0.91(m,2H),0.60(d,J＝1.6Hz,2H).
Example 130 preparation
4- (7-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-)
Methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a mixture of 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (20 mg,37.00 μmol) in MeCN (0.5 mL) was added NCS (2.47 mg,18.50 μmol) at 0 ℃. The mixture was then stirred at 25℃for 1 hour. The resulting solution was purified by preparative TLC (ethyl acetate: petroleum ether=1:0) and concentrated in vacuo to give the product 4- (7-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (3.30 mg,5.62 μmol,15.19% yield, 98% purity) as a yellow solid.
RT 0.583 min (method 4);m/z 574.9(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.20(s,1H),7.85(s,1H),7.09(t,J＝53.2Hz,1H),5.45(s,1H),3.47-3.45(m,4H),3.46-3.44(m,4H),2.92(s,6H),1.34(s,3H),0.99-0.97(m,2H),0.66-0.53(m,2H).
Example 131 preparation
4- (1, 7-Dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a mixture of 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (30 mg,53.71 μmol) in MeCN (0.5 mL) was added NCS (10.76 mg,80.56 μmol) at 0 ℃. The reaction mixture was then stirred for 16 hours. After filtration, the filtrate was concentrated in vacuo at low temperature. The resulting residue was purified by preparative HPLC (column Phenomenex luna C18150 x 25mm x 10 μm; mobile phase: a:0.025% aqueous formic acid, B: meCN; B%:42% -72%,10 min) and lyophilized directly to give the product 4- (1, 7-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (9.9 mg,15.62 μmol,29.08% yield, 99% purity) as a yellow solid.
RT 0.506 min (method 4),m/z 628.9(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.23(s,1H),7.08(t,J＝53.6Hz,1H),5.77(s,1H),4.28-4.16(d,J＝48.8Hz,2H),3.68-3.59(m,4H),3.44-3.39(m,2H),3.14-3.12(m,2H),2.91(s,6H),1.23-1.22(m,2H),0.91-0.89(m,2H).
Example 132 preparation
4- (7-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a mixture of 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (30 mg,53.71 μmol) in MeCN (1 mL) was added NCS (5.74 mg,42.96 μmol) at 0 ℃. The reaction mixture was stirred for 16 hours. After filtration, the filtrate was concentrated in vacuo at low temperature. The resulting residue was purified by preparative TLC (ethyl acetate: petroleum ether=1:0), concentrated in vacuo and lyophilized directly to give the product 4- (7-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (8.03 mg,13.27 μmol,24.71% yield, 98% purity) as a yellow solid.
RT 0.451 min (method 4);m/z 593.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.18(s,1H),7.85(s,1H),7.08(t,J＝54.0Hz,1H),5.82(s,1H),4.29-4.17(d,J＝48.8Hz,2H),3.48-3.46(m,8H),2.92(s,6H),1.22-1.20(m,2H),0.90-0.86(m,2H).
Example 133.A preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperidine-1-carboxylic acid tert-butyl ester
To a mixture of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (80 mg,141.18 μmol) in MeOH (3 mL) was added Pd (OH) 2 (24 mg,34.18 μmol,20% purity) and Pd/C (24 mg,141.18 μmol,10% purity). The reaction was degassed with H 2 (3 times) and then stirred at 50 ℃ for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by preparative TLC (ethyl acetate: petroleum ether=1:1) to give the product tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperidine-1-carboxylate (38 mg,58.81 μmol,41.65% yield, 88% purity) as a yellow solid.
RT 0.573 min (method 4); m/z 591.2 (M+Na) +(ESI+).
Example 133 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperidin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
A mixture of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperidine-1-carboxylate (20 mg, 35.17. Mu. Mol) in HCl/dioxane (1 mL, 4N) was stirred at 25℃for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:12% -42%,8 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperidin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (1.07 mg, 2.04. Mu. Mol,5.80% yield, 89.49% purity, FA salt) as a yellow solid.
RT 0.374 min (method 1);m/z 469.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.80(s,1H),8.63-8.51(m,1H),8.49(s,1H),8.17(s,1H)7.68(t,J＝53.2Hz,1H),7.23(s,1H),3.25-3.23(m,2H),3.15-3.10(m,1H),2.91-2.85(m,2H),1.98-1.95(m,2H),1.81-1.73(m,2H),1.14(s,3H),0.71(br,2H),0.46(br,2H).
Example 134 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperidine-1-carboxamide
To a mixture of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperidin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg, 21.34. Mu. Mol) in THF (0.5 mL) and H 2 O (0.5 mL) at 0deg.C were added K 2CO3 (8.85 mg, 64.03. Mu. Mol) and dimethylcarbamoyl chloride (3.44 mg, 32.01. Mu. Mol, 2.94. Mu. L). The mixture was stirred at 0deg.C for 15 min, poured into water (10 mL) and extracted with EtOAc (15 mL;2 times). The organic layers were separated, mixed, dried over Na 2SO4 and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:36% -66%,8 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperidine-1-carboxamide (1.64 mg, 2.70. Mu. Mol,12.66% yield, 88.90% purity) as a yellow solid.
RT 0.496 min (method) 4);m/z 540.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.79(s,1H),8.45(s,1H),8.19(s,1H),7.69(t,J＝53.6Hz,1H),7.26(s,1H),3.72(d,J＝13.6Hz,2H),3.32-3.24(m,1H),2.95(t,J＝12.4Hz,2H),2.78(s,6H),1.94(d,J＝12.4Hz,2H),1.72-1.68(m,2H),1.11(s,3H),0.72-0.69(m,2H),0.46-0.44(m,2H).
Example 135.1 preparation
1-Bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a mixture of 2- (6-benzylsulfonyl-8-chloro-imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (1 g,2.45 mmol) in ACN (10 mL) was added AcOH (293.73 mg,4.89mmol,279.75 μl), water (88.14 mg,4.89mmol,88.14 μl) and1, 3-dibromo-5, 5-dimethyl-imidazolidine-2, 4-dione (2.80 g,9.78 mmol) at 0 ℃. The reaction was then stirred at 0 ℃ for 2 hours. The resulting mixture was concentrated in vacuo (at 20 ℃). The residue was diluted with DCM (30 mL), washed with ice water (20 mL;4 times), separated, dried over Na 2SO4, and concentrated in vacuo (at 20 ℃). The crude product (1.6 g) was purified by flash chromatography on silica gel20gSilica flash column, eluent 0-15% ethyl acetate/petroleum, 50 mL/min) to give the product 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (800 mg,1.10mmol,44.90% yield, 69.8% purity) as a pale yellow solid.
1H NMR(CDCl3,400MHz):10.32(d,J＝1.2Hz,1H),7.47(d,J＝1.2Hz,1H),7.11(t,J＝53.6Hz,1H)。
Example 135.2 preparation
1-Bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1- (fluoromethyl) cyclopropylamine (217.29 mg,1.73mmol, HCl) in THF (8 mL) and H 2 O (8 mL) was added NaHCO 3 (660.79 mg,7.87mmol, 305.92. Mu.L) at 0deg.C. Then, a solution of 1-bromo-8-chloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] imidazo [1,5-a ] pyridine-6-sulfonyl bromide (800 mg,1.57 mmol) in THF (2 mL) was added dropwise over 10 minutes, and stirred at 0 ℃ for 2 hours. The resulting mixture was quenched with saturated brine (30 mL) and extracted with EtOAc (30 mL;3 times). The combined organic layers were separated, dried over anhydrous Na 2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel20gSilica flash column, eluent 0-20% ethyl acetate/petroleum, 30 mL/min) to give the product 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (200 mg,348.34 μmol,22.14% yield, 90% purity) as a pale yellow solid.
RT 0.497 min (method) 1);m/z 517.8(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.16(s,1H),7.38(s,1H),7.09(t,J＝53.2Hz,1H),5.59(s,1H),4.31(d,J＝48.4Hz,2H),1.19 -1.10(m,2H),0.95 -0.88(m,2H).
Example 135 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxyprop-1-yn-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
A mixture of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (100 mg, 193.52. Mu. Mol), 3-methoxyprop-1-yne (27.13 mg, 387.04. Mu. Mol, 31.91. Mu.L), allylpalladium (7.08 mg, 19.35. Mu. Mol), tri-t-butylphosphine (78.30 mg, 38.70. Mu. Mol, 90.84. Mu.L, 10% purity) and DABCO (43.42 mg, 387.04. Mu. Mol, 42.56. Mu. L) in ACN (4 mL) was degassed and purged with N 2 (3 times). Then, the mixture was stirred at 25 ℃ for 1 hour, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel12gThe silica flash column, eluent 0-55% ethyl acetate/petroleum ether, 20 mL/min) afforded the impure product which was triturated with MeOH (3 mL) at 20 ℃ for 5 min. After filtration, the filtrate was concentrated directly to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxyprop-1-yn-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (115 mg,225.04 μmol,23.26% yield, 99% purity) as a yellow solid.
RT 0.485 min (method) 1);m/z 506.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.15(d,J＝1.2Hz,1H),7.41(d,J＝1.2Hz,1H),7.09(t,J＝56.0Hz,1H),5.56(s,1H),4.45(s,2H),4.31(d,J＝48.0Hz,2H),3.52(s,3H),1.17-1.12(m,2H),0.93-0.90(m,2H).
Example 136 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxypropyl) imidazo [1,5-a ] pyridine-6-sulfonamide and example 137 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxypropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] -1- (3-methoxyprop-1-ynyl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 39.53. Mu. Mol) in MeOH (0.5 mL) was added Pd/C (5 mg,10% purity) and DIEA (5.11 mg, 39.53. Mu. Mol, 6.89. Mu. L). The reaction was degassed with H 2 (3 times) and the mixture was stirred at 50℃for 16 hours under H 2 (15 psi,1 atm). The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:42% -72%,10 min) and lyophilized to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxypropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (3.98 mg,7.49 μmol,18.95% yield, 96% purity) as a yellow solid, and 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxypropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (4.28 mg,8.55 μmol,21.63% yield, 95% purity) as a yellow solid.
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxypropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
RT 0.522 min (method) 1);m/z 510.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.08(d,J＝1.2Hz,1H),7.25(d,J＝0.8Hz,1H),7.08(t,J＝56.0Hz,1H),5.50(s,1H),4.32(d,J＝48.0Hz,1H),3.52(t,J＝8.0Hz,2H),3.38(s,3H),3.31(t,J＝8.0Hz,2H),2.15-2.04(m,2H),1.16-1.12(m,2H),0.92-0.88(m,2H).
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1- (3-methoxypropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
RT 0.492 min (method) 1);m/z 475.8(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.11(s,1H),7.72(d,J＝8.0Hz,1H),7.25(dd,J＝1.2,8.0Hz,1H),7.08(t,J＝56.0Hz,1H),5.50(s,1H),4.29(d,J＝48.0Hz,2H),3.43(t,J＝8.0Hz,2H),3.36(s,3H),3.05(t,J＝8.0Hz,2H),2.12-2.05(m,2H),1.15-1.11(m,2H),0.89-0.86(m,2H).
Preparation of intermediate 138.1
2- (8- (Benzyloxy) -6- (benzylthio) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a solution of 2- (6- (benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (2 g,4.89 mmol) in dioxane (30 mL) was added phenylmethanol (2.12 g,19.57mmol,2.03 mL), cs 2CO3 (3.19 g,9.78 mmol) and t-BuBrettPhos Pd G3 (417.94 mg, 489.15. Mu. Mol). The reaction mixture was stirred at 100℃under N 2 for 16 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel40gSilica flash column, eluent 0-20% ethyl acetate/petroleum ether, 40 mL/min) to give the product 2- (8- (benzyloxy) -6- (benzylthio) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (700 mg,1.44mmol,29.40% yield, 98.731% purity) as a yellow solid.
RT 0.754 min (method) 1),m/z 480.8(M+H)+(ESI+),1H NMR(CDCl3,400MHz):9.22(s,1H),7.77(s,1H),7.47 -7.44(m,4H),7.43-7.38(m,1H),7.34-7.29(m,5H),7.07(t,J＝52.0Hz,1H),6.24(s,1H),5.12(s,2H),4.13(s,2H).
Preparation of intermediate 138.2
6- (Benzylthio) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridin-8-ol
A solution of 2- (8- (benzyloxy) -6- (benzylthio) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (300 mg, 624.28. Mu. Mol) in TFA (3 mL) was stirred at 70℃for 24h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc (25 mL) and washed with brine. The organic phase was separated, dried over Na 2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=2/1) to give the product 6- (benzylthio) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridin-8-ol (150 mg,291.99 μmol,46.77% yield, 76% purity) as a yellow solid.
RT 0.471 min (method) 1);m/z 390.8(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.22(s,1H),7.78(s,1H),7.37-7.35(m,2H),7.30(m,1H),7.23-7.21(m,2H),7.07(t,J＝52.0Hz,1H),6.31(s,1H),4.17(s,2H).
Preparation of intermediate 138.3
2- (6- (Benzylthio) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a mixture of 6- (benzylthio) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridin-8-ol (40 mg, 102.45. Mu. Mol) in DMF (1 mL) was added K 2CO3 (28.32 mg, 204.90. Mu. Mol) and 1-bromo-3-methoxypropane (31.35 mg, 204.90. Mu. Mol). The reaction was heated to 80 ℃ and stirred for 16 hours. The reaction mixture was diluted with 20mL of H 2 O and extracted with EtOAc (10 mL,3 times). The organic layers were separated, combined, washed with brine, dried over Na 2SO4 and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=2/1) to give the product 2- (6- (benzylthio) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (40 mg,68.32 μmol,53.35% yield, 79% purity) as a yellow solid.
RT 0.537 min (method 1);m/z 463.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):8.96(s,1H),7.80(s,1H),7.65(t,J＝52.0Hz,1H),7.40-7.38(m,1H),7.30-7.25(m,2H),7.23-7.19(m,2H),6.70(s,1H),4.33(s,2H),4.26(t,J＝8.0Hz,2H),3.53(t,J＝8.0Hz,2H),3.28(s,3H),2.06-2.01(m,2H).
Preparation of intermediate 138.4
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride and 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a mixture of 2- (6- (benzylthio) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (20 mg, 43.24. Mu. Mol) in AcOH (0.4 mL) and H 2 O (0.2 mL) was added NCS (23.10 mg, 172.96. Mu. Mol) and 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (25.56 mg, 129.72. Mu. Mol) at 0deg.C. The mixture was stirred at 20℃for 6h, then diluted with DCM (15 mL), washed with brine (10 mL;4 times), dried over Na 2SO4 and concentrated in vacuo to give the crude mixture product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride and 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (17 mg, crude) as a yellow solid. The crude mixture product was used directly in the next step without further purification.
Example 138 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide and example 139 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1-methylcyclopropylamine (5.88 mg,54.69 μmol, HCl) in DCM (0.5 mL) was added DIEA (10.60 mg,82.03 μmol,14.29 μl), 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride and 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (17 mg, crude product) at-10 ℃. The mixture was stirred at 20℃for 16 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: phenomenex luna C18.150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:45% -75%,10 min) and lyophilized to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (4.81 mg,9.95 μmol,36.41% yield, 98% purity) as a pale yellow solid, and 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (2.0 mg, crude) as a yellow solid.
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
RT 0.536 min (method) 1);m/z 474.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.55(s,1H),8.44(s,1H),7.94(s,1H),7.69(t,J＝52.0Hz,1H),6.80(s,1H),4.32(t,J＝8.0Hz,2H),3.56(t,J＝8.0Hz,2H),3.28(s,3H),2.11(t,J＝8.0Hz,2H),1.17(s,3H),0.75-0.73(m,2H),0.48-0.45(m,2H).
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
RT 0.496 min (method 1); m/z 508.0 (M+H) +(ESI+).
Preparation of intermediate 140.1
2- (6- (Benzylthio) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a solution of 6- (benzylthio) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) imidazo [1,5-a ] pyridin-8-ol (60 mg, 153.68. Mu. Mol) in toluene (2 mL) were added tetrahydro-2H-pyran-4-ol (31.39 mg, 307.35. Mu. Mol, 30.77. Mu. L) and CMBP (74.18 mg, 307.35. Mu. Mol). The mixture was degassed and purged with N 2 (3 times). The mixture was stirred at 100deg.C for 16 hours, then diluted with EtOAc (45 mL). The organic layer was washed with brine (20 mL;2 times), dried over Na 2SO4 and concentrated in vacuo. The crude residue was purified by preparative TLC (petroleum ether: ethyl acetate=3/1) to give the product 2- (6- (benzylthio) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (40 mg,65.75 μmol,42.78% yield, 78% purity) as a yellow solid.
RT 0.578 min (method 1);m/z 475.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.25(s,1H),7.73(s,1H),7.38-7.36(m,2H),7.33-7.29(m,2H),7.27-7.23(m,1H),7.07(t,J＝52.0Hz,1H),6.11(s,1H),4.53-4.47(m,1H),4.16(s,2H),4.03-3.97(m,2H),3.63-3.57(m,2H),2.05-1.99(m,2H),1.88-1.80(m,2H).
Preparation of intermediate 140.2
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride and 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a mixture of 2- (6-benzylsulfonyl-8-tetrahydropyran-4-yloxy-imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (40 mg, 84.29. Mu. Mol) in AcOH (0.6 mL) and H 2 O (0.3 mL) was added 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (49.82 mg, 252.87. Mu. Mol) at 0deg.C. The mixture was stirred at 20 ℃ for 6 hours, then diluted with DCM (15 mL). The organic layer was washed with brine (20 mL;2 times), dried over Na 2SO4, filtered and concentrated in vacuo. The crude product was used directly in the next step.
Example 140 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide and example 141 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1-methylcyclopropylamine (19.09 mg, 177.44. Mu. Mol, HCl salt) in DCM (0.5 mL) was added DIEA (34.40 mg, 266.15. Mu. Mol, 46.36. Mu. L) and a mixture of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 44.36. Mu. Mol) and 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 41.21. Mu. Mol) at-10 ℃. The mixture was stirred at 20 ℃ for 1 hour and then concentrated in vacuo. The crude product was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:49% -79%,10 min) and lyophilized to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide (2.25 mg, 4.22. Mu. Mol,9.51% yield, 91% purity) as a pale yellow solid, and the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide (2.66 mg, 4.60% yield, 90% purity as a yellow solid.
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide
RT 0.511 min (method) 1);m/z 486.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.81(s,1H),7.86(s,1H),7.09(t,J＝52.0Hz,1H),6.61(s,1H),5.16(s,1H),4.82-4.79(m,1H),4.07-4.02(m,2H),3.71-3.65(m,2H),2.20-2.14(m,2H),2.02-1.94(m,2H),1.39(s,3H),0.94(t,J＝4.0Hz,2H),0.63-0.60(m,2H).
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- ((tetrahydro-2H-pyran-4-yl) oxy) imidazo [1,5-a ] pyridine-6-sulfonamide
RT 0.509 min (method 1);m/z 520.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.78(s,1H),7.08(t,J＝52.0Hz,1H),6.57(s,1H),5.07(s,1H),4.91-4.81(m,1H),4.09-4.03(m,2H),3.77-3.72(m,2H),2.18-2.10(m,2H),2.02-1.94(m,2H),1.40(s,3H),0.93(t,J＝4.0Hz,2H),0.64-0.61(m,2H).
Preparation of intermediate 142.1
2- (6- (Benzylthio) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a mixture of 2- (6- (benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (250.00 mg, 611.43. Mu. Mol) and 3-methoxypropan-1-ol (220.41 mg,2.45mmol, 233.98. Mu.L) in dioxane (5 mL) was added Cs 2CO3 (398.43 mg,1.22 mmol) and t-BuXPhos-Pd-G3 (52.24 mg, 61.14. Mu. Mol). The mixture was degassed, purged with N 2 (3 times) and stirred under an atmosphere of N 2 at 100 ℃ for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel12gSilica flash column, eluent 0-70% petroleum ether/ethyl acetate, 20 mL/min) to give the product 2- (6- (benzylthio) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (120 mg, 168.64. Mu. Mol,27.58% yield, 65% purity) as a yellow solid.
RT 0.565 minutes (method) 1);m/z 462.9(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.20(s,1H),7.72(s,1H),7.38-7.36(m,2H),7.32-7.29(m,2H),7.26-7.22(m,1H),7.07(t,J＝56.0Hz,1H),6.20(s,1H),4.17(s,2H),4.14(t,J＝4.0Hz,2H),3.59(t,J＝4.0Hz,2H),3.39(s,3H),2.15-2.13(m,2H).
Preparation of intermediate 142.2
2- (6- (Benzylthio) -1-iodo-8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole
To a mixture of 2- (6- (benzylthio) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (70.00 mg, 151.34. Mu. Mol) in MeCN (1.5 mL) was added NIS (51.07 mg, 227.01. Mu. Mol) and AcOH (27.26 mg, 454.02. Mu. Mol, 25.97. Mu. L). The reaction mixture was stirred at 25 ℃ for 4 hours. The reaction mixture was used directly in the next step.
Preparation of intermediate 142.3
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a mixture of 2- (6- (benzylthio) -1-iodo-8- (3-methoxypropoxy) imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-thiadiazole (70 mg, 118.96. Mu. Mol, theoretical amount, reaction mixture from previous step) in MeCN (1 mL) was added H 2 O (4.29 mg, 237.92. Mu. Mol, 4.29. Mu. L), acOH (14.29 mg, 237.92. Mu. Mol, 13.61. Mu. L) and 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (46.87 mg, 237.92. Mu. Mol) at 0 ℃. The mixture was then stirred at 0 ℃ for 2 hours. The reaction mixture was used directly in the next step.
Example 142 preparation
N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1-aminocyclopropane carbonitrile (30.53 mg,371.84 mmol) in pyridine (1.5 mL) was added 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (70 mg,123.95 mmol, theoretical amount, reaction mixture from the previous step) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour. The resulting mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (60 mL), separated, dried and concentrated in vacuo. The resulting residue was purified by preparative TLC (petroleum ether: ethyl acetate=1/1) to give the product N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg,22.12 μmol,17.84% yield, 90% purity) as a yellow solid.
RT 0.491 min (method 1); m/z 611.0 (M+H) +(ESI+).
Example 143 preparation
N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-iodo-8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg,24.57 μmol) in MeOH (3 mL) was added Pd/C (5 mg,10% purity). The reaction mixture was degassed with H 2 (balloon, 15 psi) (3 times) and then stirred at 20 ℃ for 2 hours. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18150 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:22% -52%,10 min) to give the product N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-methoxypropoxy) imidazo [1,5-a ] pyridine-6-sulfonamide (1.9 mg,3.92 μmol,15.96% yield, 100% purity) as a pale yellow solid.
RT 0.511 min (method) 1);m/z 485.0(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6):9.60(s,1H),7.95(s,1H),7.81(t,J＝50.8Hz,1H),6.76(s,1H),4.34(t,J＝6.4Hz,2H),3.55(t,J＝6.0Hz,2H),3.28(s,3H),2.12-2.09(m,2H),1.40(br,2H),1.31(br,2H).
Example 146a preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-fluoro-N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (10 mg, 22.84. Mu. Mol) in DMF (1 mL) was added SelectFluor (24.27 mg, 68.52. Mu. Mol). The mixture was degassed with N 2 (3 times) and stirred at 70 ℃ for 1.5 hours. The mixture was cooled to room temperature, diluted with EtOAc (10 mL) and washed with water (5 mL;3 times). The organic phase was separated, dried over Na 2SO4, filtered and concentrated in vacuo to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate=3:1) to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-fluoro-N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (5 mg,9.87 μmol,28.82% yield, 90% purity) as a yellow solid.
RT 0.511 min (method 1); m/z 455.9 (M+H) +(ESI+
Example 146 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-fluoro-6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-fluoro-N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (5 mg, 10.97. Mu. Mol), N-dimethylpiperazine-1-carboxamide (6.90 mg, 43.88. Mu. Mol) and CS 2CO3 (10.72 mg, 32.91. Mu. Mol) in dioxane (1 mL) was added Pd-PEPSI-IPentCl o-methylpyridine (1.07 mg, 1.10. Mu. Mol). The mixture was degassed with N 2 (3 times) and stirred at 100 ℃ for 30 min. The mixture was cooled to 20 ℃, filtered, and the filtrate evaporated. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=0:1) and preparative HPLC (column: unisil-100 C18 Ultra 150*25mm*10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:38% -68%,10 min) and then lyophilized to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -1-fluoro-6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (6 mg,8.85 μmol,80.63% yield, 85% purity) as a yellow solid.
RT 0.486 min (method) 1);m/z 577.1(M+H)+(ESI+);1H NMR(CDCI3 400MHz):9.76(s,1H),7.01(t,J＝54.0Hz,1H),6.53(s,1H),5.45(s,1H),4.29(d,J＝48.4Hz,2H),3.50(t,J＝4.4Hz,4H),3.25(t,J＝4.4Hz,4H),2.90(s,6H),1.18-1.14(m,2H),0.89(t,J＝6.4Hz,1H)
Example 147 preparation
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-methylimidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 38.70. Mu. Mol) in dioxane (1 mL) was added H 2O(0.1mL)、K2CO3 (10.70 mg, 77.40. Mu. Mol), 2,4, 6-trimethyl-1,3,5,2,4,6-trioxadiborane (3.5M, 5.53. Mu.L, 50% purity) and Pd (dppf) Cl 2 (2.83 mg, 3.87. Mu. Mol). The mixture was degassed, purged with N 2 (3 times) and stirred at 80 ℃ for 16 hours. After filtration, the filtrate was evaporated. The resulting residue was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN;30% -60%,10 min) and lyophilized directly to give the product 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-methylimidazo [1,5-a ] pyridine-6-sulfonamide (13 mg, 28.48. Mu. Mol,49.06% yield, 99% purity) as a pale yellow solid.
RT 0.460 min (method) 1);m/z 451.9(M+H)+(ESI+);1HNMR(DMSO-d6,400MHz):9.77(s,1H),8.95(s,1H),7.6(t,J＝53.2Hz,1H),7.33(s,1H),4.25(d,J＝48.4Hz,2H),2.78(s,3H),0.85-0.76(m,4H).
Example 148 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) -1-methylimidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -1-methylimidazo [1,5-a ] pyridine-6-sulfonamide (13 mg, 28.77. Mu. Mol) in dioxane (0.5 mL) was added N, N-dimethylpiperazine-1-carboxamide (9.05 mg, 57.54. Mu. Mol), pd-PEP-IPentCl o-methylpyridine (2.48 mg, 2.88. Mu. Mol) and CS 2CO3 (18.75 mg, 57.54. Mu. Mol). The reaction mixture was degassed with N 2 (3 times) and stirred at 100 ℃ for 30min. After filtration, the filtrate was evaporated to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN;38% -68%,10 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) -1-methylimidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (0.5 mg,7.68 e-1. Mu. Mol,2.67% yield, 88% purity) as a yellow solid.
RT 0.453 min (method) 1);m/z 573.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.57(s,1H),8.44(s,1H),7.66(t,J＝53.2Hz,1H),6.78(s,1H),4.21(d,J＝49.2Hz,2H),3.46-3.44(m,4H),3.07-3.05(m,4H),2.80(s,6H),2.71(s,3H),0.84-0.80(m,2H),0.78-0.76(m,2H).
Preparation of intermediate 149.1
(5-Bromo-3-chloropyridin-2-yl) methylamine hydrochloride
To a mixture of 5-bromo-3-chloropyridine carbonitrile (2.0 g,9.20 mmol) in tetrahydrofuran (10 mL) was added BH 3. THF (1M, 11.04 mL) at 0deg.C. The mixture was stirred at 0 ℃ for 30 minutes, then warmed to 20 ℃ and stirred at that temperature for an additional 30 minutes. The mixture was cooled to 0 ℃ and quenched by dropwise addition of methanol (10 mL) over 5 minutes. The mixture was heated to 70 ℃ and stirred at that temperature for 30 minutes. The reaction was concentrated in vacuo to give the crude product (2.2 g) as a light brown solid. The crude product was dissolved in HCl (aqueous, 2M,20 mL) and washed with dichloromethane (20 mL;2 times). The aqueous phase was concentrated in vacuo to give the product (5-bromo-3-chloropyridin-2-yl) methylamine hydrochloride (1.5 g,4.07mmol,44.26% yield, 70% purity, HCl salt) as a light brown solid.
RT 0.18 min (method 2);m/z 222.9(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):8.78(d,J＝2.0Hz,1H),8.69(br,3H),8.47(d,J＝2.0Hz,1H),4.24(d,J＝6.2Hz,2H).
Preparation of intermediate 149.2
2- (((5-Bromo-3-chloropyridin-2-yl) methyl) amino) -2-oxoacetic acid ethyl ester
To a mixture of (5-bromo-3-chloro-2-pyridinyl) methylamine (1.5 g,5.82mmol, HCl salt) in dichloromethane (30 mL) was added DIPEA (2.25 g,17.45 mmol) at 0deg.C. Then, ethyl 2-chloro-2-oxoacetate (952.77 mg,6.98 mmol) was added over 5 minutes, and the mixture was stirred at 0℃for 30 minutes. The mixture was warmed to 20 ℃ and stirred at that temperature for 30 minutes. The mixture was quenched with aqueous NaHCO 3 (50 mL) and extracted with dichloromethane (50 mL). The organic phase was separated, dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1 to 1:1) to give the product ethyl 2- (((5-bromo-3-chloropyridin-2-yl) methyl) amino) -2-oxoacetate (1300 mg,3.64mmol,62.57% yield, 65.6% purity) as a white solid.
RT 0.61 min (method 1); m/z 322.8 (M+H) +(ESI+).
Preparation of intermediate 149.3
6-Bromo-8-chloroimidazo [1,5-a ] pyridine-3-carboxylic acid ethyl ester
To a mixture of ethyl 2- (((5-bromo-3-chloropyridin-2-yl) methyl) amino) -2-oxoacetate (1300 mg,4.04 mmol) in POCI 3 (15 mL) was added phosphorus pentoxide (2.87 g,20.21 mmol) at 0deg.C. The mixture was heated to 110 ℃ and stirred at that temperature for 5 hours. The mixture was cooled to 25 ℃ and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), washed with water (30 mL) and saturated NaHCO 3 solution (30 mL), then, it was concentrated in vacuo, the residue was purified by flash chromatography on silica gel4gSilica flash column, eluent 0-30% ethyl acetate/petroleum ether gradient, 30 mL/min) to give the product 6-bromo-8-chloroimidazo [1,5-a ] pyridine-3-carboxylic acid ethyl ester (900 mg,2.97mmol,73.34% yield) as a white solid.
RT 0.718 min (method 1),m/z 304.8(M+H)+(ESI+),1H NMR(CDCI3,400MHz):9.47(s,1H),7.77(s,1H),7.20(s,1H),4.65-4.42(m,2H),1.57-1.42(m,3H).
Preparation of intermediate 149.4
6-Bromo-8-chloroimidazo [1,5-a ] pyridine-3-carboxamide
A solution of 6-bromo-8-chloro-imidazo [1,5-a ] pyridine-3-carboxylic acid ethyl ester (3 g,9.88 mmol) in NHa/MeOH (7M, 59.30 mL) is stirred at 25℃for 16 h. The mixture was filtered and washed with MeOH (5 mL) to give the product 6-bromo-8-chloroimidazo [1,5-a ] pyridine-3-carboxamide (2.6 g,9.47mmol,95.83% yield) as a white solid.
RT 0.45 min (method) 3);m/z 275.9(M+H)+(ESI+);1H NMR(CDCI3,400MHz)δ:9.62(s,1H),7.66(s,1H),7.32(s,1H),7.16(s,1H),5.55(s,1H).
Preparation of intermediate 149.5
6-Bromo-8-chloroimidazo [1,5-a ] pyridine-3-thiocarboxamide
To a suspension of 6-bromo-8-chloro-imidazo [1,5-a ] pyridine-3-carboxamide (4 g,14.57 mmol) in toluene (40 mL) was added TFA (1.66 g,14.57mmol,1.08 mL). The reaction mixture was stirred at 25 ℃ for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with toluene (40 mL). Lawsen reagent (17.68 g,43.72 mmol) was added and the reaction mixture was stirred at 110℃for 16 hours. The mixture was concentrated under reduced pressure and the residue was triturated with MeOH (60 mL) at 50 ℃ for 1 hour. After filtration, the cake was collected and dried under reduced pressure to give the product 6-bromo-8-chloroimidazo [1,5-a ] pyridine-3-thiocarboxamide (3.94 g,12.84mmol,88.10% yield, 94.68% purity) as a brown solid.
1H NMR(DMSO-d6,400MHz)δ:10.76(s,1H),9.84(s,1H),9.71(s,1H),7.84(s,1H),7.65(s,1H)。
Preparation of intermediate 149.6.
2- (6-Bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) thiazole-5-carboxylic acid ethyl ester
To a solution of ethyl 2-chloro-3-oxo-propionate (4.77 g,31.67 mmol) in toluene (15 mL) was added 6-bromo-8-chloro-imidazo [1,5-a ] pyridine-3-thiocarboxamide (2 g,6.88 mmol) and MgS0 4 (1.66 g,13.77 mmol). The mixture was stirred at 100 ℃ for 16 hours, then filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with MeOH (20 mL) at 17 ℃ for 8 minutes and the precipitate filtered and dried under reduced pressure to give the product ethyl 2- (6-bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) thiazole-5-carboxylate (2 g,4.52mmol,87.424% yield) as a brown solid.
RT 0.702 min ;m/z 385.8(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.74(s,1H),8.44(s,1H),7.72(s,1H),7.11(s,1H),4.41 -4.36(q,J＝7.2Hz,2H),1.41-1.37(t,J＝7.2Hz,3H).
Preparation of intermediate 149.7
(2- (6-Bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) thiazol-5-yl) methanol
DIBAL-H (1M, 10.35 mL) was added dropwise over 6 minutes to a solution of ethyl 2- (6-bromo-8-chloro-imidazo [1,5-a ] pyridin-3-yl) thiazole-5-carboxylate (1000 mg,2.59 mmol) in THF (30 mL) at-20℃and N 2. The reaction mixture was stirred at-20℃for 2 hours and at 0℃for a further 2 hours. The reaction mixture was quenched with NH 4 Cl (saturated aqueous solution, 4 mL) and MeOH (4 mL), then filtered through silica gel and washed with THF (20 mL;3 times). The filtrate was collected, dried over Na 2SO4 and concentrated under reduced pressure. The residue was triturated with MeOH (15 mL). The precipitate was filtered and dried in vacuo to give the product [2- (6-bromo-8-chloro-imidazo [1,5-a ] pyridin-3-yl) thiazol-5-yl ] methanol (490 mg,1.42mmol,54.98% yield, 100% purity) as a yellow solid.
RT 0.450 min (method) 4);m/z 345.9(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.75(s,1H),7.80(s,1H),7.71(s,1H),7.06(s,1H),5.96(s,2H).
Preparation of intermediate 149.8
2- (6-Bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) thiazole-5-carbaldehyde
To a solution of [2- (6-bromo-8-chloro-imidazo [1,5-a ] pyridin-3-yl) thiazol-5-yl ] methanol (500 mg,1.45 mmol) in 1, 2-dichloroethane (7 mL) was added MnO 2 (1.26 g,14.51 mmol). The reaction mixture was stirred at 80 ℃ for 20 min, filtered, and the filter cake was washed with DCM (20 ml,3 times). The filtrate was collected, dried over Na 2SO4, and concentrated under reduced pressure to give the product 2- (6-bromo-8-chloro-imidazo [1,5-a ] pyridin-3-yl) thiazole-5-carbaldehyde (327 mg,931.66 μmol,64.21% yield, 97.610% purity) as a yellow solid.
RT 0.495 min (method) 4);m/z 343.9(M+H)+(ESI+);1H NMR(CDCI3,400MHz)δ:10.01(s,1H),9.83(s,1H),8.48(s,1H),7.81(s,1H),7.18(s,1H).
Preparation of intermediate 149.9
2- (6-Bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole
To a solution of 2- (6-bromo-8-chloro-imidazo [1,5-a ] pyridin-3-yl) thiazole-5-carbaldehyde (327 mg, 954.47. Mu. Mol) in DCM (15 mL) at-15℃and N 2 was added dropwise a solution of DAST (1.54 g,9.54mmol,1.26 mL) in DCM (0.6 mL). The mixture was stirred at-15℃for 2 hours, at 0℃for 2 hours and at 20℃for 3 hours. The mixture was quenched with NH 4 Cl (saturated aqueous solution, 5 mL) at-15 ℃, diluted with water (40 mL) and extracted with DCM (20 mL,3 times). The organic phases were separated and the combined organic layers were dried over Na 2SO4 and concentrated under reduced pressure to give the product 2- (6-bromo-8-chloro-imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole (360 mg, crude product) as a yellow solid.
RT 0.542 min (method 4);m/z 366.0(M+H)+(ESI+);1H NMR(CDCI3,400MHz)δ:9.73-9.72(m,1H),8.05-8.04(t,J＝2.0Hz,1H),7.75(m,1H),7.12-6.84(m,2H).
Preparation of intermediate 149.10
2- (6- (Benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole
DIEA (197.97 mg,1.53mmol, 266.80. Mu.L) and phenyl methyl mercaptan (63.42 mg, 510.59. Mu. Mol, 59.83. Mu.L) were added to a solution of 2- (6-bromo-8-chloro-imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole (234 mg, 510.59. Mu. Mol,79.555% purity), pd 2(dba)3 (46.76 mg, 51.06. Mu. Mol) and Xanthos (29.54 mg, 51.06. Mu. Mol) in 1, 4-dioxane (4 mL) under N 2. The mixture was degassed with N 2 (3 times) and stirred under nitrogen at 100 ℃ for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=10:1) to give the product 2- (6-benzylsulfonyl-8-chloro-imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole (140 mg,338.10 μmol,66.22% yield, 98.504% purity) as a yellow solid.
RT 0.595 min (method) 4);m/z 408.1(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.43(s,1H),8.00(s,1H),7.68(s,1H),7.34-7.30(m,5H),6.97(t,J＝55.2Hz,1H),6.90(s,1H),4.15(s,2H).
Preparation of intermediate 149.11
2- (6- (Benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole
To a solution of 2- (6-benzylsulfonyl-8-chloro-imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole (74 mg, 181.42. Mu. Mol) in MeCN (3 mL) was added NIS (40.82 mg, 181.42. Mu. Mol). The mixture was stirred at 25℃for 16 hours, then AcOH (32.68 mg, 544.27. Mu. Mol, 31.13. Mu.L) was added at 25℃and the mixture was stirred for an additional 1 hour. The reaction mixture of 2- (6- (benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole was used without purification in the next step.
RT 0.766 min (method 3); m/z 533.9 (M+H) +(ESI+).
Preparation of intermediate 149.12
8-Chloro-3- (5- (difluoromethyl) thiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a previous suspension of 2- (6- (benzylthio) -8-chloro-1-iodoimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole (78 mg, 146.13. Mu. Mol, theory) in MeCN (3 mL) were successively added AcOH (17.55 mg, 292.25. Mu. Mol, 16.71. Mu.L), H 2 O (5.27 mg, 292.25. Mu. Mol, 5.27. Mu. L) and 1, 3-dichloro-5, 5-dimethyl-imidazolidine-2, 4-dione (57.58 mg, 292.25. Mu. Mol) at 0deg.C. The mixture was stirred at 0 ℃ for 1 hour. The reaction mixture (74.35 mg, theoretical weight) of 8-chloro-3- (5- (difluoromethyl) thiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride was used in the next step without purification.
RT 0.684 min (method 3); m/z 509.8 (M+H) +(ESI+);
Example 149 preparation
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) thiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 1-aminocyclopropane-1-carbonitrile (51.98 mg, 438.38. Mu. Mol, HCl salt) in pyridine (2.94 g,37.17mmol,3 mL) at 0deg.C was added dropwise a reaction mixture containing 8-chloro-3- (5- (difluoromethyl) thiazol-2-yl) -1-iodoimidazo [1,5-a ] pyridine-6-sulfonyl chloride (74.35 mg, crude, theoretical weight) for 3 min. The mixture was stirred at 0deg.C for 1 hour, quenched with water (5 mL) and extracted with EtOAc (15 mL;3 times). The organic layers were separated, combined, dried over Na 2SO4 and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=2:1) to give the product 8-chloro-N- (1-cyanocyclopropyl) -3- [5- (difluoromethyl) thiazol-2-yl ] -1-iodo-imidazo [1,5-a ] pyridine-6-sulfonamide (64 mg,97.79 μmol,66.92% yield, 84.915% purity) as a yellow solid.
RT 0.611 min (method 4);m/z 555.8(M+H)+(ESI+);1H NMR(CDCI3,400MHz)δ:10.37(s,1H),8.11(s,1H),7.32-7.31(d,J＝1.2Hz,1H),7.13(s,1H),7.13-6.85(t,J＝55.6Hz,1H),1.67-1.62(m,2H),1.27-1.24(m,2H).
Example 150 preparation
8-Chloro-N- (1-cyanocyclopropyl) -3- (5- (difluoromethyl) thiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-N- (1-cyanocyclopropyl) -3- [5- (difluoromethyl) thiazol-2-yl ] -1-iodo-imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg, 89.97. Mu. Mol) in MeOH (3 mL) was added Pd/C (50.00 mg, 46.98. Mu. Mol,10% purity). The reaction was degassed with H 2 (balloon, 15psi,3 times) and stirred at 25 ℃ for 1 hour. The mixture was filtered, washed with MeOH (3 mL;2 times), and the filtrate concentrated under reduced pressure to give the product 8-chloro-N- (1-cyanocyclopropyl) -3- [5- (difluoromethyl) thiazol-2-yl ] imidazo [1,5-a ] pyridine-6-sulfonamide (26 mg, 28.43. Mu. Mol,31.60% yield) as a yellow solid.
RT 0.558 min (method 3); m/z 430.1 (M+H) +(ESI+);
Example 151 preparation
4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) thiazol-2-yl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of N, N-dimethylpiperazine-1-carboxamide (10.97 mg, 69.79. Mu. Mol) and 8-chloro-N- (1-cyanocyclopropyl) -3- [5- (difluoromethyl) thiazol-2-yl ] imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg, 34.90. Mu. Mol) in dioxane (0.5 mL) was added CS 2CO3 (22.74 mg, 69.79. Mu. Mol) and Pd-PEPPI-IPentCl o-methylpyridine (1.70 mg, 1.74. Mu. Mol) under N 2, and the mixture was stirred at 100℃for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=0:1) to give an impure product which was purified by preparative HPLC (column: phenomenex Synergi C, 150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:40% -70%,10 min) and lyophilized directly to give the product 4- (6- (N- (1-cyanocyclopropyl) sulfamoyl) -3- (5- (difluoromethyl) thiazol-2-yl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (4.98 mg,8.16 μmol,23.38% yield) as a yellow solid.
RT 0.552 min (method 3);m/z 551.1(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6)9.67(s,1H),8.42(s,1H),8.32(s,1H),7.90(s,1H),7.50(t,J＝54.8Hz,1H),6.61(s,1H),3.38-3.36(m,4H),3.35-3.30(m,4H),2.80(s,6H),1.33-1.26(m,2H),1.25-1.18(m,2H).
Example 152 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (hydroxymethyl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 47.64. Mu. Mol) and (tributylstannyl) methanol (152.95 mg, 476.35. Mu. Mol) in dioxane (1 mL) was added Pd (PPh 3)4 (5.50 mg, 4.76. Mu. Mol.) the mixture was degassed with N 2 (3 times) and stirred at 100 ℃ for 16 hours under an atmosphere of N 2. The reaction mixture was cooled to 20 ℃, filtered, and the filtrate concentrated in vacuo. The residue was first purified by preparative TLC (petroleum ether: ethyl acetate=0:1) and then further purified by preparative HPLC (column: unisil-100 C18 Ultra150*25mm*5 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:30% -50%,10 minutes) to give the product 3- (5-dimethyl) -1, 4-thiadiazol 1-6-hydroxypropyl) as a yellow solid (60% pure solid.
RT 0.443 min (method 1); m/z 415.9 (M+H) +(ESI+)
Preparation of intermediate 152.1
8- (((Tert-butyldimethylsilyl) oxy) methyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (hydroxymethyl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg, 21.66. Mu. Mol,60% purity) and TBSCI (6.53 mg, 43.33. Mu. Mol, 5.31. Mu.L) in THF (1 mL) was added imidazole (2.95 mg, 43.33. Mu. Mol). The mixture was stirred at 20℃for 16 hours, then diluted with EtOAc (20 mL) and washed with water (30 mL;3 times). The organic layer was collected, dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=5:1) to give the product 8- (((tert-butyldimethylsilyl) oxy) methyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg,21.24 μmol,98.04% yield, 75% purity) as a yellow solid.
RT 0.631 min (method 1); m/z 530.1 (M+H) +(ESI+).
Alternative preparation of example 152
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (hydroxymethyl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
A solution of 8- (((tert-butyldimethylsilyl) oxy) methyl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg, 28.32. Mu. Mol) in HCl/dioxane (4M, 3.00 mL) was stirred at 20℃for 1 hour. The reaction mixture was concentrated in vacuo to give a residue which was triturated with MeOH (0.5 mL) at 20 ℃ for 1 hour. After filtration, the filter cake was collected and dried in vacuo to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (hydroxymethyl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (8.14 mg,18.24 μmol,64.42% yield, 93.1% purity) as a yellow solid.
RT 0.405 min (method 1);m/z 416.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.82(s,1H),8.56(s,1H),7.98(s,1H),7.69(t,J＝53.4Hz,1H),7.41(d,J＝1.4Hz,1H),5.80(t,J＝5.6Hz,1H),4.85(d,J＝5.6Hz,2H),1.19(s,3H),0.70(t,J＝5.6Hz,2H),0.46(dd,J＝6.4Hz,4.8Hz,2H).
Preparation of intermediate 153
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
3 Batches were run in parallel and pooled for processing.
To a mixture of 1-bromo-8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (500 mg,967.60 μmol) in HFIP (15 mL) and THF (15 mL) was added Pd/C (160 mg,10% purity) and DIEA (250.11 mg,1.94mmol,337.08 μL). The reaction mixture was degassed with H 2 (15 psi,3 times) and stirred at 40℃for 16 hours. The 3 reaction mixtures were combined, diluted with EtOAc (50 mL), filtered and concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 mL). The organic layer was washed with NaHCO 3 (saturated aqueous solution, 30 mL) and brine (30 mL), the organic phase was dried over Na 2SO4, filtered and concentrated in vacuo to give 1.15g of a crude mixture.
50Mg of this crude residue was purified by preparative TLC (petroleum ether: ethyl acetate=3:1) to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (11.4 mg, 28.26. Mu. Mol,24.75% yield, 100% purity) as a white solid.
RT 0.440 min (method) 1);m/z 403.9(M+H)+(ESI+);1H NMR(CDCI3,400MHz):10.20(s,1H),7.81(s,1H),7.98(s,1H),7.76(dd,J＝9.6Hz,0.8Hz,1H),7.36(dd,J＝10.8Hz,1.2Hz,1H),7.09(t,J＝53.6Hz,1H),5.50(s,1H),4.29(d,J＝48.4Hz),1.15-1.11(m,2H),0.90-0.87(dd,J＝6.4Hz,4.8Hz,2H).
The compounds listed in the following table were prepared according to the corresponding general procedure or, when illustrated in a similar manner as the related compounds, starting from the corresponding intermediates.
Example 168 preparation
Oxetan-3-yl 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate
A solution of 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid (10 mg, 22.20. Mu. Mol), oxetan-3-ol (1.97 mg, 26.64. Mu. Mol), DMAP (542.35. Mu.g, 4.44. Mu. Mol) and DCC (5.50 mg, 26.64. Mu. Mol, 5.39. Mu. L) in DCM (0.5 mL) was stirred at 20℃for 1 hour. The solution was quenched with water (10 mL) and extracted with DCM (10 mL;3 times). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na 2SO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by preparative HPLC (column: waters Xbridge C18 150X 50mm X10 μm; mobile phase: A:10mmol NH 4HCO3 in water, B: meCN; B%:25% -55%,10 min) and lyophilized directly to give the product oxetan-3-yl 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate (0.9 mg, 1.71. Mu. Mol,7.68% yield, 96% purity) as a yellow gum.
RT 0.769 min (method 1);m/z 507.3(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.46(s,1H),8.34(s,1H),6.94(s,1H),5.76-5.69(m,1H),5.04-5.00(m,2H),4.85-4.81(m,2H),3.62-3.60(m,4H),3.53-3.51(m,4H),2.89(s,6H),1.31(s,3H),0.86-0.83(m,2H),0.57-0.54(m,2H).
Preparation of intermediate 169.1
(8-Chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-3-yl) carbamic acid tert-butyl ester
To a solution of t-BuOH (2.33 g,31.37mmol,3 mL) and toluene (3 mL) of 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylic acid (280 mg, 849.11. Mu. Mol) was added TEA (214.80 mg,2.12mmol, 295.46. Mu.L), followed by DPPA (467.35 mg,1.70mmol, 367.99. Mu.L). The reaction mixture was degassed and purged with N 2 (3 times), and the mixture was stirred under an atmosphere of N 2 at 90 ℃ for 4 hours. The mixture was poured into NaHCO 3 (saturated aqueous solution, 10 mL) and extracted with EtOAc (10 mL,3 times). The combined organic layers were dried over Na 2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel12gSilica flash column, eluent 20% -50% ethyl acetate/petroleum ether gradient, 30 mL/min) to afford impure product, which was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm.10 μm; mobile phase: a:0.225% formic acid in water, B: meCN; b%:34% -64%;10 min) and freeze-dried directly to give the product (8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-3-yl) carbamic acid tert-butyl ester (75 mg,187.09 μmol,22.03% yield, 100% purity) as a yellow solid.
RT 0.768 min (method) 1);m/z 401.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.90(s,1H),8.62(s,1H),8.37(s,1H),7.66(s,1H),7.57(s,1H),1.48(s,9H),1.12(s,3H),0.64-0.73(m,2H),0.41-0.50(m,2H).
Preparation of intermediate 169.2
(8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-3-yl) carbamic acid tert-butyl ester
To a solution of tert-butyl (8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-3-yl) carbamate (75 mg, 187.09. Mu. Mol) in dioxane (2 mL) was added CS 2CO3 (121.91 mg, 374.18. Mu. Mol), N-dimethylpiperazine-1-carboxamide (58.83 mg, 374.18. Mu. Mol) and Pd-PEPSI-IPentCl o-methylpyridine (8.05 mg, 9.35. Mu. Mol). The reaction mixture was degassed, purged with N 2 (3 times), and then stirred under an atmosphere of N 2 at 100 ℃ for 4 hours. The mixture was poured into water (5 mL) and extracted with EtOAc (5 mL,3 times). The combined organic layers were dried over Na 2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm.10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:34% -64%;10 min) and lyophilized directly to give tert-butyl 8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-3-yl) carbamate (mg, 36.52. Mu. Mol,19.52% yield, 95.26% purity) as a white solid.
RT 0.839 min (method 1);m/z 522.3(M+H)+(ESI+);1H NMR(CDC3,400MHz):8.21(s,1H),7.52(s,1H),6.65(s,1H),6.25(br,1H),4.93(s,1H),3.70-3.58(m,4H),3.57-3.45(m,4H),2.89(s,6H),1.56(s,9H),1.30(s,3H),0.85(t,J＝6Hz,2H),0.85(t,J＝6Hz,2H).
Preparation of intermediate 169.3
4- (3-Amino-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
A mixture of tert-butyl (8- (4- (dimethylcarbamoyl) piperazin-1-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-3-yl) carbamate (8 mg, 15.34. Mu. Mol) in MeOH (0.5 mL) and H 2 O (0.5 mL) was stirred under microwaves at 120℃for 2 hours and the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:6% -36%;10 min) and lyophilized directly to give the product 4- (3-amino-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (0.85 mg, 2.02. Mu. Mol,13.15% yield, 100% purity) as an off-white solid.
RT 0.616 min (method) 1);m/z 422.2(M+H)+(ESI+);1H NMR(CDCI3,400MHz):8.36(s,1H),7.22(s,1H),6.55(s,1H),4.95(s,1H),3.68-3.57(m,4H),3.57-3.46(m,4H),3.18-3.41(m,2H),2.88(s,6H),1.30(s,3H),0.84(t,J＝5.6Hz,2H),0.53(t,J＝6.4Hz,2H).
Example 169 preparation
4- (3- (2-Chloroacetamido) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of 4- [ 3-amino-6- [ (1-methylcyclopropyl) sulfamoyl ] imidazo [1,2-a ] pyridin-8-yl ] -N, N-dimethyl-piperazine-1-carboxamide (10 mg,0.0237 mmol) and NaHCO 3 (10 mg,0.119 mmol) in THF (2 mL) and water (1 mL) at 0 ℃ was added 2-chloroacetyl chloride (4.0 mg,0.0356 mmol). The reaction mixture was stirred at 20 ℃ for 2 hours and poured into water (5 mL). The aqueous phase was extracted with EtOAc (5 ml,3 times). The combined organic layers were dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex luna C18150 mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:21% -51%;10 min) to give the product 4- (3- (2-chloroacetamido) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (11 mg,0.0218mmol,91.99% yield, 98.8% purity) as a white solid.
RT 0.709 min (method 1);m/z 498.2(M+H)+(ESI+);1H NMR(CDCI3,400MHz):8.37(br,1H),8.08(s,1H),7.59(s,1H),6.68(s,1H),5.08(s,1H),4.35(s,2H),3.65-3.55(m,4H),3.55-3.45(m,4H),2.89(s,6H),1.30(s,3H),0.84(s,2H),0.55(s,2H).
Example 170 preparation
4- (3- (2-Cyanoacetamido) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of 4- (3- (2-chloroacetamido) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (9.0 mg,0.0181 mmol) and trimethylsilyl nitrile (5.4 mg,0.0542 mmol) in THF (2 mL) was added TBAF (0.054 mL,0.0542 mmol). The reaction mixture was stirred at 25 ℃ for 16 hours, then poured into water (5 mL) and extracted with EtOAc (5 mL,3 times). The combined organic layers were dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:17% -47%;10 min) to give the product 4- (3- (2-cyanoacetamido) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.4 mg,0.00475mmol,26.26% yield, 96.2% purity) as an off-white solid.
RT 0.765 min (method) 1);m/z 489.2(M+H)+(ESI+);1H NMR(CDCI3,400MHz):9.23(br s,1H),8.26(s,1H),7.62(s,1H),6.64(s,1H),5.62(s,1H),3.80(s,2H),3.55-3.40(m,8H),2.89(s,6H),1.26(s,3H),0.83(t,J＝5.6Hz,2H),0.52(t,J＝5.2Hz,2H).
Preparation of intermediate 171.1
N- [8- [4- (dimethylcarbamoyl) piperazin-1-yl ] -3-iodo-imidazo [1,2-a ] pyridin-6-yl ] sulfonyl-N- (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a mixture of 4- (3-iodo-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.1 g,3.94 mmol) in DCM (30 mL) was added BOC 2 O (1.29 g,5.92mmol,1.36 mL) and DMAP (96.38 mg,788.88 μmol). The reaction mixture was stirred at 20℃for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO 2, petroleum ether/ethyl acetate=1/1 to 0/1) followed by preparative HPLC (column: waters Xbridge C18 x 50mm x 10um; mobile phase: a:0.225% NH 4HCO3 in water, B: meCN; B%:48% -68%;10 min) purification and lyophilization to give the product ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3-iodoimidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester (1.1 g,1.74mmol,44.00% yield, 99.8% purity) as a white solid.
RT 0.807 min (method 1);m/z 633.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):8.35(s,1H),7.85(s,1H),6.59(s,1H),3.62-3.50(m,4H),3.30(s,4H),2.78(s,6H),1.52(s,3H),1.28(s,9H),1.01-0.96(m,4H).
Preparation of intermediate 171.2
(8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -3- (1-ethoxyvinyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
The reaction mixture was concentrated under reduced pressure at N 2 under stirring at 100 ℃ for 2 hours to give tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (1-ethoxyvinyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (13.70 mg,37.94 μmol,12.81 μl) stannane (18 mg,31.21 μmol) and Pd (PPh 3)4 (3.65 mg,3.16 μmol) in anhydrous toluene (0.5 mL) as a yellow oil, any further purification of which was used directly in the next step.
RT 0.662 min (method 5); m/z 577.2 (M+H) +(ESI+).
Example 171 preparation
4- (3-Acetyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (1-ethoxyvinyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (18 mg, 31.21. Mu. Mol) in acetone (0.5 mL) was added HCl (12N, 13.00. Mu.L). The mixture was stirred at 20 ℃ for 1 hour, then diluted with H 2 O (30 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (30 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:30% -60%,7 min) and lyophilized directly to give the product 4- (3-acetyl-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (3.61 mg, 7.63. Mu. Mol,24.44% yield, 94.77% purity) as a yellow solid.
RT 0.820 min (method) 1);m/z 449.2(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.83(d,J＝1.2Hz,1H),8.30(s,1H),7.01(d,J＝1.2Hz,1H),5.05(s,1H),3.57-3.66(m,4H),3.49-3.57(m,4H),2.90(s,6H),2.64(s,3H),1.33(s,3H),0.81-0.92(m,2H),0.53-0.61(m,2H).
Preparation of intermediate 172.1
(3-Acetyl-8- (4- (dimethylcarbamoyl) piperazin-1-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a solution of tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (1-ethoxyvinyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (50 mg, 86.70. Mu. Mol) in acetone (0.5 mL) was added HCl (1N, 433.50. Mu.L). The mixture was stirred at 20 ℃ for 1 hour, then diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM/meoh=10/1) to give tert-butyl ((3-acetyl-8- (4- (dimethylcarbamoyl) piperazin-1-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (40 mg,72.91 μmol,84.09% yield) as a yellow solid.
RT 0.846 min (method 1); m/z 549.2 (M+H) +(ESI+).
Preparation of intermediate 172.2
(8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -3- (1-hydroxyethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a solution of tert-butyl ((3-acetyl-8- (4- (dimethylcarbamoyl) piperazin-1-yl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (30 mg, 54.68. Mu. Mol) in THF (0.2 mL) and MeOH (0.2 mL) was added NaBH 4 (10.34 mg, 273.40. Mu. Mol). The resulting mixture was stirred at 20deg.C for 1 hour, then diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo to give the product tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (1-hydroxyethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (30 mg,54.48 μmol,99.63% yield) as a yellow solid.
RT 0.581 min (method 5); m/z 551.3 (M+H) +(ESI+).
Preparation of example 172
4- (3- (1-Hydroxyethyl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (1-hydroxyethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (8 mg, 14.53. Mu. Mol) in DCM (0.3 mL) was added HCl/dioxane (4M, 240.00. Mu.L). The mixture was stirred at 20 ℃ for 1 hour, then diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex Luna C18.150.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:12% -42%,10 min) and lyophilized directly to give the product 4- (3- (1-hydroxyethyl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (1.93 mg,4.16 μmol,28.64% yield, 97.131% purity) as a yellow solid.
RT 0.705 min (method) 1);m/z 451.2(M+H)+(ESI+);1H NMR(CDCI3,400MHz)8.65(d,J＝1.2Hz,1H),7.53(s,1H),6.68(s,1H),5.20-5.27(m,1H),4.97(s,1H),3.53-3.63(m,4H),3.46-3.53(m,5H),2.88(s,6H),1.80(d,J＝6.4Hz,3H),1.30(s,3H),0.81-0.88(m,2H),0.50-0.56(m,2H).
Example 173 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyrylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulphonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol) in dioxane (0.5 mL) was added 2-methyl-1- (piperazin-1-yl) propan-1-one (17 mg,0.107 mmol), CS 2CO3 (47 mg,0.143 mmol) at room temperature. Then, pd-PEPSI-IPentCl o-methylpyridine (3.5 mg,0.00357 mmol) was added to the solution in a glove box. Outside the glove box, the mixture was stirred under argon at 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature, diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex Synergi C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:40% -70%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyrylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (3.0 mg,0.00553mmol,7.74% yield) as an off-white solid.
RT 0.619 min (method) 5);m/z 540.0(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.92(s,1H),8.19(s,1H),6.96-7.24(m,2H),5.11(s,1H),3.93(s,2H),3.82(s,2H),3.67(s,2H),3.59(s,2H),2.84-2.91(m,1H),1.37(s,3H),1.19(d,J＝6.8Hz,6H),0.89-0.94(m,2H),0.57-0.62(m,2H).
Preparation of intermediate 174.1
6- (N- (tert-Butoxycarbonyl) -N- (1-methylcyclopropyl) sulfamoyl) -8-chloroimidazo [1,2-a ] pyridine-3-carboxylic acid ethyl ester
To a solution of ethyl 8-chloro-6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridine-3-carboxylate (120 mg,0.335 mmol) in DCM (1.5 mL) was added BOC 2 O (95 mg,0.436 mmol) and DMAP (8.2 mg,0.0671 mmol). The reaction was stirred at 20deg.C for 1 hour, then diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL,2 times). The organic layer was washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo to give the product ethyl 6- (N- (tert-butoxycarbonyl) -N- (1-methylcyclopropyl) sulfamoyl) -8-chloroimidazo [1,2-a ] pyridine-3-carboxylate (120 mg,0.262mmol,78.14% yield) as a yellow solid.
RT 0.994 min (method 1); m/z 458.1 (M+H) +(ESI+).
Preparation of intermediate 174.2
(8-Chloro-3- (hydroxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a solution of ethyl 6- (N- (tert-butoxycarbonyl) -N- (1-methylcyclopropyl) sulfamoyl) -8-chloroimidazo [1,2-a ] pyridine-3-carboxylate (130 mg,0.284 mmol) in THF (1 mL) at-78deg.C was added dropwise DIBAL-H in THF (1M, 1.1mL,1.14 mmol). The reaction mixture was slowly warmed to 20 ℃ and stirred for 1 hour. The reaction mixture was then diluted with saturated NH 4 Cl (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel40g Silica flash column, eluent 0-50% ethyl acetate/petroleum ether, 60 mL/min) afforded the product ((8-chloro-3- (hydroxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester (80 mg,0.192mmol,67.76% yield) as a yellow solid.
RT 0.592 min (method 5); m/z 416.0 (M+H) +(ESI+).
Preparation of intermediate 174.3
(8-Chloro-3- (methoxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a mixture of tert-butyl ((8-chloro-3- (hydroxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (80 mg,0.192 mmol) in DMF (0.5 mL) was added NaH (12 mg,0.289mmol,60% purity) and Mel (0.036 mL,0.577 mmol) at 0deg.C. The mixture was stirred at 20deg.C for 1 hour, then diluted with NH 4 Cl (saturated aqueous solution, 20 mL) and extracted with EtOAc (20 mL,2 times). The organic layer was washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel12g Silica flash column, eluent 0-20% EtOAc/petroleum ether gradient, 60 mL/min) afforded the product ((8-chloro-3- (methoxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester (50 mg,0.116mmol,60.46% yield) as a yellow solid.
RT 0.636 min (method 5);m/z 430.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)8.84(d,J＝1.6Hz,1H),7.87(s,1H),7.68(d,J＝1.6Hz,1H),4.89(s,2H),3.26(s,3H),1.50(s,3H),1.33(s,9H),0.87-1.13(m,4H).
Preparation of intermediate 174.4
(8- (4- (Dimethylcarbamoyl) piperazin-1-yl) -3- (methoxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamic acid tert-butyl ester
To a solution of tert-butyl ((8-chloro-3- (methoxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (25 mg,0.0582 mmol) in dioxane (0.5 mL) was added N, N-dimethylpiperazine-1-carboxamide (14 mg,0.0872 mmol), CS 2CO3 (38 mg,0.116 mmol) at room temperature. Then, pd-PEPPI-IPentCl o-methylpyridine (2.8 mg,0.00291 mmol) was added to the solution in a glove box. Outside the glove box, the mixture was stirred under argon at 100 ℃ for 1 hour. The reaction mixture was cooled to room temperature, diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo to give the product tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (methoxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (30 mg,0.0545mmol,93.69% yield).
RT 0.865 min (method 1); m/z 551.2 (M+H) +(ESI+).
Example 174 preparation
4- (3- (Methoxymethyl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a mixture of tert-butyl ((8- (4- (dimethylcarbamoyl) piperazin-1-yl) -3- (methoxymethyl) imidazo [1,2-a ] pyridin-6-yl) sulfonyl) (1-methylcyclopropyl) carbamate (30 mg,0.0545 mmol) in DCM (0.5 mL) was added HCl/dioxane (4 n,0.50 mL). The reaction mixture was stirred at 20 ℃ for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex Synergi C18.150.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:22% -52%,10 min) and lyophilized directly to give 4- (3- (methoxymethyl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,2-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (3.8 mg,0.00835mmol,15.33% yield) as an off-white solid.
RT 0.506 min (method 5); m/z 451.3 (m+h) +(ESI+);1H NMR(CDCI3, 400 MHz) 8.48 (d, j=
1.2Hz,1H),7.62(s,1H),6.71(s,1H),4.99(s,1H),4.77(s,2H),3.56-3.65(m,4H),3.48-3.56(m,4H),3.36(s,3H),2.89(s,6H),1.30(s,3H),0.82-0.88(m,2H),0.51-0.57(m,2H).
Example 175 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (N, S-dimethyl-sulfonylimino) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol) in dioxane (0.5 mL) was added methyl (methylimino) (piperidin-4-yl) - λ6-sulphone (23 mg,0.107mmol, hcl salt), CS 2CO3 (70 mg,0.214 mmol) at room temperature. Then, pd-PEPSI-IPentCl o-methylpyridine (3.5 mg,0.00357 mmol) was added to the mixture at room temperature in a glove box. Outside the glove box, the mixture was stirred under Ar 2 at 100deg.C for 1 hour. The reaction mixture was purified by preparative TLC (PE/etoac=1/1) to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (N, S-dimethyl sulfonylimino) piperidin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,2-a ] pyridine-6-sulfonamide (2.2 mg,0.00367mmol,5.14% yield) as a yellow gum.
RT 0.765 min (method) 1);m/z 560.2(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.83(d,J＝1.6Hz,1H),8.11(s,1H),6.87-7.17(m,2H),5.08(s,1H),4.39-4.58(m,2H),3.10-3.22(m,1H),2.76-2.91(m,8H),2.26-2.40(m,2H),1.97-2.10(m,2H),1.29(s,3H),0.83-0.87(m,2H),0.49-0.56(m,2H).
Example 176a preparation
6- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylic acid tert-butyl ester
To a solution of tert-butyl 2, 6-diazaspiro [3.4] octane-2-carboxylate (63 mg,0.298 mmol) and 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.119 mmol) in dioxane (1.5 mL) was added CS 2CO3 (78 mg,0.238 mmol). The mixture was degassed with N 2 (3 times) and then Pd-PEPSI-IPentCl o-methylpyridine (12 mg,0.0119 mmol) was added. The mixture was stirred at 90 ℃ for 2 hours under N 2 and purified by preparative TLC (petroleum ether/etoac=2/1) to give the product tert-butyl 6- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (20 mg,0.0336mmol,28.19% yield) as a yellow solid.
RT 0.524 min (method) 1);m/z 596.4(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.38(s,1H),8.33(s,1H),8.18(s,1H),7.49-7.82(m,1H),6.13(s,1H),3.91-3.98(m,2H),3.82-3.90(m,4H),3.68(t,J＝6.8Hz,2H),2.22-2.30(m,2H),1.39(s,9H),1.19(s,3H),0.73(m,2H),0.39-0.50(m,2H).
Example 176 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2, 6-diazaspiro [3.4] oct-6-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of tert-butyl 6- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-diazaspiro [3.4] octane-2-carboxylate (20 mg,0.0336 mmol) in DCM (1 mL) was added TFA (0.67 mL,9.00 mmol). The mixture was stirred at 20 ℃ for 1 hour, then concentrated under reduced pressure. The residue was triturated with MTBE at 20 ℃ for 1 min. The resulting suspension was allowed to stand for a moment, and then the supernatant was discarded (3 times). The solid was collected and dried in vacuo. The residue was dissolved in water (10 mL) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2, 6-diazaspiro [3.4] oct-6-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (4.8 mg, 0.00013 mmol,21.25% yield, TFA salt) as a yellow solid.
RT 0.362 min (method 1);m/z 496.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.41(s,1H),8.50-8.83(m,2H),8.38(s,1H),8.15(s,1H),7.51-7.84(m,1H),6.13(s,1H),4.09-4.17(m,2H),3.91-4.02(m,4H),3.67-3.76(m,2H),2.34(m,2H),1.20(s,3H),0.70-0.77(m,2H),0.43-0.49(m,2H).
Example 177a preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylic acid tert-butyl ester
To a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (25 mg, 52.93. Mu. Mol) and piperazine-1-carboxylic acid tert-butyl ester (23.58 mg, 105.87. Mu. Mol, HCl salt) in dioxane (1.5 mL) was added Pd-PEPSI-IPentCl o-methylpyridine (2.57 mg, 2.65. Mu. Mol) and CS 2CO3 (51.74 mg, 158.80. Mu. Mol), and the mixture was degassed with N 2 (3 times). Then, the mixture was stirred at 90 ℃ for 5 hours, cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/etoac=2/1) to give the product tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylate (20 mg,28.94 μmol,54.66% yield, 90% purity) as a yellow solid.
RT 0.549 min (method) 5);m/z 622.3(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.67(s,1H),8.94(s,1H),7.76(t,J＝52.8Hz,1H),6.92(s,1H),4.29(d,J＝48.4Hz,2H),3.67-3.65(m,4H),3.15-3.12(m,4H),1.51(s,9H),0.96-0.90(m,2H),0.86-0.83(m,2H).
Example 177b preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A mixture of tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] 308-y ridine-8-yl) piperazine-1-carboxylate (30 mg, 48.23. Mu. Mol) in HCl/dioxane (1 mL,4.00mmol, 4N) was stirred at 25℃for 1 hour and concentrated in vacuo to give the crude product (30 mg). 15mg of the crude product was purified by preparative HPLC (column: phenomenex luna C, 150, 25mm 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:15% -45%,10 min) and lyophilized to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (3.21 mg, 5.43. Mu. Mol,25.51% yield, 96% purity, FA salt) as a yellow solid.
RT 0.367 min (method) 3);m/z 522.3(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.59(s,1H),8.91(br,1H),8.23(d,J＝1.6Hz,1H),7.70(t,J＝53.2,1H),6.81(s,1H),4.23(t,J＝48.4,2H),3.75-3.02(m,4H),3.02-2.96(m,4H),0.90-0.85(m,2H),0.81-0.76(m,2H).
Example 177 preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N-methylpiperazine-1-carboxamide
To a mixture of 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg,28.74 μmol) in THF (0.2 mL) and NaHCO 3 (saturated aqueous solution, 1.5 mL) was added methylcarbamoyl chloride (5.37 mg,57.47 μmol) at 0 ℃. The mixture was stirred at 20℃for 30min, then diluted with DCM (10 mL), washed with water (5 mL;3 times) and separated. The combined organic layers were dried over anhydrous Na 2SO4, filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: etoac=1/1) and preparative HPLC (column: phenomenex luna C, 150, 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:37% -67%,10 min) to give an impure product which was further purified by trituration with MeOH (0.5 ml,20 ℃ for 5 min). The solid was collected by filtration and dissolved in MeCN (1 mL). To the solution was added water (15 mL) and it was lyophilized to give the product 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N-methylpiperazine-1-carboxamide (6.04 mg,10.36 μmol,36.05% yield, 99.3% purity) as a yellow solid.
RT 0.452 min (method) 5);m/z 579.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz)9.60(s,1H),8.88(s,1H),7.69(t,J＝52.8Hz,1H),6.84(s,1H),6.59-6.57(m,1H),4.22(d,J＝48.4Hz,2H),3.62-3.52(m,4H),3.14-2.99(m,4H),2.61(d,J＝4.4Hz,3H),0.90-0.84(m,2H),0.81-0.75(m,2H).
Example 178a preparation
(S) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate
A mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (100 mg,0.238 mmol), (S) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (191 mg,0.953 mmol), pd-PEPSI-IPentCl o-methylpyridine (23 mg,0.0238 mmol), CS 2CO3 (233 mg, 0.015 mmol) in dioxane (3 mL) was degassed and purged with N 2 (3 times). The mixture was stirred under an atmosphere of N 2 at 95 ℃ for 4 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether: etoac=2/1) to give the product (S) -tert-butyl 4- (3- (5- (difluoromethyl) -l,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (65 mg,0.105mmol,43.95% yield) as a yellow solid.
RT 0.537 min (method 5);m/z 528.2(M-56+H)+(ESI+);1H NMR(CDCI3,400MHz,):9.87(s,1H),7.73(s,1H),7.09(t,J＝54Hz,1H),6.65(s,1H),5.08(s,1H),4.47-4.44(m,1H),4.07(d,J＝13.2Hz,1H),3.62-3.34(m,2H),3.37(t,J＝12.8Hz,1H),3.08-2.94(m,2H),1.52(s,9H),1.47(d,J＝6.8Hz,3H),1.39(s,3H),0.94(s,2H),0.61(s,2H).
Example 178 preparation
(S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of (S) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (50 mg,0.0857 mmol) in HCl/dioxane (2.0 mL,0.0857mmol, 4N) was stirred at 20℃for 1 hour. After concentration under reduced pressure, the crude product was triturated with MeOH (0.5 mL) at 20℃for 5 min. The solid was collected by filtration and further purified by preparative HPLC (column: phenomenex Luna C18:150:25 mm x 5 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:18% -48%,10 min) and freeze dried directly to give the product (S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (35 mg,0.0661mmol,77.15% yield, FA salt) as a yellow solid.
RT 0.358 min (method) 3);m/z 484.3(M+H)+(ESI+);1H NMR(CDCI3,400MHz):9.87(s,1H),8.31(s,1H),7.70(s,1H),7.09(t,J＝54Hz,1H),6.70(s,1H),5.44-5.38(m,1H),3.66(t,J＝15.2Hz,2H),310 3.63-3.25(m,3H),3.12(t,J＝11.6Hz,1H),2.83(t,J＝11.6Hz,1H),1.38(s,3H),1.32(d,J＝6.4Hz,3H),0.95-0.92(m,2H),0.61-0.58(m,2H).
Example 179 preparation
(S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyryl-3-methylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulphonamide
To a solution of (S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (20 mg,0.0378mmol, FA salt) in THF (0.5 mL) and water (0.5 mL) was added NaHCO 3 (25 mg,0.302 mmol) and 2-methylpropanoyl chloride (8.0 mg,0.0755 mmol). The mixture was stirred at 0deg.C for 1 hour, then diluted with water (20 mL) and extracted with EtOAc (50 mL,3 times). The combined organic layers were washed with brine (25 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:44% -74%,10 min) and lyophilized directly to give the product (S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyryl-3-methylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (3.1 mg,0.00558mmol,14.77% yield) as a yellow solid.
RT 0.487 min (method) 3);m/z 554.4(M+H)+(ESI+);1H NMR(CDC3,400MHz):9.89(s,1H),7.74(s,1H),7.09(t,J＝54Hz,1H),6.66(s,1H),5.11(s,1H),5.06-486(m,0.5H),4.78-4.56(m,0.5H),4.47-4.21(m,0.5H),4.07-3.83(m,0.5H),3.62-3.75(m,2.5H),3.16-3.32(m,0.5H),2.90-3.11(m,2H),2.77-2.88(m,1H),1.49(br d,J＝7.60Hz,2H),1.40(s,3H),1.21(br d,J＝6.64Hz,7H),0.94(br s,2H),0.61(s,2H).
Example 180a preparation
(S) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-ethylpiperazine-1-carboxylate
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol) in dioxane (0.5 mL) was added (S) -tert-butyl 2-ethylpiperazine-1-carboxylate (31 mg,0.143 mmol), CS 2CO3 (70 mg,0.214 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (7.0 mg, 0.007115 mmol). The reaction mixture was degassed with N 2 (3 times), stirred at 98 ℃ for 1 hour and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate=1:1) to give the product (S) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-ethylpiperazine-1-carboxylate (25 mg,0.0387mmol,54.14% yield, 92.4% purity) as a yellow solid.
RT 0.597 min (method 4);m/z 620.2(M+Na)+(ESI+);1H NMR(CDCI3,400MHz):9.87(s,1H),7.72(s,1H),7.08(t,J＝54.0Hz,1H),6.65(s,1H),5.09(s,1H),4.30-4.14(m,2H),3.70-3.49(m,2H),3.38-3.19(m,1H),3.11-2.88(m,2H),2.15-2.07(m,1H),1.79-1.71(m,1H),1.51(s,9H),1.39(s,3H),1.00(t,J＝7.2Hz,3H),0.96-0.90(m,2H),0.64-0.57(m,2H).
Example 180 preparation
(S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-ethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of (S) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-ethylpiperazine-1-carboxylate (25 mg,0.0402 mmol) in DCM (0.5 mL) and TFA (0.1 mL) was stirred at 25℃for 1 h. The mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (column Phenomenex luna C18:150:25 mm x 10um; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:12% -42%,15 min) and lyophilized directly to give the product (S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-ethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (9.4 mg,0.0168mmol,41.79% yield, 97.8% purity, FA salt) as a yellow solid.
RT 0.366 min (method) 4);m/z 498.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.58(s,1H),8.43(br,1H),8.23(s,1H),7.96(s,1H),7.67(t,J＝53.2Hz,1H),6.67(s,1H),3.63-3.58(m,2H),3.11-3.04(m,1H),3.02-2.94(m,1H),2.89-2.78(m,2H),2.54-2.56(m,1H),1.46-1.42(m,2H),1.15(s,3H),0.96(t,J＝7.6Hz,3H),0.77-0.67(m,2H),0.47-0.42(m,2H).
Example 181a preparation
(R) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-ethylpiperazine-1-carboxylate
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol) in dioxane (0.5 mL) was added (R) -tert-butyl 2-ethylpiperazine-1-carboxylate (31 mg,0.143 mmol), CS 2CO3 (70 mg,0.214 mmol) and Pd-PEPPI-IPentCl o-methylpyridine (7.0 mg, 0.007115 mmol). The reaction mixture was degassed with N 2 (3 times), then stirred at 98 ℃ for 1 hour and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: ethyl acetate=1:1) to give the product (R) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-ethylpiperazine-1-carboxylate (20 mg,0.0333mmol,46.56% yield, 99.4% purity) as a yellow solid.
RT 0.591 min (method 4),m/z 620.1(M+Na)+(ESI+);1H NMR(CDCI3,400MHz)9.87(s,1H),7.72(s,1H),7.08(t,J＝53.6Hz,1H),6.64(s,1H),5.09(s,1H),4.28-4.14(m,2H),3.70-3.49(m,2H),3.38-3.19(m,1H),3.11-2.88(m,2H),2.15-2.07(m,1H),1.82-1.71(m,1H),1.51(s,9H),1.39(s,3H),1.00(t,J＝7.6Hz,3H),0.96-0.90(m,2H),0.64-0.58(m,2H).
Example 181 preparation
(R) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-ethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A mixture of (R) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-ethylpiperazine-1-carboxylate (20 mg,0.0335 mmol) in DCM (0.2 mL) and TFA (0.04 mL) was stirred at 25℃for 1 hour. The mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm x 10um; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:13% -43%,10 min) and lyophilized directly to give the product (R) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (3-ethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (7.6 mg, 0.01333 mmol,39.57% yield, 95.6% purity, FA salt) as a yellow solid.
RT 0.363 min (method 4);m/z 498.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.57(s,1H),8.43(br,1H),8.19(s,1H),7.97(s,1H),7.67(t,J＝53.2Hz,1H),6.67(d,J＝0.8Hz,1H),3.63-3.60(m,2H),3.11-3.04(m,1H),3.02-2.94(m,1H),2.89-2.78(m,2H),2.56(br d,J＝10.8Hz,1H),1.51-1.42(m,3142H),1.14(s,3H),0.96(t,J＝7.6Hz,3H),0.75-0.69(m,2H),0.47-0.42(m,2H).
Preparation of intermediate 182.1
4- ((2- (Dimethylamino) ethyl) (methyl) carbamoyl) piperazine-1-carboxylic acid tert-butyl ester
To a solution of N 1,N1,N2 -trimethylethane-1, 2-diamine (80 mg,0.783 mmol) and DIEA (0.27 mL,1.57 mmol) in DCM (4 mL) was added a solution of tert-butyl 4- (chlorocarbonyl) piperazine-1-carboxylate (234 mg,0.94 mmol) in DCM (1 mL) at 0deg.C. The reaction mixture was stirred at 20 ℃ for 15 minutes and then concentrated in vacuo. The resulting residue was diluted with saturated NaHCO 3 (20 mL) and extracted with EtOAc (20 mL,2 times). The combined organic layers were washed with brine (20 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo to give tert-butyl 4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) piperazine-1-carboxylate (200 mg,0.496mmol,63.37% yield) as a white solid.
1H NMR(CDCl3,400MHz)3.40-3.45(m,4H),3.30-3.37(m,2H),3.13-3.21(m,4H),2.89(s,3H),2.49-2.57(m,2H),2.29(s,6H),1.46(s,9H).
Preparation of intermediate 182.2
N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide hydrochloride
A mixture of tert-butyl 4- ((2- (dimethylamino) ethyl) (methyl) carbamoyl) piperazine-1-carboxylate (80 mg,0.254 mmol) in HCl/dioxane (1.5 mL,0.254 mmol) was stirred at 25℃for 2 hours. The resulting mixture was concentrated in vacuo. The residue was triturated with MTBE at 20 ℃ for 1 min. The resulting suspension was allowed to stand for a moment, and then the supernatant was discarded (3 times). The solid was collected and dried under reduced pressure to give N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide hydrochloride (46 mg,0.165mmol,64.89% yield, HCl salt) as a colorless oil.
Example 182 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol) in 1, 4-dioxane (1 mL) was added N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide (36 mg,0.143mmol, hcl salt), CS 2CO3 (47 mg,0.143 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (7.0 mg, 0.007115 mmol). The mixture was degassed, purged with N 2 (3 times) and stirred under an atmosphere of N 2 at 100 ℃ for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm x 10um; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:15% -45%,10 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) -l,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide (5.8 mg,0.00956mmol,13.38% yield) as a yellow solid.
RT 0.361 min (method) 4);m/z 598.0(M+H)+(ESI+);1H NMR(CDCI3,400MHz)9.88(s,1H),7.71(s,1H),7.08(t,J＝53.6Hz,1H),6.67(s,1H),5.27(s,1H),3.51-3.55(m,4H),3.44(t,J＝6.8Hz,2H),3.33-3.37(m,4H),2.98(s,3H),2.68(t,J＝7.2Hz,2H),2.41(s,6H),1.38(s,3H),0.91-0.95(m,2H),0.57-0.62(m,2H)
Example 183a preparation
3- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-diazabicyclo [3.2.1] octane-6-carboxylic acid tert-butyl ester
A mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.119 mmol), tert-butyl 3, 6-diazabicyclo [3.2.1] octane-6-carboxylate (51 mg,0.238 mmol), pd-PEPSI-IPentCl o-methylpyridine (12 mg,0.0119 mmol) and CS 2CO3 (116 mg, 0.357mmol) in dioxane (1 mL) was degassed, purged with N 2 (3 times) and stirred at 95℃for 4 hours under an atmosphere of N 2. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/etoac=1/1) to give the product 3- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-diazabicyclo [3.2.1] octane-6-carboxylic acid tert-butyl ester (13 mg,0.0199mmol,16.68% yield) as a yellow solid.
RT 0.516 min (method 3); m/z 596.1 (M+H) +(ESI+);
Example 183 preparation
8- (3, 6-Diazabicyclo [3.2.1] oct-3-yl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
To a solution of tert-butyl 3- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -3, 6-diazabicyclo [3.2.1] octane-6-carboxylate (10 mg,0.0168 mmol) in DCM (0.5 mL) was added TFA (1.1 mL,1.32 mmol) at room temperature. The reaction mixture was stirred at 25 ℃ for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid; B%:11% -41%,5 min) to give the product 8- (3, 6-diazabicyclo [3.2.1] oct-3-yl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -imidazo [1,5-a ] pyridine-6-sulfonamide formate (2.3 mg,0.00408mmol,24.29% yield, FA salt) as a yellow solid.
RT 0.338 min (method 3); m/z 496.1 (M+H) +(ESI+);
1H NMR(D20,400MHz):9.42(s,1H),8.39(s,1H),7.84(s,1H),7.28(t,J＝53.6Hz,1H),6.59(s,1H),4.29(s,1H),3.92(d,J＝12.4Hz,1H),3.71(d,J＝11.6Hz,2H),3.46-3.31(m,1H),3.24(d,J＝12.6Hz,1H),3.11(d,J＝12.0Hz,1H),2.90(s,1H),2.12(s,2H),1.13(s,3H),0.72(m,2H),0.46(m,2H).
it should be noted that the compound may be a combination of isomers.
Example 184a preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (100 mg,0.228 mmol) in water (0.2 mL) and t-BuOH (2.0 mL) was added K 3PO4(48mg,0.228mmol)、cataCXium A-Pd-G3 (17 mg,0.0228 mmol), 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (212 mg,0.685 mmol) at room temperature. The mixture was stirred at 60 ℃ for 16 hours, then diluted with water (20 mL) and extracted with EtOAc (50 mL,3 times). The combined organic layers were washed with brine (25 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/etoac=2/1) to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (160 mg,0.271mmol,118.63% yield) as a yellow solid.
RT 0.517 min (method 3); m/z 585.1 (M+H) +(ESI+)
Example 184b preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
To a solution of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (160 mg, 0.271mmol) in MeCN (2 mL) at 20 ℃ was added NCS (181 mg,1.35 mmol). The mixture was stirred at 20 ℃ for 16 hours, then diluted with NaHCO 3 (saturated aqueous solution, 20 mL) and extracted with EtOAc (30 mL,3 times). The combined organic layers were washed with brine (30 ml,2 times), dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/etoac=2/1) to give the product tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate (100 mg,0.145mmol,53.66% yield) as a yellow solid.
RT 0.540 min (method 3);m/z 619.1(M+H)+(ESI+);1H NMR(CDCI3,400MHz):10.13(d,J＝0.88Hz,1H),7.22-6.95(m,2H),5.88(brs,1H),5.54(s,1H),4.28(d,J＝48.4Hz,2H),4.12(m,2H),3.74(t,J＝5.4Hz,2H),2.50(br s,2H),1.53(s,9H),1.12-1.20(m,2H),0.86-0.93(m,2H).
Example 184 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (100 mg,0.162 mmol) in HCl/dioxane (2.0 mL,0.162 mmol) was stirred at 25℃for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:15% -45%,10 min) to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (1, 2,3, 6-tetrahydropyridin-4-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (27 mg,0.0467mmol,28.92% yield, FA salt) as a yellow solid.
RT 0.540 min (method 3);m/z 519.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.82(s,1H),8.26(s,1H),7.70(t,J＝53.2Hz,1H),7.13(s,1H),5.92(brs,1H),4.24(d,J＝48.6Hz,2H),3.54(brs,2H),3.13(br s,2H),2.40(br s,2H),0.82-0.92(m,2H),0.70-0.81(m,2H).
Example 185 preparation
1-Chloro-8- (4-cyclopropylpiperazin-1-yl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulphonamide formate salt
To a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg, 63.52. Mu. Mol) in dioxane (1 mL) was added 1-cyclopropylpiperazine (16.03 mg, 127.04. Mu. Mol), CS 2CO3 (41.39 mg, 127.04. Mu. Mol) and Pd-PEPSI-IPentCl o-methylpyridine (6.18 mg, 6.35. Mu. Mol). The mixture was degassed with N 2 (3 times), stirred under nitrogen at 90 ℃ for 20 min, cooled to 25 ℃, filtered, and the filtrate concentrated in vacuo. The residue was purified by preparative TLC (EtOAc: petroleum ether=1:1) to give the impure product which was further purified by preparative HPLC (column: unisil-100 C18 Ultra 150*25mm*10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:20% -50%,10 min) and lyophilized directly to give the product 1-chloro-8- (4-cyclopropylpiperazin-1-yl) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (5.55 mg,9.01 μmol,14.18% yield, 98.67% purity, FA salt) as a yellow solid.
RT 0.354 min (method) 3),m/z 562.2(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.58(d,J＝0.8Hz,1H),8.89(br s,1H),8.25(s,1H)7.68(t,J＝53.2Hz,1H),6.79(d,J＝0.8Hz,1H),4.22(d,J＝48.8Hz,2H),3.13-2.94(m,4H),2.90-2.71(m,4H),1.82-1.69(m,1H),0.92-0.82(m,2H),0.81-0.72(m,2H),0.53-0.42(m,2H),0.42-0.31(m,2H).
Example 186a preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylic acid tert-butyl ester
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg, 114.20. Mu. Mol) in dioxane (2 mL) was added tert-butyl piperazine-1-carboxylate (42.54 mg, 228.39. Mu. Mol), CS 2CO3 (74.41 mg, 228.39. Mu. Mol) and Pd-PEPPI-IPentCl o-methylpyridine (11.11 mg, 11.42. Mu. Mol) at room temperature. The mixture was degassed with N 2 (3 times), stirred under nitrogen at 90 ℃ for 1 hour, cooled to 25 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC (EtOAc: petroleum ether=2:1) to give the product tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylate ((50 mg,75.73 μmol,33.16% yield, 89% purity) as a yellow solid.
RT 0.531 min (method 3),m/z 588.2(M+H)+(ESI+),1H NMR(CDCl3,400MHz):9.89(s,1H),7.72(s,1H),7.08(t,J＝53.6Hz,1H),6.64(s,1H),5.49(s,1H),4.27(d,J＝48.4Hz,2H),3.76-3.64(m,4H),3.39-3.23(m,4H),1.52(s,9H),1.20-1.13(m,2H),0.93-0.84(m,2H).
Example 187 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylate (45 mg, 76.58. Mu. Mol) in HCl/dioxane (4M, 1 mL) was stirred at 25℃for 1 hour and concentrated in vacuo. The residue was purified by preparative HPLC (column: unisil-100 C18 Ultra150*25mm*10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:12% -42%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (22.23 mg, 40.19. Mu. Mol,52.48% yield, 96.45% purity, FA salt) as a yellow solid.
RT 0.324 min (method) 3);m/z 488.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.56(s,1H),8.92-8.71(m,1H),8.23(s,1H),7.99(s,1H),7.67(t,J＝53.2Hz,1H),6.67(s,1H),4.22(d,J＝48.4Hz,2H),3.25-3.20(m,4H),3.05-2.92(m,4H),0.88-0.81(m,2H),0.80-0.74(m,2H).
Example 188 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (4-isobutyrylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulphonamide
To a solution of 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg, 30.77. Mu. Mol, FA salt) in THF (0.5 mL) and H 2 O (0.5 mL) at 0deg.C was added NaHCO 3 (25.85 mg, 307.68. Mu. Mol) followed by isobutyryl chloride (4.92 mg, 46.15. Mu. Mol, 4.82. Mu. L). The mixture was stirred at 25℃for 1 hour, then poured into water (10 mL) and extracted with EtOAc (10 mL;2 times). The organic layer was collected, dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: etoac=1:1) to give an impure product which was further purified by trituration with MeOH (2 mL) at 25 ℃ for 20 min. After filtration, the filter cake was collected and dried in vacuo to give the product 3- (5- (difluoromethyl) -l,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (4-isobutyrylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (6.43 mg,11.35 μmol,36.90% yield, 98.46% purity) as a yellow solid.
RT 0.485 min (method) 3);m/z 558.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.91-9.90(m,1H),7.74(s,1H),7.08(t,J＝53.2Hz,1H),6.65(d,J＝1.2Hz,1H),5.50(s,1H),4.27(d,J＝48.8Hz,2H),3.98-3.75(m,4H),3.45-3.25(m,4H),2.90-2.78(m,1H),1.20(d,J＝6.8Hz,6H),1.18-1.14(m,2H),0.90-0.86(m,2H).
Example 189a preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylic acid tert-butyl ester
To a solution of 1, 8-dichloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.110 mmol) in dioxane (2 mL) was added tert-butyl piperazine-1-carboxylate (41 mg,0.220 mmol), pd-PEPSI-IPentCl o-methylpyridine (11 mg, 0.011200 mmol) and CS 2CO3 (90 mg,0.275 mmol). The mixture was degassed with N 2 (3 times), stirred under nitrogen at 90 ℃ for 1 hour, cooled to 25 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC (EtOAc: petroleum ether=2:1) to give the product tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylate (18 mg,0.0275mmol,24.99% yield) as a yellow solid.
RT 0.535 min (method 3),m/z 604.0(M+H)+(ESI+),1H NMR(CDCl3,400MHz):9.90(s,1H),7.08(t,J＝54.0Hz,1H),6.73(s,1H),5.07(s,1H),3.84-3.58(m,4H),3.24-3.02(m,4H),1.51(s,9H),1.39(s,3H),0.94-0.90(m,2H),0.63-0.61(m,2H).
Example 189 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) piperazine-1-carboxylate (12 mg,0.0199 mmol) in HCl/dioxane (4M, 1 mL) was stirred at 25℃for 16 h. The reaction mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:15% -45%,10 min) and lyophilized directly to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (7.26 mg,0.0132mmol,66.45% yield, FA salt) as a yellow solid.
RT 0.340 min (method) 3);m/z 504.1(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.61(s,1H),8.61-8.44(m,1H),8.20(s,1H),7.69(t,J＝53.2Hz,1H),6.81(s,1H),3.08-3.02(m,4H),3.02-2.97(m,4H),1.18(s,3H),0.82-0.66(m,2H),0.56-0.36(m,2H).
Example 190a preparation
2- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-diazaspiro [3.4] octane-6-carboxylic acid tert-butyl ester
To a solution of 1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.110 mmol) in dioxane (0.5 mL) was added tert-butyl 2, 6-diazaspiro [3.4] octane-6-carboxylate (47 mg,0.220 mmol), CS 2CO3 (108 mg,0.330 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (11 mg, 0.01750 mmol) at room temperature. The mixture was degassed with N 2 (3 times), stirred under nitrogen at 98 ℃ for 1 hour, cooled to 25 ℃ and filtered.
The filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC (EtOAc: petroleum ether=1:1) to give the product tert-butyl 2- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-diazaspiro [3.4] octane-6-carboxylate (32 mg,0.0486mmol,44.14% yield) as a yellow solid.
RT 0.531 min (method 3),m/z 630.3(M+H)+(ESI+),1H NMR(CDCl3,400MHz):9.82(s,1H),7.08(t,J＝53.6Hz,1H),6.60(s,1H),5.08(s,1H),4.04-3.98(m,2H),3.98-3.91(m,2H),3.61(s,2H),3.51(t,J＝6.8Hz,2H),2.29(t,J＝6.8Hz,2H),1.46(s,9H),1.39(s,3H),0.97-0.90(m,2H),0.65-0.55(m,2H).
Example 190 preparation
1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2, 6-diazaspiro [3.4] oct-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
To a solution of tert-butyl 2- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-diazaspiro [3.4] octane-6-carboxylate (32 mg,0.0486 mmol) in DCM (0.5 mL) was added TFA (0.1 mL,0.250 mmol) at 0 ℃. The mixture was stirred at 25 ℃ for 30 minutes and then concentrated in vacuo. The residue was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:16% -46%,10 min) and lyophilized directly to give the product 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (2, 6-diazaspiro [3.4] oct-2-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (9.97 mg,0.0167mmol,34.47% yield, FA salt) as a yellow solid.
RT 0.340 min (method) 3);m/z 530.0(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.55(s,1H),9.01-8.11(m,2H),7.69(t,J＝53.2Hz,1H),6.67(s,1H),3.93-3.79(m,4H),3.64-3.58(m,4H),2.26(t,J＝6.8Hz,2H),1.18(s,3H),0.77-0.67(m,2H),0.49-0.39(m,2H).
Example 191a preparation
(S) -tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate
To a solution of 1, 8-dichloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.110 mmol) in dioxane (2 mL) was added (S) -tert-butyl 2-methylpiperazine-1-carboxylate (88 mg,0.440 mmol), CS 2CO3 (108 mg,0.330 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (11 mg,0.0110 mmol). The mixture was degassed with N 2 (3 times), stirred under nitrogen at 98 ℃ for 1 hour, cooled to 25 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC (ethyl acetate: petroleum ether=1:1) to give the product (S) -tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol 2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (10 mg,0.0121mmol,10.96% yield, 74.56% purity) as a yellow solid.
RT 0.552 min (method 4), M/z 618.2 (M+H) +(ESI+.
Example 191 preparation
(S) -1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
To a solution of (S) -tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (8.0 mg,0.00965 mmol) in DCM (1.5 mL) was added TFA (0.3 mL). The mixture was stirred at 25 ℃ for 1 hour and then concentrated in vacuo. The residue was purified by preparative HPLC (column Phenomenex luna C, 150, 25mm x 10um; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:16% -46%,10 min) and lyophilized directly to give the product (S) -1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (1.38 mg,0.00243mmol,25.17% yield, 99.28% purity, FA salt) as a yellow solid.
RT 0.377 min (method 4);m/z 518.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.91(s,1H),8.26(s,1H),7.08(t,J＝53.6Hz,1H),6.81(s,1H),5.44(s,1H),3.56-3.26(m,5H),3.18-3.03(m,1H),2.88-2.69(m,1H),1.38(s,3H),1.35(d,J＝6.0Hz,3H),0.96-0.90(m,2H),0.65-0.58(m,2H).
Example 192a preparation
(R) -tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate
To a solution of 1, 8-dichloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.110 mmol) in dioxane (2 mL) was added (R) -tert-butyl 2-methylpiperazine-1-carboxylate (88 mg,0.440 mmol), CS 2CO3 (108 mg,0.330 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (11 mg,0.0110 mmol). The mixture was degassed with N 2 (3 times), stirred at 98 ℃ for 1 hour under an atmosphere of N 2, cooled to 25 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC (ethyl acetate: petroleum ether=1:1) to give the product (R) -tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol 2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (10 mg,0.0148mmol,13.45% yield, 91.50% purity) as a yellow solid.
RT 0.546 min (method 4), M/z 618.2 (M+H) +(ESI+.
Example 192 preparation
(R) -1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide 2, 2-trifluoroacetate salt
To a solution of (R) -tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (8.0 mg,0.0118 mmol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred at 25 ℃ for 1 hour and concentrated in vacuo. The resulting residue was purified by preparative HPLC (column Phenomenex luna C, 150 x 25mm x 10um; mobile phase: a:0.1% aqueous TFA, B: meCN; B%:25% -55%,10 min) and lyophilized directly to give the product (R) -1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide 2, 2-trifluoroacetate (7.33 mg,0.00978mmol,82.56% yield, 99.51% purity, 2TFA salt) as a yellow solid.
RT 0.383 min (method) 4);m/z 518.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):10.01(br,1H),9.94(s,1H),9.37(br,1H),7.09(t,J＝53.6Hz,1H),6.89(s,1H),5.93(s,1H),3.85-3.70(m,1H),3.69-3.51(m,3H),3.50-3.24(m,2H),3.19-3.03(m,1H),1.51(d,J＝6.4Hz,3H),1.35(s,3H),1.01-0.82(m,2H),0.66-0.49(m,2H).
Preparation of intermediate 193.1
1, 8-Dichloro-3- (5- (difluoromethyl) thiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride
To a mixture of 2- (6- (benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) thiazole (65 mg, 159.36. Mu. Mol) in MeCN (2 mL) was added AcOH (19.14 mg, 318.72. Mu. Mol, 18.23. Mu.L) and H 2 O (5.74 mg, 318.72. Mu. Mol, 5.74. Mu.L) at room temperature. The mixture was cooled to-10℃and sulfuryl dichloride (75.28 mg, 557.75. Mu. Mol, 55.76. Mu.L) was added. The reaction mixture was stirred at-10 ℃ for 1 hour, then quenched with ice water (8 mL). The yellow precipitate was collected by filtration and dried in vacuo to give the crude product 1, 8-dichloro-3- (5- (difluoromethyl) thiazol-2-yl) imidazo [1,5-a ] pyridine-6-sulfonyl chloride (65 mg, crude) which was used in the next step without any further purification.
Example 193 preparation
1, 8-Dichloro-3- (5- (difluoromethyl) thiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1- (fluoromethyl) cyclopropylamine (22.50 mg, 138.83. Mu. Mol, HCl salt) in DCM (1 mL) was added DIEA (46.31 mg, 358.29. Mu. Mol, 62.41. Mu. L) and 1, 8-dichloro-3- [5- (difluoromethyl) thiazol-2-yl ] imidazo [1,5-a ] pyridine-6-sulfonyl chloride (50 mg, 119.43. Mu. Mol) at-10 ℃. The reaction mixture was stirred at-10℃for 2 hours, then quenched with brine (5 mL) and NaHCO 3 (saturated aqueous, 5 mL) and extracted with EtOAc (12 mL;2 times). The organic layers were separated, combined, dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/etoac=3/1) to give the product 1, 8-dichloro-3- [5- (difluoromethyl) thiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] imidazo [1,5-a ] pyridine-6-sulfonamide (35 mg,69.65 μmol,58.32% yield, 93.79% purity) as a yellow solid.
RT 0.531 min (method 3); m/z 471.0 (M+H) +(ESI+)
Example 194 preparation
4- (1-Chloro-3- (5- (difluoromethyl) thiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
And example 195 preparation
4- (3- (5- (Difluoromethyl) thiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
A mixture of 1, 8-dichloro-3- [5- (difluoromethyl) thiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg, 42.44. Mu. Mol), N-dimethylpiperazine-1-carboxamide (13.34 mg, 84.87. Mu. Mol), pd-PEPSI-IPentCl o-methylpyridine (3.65 mg, 4.24. Mu. Mol) and CS 2CO3 (41.48 mg, 127.31. Mu. Mol) in dioxane (0.5 mL) was degassed with N 2 (3 times). Then, the mixture was stirred at 90 ℃ for 1 hour, then cooled to room temperature, filtered and the filtrate concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: etoac=0:1) to give the product 4- (1-chloro-3- (5- (difluoromethyl) thiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (2.64 mg,4.22 μmol,9.94% yield, 94.74% purity) as a yellow solid, and the impure fraction (10 mg,80% purity) was further purified by preparative HPLC (column: unisil-100 C18 Ultra 150*50mm*3 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN;38% -68%,10 min) and lyophilized directly to give the product 4- (3- (5- (difluoromethyl) thiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (0.87 mg, 0.33% yield, 498% mmol) as a yellow solid.
4- (1-Chloro-3- (5- (difluoromethyl) thiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
RT 0.492 min (method) 3);m/z 592.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.95(s,1H),8.07(s,1H),6.97(t,J＝55.2Hz,1H),6.60(s,1H),5.45(s,1H),4.26(d,J＝52.4Hz,2H),3.62-3.43(m,4H),3.27-3.06(m,4H),2.90(s,6H),1.13-1.12(m,2H),0.87-0.84(m,2H).
4- (3- (5- (Difluoromethyl) thiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
RT 0.459 min (method 3),m/z 558.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz),9.94(s,1H),8.07(s,1H),7.63(s,1H),6.97(t,J＝53.2Hz,1H),6.53(s,1H),5.45(s,1H),4.26(d,J＝48.4Hz,2H),3.61-3.43(m,4H),3.42-3.22(m,4H),2.91(s,6H),1.14-1.11(m,2H),0.86-0.81(m,2H).
Example 196 preparation
1-Chloro-3- (5- (difluoromethyl) thiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 1, 8-dichloro-3- [5- (difluoromethyl) thiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg, 31.83. Mu. Mol) in dioxane (0.5 mL) was added 2-oxa-7-azaspiro [3.5] nonane (8.10 mg, 63.65. Mu. Mol), CS 2CO3 (31.11 mg, 95.48. Mu. Mol) and Pd-PEPPSI-IPentCl o-methylpyridine (2.74 mg, 3.18. Mu. Mol), and the reaction mixture was degassed with N 2 (3 times). The mixture was stirred at 90 ℃ for 30 minutes, then cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc: petroleum ether=3:1) followed by preparative HPLC (column: phenomenex luna C, 150, 25mm x10 μm; mobile phase: a:0.225% aqueous formic acid; B: meCN; B%:50% -80%,10 min) and freeze-dried to give the product 1-chloro-3- [5- (difluoromethyl) thiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (1.71 mg,2.83 μmol,8.89% yield, 93.04% purity) as a yellow solid.
RT 0.514 min (method 3),m/z 562.3(M+H)+(ESI+);1H NMR(CDCI3,400MHz),9.92(s,1H),8.06(s,1H),6.97(t,J＝55.2Hz,1H),6.56(s,1H),5.44(s,1H),4.53(s,4H),4.25(d,J＝48.4,2H),3.16-2.93(m,4H),2.31-2.06(m,4H),1.13-1.11(m,2H),0.87-0.82(m,2H).
Example 197a preparation
(R) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (80 mg,0.191 mmol) in dioxane (1.5 mL) was added tert-butyl (R) -2-methylpiperazine-1-carboxylate (153 mg, 0.282 mmol), CS 2CO3 (217 mg,0.667 mmol) and Pd-PEPPI-IPentCl o-methylpyridine (19 mg,0.0191 mmol). The mixture was degassed and purged with N 2 (3 times) then stirred under an atmosphere of N 2 at 90 ℃ for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: etoac=2:1) to give the product (R) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (28 mg,0.0437mmol,31.85% yield) as a yellow solid.
RT 0.539 min (method 3);m/z 584.4(M+H)+(ESI+);1H NMR(CDCl3,400MHz)9.87(s,1H),7.73(s,1H),7.08(t,J＝53.6Hz,1H),6.64(s,1H),5.10(s,1H),4.46(br s,1H),4.08(d,J＝12.8Hz,1H),3.62-3.53(m,2H),3.40-3.33(m,1H),3.07-2.95(m,2H),1.51(s,9H),1.47(d,J＝6.8Hz,3H),1.39(s,3H),0.97-0.90(m,2H),0.65-0.57(m,2H).
Example 197 preparation
(R) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A mixture of (R) -tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (28 mg,0.0480 mmol) in HCl/dioxane (1.0 mL,4.00mmol, 4N) was stirred at 25℃for 1 hour and then concentrated in vacuo. The crude product was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*25mm*10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:12% -42%,10 min) and lyophilized directly to give the product (R) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (1.4 mg,0.00258mmol,5.38% yield, FA salt) as a yellow solid.
RT 0.369 min (method) 3);m/z 484.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.87(s,1H),8.30(br 1H),7.70(s,1H),7.08(t,J＝53.6Hz,1H),6.69(s,1H),5.35(s,1H),3.69-3.61(m,2H),3.32-3.27(m,2H),3.12-3.06(m,2H),2.81-2.76(m,1H),1.38(s,3H),1.29(d,J＝6.4Hz,3H),0.95-0.92(m,2H),0.61-0.58(m,2H).
Example 198 preparation
(R) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyryl-3-methylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [15-a ] pyridine-6-sulphonamide
To a mixture of (R) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (22 mg,0.0414 mmol) in THF (0.5 mL) and water (0.5 mL) was added 2-methylpropanoyl chloride (8.8 mg,0.0827 mmol) and NaHCO 3 (3.5 mg,0.0414 mmol) at 0deg.C. The reaction mixture was stirred at 0deg.C for 15 min, then quenched with water (6 mL) and extracted with EtOAc (6 mL;2 times). The organic layers were separated, combined, dried over anhydrous Na 2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (column: unisil-100 C18Ultra 150*25mm*10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:45% -75%,10 min) and lyophilized directly to give the product (R) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4-isobutyryl-3-methylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (3.3 mg,0.00578mmol,13.98% yield) as a yellow solid.
RT 0.483 min (method 1),m/z 554.4(M+H)+(ESI+),1H NMR(CDCl3,400MHz)9.88(s,1H),7.74(br,1H),7.08(t,J＝53.6Hz,1H),6.65(s,1H),5.09(s,1H),5.00-4.46(m,1H),4.39-3.88(m,1H),3.68-3.61(m,2H),3.02-2.97(m,2H),2.96-2.86(m,1H),1.49-1.48(m,1H),1.39(s,3H),1.27-1.05(m,9H),,0.97-0.89(m,2H),0.58-0.63(m,2H).
Example 199 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0685 mmol) in dioxane (0.5 mL) was added 2-oxa-7-azaspiro [3.5] nonane (17 mg,0.137 mmol), pd-PEPPSI-IPentCl o-picoline (5.9 mg,0.00685 mmol) and CS 2CO3 (67 mg,0.206 mmol). The reaction mixture was degassed with N 2 (3 times), stirred at 90 ℃ for 30min, and then concentrated in vacuo. The resulting residue was diluted with MeOH (3 mL), filtered, and the filtrate was purified by preparative HPLC (column: phenomenex luna C18.150X 25mm X10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:40% -70%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (2-oxa-7-azaspiro [3.5] non-7-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (2.8 mg,0.00518mmol,7.55% yield) as a yellow solid.
RT 0.458 min (method 1);m/z 529.3(M+H)+(ESI+),1H NMR(CDCl3,400MHz)9.85(s,1H),7.70(s,1H),7.08(t,J＝54.0Hz,1H),6.61(s,1H),5.47(s,1H),4.54(s,4H),4.26(d,J＝48.4Hz,2H),3.27-3.24(m,4H),2.16-2.14(m,4H),1.18-1.14(m,2H),0.88-0.85(m,2H).
Preparation of example 200 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (4-isobutyrylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulphonamide
To a solution of 1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (15 mg, 28.74. Mu. Mol, sold by FA) in THF (0.5 mL) and H 2 O (0.25 mL) at 0deg.C was added K 2CO3 (11.92 mg, 86.21. Mu. Mol) followed by isobutyryl chloride (6.12 mg, 57.47. Mu. Mol, 6.00. Mu.L). The mixture was stirred at 25 ℃ for 1 hour, then diluted with brine (15 mL) and extracted with EtOAc (7 mL,3 times). The organic layers were separated, combined, dried over anhydrous Na 2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% formic acid in water, B: meCN; B%:40% -70%,10 min) and lyophilized to give the product 1-chloro-3- (5- (difluoromethyl) -l,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (4-isobutyrylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (5.26 mg, 8.53. Mu. Mol,29.68% yield, 96% purity) as a yellow solid.
RT 0.499 min (method) 3);m/z 592.3(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.92(s,1H),7.09(t,J＝53.6Hz,1H),6.73(s,1H),5.52(s,1H),4.27(d,J＝48.4Hz,2H),3.65-3.41(m,4H),3.27-3.17(m,4H),2.88-2.81(m,1H),1.20(s,3H),1.19(s,3H),1.18-1.14(m,2H),0.91-0.82(m,2H).
The compounds listed in the following table were prepared according to the corresponding general procedure or, when illustrated in a similar manner as the related compounds, starting from the corresponding intermediates.
Example 278 preparation
4- (1-Chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide
To a solution of1, 8-dichloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0660 mmol) in dioxane (1 mL) was added N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide hydrochloride (33 mg,0.132mmol, HCl salt), cs 2CO3 (54 mg,0.165 mmol) and Pd-PEPPPSI-IPentCl o-methylpyridine (6.4 mg,0.0066 mmol). The mixture was degassed and purged with N 2 (3 times) then stirred under an atmosphere of N 2 at 100 ℃ for 2 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm. 10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:20% -50%,10 min) and lyophilized to give the product 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N- (2- (dimethylamino) ethyl) -N-methylpiperazine-1-carboxamide (5.4 mg, 0.008231 mmol,12.4% yield) as a yellow solid.
RT 0.415 min (method 4);m/z 632.3(M+H)+(ESI+),1H NMR(CDCl3,400MHz):9.89(s,1H),7.08(t,J＝53.6Hz,1H),6.76(s,1H),5.34(br,1H),3.61-3.51(m,4H),3.48(t,J＝6.8Hz,2H),3.25-3.15(m,4H),2.98(s,3H),2.76(t,J＝6.8Hz,2H),2.47(s,6H),1.38(s,3H),0.94-0.90(m,2H),0.63-0.58(m,2H).
Example 279a preparation
Tert-butyl-3- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid ester
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (100 mg,0.238 mmol) in tert-butanol (2 mL) was added water (0.2 mL), K 3PO4 (51 mg,0.238 mmol), cataCXium A-Pd-G3 (17 mg,0.0238 mmol) and 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylic acid tert-butyl ester (240 mg, 0.015 mmol). The mixture was stirred under an atmosphere of N 2 at 60℃for 16 hours. The resulting mixture was concentrated and the residue was purified by preparative TLC (petroleum ether: ethyl acetate=2:1) to give the product tert-butyl-3- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (35 mg,0.0555mmol,23.3% yield) as a yellow solid.
RT 0.550 min (method) 4);m/z 593.1(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.84(s,1H),8.50(s,1H),8.03(s,1H),7.69(t,J＝53.2Hz,1H),7.26(s,1H),6.86(d,J＝5.2Hz,1H),4.46-4.52(m,1H),4.35-4.43(m,1H),3.03-3.18(m,1H),2.28-2.35(m,1H),2.01-2.12(m,2H),1.75-1.88(m,2H),1.41(s,9H),1.15(s,3H),0.67-0.74(m,2H),0.48-0.44(m,2H).
Example 279b preparation
Tert-butyl-3- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate
To a solution of tert-butyl-3- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (35 mg,0.0591 mmol) in MeCN (1.2 mL) was added NCS (13 mg,0.094 mmol) at 25 ℃. The mixture was stirred at 25℃for 18 hours. NCS (6.5 mg,0.0472 mmol) was added to the solution, and the mixture was stirred for 16 hours. The resulting solution was diluted with water (10 mL) and extracted with EtOAc (15 mL,3 times). The combined organic phases were washed with brine (15 ml,2 times), dried over anhydrous Na 2SO4, filtered, and the filtrate concentrated in vacuo to give the product tert-butyl-3- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (32 mg,0.0459mmol,77.77% yield) as a yellow solid.
RT 0.577 min (method 4);m/z 571.0(M-56+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.83(s,1H),8.56(s,1H),7.70(t,J＝53.2Hz,1H),7.10(s,1H),6.25(d,J＝5.2Hz,1H),4.45(t,J＝5.2Hz,1H),4.37-4.28(m,1H),2.26-2.16(m,2H),2.08-2.00(m,2H),1.96-2.03(m,2H),1.43(s,9H),1.23(s,3H),0.72(m,2H),0.47(m,2H).
Example 279 preparation
8-Azabicyclo [3.2.1] oct-2-en-3-yl) -1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of tert-butyl-3- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -8-azabicyclo [3.2.1] oct-2-ene-8-carboxylate (25 mg,0.0399 mmol) in TFA (1.0 mL) and DCM (0.5 mL) was stirred at 25℃for 1 hour. The mixture was concentrated and the residue was purified by reverse phase HPLC (column: phenomenex luna C, 150 x 25mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:14% -44%,10 min) to give the product 8-azabicyclo [3.2.1] oct-2-en-3-yl) -1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (5.0 mg,0.00867mmol,21.76% yield, FA salt) as a yellow solid.
RT 0.393 min (method 4);m/z 527.1(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.84(s,1H),8.57(br,1H),8.31(s,1H),7.70(t,J＝53.2Hz,1H),7.15(s,1H),6.17(d,J＝5.2Hz,1H),3.89-3.82(m,2H),2.89-2.78(m,1H),2.14-2.24(m,1H),2.11-1.99(m,2H),1.92-1.81(m,2H),1.19(s,3H),0.74-0.72(m,2H),0.52-0.50(m,2H).
Preparation of intermediate 280.1
4- (2-Chloropropionyl) piperazine-1-carboxylic acid benzyl ester
To a solution of benzyl piperazine-1-carboxylate (2.00 g,9.08 mmol) in DCM (20 mL) at 0deg.C was added TEA (2.5 mL,18.2 mmol) and 2-chloropropionyl chloride (1.27 g,9.99 mmol), and the mixture was stirred at 25deg.C for 1 hr. The resulting mixture was concentrated in vacuo to give benzyl 4- (2-chloropropionyl) piperazine-1-carboxylate as a crude product (2.10 g, crude, 80.8% purity based on LMCS) as a white solid.
RT 0.385 min (method) 4);m/z 311.2(M+H)+(ESI+),1H NMR(CDCl3,400MHz):7.40-7.27(m,5H),5.12(s,2H)3.80-3.50(m,4H),3.49-3.32(m,4H),3.39(q,J＝6.8Hz,1H),1.65(d,J＝6.8Hz,3H).
Preparation of intermediate 280.2
4- (Dimethylalanyl) piperazine-1-carboxylic acid benzyl ester formate
To a solution of benzyl 4- (2-chloropropionyl) piperazine-1-carboxylate (500 mg,1.30mmol,80.8% purity) in MeCN (5 mL) was added dimethylamine hydrochloride (1599 mg,1.95mmol, hcl salt). The mixture was stirred at 80℃for 16 hours. The resulting mixture was filtered and the filtrate concentrated in vacuo to give a residue which was purified by preparative HPLC (column: unisil-100C18 Ultra 150*25mm*10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:0% -30%,10 min) and lyophilized directly to give benzyl 4- (dimethylalanyl) piperazine-1-carboxylate (70 mg,0.184mmol,14.1% yield, 96.0% purity, FA salt) as a colorless oil.
RT 0.253 min (method 4);m/z 320.2(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):8.30(br,1H),7.57-7.16(m,5H),5.10(s,2H),3.72-3.51(m,9H),2.14(s,6H),1.00(d,J＝6.6Hz,3H).
Preparation of intermediate 280.3
2- (Dimethylamino) -1- (piperazin-1-yl) propan-1-one
To a suspension of Pd/C (20 mg,10% purity) in MeOH (2 mL) was added benzyl 4- (dimethylalanyl) piperazine-1-carboxylate formate (50 mg,0.131mmol,96.0% purity, FA salt). The suspension was degassed in vacuo and purged with H 2 (3 times), then the mixture was stirred under an atmosphere of H 2 at 25 ℃ for 4 hours. The suspension was filtered through a pad of celite and the filter cake was washed with MeOH (3 ml,4 times). The combined filtrates were concentrated in vacuo to give the crude 2- (dimethylamino) -1- (piperazin-1-yl) propan-1-one (34 mg,0.110mmol,83.80% yield) as a colorless oil, which was used in the next step without further purification.
RT 0.060 min (method 4); m/z 186.2 (M+H) +(ESI+).
Example 280 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (dimethylalanyl) piperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol) in dioxane (1 mL) was added 2- (dimethylamino) -1- (piperazin-1-yl) propan-1-one (33 mg, 0.178 mmol), cs 2CO3 (70 mg,0.21 mmol) and Pd-PEPPI-IPentCl o-methylpyridine (7.0 mg, 0.007115 mmol). The mixture was degassed and purged with N 2 (3 times) then stirred under an atmosphere of N 2 at 100 ℃ for 16 hours. The reaction mixture was cooled to 25 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex C18:150:25 mm:10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:14% -44%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (dimethylalanyl) piperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (3.76 mg,0.00609mmol,8.53% yield, 99.63% purity, FA salt) as a yellow solid.
RT 0.337 min (method 4);m/z 569.3(M+H)+(ESI+),1H NMR(CDCl3,400MHz):9.88(s,1H),8.37(s,1H),7.72(s,1H),7.08(t,J＝53.6Hz,1H),6.69(s,1H),5.56(br,1H),4.16-4.01(m,2H),3.98(q,J＝6.8Hz,1H),3.85-3.70(m,2H),3.45-3.32(m,3H),3.28-3.17(m,1H),2.52(s,6H),1.38(s,3H),1.34(d,J＝6.8Hz,3H),0.96-0.88(m,2H),0.63-0.55(m,2H).
Preparation of intermediate 281.1
4- (1-Methylazetidine-3-carbonyl) piperazine-1-carboxylic acid benzyl ester formate salt
To a solution of 1-methylazetidine-3-carboxylic acid (300 mg,2.61 mmol) in DMF (15 mL) was added HATU (604 mg,1.59 mmol) and DIEA (0.33 mL,1.99 mmol). The mixture was stirred at 25℃for 30 minutes, then benzyl piperazine-1-carboxylate (175 mg,0.794 mmol) was added, and the mixture was stirred at 25℃for 16 hours. The resulting mixture was poured into water (30 mL), extracted with ethyl acetate (30 mL;2 times) and washed with brine (30 mL;3 times). The combined organic phases were dried over anhydrous Na 2SO4, filtered and the filtrate concentrated in vacuo to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*25mm*10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:0% -28%,10 min) and lyophilized directly to give the product benzyl 4- (1-methylazetidine-3-carbonyl) piperazine-1-carboxylate formate (50 mg,0.120mmol,15.07% yield, FA salt) as a brown solid.
RT 0.249 min (method 4);m/z 318.2(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):7.46-7.34(m,5H),5.10(s,2H),4.43-4.01(m,2H),3.98-3.82(m,1H),3.65-3.55(m,2H),3.55-3.46(m,2H),3.44-3.38(m,4H),3.14-3.07(m,2H),2.81(s,3H).
Preparation of intermediate 281.2
(1-Methylazetidin-3-yl) (piperazin-1-yl) methanone
To a suspension of Pd/C (17 mg,10% purity) in MeOH (2 mL) was added 4- (1-methylazetidine-3-carbonyl) piperazine-1-carboxylic acid benzyl ester formate (50 mg,0.137mmol, FA salt). The suspension was degassed in vacuo and purged with H 2 (3 times), then the mixture was stirred under an atmosphere of H 2 at 25 ℃ for 4 hours. The suspension was filtered through a pad of celite and the filter cake was washed with MeOH (3 ml,4 times). The combined filtrates were concentrated in vacuo to give the crude product (1-methylazetidin-3-yl) (piperazin-1-yl) methanone (38 mg,0.124mmol,90.78% yield) as a colorless oil, which was used in the next step without further purification.
RT 0.060 min (method 4); m/z 184.2 (M+H) +(ESI+
Example 281 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-methylazetidine-3-carbonyl) piperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30.0 mg,0.0715 mmol) in dioxane (1 mL) was added (1-methylazetidin-3-yl) (piperazin-1-yl) methanone (33.0 mg, 0.178 mmol), cs 2CO3 (70 mg,0.21 mmol) and Pd-PEPPI-IPentCl o-methylpyridine (7.0 mg, 0.007115 mmol). The mixture was degassed and purged with N 2 (3 times), then the mixture was stirred under an atmosphere of N 2 at 100 ℃ for 16 hours. The reaction mixture was cooled to 25 ℃ and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: unisil-100 C18 Ultra 150*25mm*10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:13% -43%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- (4- (1-methylazetidin-3-carbonyl) piperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (12.94 mg,0.022mmol,28.61% yield, 96.78% purity, FA salt) as a yellow solid.
RT 0.337 min (method 4);m/z 567.2(M+H)+(ESI+),1H NMR(DMSO-d6,400MHz):9.60(s,1H),8.44(br,1H),8.21(s,1H),8.05(s,1H),7.67(t,J＝53.2Hz,1H),6.68(s,1H),3.75-3.71(m,2H),3.55-3.54(m,3H),3.55-3.54(m,2H),3.52-3.31(m,2H),3.30-3.25(m,4H),2.29(s,3H),1.15(s,3H),0.75-0.68(m,2H),0.47-0.41(m,2H).
Example 282a preparation
(R) -4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
To a solution of 1, 8-dichloro-3- [5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] imidazo [1,5-a ] pyridine-6-sulfonamide (50.0 mg,0.106 mmol) in dioxane (1 mL) was added rac- (2R) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (42.0 mg,0.212 mmol), followed by Cs 2CO3 (103 mg,0.318 mmol) and Pd-PEPPSI-IPentCl (10.0 mg,0.0106 mmol). The mixture was degassed and purged with N 2 (3 times) then stirred at 100 ℃ for 1 hour. The resulting mixture was cooled to 20 ℃, diluted with EtOAc (10 mL) and filtered. The filtrate was concentrated in vacuo to give a residue which was purified by preparative TLC to give the product (R) -tert-butyl 4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (10.0 mg,0.0138mmol,13.05% yield, 87.91% purity) as a yellow solid.
RT 0.855 min (method 2);m/z 636.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.90(s,1H),7.08(t,J＝53.6Hz,1H),6.71(s,1H),5.59(s,1H),4..45-4.57(m,1H),4.28(d,J＝48.4Hz,2H),4.02-3.94(m,1H),3.65-3.53(m,2H),3.19-3.07(m,2H),2.70-2.58(m,1H),1.51(s,9H),1.39(d,J＝6.8Hz,3H),1.19-1.14(m,2H),0.91-0.87(m,2H).
Preparation of example 282
R-1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulphonamide bis (2, 2-trifluoroacetate)
To a solution of tert-butyl (R) -4- (1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylate (10.0 mg,0.0157 mmol) in DCM (1 mL) was added TFA (0.20 mL,2.63 mmol) and the mixture stirred at 22℃for 1 h. The mixture was concentrated in vacuo at 32 ℃. The residue was dissolved in MeCN (2 mL), filtered, and the filtrate was purified by preparative HPLC (column: welch Xtimate C18.25 mm x 5 μm; mobile phase: a:0.075% TFA in water, B: meCN; B%:20% -50%,8 min) and lyophilized directly to give the product (R) -1-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide bis (2, 2-trifluoroacetate) (4.3 mg,0.0056mmol,35.69% yield, 99.46% purity, 2TFA salt) as a yellow solid.
RT 0.370 min (method 1);m/z 536.2(M+H)+(ESI+);1H NMR(400MHz,DMSO-d6):9.62(s,1H),9.21-9.02(m,1H),8.90(s,1H),8.79-8.65(m,1H),7.69(t,J＝52.8Hz,1H),6.94-6.87(m,1H),4.23(t,J＝48.4,2H),3.57-3.51(m,5H),3.07-2.98(m,1H),2.89-2.81(m,1H),1.30(d,J＝6.4Hz,3H),0.90-0.85(m,2H),0.82-0.76(m,2H).
Example 283.1 preparation
(2R, 6R) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50.0 mg,0.119 mmol) and tert-butyl (2R, 6R) -2, 6-dimethylpiperazine-1-carboxylate (51.0 mg,0.238 mmol) in dioxane (1 mL) was added Cs 2CO3 (116 mg, 0.357mmol) and Pd-PEPPI-IPentCl o-methylpyridine (12.0 mg,0.0119 mmol). The mixture was degassed and purged with N 2 (3 times) then stirred under an atmosphere of N 2 at 100 ℃ for 4 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=2:1) to give the product (2 r,6 r) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (15.0 mg,0.0246mmol,20.65% yield) as a yellow solid.
RT 0.498 min (method 4); m/z 598.1 (M+H) +(ESI+);
Example 283 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- ((3R, 5R) -3, 5-dimethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
To a solution of (2 r,6 r) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (15.0 mg,0.0246 mmol) in DCM (1 mL) was added TFA (0.2 mL) at 20 ℃ and the mixture stirred for 2 hours at 20 ℃. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: phenomenex luna C18.150.25 mm x 10 μm; mobile phase: a:0.225% aqueous formic acid, B: meCN; B%:13% -43%,10 min) and lyophilized to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- ((3 r,5 r) -3, 5-dimethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (1.6 mg,0.0028mmol,11.52% yield, FA salt) as a yellow solid.
RT 0.333 min (method 4);m/z 498.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.88(s,1H),8.47(s,1H),7.70(s,1H),7.09(t,J＝53.6Hz,1H),6.71(s,1H),5.49(br s,1H),3.60-3.72(m,2H),3.36-3.45(m,2H),3.20-3.28(m,2H),1.49(d,J＝6.0Hz,6H),1.38(s,3H),0.96-0.90(m,2H),0.63-0.56(m,2H).
Preparation of intermediate 284.1
(2S, 6S) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester
To a mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol) in dioxane (0.5 mL) was added (2 s,6 s) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (15 mg,0.0715 mmol), cs 2CO3 (70 mg,0.214 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (7.0 mg, 0.007115 mmol). The reaction mixture was degassed with N 2 (3 times) and then stirred at 98 ℃ for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=1:2) to give the product (2 s,6 s) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (16 mg,0.0238mmol,33.34% yield) as a yellow solid.
RT 0.573 min (method 4);m/z 598.1(M+H+)(ESI+);1H NMR(CDCl3,400MHz):9.74(s,1H),7.83(s,1H),7.08(t,J＝53.6Hz,1H),6.36(s,1H),5.06(s,1H),4.20-4.37(m,2H),4.14-4.11(m,2H),3.67-3.48(m,2H),1.52(s,9H),1.40(s,3H),1.34(d,J＝6.8Hz,6H),0.98-0.96(m,2H),0.63-0.58(m,2H).
Example 284 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- ((3 s,5 s) -3, 5-dimethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate salt
A solution of (2S, 6S) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2, 6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (16 mg,0.0322 mmol) in DCM (0.5 mL) and TFA (0.1 mL) was stirred at 25℃for 1 hour. The mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:14% -44%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -8- ((3S, 5S) -3, 5-dimethylpiperazin-1-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide formate (4.0 mg,0.0072 mmol,22.56% yield, FA salt) as a yellow solid.
RT 0.362 min (method 4);m/z 498.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.57(s,1H),8.43(s,1H),8.22(s,1H),7.89(s,1H),7.67(t,J＝53.2Hz,1H),6.66(s,1H),3.30-3.27(m,2H),3.26-3.22(m,2H),3.06-3.01(m,2H),1.23(d,J＝6.4Hz,6H),1.15(s,3H),0.77-0.67(m,2H),0.45-0.47(m,2H).
Preparation of intermediate 285.1
2- (6-Bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-oxadiazole
To a solution of 6-bromo-8-chloro-N' - (2, 2-difluoroacetyl) imidazo [1,5-a ] pyridine-3-carbohydrazide (2000 mg,5.44 mmol) in THF (3 mL) was added the Bogerus reagent (3890 mg,16.3 mmol) and the reaction mixture was stirred at 65℃for 16 hours. The mixture was cooled to 20 ℃ and concentrated to give a residue which was triturated with MeOH (5 mL) for 30 min. After filtration, the filter cake was collected and dried to give the product 2- (6-bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-oxadiazole (750 mg,2.10mmol,38.53% yield) as a yellow solid.
RT 0.449 min (method 4);m/z 350.9(M+H)+(ESI+);H NMR(CDCl3,400MHz):9.52(s,1H),7.93(s,1H),7.28(s,1H),7.10-6.85(t,J＝51.6Hz,1H).
Preparation of intermediate 285.2
2- (6- (Benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-oxadiazole
To a solution of 2- (6-bromo-8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-oxadiazole (1500 mg,4.22 mmol) in 1, 4-dioxane (15 mL) was added phenyl methyl mercaptan (0.49 mL,4.22 mmol), pd 2(dba)3 (3836 mg,0.422 mmol), xantphos (244 mg,0.422 mmol) and DIEA (2.2 mL,12.6 mmol) at 25℃and the reaction mixture was stirred at 100℃for 1 hour under an atmosphere of N 2. After cooling, the reaction mixture was diluted with DCM (20 mL) and filtered through a pad of silica gel. The filtrate was collected and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (Phenomenex luna C18.150.25 mm.10 μm; mobile phase: 0.225% aqueous formic acid; B:61% -91%,10 min) to give the product 2- (6- (benzylthio) -8-chloroimidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-oxadiazole (710 mg,1.81mmol,42.88% yield) as a white solid.
RT 0.483 min (method 4);m/z 393.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz)δ9.17(s,1H),7.85(s,1H),7.37-7.34(m,2H),7.34-7.28(m,2H),7.26-7.18(m,1H),7.03(s,1H),6.96(t,J＝51.6Hz,1H),4.19(s,2H).
Preparation of intermediate 285.3
8-Chloro-3- (5- (difluoromethyl) -1,3, 4-oxadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide
To a solution of 2- (6-benzylsulfonyl-8-chloro-imidazo [1,5-a ] pyridin-3-yl) -5- (difluoromethyl) -1,3, 4-oxadiazole (200 mg,0.509 mmol) in AcOH (3.0 ml,1.02 mmol) and H 2 O (1.5 ml,0.509 mmol) at 0 ℃ was added 1, 3-dichloro-5, 5-dimethylimidazolidine-2, 4-dione (2.5 eq,251mg,1.27 mmol) and the reaction mixture was stirred at 0 ℃ for 0.5 hours. The mixture was quenched with H 2 O (5 mL) at 0deg.C and extracted with DCM (10 mL. Times.3). The combined organic layers were dried over Na 2SO4 and concentrated under reduced pressure to give the crude product, which was used in the next step without further purification.
DIEA (0.19 mL,1.08 mmol) was added dropwise to a solution of 1- (fluoromethyl) cyclopropylamine hydrochloride (102 mg,0.81 mmol) in DCM (20 mL) at-15 ℃. Then a solution of 8-chloro-3- [5- (difluoromethyl) -1,3, 4-oxadiazol-2-yl ] imidazo [1,5-a ] pyridine-6-sulfonyl chloride (200 mg, 0.552 mmol) in DCM (5 mL) was added dropwise at-15 ℃ and the reaction mixture stirred at-15 ℃ for 1 hour. The reaction mixture was diluted with DCM (10 mL) and extracted with H 2 O (10 mL. Times.3). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by preparative TLC (petroleum ether: etoac=2:1) to give the product 8-chloro-3- [5- (difluoromethyl) -1,3, 4-oxadiazol-2-yl ] -N- [1- (fluoromethyl) cyclopropyl ] imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.106mmol,19.48% yield) as a white solid.
RT 0.376 min (method 1);m/z 422.1(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.89(s,1H),8.00(s,1H),7.43(s,1H),7.12(t,J＝51.2Hz,1H),5.89(s,1H),4.31(d,J＝48.4Hz,2H),1.08-1.04(m,2H),0.85-0.82(m,2H).
Example 285 preparation
4- (3- (5- (Difluoromethyl) -1,3, 4-oxadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-oxadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (20 mg,0.047 mmol) in dioxane (1 mL) was added N, N-dimethylpiperazine-1-carboxamide (15 mg,0.0948 mmol) followed by Cs 2CO3 (46 mg,0.142 mmol) and Pd-PEPPSI-IPentCl o-methylpyridine (4.6 mg,0.0047 mmol) in a glove box at 25 ℃. Outside the glove box, the reaction mixture was heated to 100 ℃ and stirred for 1.33 hours. The mixture was cooled to 25 ℃, diluted with EtOAc (15 mL), filtered, and the filter cake was washed with EtOAc (3 mL,3 times). The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=0:1) to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-oxadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -N, N-dimethylpiperazine-1-carboxamide (1.2 mg,0.00208mmol,4.38% yield) as a yellow solid.
RT 0.597 min (method 4);m/z 543.0(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.65(s,1H),7.81(s,1H),6.98(t,J＝51.6Hz,1H),6.68(s,1H),5.51(s,1H),4.27(d,J＝48.4Hz,2H),3.54-3.51(m,4H),3.39-3.36(m,4H),2.92(s,6H),1.27-1.25(m,2H),0.89-0.87(m,2H).
Preparation of intermediate 286.1
(S) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester
To a solution of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (50 mg,0.114 mmol) in dioxane (1 mL) was added tert-butyl (S) -2-methylpiperazine-1-carboxylate (46 mg,0.228 mmol) followed by Cs 2CO3 (112 mg,0.343 mmol) and Pd-PEPPI-IPentCl o-methylpyridine (11 mg,0.01 mmol) at 22 ℃. The mixture was degassed and purged with N 2 (3 times) then heated to 100 ℃ and stirred for 1 hour. The resulting mixture was cooled to 22 ℃, diluted with EtOAc (10 mL), filtered, and the filter cake was washed with EtOAc (3 mL,3 times). The combined filtrates were concentrated in vacuo. The residue was purified by preparative TLC (SiO 2, petroleum ether: ethyl acetate=2:1) to give the product (S) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (42 mg,0.0619mmol,54.18% yield, 88.63% purity) as a yellow solid.
RT 0.800 min (method 2); m/z 602.0 (M+H) +(ESI+);
Example 286 preparation
(S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulphonamide
To a solution of (S) -4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1- (fluoromethyl) cyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester (42 mg,0.070 mmol) in DCM (2 mL) was added TFA (0.4 mL) at 22 ℃. The reaction mixture was stirred at 22℃for 0.5 h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: welch Xtimate C18.150.25 mm. 5 μm; mobile phase: A:10mmol NH 3·H2 O in water, B: meCN; B%:25% -55%,10 min) and lyophilized directly to give the product (S) -3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1- (fluoromethyl) cyclopropyl) -8- (3-methylpiperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (9.5 mg,0.0188mmol,26.97% yield, 99.7% purity) as a yellow solid.
RT 0.345 min (method 4);m/z 502.2(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.55(s,1H),8.80(br s,1H),7.98(s,1H),7.67(t,J＝53.2Hz,1H),6.68(s,1H),4.22(d,J＝48.4Hz,2H),3.63-3.51(m,2H),3.03-2.92(m,3H),2.82-2.75(m,1H),2.48-2.44(m,1H),1.06(d,J＝6.0Hz,3H),0.88-0.81(m,2H),0.80-0.74(m,2H).
Preparation of intermediate 287.1
4- (3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2- (trifluoromethyl) piperazine-1-carboxylic acid tert-butyl ester
A mixture of 8-chloro-3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) imidazo [1,5-a ] pyridine-6-sulfonamide (30 mg,0.0715 mmol), tert-butyl 2- (trifluoromethyl) piperazine-1-carboxylate (36 mg,0.143 mmol), cs 2CO3 (70 mg,0.214 mmol) and Pd-PEPSI-IPentCl o-methylpyridine (7.0 mg, 0.00710 mmol) in dioxane (0.5 mL) was degassed with N 2 (3 times) and stirred for 1 hour at 100 ℃. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether: ethyl acetate=2:1) to give the product 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2- (trifluoromethyl) piperazine-1-carboxylic acid tert-butyl ester (10 mg,0.0138mmol,19.30% yield) as a yellow solid.
RT 0.579 min (method) 4);m/z 638.2(M+H)+(ESI+);1H NMR(CDCl3,400MHz):9.91(s,1H),7.78(s,1H),7.08(t,J＝53.6Hz,1H),6.69(s,1H),5.10(br,1H),4.87-4.56(m,1H),4.16-4.09(m,2H),3.65-3.47(m,2H),3.13-3.01(m,2H),1.40(s,3H),1.26(s,9H),0.95-0.93-(m,2H),0.65-0.57(m,2H).
Example 287 preparation
3- (5- (Difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3- (trifluoromethyl) piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide
A solution of tert-butyl 4- (3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -6- (N- (1-methylcyclopropyl) sulfamoyl) imidazo [1,5-a ] pyridin-8-yl) -2- (trifluoromethyl) piperazine-1-carboxylate (10 mg,0.016 mmol) in DCM (0.2 mL) and TFA (0.04 mL) is stirred at 25℃for 1 hour. The mixture was concentrated in vacuo to give a residue which was purified by preparative HPLC (column: phenomenex luna C18:150:25 mm:10 μm; mobile phase: A:0.225% aqueous formic acid, B: meCN; B%:34% -64%,10 min) and lyophilized directly to give the product 3- (5- (difluoromethyl) -1,3, 4-thiadiazol-2-yl) -N- (1-methylcyclopropyl) -8- (3- (trifluoromethyl) piperazin-1-yl) imidazo [1,5-a ] pyridine-6-sulfonamide (0.60 mg,0.001mmol,6.6% yield) as a yellow solid.
RT 0.411 min (method 4);m/z 538.3(M+H)+(ESI+);1H NMR(DMSO-d6,400MHz):9.91(s,1H),7.71(s,1H),7.09(t,J＝53.2Hz,1H),6.69(s,1H),5.10(s,1H),3.86-3.80(m,1H),3.68-3.58(m,2H),3.39-3.30(m,1H),3.23-3.16(m,1H),3.15-3.02(m,2H),1.40(s,3H),0.98-0.89(m,2H),0.62-0.59(m,2H).
The compounds listed in the following table were prepared according to the corresponding general procedure or, when illustrated in a similar manner as the related compounds, starting from the corresponding intermediates.
Table 1 below provides an overview of the compounds described in the examples section:
TABLE 1
Biological evaluation of exemplary Compounds
Exemplary compounds of formula (I) are tested one or more times in selected biological and/or physicochemical assays. When the test is more than once, the data is reported as an average or median value, where the average (also referred to as the arithmetic average) represents the sum of the resulting values divided by the number of tests, and the median value represents the median of the set of values when arranged in ascending or descending order. If the number of values in the dataset is an odd number, the median is the median. If the number of values in the dataset is even, the median is the arithmetic mean of the two median values. The in vitro pharmacological, pharmacokinetic and physicochemical properties of the compounds may be determined according to the following assays and methods.
PARG protein expression and purification
The codon optimized genes encoding human PARG (448-976 [ H4476G, L4477S, L473S, N479S, S803A, R611K, M8413, S858P, I916T, T924D, D927K, C963S, A967T ]) were synthesized from Genscript and cloned into pET15b (Ncol/BamHI) with an N-terminal thrombin protease cleavable 6His-TWINSTREP tag. Expression of the protein in E.coli BL21 (DE 3) was induced by adding 0.2mM IPTG to shake flask cultures grown to OD600 = 0.8 at 37 ℃. Growth was continued for 20 hours at 30℃and then cell pellet was collected by centrifugation and stored at-80 ℃.
Purification of proteins by IMAC and SEC: frozen cell pellets (typically wet weight 40 g) were resuspended by homogenization in 5 volumes of buffer A (25 mM Tris/HCl pH 8.0, 200mM NaCl,2mM DTT) supplemented with 1mg DNase I (Sigma-Aldrich) from bovine pancreas and protease inhibitor (Roche, complete TM protease inhibitor tablet without EDTA) and lysed by a constant system BasicZ homogenizer. Lysates were clarified by centrifugation at 25000g for 60 min at 4 ℃ and lysate supernatant was loaded onto 5mL StreptTrap HP (Cytiva) pre-equilibrated with buffer a. The column was washed with buffer A (about 10 CV), then with buffer B (about 5 CV) containing 1M KCl, and then the protein was eluted with buffer A containing 2.5mM d-desulphated biotin. Pooled fractions containing 6His TwinStrep-TEV-hPARG were incubated with TEV protease overnight at 4 ℃. hPARG was separated from uncleaved material and thrombin protease by gel filtration using Superdex75 fractionation column (GE HEALTHCARE) pre-equilibrated with SEC buffer (15 mM Tris/HCl pH 8.5,100mM NaCl,2mM DTT). Pooled fractions containing pure hPARG were concentrated to 10mg/mL using a 10k MWCO spin concentrator (VivaSpin) and then immediately used for crystallization or flash frozen in liquid nitrogen for storage at-80 ℃.
PARG enzyme IC 50 assay
PARG enzyme was incubated with compound or carrier (DMSO) in 384 well plates for 15 minutes or 2 hours. After addition of the PARG substrate ADP-ribose-pNP, the absorbance intensity of the plate was read at 405 nm. A carrier with high absorbance intensity (DMSO) indicates no inhibition of the enzymatic reaction, whereas a low control with low absorbance intensity (no enzyme) indicates complete inhibition of the enzymatic reaction.
Materials:
hPARG: peak protein, 30nM
A substrate: ADP-pNP, 800. Mu.M, jena Bioscience, catalog number NU-955
Reaction time: 60 minutes
Assay buffer: 50mM Tris-HCl pH 8.0, 100mM NaCl, 2mM DTT
Temperature: 30 DEG C
Total volume: 30 mu L
Control:
0% inhibition control: DMSO (DMSO)
100% Inhibition control: enzyme-free
The protocol for the enzymatic reaction and detection is as follows:
1. A final concentration of 100nL of test compound or carrier (DMSO) was transferred to the appropriate wells of the microtiter plate.
2. Plates were centrifuged at 1000rpm for 1 min.
3. 14.6. Mu.L of a 2 Xfinal concentration of enzyme assay buffer solution or assay buffer alone was transferred to the appropriate wells.
4. Plates were centrifuged at 1000rpm for 1 min.
5. Plates were incubated for 15 minutes or 2 hours at room temperature.
6. 15.4. Mu.L of the 2 Xsubstrate assay buffer solution was transferred to all test wells.
7. Plates were centrifuged at 1000rpm for 1 min.
8. The board is read on a board reader (e.g., SPARK TECAN).
The absorbance IC 50 values for the compounds of formula (I) in examples 1 to 299 are provided in table 2 below.
Cellular PAR chain assay
U2OS cells pretreated with the compound for 1 hour after 1 hour treatment with Temozolomide (TMZ), with or without DNA alkylating agent, assess the ability of the compound to inhibit PARG in response to DNA damage. Cells were harvested and fixed in 70% ethanol, rehydrated with PBS solution of glucose and EDTA, followed by blocking with PBS, 1% BSA and 0.01% Tween-20 (PBT) for 1 hour. Cells were incubated with mouse monoclonal antibodies against poly (ADP) ribose (PAR) polymers for 2 hours at room temperature. Cells were washed and incubated with anti-mouse Alexa-488 conjugated secondary antibody for 1 hour at room temperature. Propidium iodide staining was used to determine the DNA content in the cells (staining overnight at 4 ℃). The fluorescence intensity of the cells was assessed by flow cytometry (Cytoflex from Beckmann) and the percentage of PAR chain positive cells (gated relative to tmz+dmso treated control) was determined. PAR chain EC 50 values were generated by fitting the% PAR chain positive cells to compound concentrations using a4 parameter log-logistic function:
PAR chain EC 50 values for the compounds of formula (I) in examples 1 to 25 are provided in table 2 below.
Cell viability assay
NCIH-460 as a PARG inhibition-sensitive cell line and U2OS as a PARG inhibition-insensitive cell line were seeded at 1000 cells/well and 2000 cells/well, respectively, in 96-well white plates with transparent flat bottoms. After 24 hours, the compound was added in duplicate using a Tecan digital dispenser (D300 e). The outer holes of the plate are excluded. After 96 hours of incubation, 150. Mu.l of growth medium was removed and 50. Mu. L CELL TITER-Gio (Promega) was added to each well. After incubation for 10 minutes, luminescence values were read using a plate reader (Tecan). The average of the samples was normalized to DMSO-treated control samples. Curves were fitted to log of% of control versus compound concentration using a 4 parameter log-logistic function:
the PARGi (NCIH-460 and U2 OS) cell viability EC 50 values for the compounds of formula (I) in examples 1 to 299 are provided in Table 2 below.
Table 2: inhibition and cellular activity of PARG by the compounds according to the invention.
IC 50 (inhibitory concentration at 50% maximum effect) values are expressed in μm and blanks indicate that the corresponding compounds were not tested in the corresponding assays.
① Examples numbering
③ IC 50 (in. Mu.M) determined in the PARG enzyme assay (PARG protein and 15 min incubation) according to PARG enzyme IC 50 assay
④ IC 50 (in. Mu.M) determined in the PARG enzyme assay (PARG protein and 2 hour incubation) according to PARG enzyme IC 50 assay
⑤ EC 50 (in μm) was determined in the cellular assay as described in accordance with the cellular PAR chain assay (conditions with TMZ treatment).
⑥ EC 50 (in μm) was determined in the cellular assay as described in accordance with the cellular PAR chain assay (without TMZ treatment).
⑦ EC 50 (in μm) was determined in NCIH-460 cells as described in the cell viability assay.
⑧ EC 50 (in μm) was determined in U2OS cells as described according to the cell viability assay.
TABLE 2
Further measurement
Kinetic solubility determination
Dynamic solubility determination was performed using an shake flask method followed by HPLC-UV analysis. For the exemplary compounds, kinetic solubility was measured according to the following protocol:
1) The samples were weighed and dissolved in 100% DMSO to prepare a 10mM stock solution. The assay requires about 100 μl of stock solution.
2) Test compounds and controls (10 mM DMSO solution, 10. Mu.L/tube) were added to buffer (490. Mu.L/well) placed in Minni-Uniprep filter. Buffers were prepared according to the customer's requirements.
3) Vortex kinetic solubility samples for 2 minutes.
4) The solubility solution was incubated at room temperature on an orbital shaker and shaken for 24 hours.
5) When the sample was directly filtered by a non-needle type filtration device, 200. Mu.L of each of the solubility solutions was transferred to 96 deep holes for analysis.
6) The filtrate was assayed for test compound concentration using HPLC-UV.
7) Three UV standard solutions were injected into HPLC from low to high concentration, followed by testing of k.s. supernatants. Test samples were injected in duplicate.
Bi-directional permeability in Caco2
For exemplary compounds of formula (I), the bi-directional permeability assay in Caco-2 cells was performed according to the following protocol:
1. caco-2 cells purchased from ATCC were seeded at 1X 10 5 cells/cm 2 onto polyethylene film (PET) in 96 well BD insert plates and medium was changed every 4-5 days until confluent monolayers were formed on days 21-28.
2. The integrity of the monolayer was verified by performing a fluorescent yellow exclusion assay.
3. The quality of the monolayer was verified by measuring the unidirectional (a→b) permeability of fenoterol/nadolol (low permeability marker), propranolol/metopronolol (high permeability marker) and the bidirectional permeability of digoxin (P-glycoprotein substrate marker) in duplicate wells.
4. Standard assay conditions for test compounds:
-test concentration: 2 mu M (DMSO. Ltoreq.1%);
-repeating: n=2;
-direction: bidirectional transmission, including a→b and b→a;
-incubation time: single time point, 2 hours;
Transport buffer: HBSS, pH 7.40.+ -. 0.05, containing 10mM HEPES;
Incubation conditions: 37.+ -. 1 ℃,5% CO 2, relative saturation humidity.
5. The labeled dosing solution was added and mixed with transport buffer and stop solution (containing the appropriate Internal Standard (IS)) as T0 samples.
6. At the end of the incubation, the sample solutions from the donor and acceptor wells were immediately mixed with the stop solution.
7. All samples were analyzed using LC/MS, including T0 samples, donor samples, and acceptor samples. In the absence of a standard curve, the concentration of the test compound IS expressed as the peak area ratio of analyte to IS.
Microsomal Metabolic Stability (MMS) assay
Stability of exemplary compounds was measured in microsomal metabolic stability assays as follows:
1) The test compounds were incubated with 1. Mu.M liver microsomes (pooled from multiple donors) at 37℃in the presence of an NADPH regeneration system containing 0.5mg/mL microsome protein.
2) Positive controls included testosterone (3 A4 substrate), propafenone (2D 6), and diclofenac (2C 9). They are incubated with microsomes in the presence of an NADPH regeneration system.
3) Time samples (0 min, 5 min, 15 min, 30min, 45 min and 60 min) were taken and immediately mixed with cold acetonitrile containing Internal Standard (IS). Also included are test compounds that were incubated with microsomes for 60 minutes without the NADPH regeneration system.
4) A single point for each test condition (n=1).
5) Analyzing the sample by LC/MS; the disappearance of the test compounds was assessed based on the peak area ratio of analyte/IS (no standard curve).
6) Summary of excel data, calculated intrinsic clearance, and t1/2 values are provided.
7) Microsomal clearance was calculated using the following equation:
int (mic) =0.693/half-life/milligram microsomal protein/milliliter body weight: rats, monkeys, dogs, humans, and mice were 40g/kg, 30g/kg, 32g/kg, 20g/kg, and 88g/kg, respectively. Clint (mic) for calculating the clearance of the whole liver: microsomal protein/gram liver weight: 5 species 45mg/g, int (liver) =clint (mic) mg microsomal protein/gram liver weight/kg body weight.
In vitro metabolic stability of test Compounds in CD-1 mice, SD rats, beagle dogs, cynomolgus monkeys and human cryopreserved hepatocytes
1. Test compounds (1 μm) were incubated with cryopreserved hepatocytes (0.5×10 6 cells/mL) at 37 ℃ in duplicate (n=2) using 96-well plates.
2. Time points were 0, 15, 30, 60 and 90 minutes, respectively, with incubation on different plates, while incubation of cell-free media control samples was performed at 0 and 90 minutes. At each time point, the reaction was terminated by adding an organic solution containing an Internal Standard (IS).
3. Positive controls 7-ethoxycoumarin and 7-hydroxycoumarin are also included.
4. Samples were analyzed by LC-MS/MS. The disappearance of the test compounds was evaluated based on the peak area ratio of analyte/IS (no standard curve).
Other embodiments of the present invention are disclosed in the following numbered items.
1. A compound of formula (I):
or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystalline form, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl, (C 1-2) haloalkyl, - (C 1-2 alkylene) -OH and- (C 1-2 alkylene) -O- (C 1-2 alkyl), preferably wherein R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl;
R 2 and R 3 are each independently (C 1-2) alkyl or (C 1-2) haloalkyl, or R 2 and R 3 together with the carbon atoms to which they are attached form cyclopropyl;
W is selected from -NHS(O)y-、-S(O)yNH-、-NHS(O)(NH)-、-NHS(O)(NCH3)-、-S(O)(NH)-NH-、-S(O)(NCH3)-NH-, wherein y is 1 or 2;
X 1 and X 3 are independently selected from N, CH and CF;
X 2 is N or C-Y C2-RC2,
Wherein Y C2 is selected from the group consisting of a covalent bond, C 1-5 alkylene, C 2-5 alkenylene, C 2-5 alkynylene, cycloalkylene, and heterocycloalkylene, wherein each of said alkylene, said alkenylene, and said alkynylene is optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, SH, S (C 1-5 alkyl), -S (C 1-5 haloalkyl), NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), CONH 2 alkyl), CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C2 alkyl), N (C 1-5 alkyl), NHCO- (C 1-5 alkyl), CONH 2 alkyl (C 1-5 alkyl), preferably selected from halogen, CN, OH, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units comprised in the alkylene, the alkenylene or the alkynylene are each optionally substituted with a group independently selected from-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-and SO 2 -, and further wherein the cycloalkylene and the heterocycloalkylene are each optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 15 alkyl), -S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), N (C728 alkyl) (C 1-5 alkyl), N (C8235 haloalkyl), -N (C3757 alkyl), -N- (C 1-5 alkyl), -N- (C 1-5 alkyl), -N (C3757 alkyl) N (C alkyl) -CO- (C alkyl), NHCONH alkyl), NHCON (C alkyl), N (C alkyl) CONH- (C alkyl) and N (C alkyl) CON (C alkyl), - (C alkylene) -CN, - (C alkylene) OH, - (C alkylene) O (C alkyl), - (C alkylene) -O (C haloalkyl), - (C alkylene) SH, - (C alkylene) S (C alkyl), - (C alkylene) -S (C haloalkyl), - (C alkylene) NH (C alkyl), - (C alkylene) -NH (C haloalkyl), - (C alkylene) N (C alkyl), - (C alkylene) (C alkyl) (N=heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH 2、-(C1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2、-(C1-5 alkylene) NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) N- (C 1-5 alkyl) and- (C 1-5 alkylene) N (C2 alkyl) (C 1-5 alkyl), preferably selected from the group consisting of C 1-5 alkyl, C 1-5, and 1-5 alkyl, and 393 alkyl (OH, preferably, 3 and 3C 393 alkyl NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl),
Preferably wherein Y C2 is selected from the group consisting of covalent bond, C 1-5 alkylene, C 2-5 alkenylene and C 2-5 alkynylene, wherein the alkylene, the alkenylene and the alkynylene are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, SH, S (C 1-5 alkyl), -S (C 1-5 haloalkyl), NH 1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), - (N-heterocycloalkyl), -CO (C 1-5 alkyl), CONH 2 alkyl), CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C 1-5 alkyl), N (C 1-5 alkyl) -CO- (C 1-5 alkyl), NHCONH 2 alkyl (C 1-5 alkyl), N (C 1-5 alkyl) preferably selected from the group consisting of C 1-5 alkyl, N (1-5 alkyl) and C 1-5 alkyl (C 1-5 alkyl) OH, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2- units contained in the alkylene, alkenylene or alkynylene group are each optionally replaced by a group independently selected from-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-and SO 2 -, and
Wherein R C2 is selected from the group consisting of hydrogen, halogen, -OH, -NH 2、-SH、-CN、C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
Wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C2 alkyl), -N (C 1-5 alkyl), -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl), -CONH 2 alkyl), -CONH 1-5 alkyl), -N (C 1-5 alkyl), -C 1-5 alkyl) -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)) and-P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -CO (1-5 alkyl), -CONH 2 alkyl) and-C 1-5 alkyl), and-C 1-5 alkyl
Wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5)、-O(C1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -C35 alkyl), -CO- (C 1-5 alkyl) -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C39348 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl) and-N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -P (C 1-5 alkylene) -S (1-5 alkyl), -S (C 1-5 alkyl), -S (1-5 alkyl) - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkyl) -N (C 1-5 alkyl), (C 1-5 alkylene) -N (C 1-5 alkyl), (CO) CO 2 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -C 1-5 alkylene-OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -S (C 1-5 alkylene) -SH, -C 1-5 alkylene) -S (C 1-5 alkyl), -S (C 1-5 alkylene), -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -C 1-5 alkylene) -NH (C 1-5 haloalkyl), -C 1-5 alkylene) -N (C 1-5 alkyl), -C 1-5 alkyl) (C 1-5 alkylene) -N (C 1-5 haloalkyl), -CO (C 1-5 alkyl), -CONH 2 alkyl) and-CON (C 1-5 alkyl) are preferably selected from the group consisting of, more preferably, OH, - 1-5 alkyl, and-CN, - 1-5 alkyl C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl);
x 4 is N or C-R C4,
Wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), -CO (C 1-6 alkyl), C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -S (C 1-6 haloalkyl), -NH (C 1-6 haloalkyl), -N (C 1-6 haloalkyl) 2、-CO-(C1-6 haloalkyl), -C 0-3 alkylene) -cycloalkyl, -O- (C 0-3 alkylene) -cycloalkyl, -CO- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -O- (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -heteroaryl, -O- (C 0-3 alkylene) -heteroaryl and-CO- (C 0-3 alkylene) -heteroaryl,
Wherein the alkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C2 alkyl) (2、-NHCONH-(C1-5 alkyl), -N (C2 alkyl) CONH 2 alkyl), CONH 2 alkyl and- 2、-NHCONH-(C1-5 alkyl are preferably selected from halogen, -CN (C 2、-NHCONH-(C1-5 alkyl) -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and
Wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C2 alkyl), -CO- (C2 alkyl), -NHCONH 2 alkyl), -nhcon2 alkyl, -nh2 alkyl, -C 1-5 alkyl), and-C 1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl) is preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S 1-5 haloalkyl, -NH (1-5) alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl);
X 5 is N or C-R C5,
Wherein R C5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), and C 1-6 haloalkyl;
R 4 is Y R5-RR5, which is a compound,
Wherein Y R5 is selected from the group consisting of a covalent bond, C 1-4 alkylene, C 2-4 alkenylene, and C 2-4 alkynylene, wherein the alkylene, the alkenylene, and the alkynylene are each optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), O (C 1-5 haloalkyl) SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl) NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), and N (C 1-5 haloalkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units contained in the alkylene, the alkenylene, and the alkynylene are each optionally substituted with a group independently selected from the group consisting of-O-, NH-, N (C 1-5 alkyl) -, CO-, -COO S-, -SO-, and SO 2 -, and
Wherein R R5 is selected from the group consisting of C 1-12 alkyl, C 1-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
Wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from halogen, CN, OH, O (C 1-5 alkyl), O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl), and CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), O 1-5 haloalkyl, SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl), N 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 alkyl), and con3932 alkyl.
2. The compound of clause 1, wherein R 1 is selected from cyano, (C 1-2) alkyl, and (C 1-2) haloalkyl.
3. The compound of clause 1 or 2, wherein R 1 is selected from cyano, methyl, and fluoromethyl.
4. The compound according to any one of items 1 to 3, wherein R 1 is cyano.
5. The compound of any one of clauses 1 to 4, wherein R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl.
6. The compound of any one of clauses 1 to 5, wherein W is-NHS (O) 2 -.
7. The compound of any one of clauses 1 to 6, wherein X 1 and X 3 are each CH.
8. The compound of any one of clauses 1 to 7, wherein X 2 is C-Y C2-RC2.
9. The compound of clause 8, wherein-Y C2-RC2 is selected from the group consisting of-O-C 1-12 alkyl, -NH-C 1-12 alkyl, -N (C 1-5 alkyl) -C 1-12 alkyl, -O-C 2-12 alkenyl, -NH-C 2-12 alkenyl, -N (C 1-5 alkyl) -C 2-12 alkenyl, -O-C 2-12 alkynyl, -NH-C 2-12 alkynyl, -N (C 1-5 alkyl) -C 2-12 alkynyl, - (C 0-3 alkylene) -cycloalkyl, -CO- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -CO-cycloalkyl, -CONH- (C 0-3 alkylene) -cycloalkyl, (C 0-3 alkylene) -NH-cycloalkyl, -NHCO- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -NHCO-cycloalkyl, -NH- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -NH-cycloalkyl, -O- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO 2 cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 heterocycloalkyl, - (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CO-aryl -CONH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) -aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NH-aryl -O- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 heteroaryl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、NH(-C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl) -N (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 42 alkyl, -C5352 alkyl), -CO (C5326 alkyl), -CO- (C35 alkyl) 35 alkyl -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl), -P (C 1-5 alkyl) (O) (C 1-5 alkyl)) and-P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -SH (1-5 alkyl) -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5), and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) 2 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (1-5 alkyl), -N (C 1-5 alkyl), -n=s (C 1-5 alkyl), -C 1-5 haloalkyl, -C 1-5 alkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl, -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) CONH- (C 2、-NHCONH-(C1-5 alkyl) -N (C 2、-NHCONH-(C1-5 alkyl) CON (C 2、-NHCONH-(C1-5 alkyl), -P (O) (C 2、-NHCONH-(C1-5 alkyl), -P (O) (O (C 2、-NHCONH-(C1-5 alkyl))), -P (O) (O (C 2、-NHCONH-(C1-5 alkyl)) (C 2、-NHCONH-(C1-5 alkyl), -C 2、-NHCONH-(C1-5 alkylene) -CN, - (C 2、-NHCONH-(C1-5 alkylene) OH-, - (C 2、-NHCONH-(C1-5 alkylene) 0- (C 2、-NHCONH-(C1-5 alkyl), -C 2、-NHCONH-(C1-5 alkylene) -O (C 2、-NHCONH-(C1-5 haloalkyl), -and, - (C 1-5 alkylene) SH-, - (C 1-5 alkylene) S- (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl) - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) NH (-C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) N (-C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (-C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) N (-C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) CONH (-C 1-5 alkyl), - (C 1-5 alkylene) CON (-C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (-C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH (-C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (-C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (-C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) N (-C 1-5 alkyl) CON (C 1-5 alkyl), preferably selected from-CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -OH- (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -, -S (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene), -S (C 1-5 alkyl), -S (C 1-5 alkylene), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH (C 1-5 alkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2 alkyl) and-CONH (-C 1-5 alkyl) (C 1-5 alkyl).
10. The compound of clause 8 or 9, wherein-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CO-aryl, -CONH (0-3 alkylene) -aryl - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) -aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -N (C5243 haloalkyl), -N (C7275 alkyl), -N (C3243 haloalkyl), -N (C7275 alkyl) - (N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 haloalkylene - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene), -S (C 1-5 haloalkyl), -NH 2 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N 1-5 haloalkyl - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl), more preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -CO (C 1-5 alkyl), and-CONH 1-5 alkyl) and-CON (C 1-5 alkyl).
11. The compound of any one of clauses 8 to 10, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 heterocycloalkyl, - (C 0-3 alkylene) aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 alkyl), -S (C 1-5) S (C 2(C1-5) alkyl -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 2、-CONH(C1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl) -CO- (C 2、-CONH(C1-5 alkyl), -NHCONH 2、-CONH(C1-5 alkyl), -nhCON (C 2、-CONH(C1-5 alkyl), -NHCON (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl) CONH 2、-CONH(C1-5 alkyl), -CONH- (C 2、-CONH(C1-5 alkyl), -N (C 2、-CONH(C1-5 alkyl) CONH (C 2、-CONH(C1-5 alkyl), -C 2、-CONH(C1-5 alkyl -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl), -C 1-5 alkylene) -S (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)), (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycle), - (C 1-5 alkylene), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (1-5 SH), -S (1-5 alkyl) - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl) and-CON (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH 1-5 alkyl), -N (C 1-5 alkyl), and, -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
12. The compound of any one of claims 8 to 11, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, and- (C 0-3 alkylene) -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl), and CON (C 1-5 alkyl) (C 1-5 alkyl).
13. The compound of any one of clauses 8 to 12, wherein-Y C2-RC2 is selected from heterocycloalkyl, aryl, and heteroaryl, preferably heterocycloalkyl and heteroaryl, more preferably heterocycloalkyl, wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 15 haloalkyl), S (C 15 alkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl), and CON (C 1-5 alkyl) (C 1-5 alkyl).
14. The compound according to any one of clauses 8 to 13, wherein-Y C2-RC2 is optionally substituted aryl, preferably-Y C2-RC2 is phenyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
15. The compound of any one of clauses 8 to 13, wherein-Y C2-RC2 is optionally substituted heteroaryl, preferably wherein-Y C2-RC2 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or indazolyl, wherein heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
16. The compound of any one of clauses 8 to 13, wherein-Y C2-RC2 is optionally substituted heterocycloalkyl, preferably wherein-Y C2-RC2 is morpholinyl, 1-dioxothiomorpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 6-oxo-1, 6-dihydropyridinyl, or piperazinyl, wherein the heterocycloalkyl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl), and CON (C 1-5 alkyl) (C 1-5 alkyl).
17. The compound of clause 16, wherein-Y C2-RC2 is piperazinyl optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl), preferably piperazinyl (preferably N-piperazinyl) wherein-Y C2-RC2 is piperazinyl (preferably N-piperazinyl) optionally substituted with CO (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl), more preferably wherein-Y2 is piperazinyl (preferably N- 1-5 alkyl) substituted with C 1-5 alkyl, preferably with N, and the preferred ring system of formula (1-5) is piperazine as shown in the preferred ring system.
18. The compound of clause 16, wherein-Y C2-RC2 is 2-oxaspiro [3.5] non-6-en-7-yl, 2-oxaspiro [3.5] non-7-yl, 2-oxa-8-azaspiro [4.5] dec-8-yl, 9-oxa-3-azaspiro [5.5] undecan-3-yl, 2-oxa-6-azaspiro [3.4] oct-6-yl, 1-oxa-7-azaspiro [3.5] non-7-yl, 1-oxa-8-azaspiro [4.5] dec-8-yl, 6-oxa-2-azaspiro [3.3] hept-2-yl, 2, 8-diazaspiro [4.5] dec-8-yl, 7-oxa-3-azabicyclo [3.3.0] oct-3-yl, 8-oxa-3-azabicyclo [3.5] non-7-azaspiro [3.5] non-7-yl, 1-oxa-7-azaspiro [3.5] non-7-yl, 6-oxa-8-yl, 6-oxa-azaspiro [ 3.3.5 ] dec-8-yl, 7-oxa-3.0 ] oxa-yl, 8-oxa-3-yl, 7-oxa-azol [3.5] non-3-yl, 3.5] oxa-yl.
19. The compound of any one of clauses 1 to 16, wherein X 4 is C-R C4, wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, C 1-6 haloalkyl, - (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, and- (C 0-3 alkylene) -heteroaryl, wherein the alkyl is optionally substituted with one or more groups, the one or more groups are independently selected from halogen, CN, OH, O (C 0-3 alkyl), O (C 0-3 haloalkyl), SH, S (C 0-3 alkyl), O (C 0-3 haloalkyl), NH 0-3 alkyl), NH (C 0-3 haloalkyl), N (C 0-3 alkyl), N (C 0-3 haloalkyl) (C 0-3 alkyl), CONH 0-3 alkyl), and CON (C 0-3 alkyl), and wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally substituted with one or more groups independently selected from halogen, CN, OH, C 0-3 alkyl, C 0-3 haloalkyl, O (C 0-3 alkyl), O (C 0-3 haloalkyl), SH, S (C 1-5 haloalkyl), S (C 1-5 alkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl).
20. The compound of clause 19, wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, and C 1-6 haloalkyl, preferably wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-2 alkyl, and C 2-3 alkynyl, more preferably wherein R C4 is selected from the group consisting of hydrogen, halogen, and C 1-2 alkyl, even more preferably wherein R C4 is hydrogen or halogen.
21. The compound of clause 19, wherein R C4 is selected from- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, and- (C 0-3 alkylene) -heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
22. The compound of clause 19 or 21, wherein R C4 is selected from- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, and- (C 0-3 alkylene) -heteroaryl, preferably wherein R C4 is selected from cycloalkyl, heterocycloalkyl, and heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -NH (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
23. The compound of clause 21, wherein R C4 is selected from heterocycloalkyl and heteroaryl, wherein the heterocycloalkyl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -NH (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
24. The compound of clause 19, wherein R C4 is selected from-CH 2 -cycloalkyl, -CH 2 -heterocycloalkyl, -CH 2 -aryl, and-CH 2 -heteroaryl, more preferably wherein R C4 is selected from-CH 2 -heterocycloalkyl, and-CH 2 heteroaryl, wherein the cycloalkyl, heterocycloalkyl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
25. The compound of clause 23, wherein R C4 is heteroaryl, preferably wherein R C4 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or indazolyl, wherein the heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
26. The compound of clause 23, wherein R C4 is heterocycloalkyl, preferably wherein R C4 is morpholinyl, 1-dioxothiomorpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 6-oxo-1, 6-dihydropyridinyl, or piperazinyl, wherein the heterocycloalkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
27. The compound of clause 26, wherein R C4 is piperazinyl, preferably wherein R C4 is piperazinyl (preferably N-piperazinyl) substituted with-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably with-CON (CH 3)2) (preferably N-substituted, preferably at an N atom different from the N atom attached to the ring system shown in formula (I)).
28. The compound of clause 23, wherein R C4 is heterocycloalkyl, preferably wherein R C4 is 2-oxaspiro [3.5] non-6-en-7-yl, 2-oxaspiro [3.5] non-7-yl, 2-oxa-8-azaspiro [4.5] dec-8-yl, 9-oxa-3-azaspiro [5.5] undec-3-yl, 2-oxa-6-azaspiro [3.4] oct-6-yl, 1-oxa-7-azaspiro [3.5] non-7-yl, 1-oxa-8-azaspiro [4.5] dec-8-yl, 6-oxa-2-azaspiro [3.3] hept-2-yl, 2, 8-diazaspiro [4.5] dec-8-yl, 7-oxa-3-azabicyclo [3.3.0] oct-3-yl, 8-oxa-3-azabicyclo [4.3.0] non-3-yl, 1-oxa-3-azaspiro [3.5] non-6-yl, 1-oxa-8-oxa-azaspiro [3.5] non-azol-3.5 ] non-yl, 1-oxa-8-yl, 1-oxa-8-yl, 3-oxa-azaspiro [3.5] dec-3-yl, 3-oxa-3-yl.
29. The compound of any one of clauses 1 to 28, wherein if X 2 comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then X 4 is C-R C4, wherein R C4 is selected from hydrogen, halogen, C 1-6 alkyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, and C 1-6 haloalkyl; preferably wherein R c4 is selected from hydrogen and halogen.
30. The compound of any one of clauses 1 to 28, wherein if X 4 comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, X 2 does not comprise any group selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.
31. The compound of any one of clauses 1 to 28, wherein if X 2 comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and X 4 comprises cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, then R C4 and-Y C2-RC2 together comprise no more than 12 non-hydrogen atoms, preferably no more than 10 non-hydrogen atoms.
32. The compound of any one of clauses 1 to 31, wherein X 5 is C-R C5, wherein R C5 is selected from hydrogen, halogen, C 1-3 alkyl, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -NH-C 1-3 alkyl, and C 1-3 haloalkyl, preferably wherein R C5 is selected from hydrogen, halogen, C 1-3 alkyl, and C 1-3 haloalkyl.
33. The compound of any one of clauses 1 to 32, wherein Y R5 is selected from the group consisting of covalent bond, C 1-2 alkylene, -CO- (C 1-2 alkylene), -C 1-2 alkylene) -CO-, -CONH- (C 1-2 alkylene) -, - (C 1-2 alkylene) -CONH-, -NHCO- (C 1-2 alkylene) -, - (C 1-2 alkylene) -NHCO-, -NH- (C 1-2 alkylene) -, - (C 1-2 alkylene) -NH-, -O- (C 1-2 alkylene) -, - (C 1-2 alkylene) -O-, SO 2-(C1-2 alkylene) -, - (C 1-2 alkylene) SO 2-、-CONH-、CON(C1-5 alkyl) -, -NHCO-, -N (C 1-5 alkyl) CO-, -NH-, -O-, -CO-, -COO-, and SO 2 -.
34. The compound of any one of clauses 1 to 33, wherein R R5 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, preferably wherein R R5 is selected from heterocycloalkyl, aryl, and heteroaryl, more preferably wherein R R5 is selected from aryl and heteroaryl, most preferably wherein R R5 is heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl), and CON (C 1-5 alkyl) (C 1-5 alkyl).
35. The compound of any one of clauses 1 to 34, wherein Y R5 is selected from the group consisting of covalent bond, C 1-2 alkylene, -CO- (C 1-2 alkylene) -, - (C 1-2 alkylene) -CO-, -CONH- (C 1-2 alkylene) -, - (C 1-2 alkylene) -CONH-, -NHCO- (C 1-2 alkylene), -C 1-2 alkylene) -NHCO-, -NH- (C 1-2 alkylene), -C 1-2 alkylene) -NH-, -O- (C 1-2 alkylene), -C 1-2 alkylene) -O-, -SO 2-(C1-2 alkylene) -, - (C 1-2 alkylene) -SO 2 -, -CONH-, -NHCO-, -NH-, -O-, -CO, and-SO 2 -.
36. The compound of clause 34 or 35, wherein R 4 is selected from- (C 0-2 alkylene) -cycloalkyl, -CO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CO-cycloalkyl, -CONH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NHCO-cycloalkyl, -NH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NH-cycloalkyl, -O- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -O-cycloalkyl, -SO 2-(C0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO 2 -cycloalkyl, - (C 0-2 alkylene) -heterocycloalkyl, -CO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-2 alkylene) -heterocycloalkyl - (C 0-2 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NH-heterocycloalkyl, -O- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -O-heterocycloalkyl, -SO 2-(C0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-2 alkylene) -aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, -SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-heteroaryl, -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, -SO 2-(C0-2 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -CO-heteroaryl and-SO 2 -heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
37. The compound of clause 36, wherein R 4 is selected from the group consisting of- (C 0-2 alkylene) aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, -SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-heteroaryl -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, -SO 2-(C0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C5342 alkyl), -N (C5326 alkyl), -N (C5342 alkyl) -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
38. The compound of any one of clauses 1 to 32, wherein R 4 is selected from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, preferably wherein R 4 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably wherein R 4 is selected from aryl and heteroaryl, even more preferably wherein R 4 is heteroaryl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups, the one or more groups are independently selected from halogen, CN, OH, O (C 1-5 alkyl), O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 1-5 alkyl), and CON (C 1-5 alkyl), and wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), O (C 1-5 haloalkyl), SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 1-5 alkyl), NH (C 1-5 haloalkyl), SH, N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl), and CON (C 1-5 alkyl) (C 1-5 alkyl).
39. The compound of clause 37 or 38, wherein R 4 is five-membered heteroaryl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
40. The compound of clause 39, wherein the five-membered heteroaryl is selected from imidazolyl, isoxazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl, or 1,3, 4-thiadiazolyl, preferably wherein the five-membered heteroaryl is 1,2, 4-thiadiazolyl optionally substituted with one or more groups independently selected from halo, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably optionally substituted with C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -C 1-5 alkyl, -C 1-5 haloalkyl, -C3754 alkyl, preferably substituted with C3754, more preferably with C3754 alkyl.
41. A pharmaceutical composition comprising a compound according to any one of items 1 to 40, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
42. A compound according to any one of clauses 1 to 40, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to clause 41, for use in therapy.
43. The compound for use or the pharmaceutical composition for use according to item 42, for use in a method of treating a disease or disorder in which PARG activity is implicated.
44. A method of treating a proliferative disorder according to the compound for use or the pharmaceutical composition for use of item 42.
45. The compound for use or the pharmaceutical composition for use according to item 44, wherein the proliferative disorder is cancer, preferably human cancer.
Other embodiments of the invention are disclosed in the following numbered paragraphs.
1. A compound of formula (I):
or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystalline form, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is selected from the group consisting of hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl and (C 1-2) haloalkyl;
R 2 and R 3 are each independently (C 1-2) alkyl or (C 1-2) haloalkyl, or R 2 and R 3 together with the carbon atoms to which they are attached form cyclopropyl;
w is selected from -NHS(O)y-、-S(O)yNH-、-NHS(O)(NH)-、-NHS(O)(NCH3)-、-S(O)(NH)-NH-、-S(O)(NCH3)-NH-, wherein y is 1 or 2;
X 1 and X 3 are independently selected from N, CH and CF;
X 2 is N or C-Y C2-RC2,
Wherein Y C2 is selected from the group consisting of a covalent bond, C 1-5 alkylene, C 2-5 alkenylene, and C 2-5 alkynylene, wherein the alkylene, the alkenylene, and the alkynylene are each optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), SH, S (C 1-5 alkyl), NH 2、NH(C1-5 alkyl), and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units contained in the alkylene, the alkenylene, or the alkynylene are each optionally replaced with a group independently selected from the group consisting of-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-, and SO 2 -, and
Wherein R C2 is selected from the group consisting of hydrogen, halogen, -OH, -NH 2、-SH、-CN、C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
Wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and
Wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl);
x 4 is N or C-R C4,
Wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), -CO (C 1-6 alkyl), C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -S (C 1-6 haloalkyl), -NH (C 1-6 haloalkyl), -N (C 1-6 haloalkyl) 2、-CO-(C1-6 haloalkyl), -C 0-3 alkylene) -cycloalkyl, -O- (C 0-3 alkylene) -cycloalkyl, -CO- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -O- (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -heteroaryl, -O- (C 0-3 alkylene) -heteroaryl and-CO- (C 0-3 alkylene) -heteroaryl,
Wherein the alkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl), and
Wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl);
X 5 is N or C-R C5,
Wherein R C5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), and C 1-6 haloalkyl;
R 4 is Y R5-RR5, which is a compound,
Wherein Y R5 is selected from the group consisting of a covalent bond, C 1-4 alkylene, C 2-4 alkenylene, and C 2-4 alkynylene, wherein the alkylene, the alkenylene, and the alkynylene are each optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), O (C 1-5 haloalkyl) SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl) NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), and N (C 1-5 haloalkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units contained in the alkylene, the alkenylene, and the alkynylene are each optionally substituted with a group independently selected from the group consisting of-O-, NH-, N (C 1-5 alkyl) -, CO-, -COO S-, -SO-, and SO 2 -, and
Wherein R R5 is selected from the group consisting of C 1-12 alkyl, C 1-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
Wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C5348 haloalkyl), -N (C 1-5 alkyl), -N 1-5 alkyl) is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -N (C3748 haloalkyl), -N (C3757 alkyl) -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
2. The compound of paragraph 1 wherein R 1 is cyano.
3. A compound according to paragraph 1 or 2, wherein R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl.
4. A compound according to any one of paragraphs 1 to 3, wherein W is-NHS (O) 2-.
5. The compound of any one of paragraphs 1 to 4, wherein X 1 and X 3 are each CH.
6. The compound of any one of paragraphs 1 to 5, wherein X 2 is C-Y C2-RC2, wherein-Y C2-RC2 is selected from-O-C 1-12 alkyl, -NH-C 1-12 alkyl, -N (C 1-5 alkyl) -C 1-12 alkyl, -O-C 2-12 alkenyl, -NH-C 2-12 alkenyl, -N (C 1-5 alkyl) -C 2-12 alkenyl, -O-C 2-12 alkynyl, -NH-C 2-12 alkynyl, -N (C 2-12 alkyl) -C 2-12 alkynyl, - (C 2-12 alkylene) -cycloalkyl, -CO- (C 2-12 alkylene) -cycloalkyl, - (C 2-12 alkylene) -CO-cycloalkyl, -CONH- (C 2-12 alkylene) -cycloalkyl, (C 2-12 alkylene) -CONH-cycloalkyl, -NHCO- (C 2-12 alkylene) -cycloalkyl, - (C 2-12 alkylene) -NHCO-cycloalkyl, -NH- (C 2-12 alkylene) -cycloalkyl, - (C 2-12 alkylene) -O-cycloalkyl, - (C 2-12 alkylene) -SO 2 cycloalkyl -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO 2 -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, SO 2-(C0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CO- 0-3 alkylene), -CONH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -O-aryl, SO 2-(C0-3 alkylene) -aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NH-aryl -O- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, SO 2-(C0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and SO 2 -heteroaryl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from halogen, CN, OH, O (C 1-5 alkyl), O (C 1-5 haloalkyl), C 1-5 haloalkyl, SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C8238 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), CONH 35 alkyl), and CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein the heterocycle, alkyl, or aryl, is optionally substituted with one or more groups selected from halogen, CN, C 1-5 alkyl, SH, S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH (C3933 haloalkyl), N (C 1-5 alkyl), N (C 1-5 alkyl), N (C82348 haloalkyl) (C 1-5 alkyl), CONH 35 alkyl), and CON (C 1-5 alkyl), and wherein the heterocycle is optionally substituted with one or more groups selected from halogen, C 1-5 alkyl S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl),
Preferably wherein-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) -aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and-SO 2 -heteroaryl, wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
More preferably wherein-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein said heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl, -N (C 1-5 alkyl) (C3825 alkyl), -C35 alkyl) (C 1-5 alkyl) (C4638 alkyl) -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
Even more preferably wherein-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl and- (C 0-3 alkylene) -heteroaryl, wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH2, -NH (C 1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
Even more preferably wherein-Y C2-RC2 is selected from heterocycloalkyl, aryl and heteroaryl, preferably heterocycloalkyl and heteroaryl, more preferably heterocycloalkyl, wherein said heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 haloalkyl), -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
7. A compound according to paragraph 6, wherein-Y C2-RC2 is optionally substituted aryl, preferably-Y C2-RC2 is phenyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), or wherein-Y C2-RC2 is optionally substituted heteroaryl, preferably wherein-Y C2-RC2 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or indazolyl, wherein optionally one or more groups are optionally substituted with one or more groups selected from the group consisting of halogen, -SH, -3, 3 (C 1-5, C 1-5 alkyl), -C 1-5 haloalkyl, -3 alkyl), and-C 1-5 haloalkyl -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
Or wherein-Y C2-RC2 is optionally substituted heterocycloalkyl, preferably wherein-Y C2-RC2 is morpholinyl, 1-dioxothiomorpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 6-oxo-1, 6-dihydropyridinyl or piperazinyl, wherein heterocycloalkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
8. A compound according to paragraph 6 or 7, wherein-Y C2-RC2 is piperazinyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably wherein-Y C2-RC2 is piperazinyl (preferably N-substituted) optionally substituted with CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C2 alkyl), more preferably wherein-Y is piperazinyl (preferably N-substituted with- 1-5 alkyl) (C 1-5) is more preferably substituted with- 1-5 alkyl, preferably at a different N atom than the N atom attached to the ring system as shown in formula (I), a piperazinyl group (preferably an N-piperazinyl group).
9. The compound of any one of paragraphs 1 to 8, wherein X 4 is C-R C4, wherein R C4 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, C 1-6 haloalkyl, - (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, and- (C 0-3 alkylene) -heteroaryl, wherein the alkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -O (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C2 alkyl), -CONH 2 alkyl), and-conalkyl (C 1-5 alkyl), and wherein the one or more groups are independently selected from halogen, -CN, -O (C 1-5 alkyl), -SH, -S (C82348 alkyl), -O (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 alkyl), -N (1-5 haloalkyl), -CONH 2 alkyl, and-alkyl, and wherein the one or more groups are independently selected from halogen, -OH, - 1-5 alkyl, and the groups are optionally substituted with one or more groups C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 haloalkyl), -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
Preferably wherein R C4 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, and C 1-6 haloalkyl, preferably wherein R C4 is selected from hydrogen, halogen, C 1-2 alkyl, and C 2-3 alkynyl, more preferably wherein R C4 is selected from hydrogen, halogen, and C 1-2 alkyl, even more preferably wherein R C4 is hydrogen or halogen.
11. A compound according to any one of paragraphs 1 to 10, wherein X 5 is C-R C5, wherein R C5 is selected from hydrogen, halogen, C 1-3 alkyl, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -NH-C 1-3 alkyl and C 1-3 haloalkyl, preferably wherein R C5 is selected from hydrogen, halogen, C 1-3 alkyl and C 1-3 haloalkyl.
12. A compound according to any one of paragraphs 1 to 11, wherein R 4 is selected from- (C 0-2 alkylene) -cycloalkyl, -CO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CO-cycloalkyl, -CONH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NHCO-cycloalkyl, -NH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NH-cycloalkyl, -O- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -O-cycloalkyl, SO 2-(C0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO 2 -cycloalkyl, - (C 0-2 alkylene) -heterocycloalkyl, -CO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-2 alkylene) -heterocycloalkyl - (C 0-2 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NH-heterocycloalkyl, -O- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -O-heterocycloalkyl, SO 2-(C0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO 2 -heterocycloalkyl, - (C 0-2 alkylene) -aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-heteroaryl, -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, SO 2-(C0-2 alkylene) heteroaryl, - (C 0-2 alkylene) SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -CO-32, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), O (C 15 haloalkyl), SH, S (C 15 alkyl), S (C 15 haloalkyl), NH 2、NH(C1-5 alkyl), NH (C 15 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl) and CON (C 1-5 alkyl) (C 1-5 alkyl),
Preferably wherein R 4 is selected from the group consisting of- (C 0-2 alkylene) aryl, -CO- (C 0-2 alkylene) -aryl- (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl-NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl-SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-heteroaryl, -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, -SO 2-(C0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and-SO 2 -heteroaryl, wherein said aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C4332 alkyl), -N (C328 alkyl) (CON 43 alkyl) and (C 1-5) (C8235 alkyl),
Or wherein R 4 is selected from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, preferably wherein R 4 is selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, more preferably wherein R 4 is selected from aryl and heteroaryl, even more preferably wherein R 4 is heteroaryl, wherein said alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halo, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, -CN, -OH, -O (C 1-5 alkyl), -SH, -S (C 1-5, -SH, -39356 haloalkyl), -NH 2、-NH(C1-5 alkyl, -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -C 1-5 haloalkyl, -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl, and wherein said cycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halo, -CN, -3, 3 and-alkyl, -3 -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
Preferably wherein R 4 is a five membered heteroaryl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably wherein the five membered heteroaryl is selected from imidazolyl, isoxazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl or 1,3, 4-thiadiazolyl, preferably wherein the five membered heteroaryl is 1,2, 4-thiadiazolyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -N (C 1-5 alkyl), N (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably optionally substituted with C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), more preferably optionally substituted with C 1-5 alkyl, C 1-5 haloalkyl, even more preferably optionally substituted with C 1-5 haloalkyl, preferably selected from-CH 2F、-CHF2 and CF 3, most preferably optionally substituted with-CHF 2.
13. A pharmaceutical composition comprising a compound according to any one of paragraphs 1 to 12, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
14. A compound according to any one of paragraphs 1 to 12, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to paragraph 13, for use in therapy.
15. The compound for use according to paragraph 14 or the pharmaceutical composition for use in a method of treating a disease or disorder in which PARG activity is implicated, or in a method of treating a proliferative disorder, preferably wherein the proliferative disorder is cancer, preferably human cancer.

Claims (40)

1. A compound of formula (I):
or an enantiomer, diastereomer, tautomer, pharmaceutically acceptable solvate, pharmaceutically acceptable crystalline form, pharmaceutically acceptable salt or prodrug thereof, wherein:
r 1 is selected from the group consisting of hydrogen, chlorine, fluorine, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl, (C 1-2) haloalkyl- (C 1-2 alkylene) -OH and- (C 1-2 alkylene) -O- (C 1-2 alkyl);
R 2 and R 3 are each independently (C 1-2) alkyl or (C 1-2) haloalkyl, or R 2 and R 3 together with the carbon atoms to which they are attached form cyclopropyl;
W is selected from -NHS(O)y-、-S(O)yNH-、-NHS(O)(NH)-、-NHS(O)(NCH3)-、-S(O)(NH)-NH-、-S(O)(NCH3)-NH-, wherein y is 1 or 2;
X 1 and X 3 are independently selected from N, CH, C (C 1-2 alkyl), C-Cl and C-F;
X 2 is N or C-Y C2-RC2,
Wherein Y C2 is selected from the group consisting of covalent bond, C 1-5 alkylene, C 2-5 alkenylene, C 2-5 alkynylene, cycloalkylene, cycloalkenylene, heterocycloalkylene, and heterocycloalkenylene, wherein each of said alkylene, said alkenylene, and said alkynylene is optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, SH, S (C 1-5 alkyl), -S (C 1-5 haloalkyl), NH 1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), CONH 1-5 alkyl), CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C 1-5 alkyl), N (C 1-5 alkyl) -CO- (C 1-5 alkyl), NH3932 alkyl), CONH 2 alkyl (C 1-5 alkyl), preferably selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units comprised in the alkylene, the alkenylene or the alkynylene are each optionally substituted with a group independently selected from the group consisting of-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-and SO 2 -, and further wherein the cycloalkylene, the cycloalkenylene, the heterocycloalkylene and the heterocycloalkenylene are each optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, S (C 15 alkyl), -S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl), -N (C4369 alkyl), -N (C43969 alkyl), -N (C4635 alkyl), C4357 alkyl NHCO- (C alkyl), N (C alkyl) -CO- (C alkyl), NHCONH alkyl, NHCON (C alkyl), N (C alkyl) CONH- (C alkyl) and N (C alkyl) CON (C alkyl), - (C alkylene) -CN, - (C alkylene) OH, - (C alkylene) O (C alkyl), - (C alkylene) -O (C haloalkyl), - (C alkylene) SH, - (C alkylene) S (C alkyl), - (C alkylene) -S (C haloalkyl), - (C alkylene) NH (C alkyl), - (C alkylene) -NH (C haloalkyl), - (C alkylene) N (C alkyl), - (C alkylene) N (C alkyl) (C haloalkyl), - (C alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH 2、-(C1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2、-(C1-5 alkylene) NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) N- (C 1-5 alkyl) and- (C 1-5 alkylene) N (C 1-5 alkyl) CONH (C 1-5 alkyl), preferably selected from the group consisting of C 1-5 alkyl, and 393 alkyl (393, 3O 2 alkyl, 3C 393 alkyl, 3, and 3 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and
Wherein R c2 is selected from the group consisting of hydrogen, halogen, -OH, -NH 2、-SH、-CN、C1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl,
Wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C2 alkyl), -N (C 1-5 alkyl), -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl), -CONH 2 alkyl), -CONH 1-5 alkyl), -N (C 1-5 alkyl), -C 1-5 alkyl) -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)) and-P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl) -, -O (C 1-5 haloalkyl) -, C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -CO (1-5 alkyl), -CONH 2 alkyl) and-CONH 2 alkyl, preferably selected from halogen, -CN, - 1-5 alkyl -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 1-5 alkyl), -CON (C 1-5 alkyl), a-CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), and-N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), C 1-5 alkyl, -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)) and-P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and
Wherein the cycloalkyl group 、Cycloalkenyl group 、Heterocycloalkyl group 、Heterocycloalkenyl 、Aryl or heteroaryl optionally substituted with one or more groups ，The one or more groups are independently selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-CO(C1-5Haloalkyl )、-CO-Cycloalkyl radicals 、-COO(C1-5Alkyl group )、-COO(C1-5Haloalkyl )、-COO-Cycloalkyl radicals 、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-OCONH2、-OCONH-(C1-5Alkyl group )、-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-NHCOO(C1-5Alkyl group )、-N(C1-5Alkyl group )COO-(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-CN、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-S(O)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)2(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(NH)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Haloalkyl )、-(C1-5Alkylene group )-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Haloalkyl )、-(C1-5Alkylene group )-CO-Cycloalkyl radicals 、-(C1-5Alkylene group )-CONH2、-(C1-5Alkylene group )-CONH(C1-5Alkyl group )、-(C1-5Alkylene group )-CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-NHCO-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCONH2、-(C1-5Alkylene group )-NHCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH2、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-OCONH2、-(C1-5Alkylene group )-OCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCOO(C1-5Alkyl group )And -(C1-5Alkylene group )-N(C1-5Alkyl group )COO-(C1-5Alkyl group )，Preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-COO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-OCONH2、-OCONH-(C1-5Alkyl group )、-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-NHCOO(C1-5Alkyl group )、-N(C1-5Alkyl group )COO-(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-CN、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-S(O)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)2(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(NH)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Haloalkyl )、-(C1-5Alkylene group )-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Alkyl group )、-(C1-5Alkylene group )-CONH2、-(C1-5Alkylene group )-CONH(C1-5Alkyl group )、-(C1-5Alkylene group )-CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-NHCO-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCONH2、-(C1-5Alkylene group )-NHCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH2、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-OCONH2、-(C1-5Alkylene group )-OCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCOO(C1-5Alkyl group )And -(C1-5Alkylene group )-N(C1-5Alkyl group )COO-(C1-5Alkyl group )，More preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-CN、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-S(O)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)2(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(NH)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Haloalkyl )、-(C1-5Alkylene group )-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Alkyl group )、-(C1-5Alkylene group )-CONH2、-(C1-5Alkylene group )-CONH(C1-5Alkyl group )、-(C1-5Alkylene group )-CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-NHCO-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCONH2、-(C1-5Alkylene group )-NHCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH2、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、And -(C1-5Alkylene group )-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )，More preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )And -CON(C1-5Alkyl group )(C1-5Alkyl group )，More preferably selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )And -CON(C1-5Alkyl group )(C1-5Alkyl group )；
X 4 is N or C-R C4,
Wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) cycloalkenyl, -O- (C 0-3 alkylene) -cycloalkenyl, -CO- (C 0-3 alkylene) -cycloalkenyl, - (C2 alkylene) -heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, -C 0-3 alkylene) -heterocycloalkenyl, and- (C 0-3 alkylene) wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl), -C 1-6 alkyl), -CO (C 1-6 alkyl), -C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -S (C 1-6 haloalkyl), -NH (C 1-6 haloalkyl), -N (C 1-6 haloalkyl), - 2、-CO(C1-6 alkylene), -cycloalkyl, -O- (C 0-3 alkylene) -cycloalkyl, -CO- (C 0-3 alkylene) -cycloalkenyl, -O- (C 0-3 alkylene) -cycloalkenyl, -C 0-3 alkylene, -C- (C 0-3 alkylene) -O- (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -heteroaryl, -O- (C 0-3 alkylene) -heteroaryl and-CO- (C 0-3 alkylene) -heteroaryl,
Wherein said alkyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCON (C 2、-NHCONH-(C1-5 alkyl), -N (C2 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl), -CONH 2 alkyl) and-C393 2 alkyl), preferably selected from halogen, -C 2、-NHCONH-(C1-5 alkyl, -C393 2 alkyl) -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and
Wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C2 alkyl), -CO- (C2 alkyl), -NHCONH 2 alkyl), -nhcon2 alkyl, -nh2 alkyl, -C 1-5 alkyl), and-C 1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C2 alkyl), preferably selected from the group consisting of halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S 1-5 haloalkyl), -NH (1-5 alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl);
X 5 is N or C-R C5,
Wherein R C5 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), and C 1-6 haloalkyl;
R 4 is Y R5-RR5, which is a compound,
Wherein Y R5 is selected from the group consisting of covalent bond, C 1-4 alkylene, C 2-4 alkenylene, and C 2-4 alkynylene, wherein the alkylene, the alkenylene, and the alkynylene are each optionally substituted with one or more groups independently selected from the group consisting of halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 2(C1-5 alkyl), -S (C 1-5 haloalkyl), -SO (C 1-5 haloalkyl), -SO 2(C1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), and-N (C 1-5 haloalkyl) (C 1-5 alkyl), and further wherein one or more of the-CH 2 -units contained in the alkylene, the alkenylene, or the alkynylene are each optionally independently selected from the group consisting of-O-, N (C62-, CO-, -COO-and- 2 -substituted SO) -, and SO-3454 haloalkyl
Wherein R R5 is selected from the group consisting of C 1-12 alkyl, C 1-12 alkenyl, C 2-12 alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl,
Wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C8 haloalkyl), -SH, -S (C 1-5 alkyl), -C 1-5 haloalkyl), -C8232 haloalkyl, -SO (C3563 alkyl), -SO 35 haloalkyl), -SO (C3775 haloalkyl), -SO 35 haloalkyl -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
2. The compound of claim 1, wherein R 1 is selected from hydrogen, chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl, and (C 1-2) haloalkyl.
3. The compound of claim 1 or 2, wherein R 1 is selected from chloro, fluoro, cyano, formyl, (C 1-2) alkyl, (C 2) alkenyl, (C 2) alkynyl, and (C 1-2) haloalkyl.
4. A compound according to any one of claims 1 to 3, wherein R 1 is selected from cyano, (C 1-2) alkyl and (C 1-2) haloalkyl.
5. The compound according to any one of claims 1 to 4, wherein R 1 is selected from cyano, methyl and fluoromethyl.
6. The compound according to any one of claims 1 to 5, wherein R 1 is cyano.
7. The compound according to any one of claims 1 to 5, wherein R 1 is methyl.
8. The compound according to any one of claims 1 to 5, wherein R 1 is fluoromethyl.
9. The compound according to any one of claims 1 to 9, wherein R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl.
10. The compound according to any one of claims 1 to 9, wherein W is-NHS (O) 2 -, preferably wherein the left side of W as defined herein is attached to a carbon atom bearing R 1、R2 and R 3, and the right side of W as defined herein is attached to a ring system as shown in formula (I).
11. The compound according to any one of claims 1 to 10, wherein X 1 and X 3 are independently selected from N, CH and CF.
12. The compound according to any one of claims 1 to 11, wherein X 1 and X 3 are each CH.
13. The compound of any one of claims 1 to 12, wherein Y C2 is selected from the group consisting of a covalent bond, C 1-5 alkylene, C 2-5 alkenylene, C 2-5 haloalkylene, cycloalkylene, and heterocycloalkylene, wherein the alkylene, the alkenylene, and the alkynylene are each optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, SH, S (C 15 alkyl), -S (C 1-5 haloalkyl), NH 2、NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), N (C 1-5 alkyl) (C 1-5 alkyl), N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), CONH 2、CONH(C1-5 alkyl), CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C 1-5 alkyl), N (C3675 alkyl) -nh3752 alkyl), CONH (C3735 alkyl), CONH 2、NHCONH-(C1-5 alkyl N (C 1-5 alkyl) CONH 2、N(C1-5 alkyl) CONH- (C 1-5 alkyl) and N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, CN, OH, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units comprised in said alkylene, said alkenylene or said alkynylene are each optionally replaced by a group independently selected from-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-and SO 2 -, and further wherein said cycloalkylene and said heterocycloalkyl are each optionally substituted by one or more groups independently selected from halogen, CN, OH, C 1-5 alkyl, C 1-5 haloalkyl, O (C 1-5 alkyl), -O (C 1-5 haloalkyl), S (C2 alkyl), -C 15 haloalkyl, -N (15 alkyl), -N 15 (15 alkyl), -N 15 alkyl CONH 2、CONH(C1-5 alkyl), CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、NHCONH-(C1-5 alkyl), NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、N(C1-5 alkyl) CONH- (C 1-5 alkyl) and N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), -C 1-5 alkylene) -CN, -C 1-5 alkylene-OH, -C 1-5 alkylene-O (C 1-5 alkyl), -C 1-5 alkylene-O (C 1-5 haloalkyl), -C 1-5 alkylene) SH, -C 1-5 alkylene) S (C 15 alkyl), -C 1-5 alkylene-S (C 1-5 haloalkyl), -C 1-5 alkylene) NH 2、-(C1-5 alkylene-NH (C 1-5 alkyl), -C 1-5 alkylene) -C 1-5 alkylene, -C 1-5 alkyl) (1-5 alkyl) - (C 1-5 alkylene) N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) (N-heterocycloalkyl), - (C 1-5 alkylene) N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) CONH 2、-(C1-5 alkylene) CONH (C 1-5 alkyl), - (C 1-5 alkylene) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) CO- (N-heterocycloalkyl), - (C 1-5 alkylene) NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) NHCONH 2、-(C1-5 alkylene) NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, CN, OH, C 1-5 alkyl, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl) and N (C 1-5 alkyl) (C 1-5 alkyl).
14.According to claim 1To the point of 13A compound according to any one of the preceding claims ，Wherein the method comprises the steps of X2yesC-YC2-RC2，Wherein the method comprises the steps of -YC2-RC2Selected from the group consisting of -O-C1-12Alkyl group 、-NH-C1-12Alkyl group 、-N(C1-5Alkyl group )-C1-12Alkyl group 、-O-C2-12Alkenyl groups 、-NH-C2-12Alkenyl groups 、-N(C1-5Alkyl group )-C2-12Alkenyl groups 、-O-C2-12Alkynyl group 、-NH-C2-12Alkynyl group 、-N(C1-5Alkyl group )-C2-12Alkynyl group 、(C0-3Alkylene group )-Cycloalkyl radicals 、-CO-(C0-3Alkylene group )Cycloalkyl radicals 、(C0-3Alkylene group )-CO-Cycloalkyl radicals 、-CONH-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-CONH-Cycloalkyl radicals 、-NHCO-(C0-3Alkylene group )Cycloalkyl radicals 、(C0-3Alkylene group )-NHCO-Cycloalkyl radicals 、-NH-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-NH-Cycloalkyl radicals 、-O-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-O-Cycloalkyl radicals 、-SO2-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-SO2-Cycloalkyl radicals 、-CONH-Cycloalkyl radicals 、-NHCO-Cycloalkyl radicals 、-NH-Cycloalkyl radicals 、-O-Cycloalkyl radicals 、-CO-Cycloalkyl radicals 、-SO2-Cycloalkyl radicals 、(C0-3Alkylene group )-Cycloalkenyl group 、-CO-(C0-3Alkylene group )Cycloalkenyl group 、(C0-3Alkylene group )-CO-Cycloalkenyl group 、-CONH-(C0-3Alkylene group )Cycloalkenyl group 、-(C0-3Alkylene group )-CONH-Cycloalkenyl group 、-NHCO-(C0-3Alkylene group )Cycloalkenyl group 、(C0-3Alkylene group )-NHCO-Cycloalkenyl group 、-NH-(C0-3Alkylene group )Cycloalkenyl group 、-(C0-3Alkylene group )-NH-Cycloalkenyl group 、-O-(C0-3Alkylene group )Cycloalkenyl group 、-(C0-3Alkylene group )-O-Cycloalkenyl group 、-SO2-(C0-3Alkylene group )Cycloalkenyl group 、-(C0-3Alkylene group )-SO2-Cycloalkenyl group 、-CONH-Cycloalkenyl group 、-NHCO-Cycloalkenyl group 、-NH-Cycloalkenyl group 、-O-Cycloalkenyl group 、-CO-Cycloalkenyl group 、-SO2-Cycloalkenyl group 、-(C0-3Alkylene group )-Heterocycloalkyl group 、-CO-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-CO-Heterocycloalkyl group 、-CONH-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-CONH-Heterocycloalkyl group 、-NHCO-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-NHCO-Heterocycloalkyl group 、-NH-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-NH-Heterocycloalkyl group 、-O-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-O-Heterocycloalkyl group 、-SO2-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-SO2-Heterocycloalkyl group 、-CONH-Heterocycloalkyl group 、-NHCO-Heterocycloalkyl group 、-NH-Heterocycloalkyl group 、-O-Heterocycloalkyl group 、-CO-Heterocycloalkyl group 、-SO2-Heterocycloalkyl group 、-(C0-3Alkylene group )-Heterocycloalkenyl 、-CO-(C0-3Alkylene group )Heterocycloalkenyl 、-(C0-3Alkylene group )-CO-Heterocycloalkenyl 、-CONH-(C0-3Alkylene group )Heterocycloalkenyl 、-(C0-3Alkylene group )-CONH-Heterocycloalkenyl 、-NHCO-(C0-3Alkylene group )Heterocycloalkenyl 、-(C0-3Alkylene group )-NHCO-Heterocycloalkenyl 、-NH-(C0-3Alkylene group )Heterocycloalkenyl 、-(C0-3Alkylene group )-NH-Heterocycloalkenyl 、-O-(C0-3Alkylene group )Heterocycloalkenyl 、-(C0-3Alkylene group )-O-Heterocycloalkenyl 、-SO2-(C0-3Alkylene group )Heterocycloalkenyl 、-(C0-3Alkylene group )-SO2-Heterocycloalkenyl 、-CONH-Heterocycloalkenyl 、-NHCO-Heterocycloalkenyl 、-NH-Heterocycloalkenyl 、-O-Heterocycloalkenyl 、-CO-Heterocycloalkenyl 、-SO2-Heterocycloalkenyl 、(C0-3Alkylene group )Aryl group 、-CO-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-CO-Aryl group 、-CONH-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-CONH-Aryl group 、-NHCO-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-NHCO-Aryl group 、-NH-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-NH-Aryl group 、-O-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-O-Aryl group 、-SO2-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-SO2-Aryl group 、-CONH-Aryl group 、-NHCO-Aryl group 、-NH-Aryl group 、-O-Aryl group 、-CO-Aryl group 、-SO2-Aryl group 、-(C0-3Alkylene group )Heteroaryl group 、-CO-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-CO-Heteroaryl group 、-CONH-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-CONH-Heteroaryl group 、-NHCO-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-NHCO-Heteroaryl group 、-NH-(C0-3Alkylene group )Heteroaryl group 、(C0-3Alkylene group )-NH-Heteroaryl group 、-O-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-O-Heteroaryl group 、-SO2-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-SO2-Heteroaryl group 、-CONH-Heteroaryl group 、-NHCO-Heteroaryl group 、-NH-Heteroaryl group 、-O-Heteroaryl group 、-CO-Heteroaryl group -SO2-Heteroaryl group ，Preferably -YC2-RC2Selected from the group consisting of -O-C1-12Alkyl group 、-NH-C1-12Alkyl group 、-N(C1-5Alkyl group )-C1-12Alkyl group 、-O-C2-12Alkenyl groups 、-NH-C2-12Alkenyl groups 、-N(C1-5Alkyl group )-C2-12Alkenyl groups 、-O-C2-12Alkynyl group 、-NH-C2-12Alkynyl group 、-N(C1-5Alkyl group )-C2-12Alkynyl group 、(C0-3Alkylene group )-Cycloalkyl radicals 、-CO-(C0-3Alkylene group )Cycloalkyl radicals 、(C0-3Alkylene group )-CO-Cycloalkyl radicals 、-CONH-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-CONH-Cycloalkyl radicals 、-NHCO-(C0-3Alkylene group )Cycloalkyl radicals 、(C0-3Alkylene group )-NHCO-Cycloalkyl radicals 、-NH-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-NH-Cycloalkyl radicals 、-O-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-O-Cycloalkyl radicals 、-SO2-(C0-3Alkylene group )Cycloalkyl radicals 、-(C0-3Alkylene group )-SO2-Cycloalkyl radicals 、-CONH-Cycloalkyl radicals 、-NHCO-Cycloalkyl radicals 、-NH-Cycloalkyl radicals 、-O-Cycloalkyl radicals 、-CO-Cycloalkyl radicals 、-SO2-Cycloalkyl radicals 、-(C0-3Alkylene group )-Heterocycloalkyl group 、-CO-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-CO-Heterocycloalkyl group 、-CONH-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-CONH-Heterocycloalkyl group 、-NHCO-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-NHCO-Heterocycloalkyl group 、-NH-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-NH-Heterocycloalkyl group 、-O-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-O-Cycloalkyl radicals 、-SO2-(C0-3Alkylene group )Heterocycloalkyl group 、-(C0-3Alkylene group )-SO2-Heterocycloalkyl group 、-CONH-Heterocycloalkyl group 、-NHCO-Heterocycloalkyl group 、-NH-Heterocycloalkyl group 、-O-Heterocycloalkyl group 、-CO-Heterocycloalkyl group 、-SO2-Heterocycloalkyl group 、(C0-3Alkylene group )Aryl group 、-CO-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-CO-Aryl group 、-CONH-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-CONH-Aryl group 、-NHCO-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-NHCO-Aryl group 、-NH-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-NH-Aryl group 、-O-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-O-Aryl group 、-SO2-(C0-3Alkylene group )Aryl group 、-(C0-3Alkylene group )-SO2-Aryl group 、-CONH-Aryl group 、-NHCO-Aryl group 、-NH-Aryl group 、-O-Aryl group 、-CO-Aryl group 、-SO2-Aryl group 、-(C0-3Alkylene group )Heteroaryl group 、-CO-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-CO-Heteroaryl group 、-CONH-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-CONH-Heteroaryl group 、-NHCO-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-NHCO-Heteroaryl group 、-NH-(C0-3Alkylene group )Heteroaryl group 、(C0-3Alkylene group )-NH-Heteroaryl group 、-O-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-O-Heteroaryl group 、-SO2-(C0-3Alkylene group )Heteroaryl group 、-(C0-3Alkylene group )-SO2-Heteroaryl group 、-CONH-Heteroaryl group 、-NHCO-Heteroaryl group 、-NH-Heteroaryl group 、-O-Heteroaryl group 、-CO-Heteroaryl group -SO2-Heteroaryl group ，Wherein the alkyl group 、Alkenyl or alkynyl groups optionally substituted with one or more groups ，The one or more groups are independently selected from halogen 、-CN、-OH、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、C1-5Haloalkyl 、-SH、-S(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))And -P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )，Preferably selected from halogen 、-CN、-OH、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-C1-5Haloalkyl 、-SH、-S(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-CO(C1-5Alkyl group )、-CONH2、-CONH(C1-5Alkyl group )And -CON(C1-5Alkyl group )(C1-5Alkyl group )，And wherein the cycloalkyl group 、Cycloalkenyl group 、Heterocycloalkyl group 、Heterocycloalkenyl 、Aryl or heteroaryl optionally substituted with one or more groups ，The one or more groups are independently selected from halogen 、-CN、-OH、C1-5Alkyl group 、C1-5Haloalkyl 、-O(C1-5Alkyl group )、-O(C1-5Haloalkyl )、-SH、-S(C1-5Alkyl group )、-S(O)(C1-5Alkyl group )、-S(O)2(C1-5Alkyl group )、-S(O)(NH)(C1-5Alkyl group )、-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-N＝S(O)(C1-5Alkyl group )(C1-5Alkyl group )、-S(C1-5Haloalkyl )、-NH2、-NH(C1-5Alkyl group )、-NH(C1-5Haloalkyl )、-N(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(N-Heterocycloalkyl group )、-CO(C1-5Alkyl group )、-CO(C1-5Haloalkyl )、-CO-Cycloalkyl radicals 、-COO(C1-5Alkyl group )、-COO(C1-5Haloalkyl )、-COO-Cycloalkyl radicals 、-CONH2、-CONH(C1-5Alkyl group )、-CON(C1-5Alkyl group )(C1-5Alkyl group )、-CO-(N-Heterocycloalkyl group )、-NHCO-(C1-5Alkyl group )、-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-NHCONH2、-NHCONH-(C1-5Alkyl group )、-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-N(C1-5Alkyl group )CONH2、-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-OCONH2、-OCONH-(C1-5Alkyl group )、-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-NHCOO(C1-5Alkyl group )、-N(C1-5Alkyl group )COO-(C1-5Alkyl group )、-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-CN、-(C1-5Alkylene group )-OH、-(C1-5Alkylene group )-O(C1-5Alkyl group )、-(C1-5Alkylene group )-O(C1-5Haloalkyl )、-(C1-5Alkylene group )-SH、-(C1-5Alkylene group )-S(C1-5Alkyl group )、-(C1-5Alkylene group )-S(C1-5Haloalkyl )、-(C1-5Alkylene group )-S(O)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)2(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(NH)(C1-5Alkyl group )、-(C1-5Alkylene group )-S(O)(N(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(O(C1-5Alkyl group ))、-(C1-5Alkylene group )-P(O)(O(C1-5Alkyl group ))(C1-5Alkyl group )、-(C1-5Alkylene group )-NH2、-(C1-5Alkylene group )-NH(C1-5Alkyl group )、-(C1-5Alkylene group )-NH(C1-5Haloalkyl )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )(C1-5Haloalkyl )、-(C1-5Alkylene group )-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-N(C1-5Haloalkyl )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Alkyl group )、-(C1-5Alkylene group )-CO(C1-5Haloalkyl )、-(C1-5Alkylene group )-CO-Cycloalkyl radicals 、-(C1-5Alkylene group )-CONH2、-(C1-5Alkylene group )-CONH(C1-5Alkyl group )、-(C1-5Alkylene group )-CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-CO-(N-Heterocycloalkyl group )、-(C1-5Alkylene group )-NHCO-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )-CO-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCONH2、-(C1-5Alkylene group )-NHCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH2、-(C1-5Alkylene group )-N(C1-5Alkyl group )CONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-N(C1-5Alkyl group )CON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-OCONH2、-(C1-5Alkylene group )-OCONH-(C1-5Alkyl group )、-(C1-5Alkylene group )-OCON(C1-5Alkyl group )(C1-5Alkyl group )、-(C1-5Alkylene group )-NHCOO(C1-5Alkyl group )And -(C1-5Alkylene group )-N(C1-5Alkyl group )COO-(C1-5Alkyl group )。
15. The compound of any one of claims 1 to 14, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) heterocycloalkyl, (C 0-3 alkylene) -O-cycloalkyl, (C 0-3 alkylene) -O-heterocycloalkyl, -SO 2-(C0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, -CO- (C 0-3 alkylene) -alkylene, - (C 0-3 alkylene) -CO- 0-3 alkylene -CONH- (C 0-3 alkylene) heterocycloalkenyl, - (C 0-3 alkylene) -CONH-heterocycloalkenyl, -NHCO- (C 0-3 alkylene) heterocycloalkenyl, - (C 0-3 alkylene) -NHCO-heterocycloalkenyl, -NH- (C 0-3 alkylene) heterocycloalkenyl, - (C 0-3 alkylene) -NH-heterocycloalkenyl, -O- (C 0-3 alkylene) heterocycloalkenyl, (C 0-3 alkylene) -O-heterocycloalkenyl, -SO 2-(C0-3 alkylene) heterocycloalkenyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -SO 2 -heterocycloalkenyl, - (C 0-3 alkylene) aryl, -CO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) aryl, -NHCO-aryl, -NH- (C3496 alkylene) -NH-aryl, -NH- (C 0-3 alkylene) aryl -O- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH- 2, preferably-Y C2-RC2 is selected from the group consisting of- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) heterocycloalkyl- (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl-NHCO- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) heterocycloalkyl (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) aryl, -CO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NHCO-aryl, - (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) heteroaryl, - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) heteroaryl, - (C 2-(C0-3 alkylene) -O-heteroaryl, -SO 0-3 heteroaryl - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C4395 alkyl), -N (C 1-5 alkyl), -N (C438 alkyl) -CO (C 1-5 haloalkyl), -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) CONH- (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) CON (C 2、-NHCONH-(C1-5 alkyl), -OCONH 2、-NHCONH-(C1-5 alkyl), -OCON (C 2、-NHCONH-(C1-5 alkyl), -NHCOO (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) COO- (C 2、-NHCONH-(C1-5 alkyl), -P (O) (C 2、-NHCONH-(C1-5 alkyl)), -P (C 2、-NHCONH-(C1-5 alkyl), -P (C 2、-NHCONH-(C1-5 alkyl) - (C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), - (C 1-5 alkylene) -O (C 1-5 haloalkyl), - (C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), - (C 1-5 alkylene) -S (O) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)), (C 1-5 alkyl) -P (O) (C 1-5 alkyl), (C 1-5 alkyl)) - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO-cycloalkyl, - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N- (1-5 alkyl), - (C 1-5 alkylene) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH 2、-(C1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) COO- (C 1-5 alkyl).
16. The compound of any one of claims 1 to 15, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, -SO 2 -heterocycloalkenyl, - (C 0-3 alkylene) aryl, -CONH-aryl, -NHCO-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, preferably-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-5698-alkyl, -SO-heterocycloalkyl, -C5698-alkylene -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl), -S (C 1-5 alkyl), -C 1-5 haloalkyl), -C 2、-NH(C1-5 haloalkyl, -C6593 alkyl, -NH (C6235 alkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl, -CO (C 1-5 alkyl), -CO (C 1-5 haloalkyl), -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) CONH- (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl) CON (C 2、-NHCONH-(C1-5 alkyl), -OCONH 2、-NHCONH-(C1-5 alkyl), -OCON (C 2、-NHCONH-(C1-5 alkyl), -on (C 2、-NHCONH-(C1-5 alkyl), -NHCOO (C 2、-NHCONH-(C1-5 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl), -N 2、-NHCONH-(C1-5 alkyl) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl), -C 1-5 alkylene) -S (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO- 1-5 cycloalkyl, - (C 1-5 alkylene) -CONH 2 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkyl) -CONH (C 1-5 alkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkyl).
17. The compound of any one of claims 1 to 16, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -heterocycloalkenyl, - (C 0-3 alkylene) aryl and- (C 0-3 alkylene) heteroaryl, preferably-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) aryl and- (C 0-3 alkylene) heteroaryl, wherein the heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (NH) (C 1-5 alkyl), -S (O) (C4332 alkyl), -N (C5243 alkyl), -c=c 3443 alkyl), -C 1-5 haloalkyl, -S (C5248 alkyl), -S (C 1-5 alkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CO (C 1-5 haloalkyl), -CO-cycloalkyl, -COO (C 1-5 alkyl), -COO (C 1-5 haloalkyl), -COO-cycloalkyl, -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -och 1-5 alkyl), -oc2 alkyl, -OCON (C 1-5 alkyl), -C 1-5 alkyl -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -C 1-5 alkylene) -O (C 1-5 haloalkyl), -C 1-5 alkylene) -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -C 1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkylene) -S (O) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) 2(C1-5 alkyl), -C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), -C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -C 1-5 alkylene) -P (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 haloalkyl), - (C 1-5 alkylene) -CO- 1-5 cycloalkyl, - (C 1-5 alkylene) -CONH 2 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkyl) -CONH (C 1-5 alkyl), (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCON (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl), - (C 1-5 alkylene) -OCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -OCON (C 1-5 alkyl), - (C 1-5 alkylene) -NHCOO (C 1-5 alkyl) and- (C 1-5 alkyl).
18. The compound according to any one of claim 1 to 12,
Wherein Y C2 is selected from the group consisting of a covalent bond, C 1-5 alkylene, C 2-5 alkenylene, and C 2-5 alkynylene, wherein the alkylene, the alkenylene, and the alkynylene are each optionally substituted with one or more groups independently selected from the group consisting of halogen, CN, OH, O (C 1-5 alkyl), SH, S (C 15 alkyl), NH 2、NH(C1-5 alkyl), and N (C 1-5 alkyl) (C 1-5 alkyl), and further wherein one or more-CH 2 -units contained in the alkylene, the alkenylene, or the alkynylene are each optionally replaced with a group independently selected from the group consisting of-O-, NH-, N (C 1-5 alkyl) -, CO-, S-, -SO-, and SO 2 -, and
Wherein R C2 is selected from the group consisting of hydrogen, halogen, -OH, -NH 2、-SH、-CN、C1-2 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,
Wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C2 alkyl), -N (C 1-5 alkyl), -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl), -CONH 2 alkyl), -CONH 1-5 alkyl), -N (C 1-5 alkyl), -C 1-5 alkyl) -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl) (C 1-5 alkyl), -P (O) (C 1-5 alkyl)) (O (C 1-5 alkyl)) and-P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl), -CO (C 1-5 alkyl), -CONH 2 alkyl) and-C 1-5 alkyl), and- 1-5 alkyl
Wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (O) (C 1-5 alkyl), -S (O) 2(C1-5 alkyl), -S (O) (NH) (C 1-5 alkyl), -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), -n=s (O) (C 1-5 alkyl) (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C35 alkyl), -CONH 43 alkyl), -CONH (C 1-5 alkyl), -CONH (C 1-5 alkyl) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2、-NHCONH-(C1-5 alkyl), -NHCON (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 alkyl) CONH 2、-N(C1-5 alkyl) CONH- (C 1-5 alkyl), -N (C 1-5 alkyl) CON (C 1-5 alkyl), -P (O) (O (C 1-5 alkyl)), -P (O) (O (C 1-5 alkyl)), (C 1-5 alkyl), -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -O (C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -P (1-5 alkylene) -S (C 1-5 haloalkyl), -C 1-5 alkyl), -S (C 1-5 alkyl) - (C 1-5 alkylene) -S (O) 2(C1-5 alkyl), - (C 1-5 alkylene) -S (O) (NH) (C 1-5 alkyl), - (C 1-5 alkylene) -S (O) (N (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (O (C 1-5 alkyl)), - (C 1-5 alkylene) -P (O) (O (C 1-5 alkyl)) (C 1-5 alkyl), - (C 1-5 alkylene) -NH 2、-(C1-5 alkylene) -NH (C 1-5 alkyl), - (C 1-5 alkylene) -NH (C 1-5 haloalkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 1-5 alkyl) -N (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) are preferably selected from the group consisting of halogen, CN, - 1-5 alkyl C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -OH, -C 1-5 alkylene, -O (C 1-5 alkyl), -C 1-5 alkylene, -O (C 1-5 haloalkyl), -SH-S (C 1-5 alkyl), -S (C 1-5 haloalkyl), - - (C 1-5 alkylene) -SH- (C 1-5 alkylene) -S (C 1-5 alkyl), - (C 1-5 alkylene) -S (C 1-5 haloalkyl), -NH 1-5 alkyl) -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -NH 1-5 alkylene) -NH (C 1-5 alkyl), -NH (C 1-5 alkylene) -NH (C 1-5 haloalkyl), -C 1-5 alkylene-N (C 1-5 alkyl), -C 1-5 alkylene-N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), more preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
19. The compound of claim 18, wherein X 2 is C-Y C2-RC2, wherein-Y C2-RC2 is selected from the group consisting of-O-C 1-12 alkyl, -NH-C 1-12 alkyl, -N (C 1-5 alkyl) -C 1-12 alkyl, -O-C 2-12 alkenyl, -NH-C 2-12 alkenyl, -N (C 1-5 alkyl) -C 2-12 alkenyl, -O-C 2-12 alkynyl, -NH-C 2-12 alkynyl, -N (C 1-5 alkyl) -C 2-12 alkynyl, - (C 0-3 alkylene) -cycloalkyl, -CO- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -CO-cycloalkyl, -CONH- (C 0-3 alkylene) -cycloalkyl, (C 0-3 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -NHCO-cycloalkyl, -NH- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -NH-cycloalkyl, -O- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) -C 0-3 cycloalkyl, - (C 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO 2 -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) -aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) -heteroaryl - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and-SO 2 -heteroaryl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH (C5352 alkyl) and wherein the heteroaryl, one or more groups are optionally substituted with one or more groups, the one or more groups are independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
20. The compound of claim 18 or 19, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -NH-heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -O-cycloalkyl, -SO 2-(C0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -CO-aryl, -CONH- 0-3 alkylene) -aryl - (C 0-3 alkylene) -CONH-aryl, -NHCO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NHCO-aryl, -NH- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -NH-aryl, -O- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -O-aryl, -SO 2-(C0-3 alkylene) -aryl, - (C 0-3 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CO-heteroaryl, -CONH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -CONH-heteroaryl, -NHCO- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NHCO-heteroaryl, -NH- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -NH-heteroaryl, -O- (C 0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -O-heteroaryl, -SO 2-(C0-3 alkylene) -heteroaryl, - (C 0-3 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and-SO 2 -heteroaryl, wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
21. The compound of any one of claims 18 to 20, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-3 alkylene) aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-3 alkylene) -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl, -C3735 alkyl), -N (C4632 alkyl), -N (C4632 alkyl), (C4632 alkyl) -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
22. The compound of any one of claims 18 to 21, wherein-Y C2-RC2 is selected from- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, and- (C 0-3 alkylene) -heteroaryl, wherein the heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
23. The compound according to any one of claims 18 to 22, wherein-Y C2-RC2 is selected from heterocycloalkyl, aryl and heteroaryl, preferably heterocycloalkyl and heteroaryl, more preferably heterocycloalkyl, wherein the heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 haloalkyl), -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
24. The compound of any one of claims 18 to 23, wherein-Y C2-RC2 is optionally substituted aryl, preferably-Y C2-RC2 is phenyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
Or wherein-Y C2-RC2 is optionally substituted heteroaryl, preferably wherein-Y C2-RC2 is imidazolyl, pyridazinyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or indazolyl, wherein heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl),
Or wherein-Y C2-RC2 is optionally substituted heterocycloalkyl, preferably wherein-Y C2-RC2 is morpholinyl, 1-dioxothiomorpholinyl, azetidinyl, pyrrolidinyl, piperidinyl, 6-oxo-1, 6-dihydropyridinyl or piperazinyl, wherein heterocycloalkyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
25. The compound of any one of claims 18 to 24, wherein-Y C2-RC2 is piperazinyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably wherein-Y C2-RC2 is piperazinyl optionally substituted (preferably N) with CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (1-5 alkyl), more preferably wherein-Y is piperazine (preferably N) is substituted (C 1-5 alkyl), preferably at a different N atom than the N atom attached to the ring system as shown in formula (I), a piperazinyl group (preferably an N-piperazinyl group).
26. The compound of any one of claims 1 to 25, wherein X 4 is C-R C4, wherein R C4 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O (C 1-6 alkyl), -S (C 1-6 alkyl), -NH (C 1-6 alkyl), -N (C 1-6 alkyl) (C 1-6 alkyl), -CO (C 1-6 alkyl), C 1-6 haloalkyl, -O (C 1-6 haloalkyl), -S (C 1-6 haloalkyl), -NH (C 1-6 haloalkyl), -N (C 1-6 haloalkyl) 2、-CO(C1-6 haloalkyl), -C 0-3 alkylene cycloalkyl, -O- (C 0-3 alkylene) -cycloalkyl, -CO- (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, -O- (C 0-3 alkylene) -heterocycloalkyl, -CO- (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, -O- (C 0-3 alkylene) -aryl, -CO- (C 0-3 alkylene) -aryl, - (C 0-3 alkylene) -heteroaryl -O- (C 0-3 alkylene) -heteroaryl and-CO- (C 0-3 alkylene) -heteroaryl;
Wherein said alkyl or said alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), C 1-5 haloalkyl, -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -N-heterocycloalkyl), -CO (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), -CON (C 1-5 alkyl) (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 2 alkyl), -NHCON (C 2、-NHCONH-(C1-5 alkyl), -N (C2 alkyl), -N (C 2、-NHCONH-(C1-5 alkyl), -CONH 2 alkyl) and-C393 2 alkyl), preferably selected from halogen, -C 2、-NHCONH-(C1-5 alkyl, -C393 2 alkyl) -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein the cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2 alkyl), -NH (C 1-5 haloalkyl), -N (C2 alkyl), -N (C 1-5 alkyl), -N 1-5 haloalkyl), -N (C 1-5 alkyl), -CO 2 alkyl -CON (C 1-5 alkyl), -CO- (N-heterocycloalkyl), -NHCO- (C 1-5 alkyl), -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), -NHCONH 1-5 alkyl), -NHCON (C 1-5 alkyl), -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and-N (C 1-5 alkyl) CON (C 1-5 alkyl), -C 1-5 alkylene) -CN, - (C 1-5 alkylene) -OH, - (C 1-5 alkylene) -O (C 1-5 alkyl), -O (C 1-5 alkylene) -O (C 1-5 haloalkyl), -SH, - (C 1-5 alkylene) -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2 alkylene) -NH (C 1-5 alkyl), -C 1-5 alkylene), -NH (C 1-5 alkyl), -C 1-5 haloalkyl - (C 1-5 alkylene) -N (C 1-5 alkyl) (C 1-5 haloalkyl), - (C 1-5 alkylene) - (N-heterocycloalkyl), - (C 1-5 alkylene) -N (C 1-5 haloalkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO (C 1-5 alkyl), - (C 1-5 alkylene) -CONH 2、-(C1-5 alkylene) -CONH (C 1-5 alkyl), - (C 1-5 alkylene) -CON (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -CO- (N-heterocycloalkyl), - (C 1-5 alkylene) -NHCO- (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) -CO- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH 2、-(C1-5 alkylene) -NHCONH- (C 1-5 alkyl), - (C 1-5 alkylene) -NHCONH (C 1-5 alkyl) (C 1-5 alkyl), - (C 1-5 alkylene) -N (C 1-5 alkyl) CONH 2、-(C1-5 alkylene) -N (C 1-5 alkyl) CONH- (C 1-5 alkyl) and- (C 1-5 alkylene) -N (C 1-5 alkyl) CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
27. The compound of any one of claims 1 to 26, wherein X 4 is C-R C4, wherein R C4 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, C 1-6 haloalkyl, - (C 0-3 alkylene) -cycloalkyl, - (C 0-3 alkylene) -heterocycloalkyl, - (C 0-3 alkylene) -aryl, and- (C 0-3 alkylene) -heteroaryl, wherein said alkyl is optionally substituted with one or more groups, the one or more groups are independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -O (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 1-5 alkyl), and-CON (C 1-5 alkyl), wherein the cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 haloalkyl), -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl).
28. The compound of claim 27, wherein R C4 is selected from hydrogen, halogen, C 1-6 alkyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -S-C 1-6 alkyl, -NH-C 1-6 alkyl, and C 1-6 haloalkyl, preferably wherein R C4 is selected from hydrogen, halogen, C 1-2 alkyl, and C 2-3 alkynyl, more preferably wherein R C4 is selected from hydrogen, halogen, and C 1-2 alkyl, even more preferably wherein R C4 is hydrogen or halogen.
29. The compound of any one of claims 1 to 28, wherein X 5 is C-R C5, wherein R C5 is selected from hydrogen, halogen, C 1-3 alkyl, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -NH-C 1-3 alkyl, and C 1-3 haloalkyl, preferably wherein R C5 is selected from hydrogen, halogen, C 1-3 alkyl, and C 1-3 haloalkyl.
30. The compound according to any one of claims 1 to 29, wherein R R5 is selected from the group consisting of C 1-12 alkyl, C 1-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl,
Wherein the alkyl, alkenyl or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -C 1-5 alkyl), -C 1-5 alkyl), -SO (C3557 haloalkyl), -SO (C3775 haloalkyl) -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
31. The compound of any one of claims 1 to 29, wherein R 4 is selected from- (C 0-2 alkylene) -cycloalkyl, -CO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CO-cycloalkyl, -CONH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NHCO-cycloalkyl, -NH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NH-cycloalkyl, -O- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -O-cycloalkyl, SO 2-(C0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, SO 2 -cycloalkyl, - (C 0-2 alkylene) -cycloalkenyl, -CO- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -CO-cycloalkenyl, -CONH- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -CONH-cycloalkenyl, - (C 0-2 alkylene) -CONH-cycloalkyl -NHCO- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -NHCO-cycloalkenyl, -NH- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -NH-cycloalkenyl, -O- (C 0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) -O-cycloalkenyl, SO 2-(C0-2 alkylene) -cycloalkenyl, - (C 0-2 alkylene) SO 2 -cycloalkenyl, -CONH-cycloalkenyl, -NHCO-cycloalkenyl, -NH-cycloalkenyl, -O-cycloalkenyl, -CO-cycloalkenyl, SO 2 -cycloalkenyl, - (C 0-2 alkylene) -heterocycloalkyl, -CO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NH-heterocycloalkyl, -C 0-2 alkylene-NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -O-heterocycloalkyl, SO 2-(C0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, SO 2 -heterocycloalkyl, - (C 0-2 alkylene) -heterocycloalkenyl, -CO- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -CO-heterocycloalkenyl, -CONH- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -CONH-heterocycloalkenyl, -NHCO- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -NHCO-heterocycloalkenyl, -NH- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -NH-heterocycloalkenyl, -O- (C 0-2 alkylene) -heterocycloalkenyl, - (C 0-2 alkylene) -O-heterocycloalkenyl, SO 2-(C0-2 alkylene, - (C 0-2 alkylene) -SO 2 -heterocycloalkenyl, -CONH-heterocycloalkenyl, -NHCO-heterocycloalkenyl, -NH-heterocycloalkenyl, -O-heterocycloalkenyl, -CO-heterocycloalkenyl, SO 2 -heterocycloalkenyl, - (C 0-2 alkylene) -aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, -CONH- (C 0-2 alkylene) -CONH-aryl, -C 0-2 alkylene) -heteroaryl - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, SO 2-(C0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl and SO 2 -heteroaryl, wherein said cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -SO (C 1-5 alkyl), -SO 42 alkyl), -S (C 1-5 haloalkyl), -SO 5326 alkyl), -N (438) haloalkyl, -NH (1-5) haloalkyl, -N (65343 alkyl) -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably selected from halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
32. The compound of any one of claims 1 to 31, wherein R 4 is selected from- (C 0-2 alkylene) -cycloalkyl, -CO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CO-cycloalkyl, -CONH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -CONH-cycloalkyl, -NHCO- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NHCO-cycloalkyl, -NH- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -NH-cycloalkyl, -O- (C 0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -O-cycloalkyl, -SO 2-(C0-2 alkylene) -cycloalkyl, - (C 0-2 alkylene) -SO 2 -cycloalkyl, -CONH-cycloalkyl, -NHCO-cycloalkyl, -NH-cycloalkyl, -O-cycloalkyl, -CO-cycloalkyl, -SO 2 -cycloalkyl, - (C 0-2 alkylene) -heterocycloalkyl, -CO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -CO-heterocycloalkyl, -CONH- (C 0-2 alkylene) -heterocycloalkyl - (C 0-2 alkylene) -CONH-heterocycloalkyl, -NHCO- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NHCO-heterocycloalkyl, -NH- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -NH-heterocycloalkyl, -O- (C 0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -O-heterocycloalkyl, -SO 2-(C0-2 alkylene) -heterocycloalkyl, - (C 0-2 alkylene) -SO 2 -heterocycloalkyl, -CONH-heterocycloalkyl, -NHCO-heterocycloalkyl, -NH-heterocycloalkyl, -O-heterocycloalkyl, -CO-heterocycloalkyl, -SO 2 -heterocycloalkyl, - (C 0-2 alkylene) -aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, -SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-heteroaryl, -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, -SO 2-(C0-2 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -CO-heteroaryl and-SO 2 -heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, -C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
33. The compound of any one of claims 1 to 32, wherein R 4 is selected from- (C 0-2 alkylene) -aryl, -CO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CO-aryl, -CONH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -CONH-aryl, -NHCO- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NHCO-aryl, -NH- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -NH-aryl, -O- (C 0-2 alkylene) -aryl, - (C 0-2 alkylene) -O-aryl, -SO 2-(C0-2 alkylene) -aryl, - (C 0-2 alkylene) -SO 2 -aryl, -CONH-aryl, -NHCO-aryl, -NH-aryl, -O-aryl, -CO-aryl, -SO 2 -aryl, - (C 0-2 alkylene) -heteroaryl, -CO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CO-heteroaryl, -CONH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -CONH-aryl -NHCO- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NHCO-heteroaryl, -NH- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -NH-heteroaryl, -O- (C 0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -O-heteroaryl, -SO 2-(C0-2 alkylene) -heteroaryl, - (C 0-2 alkylene) -SO 2 -heteroaryl, -CONH-heteroaryl, -NHCO-heteroaryl, -NH-heteroaryl, -O-heteroaryl, -CO-heteroaryl, and-SO 2 -heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C5342 alkyl), -N (C5326 alkyl), -N (C5342 alkyl) -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
34. The compound of any one of claims 1 to 32, wherein R 4 is selected from C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, preferably wherein R 4 is selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, more preferably wherein R 4 is selected from aryl and heteroaryl, even more preferably wherein R 4 is heteroaryl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more groups independently selected from halogen, -CN, -OH, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl), and-CON (C 1-5 alkyl) (C 1-5 alkyl), and wherein the heterocycle, alkyl, O (C 1-5 alkyl), SH, -S (C 1-5 alkyl), S (C 1-5 haloalkyl), NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl), N (C 1-5 alkyl), CONH 2、-CONH(C1-5 alkyl), and-CON (C82348 alkyl), and wherein the heterocycle, alkyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from C 1-5 alkyl, -SH, -C39352 haloalkyl, alkyl, 3, alkyl, and C393 alkyl -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl).
35. The compound of claim 34, wherein R 4 is five-membered heteroaryl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -O (C 1-5 haloalkyl), -SH, -S (C 1-5 alkyl), -S (C 1-5 haloalkyl), -NH 2、-NH(C1-5 alkyl), -NH (C 1-5 haloalkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -N (C 1-5 haloalkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably wherein the five membered heteroaryl is selected from imidazolyl, isoxazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, thiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 4-thiadiazolyl or 1,3, 4-thiadiazolyl, preferably wherein the five membered heteroaryl is 1,2, 4-thiadiazolyl optionally substituted with one or more groups independently selected from halogen, -CN, -OH, C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), -NH 2、-NH(C1-5 alkyl), -N (C 1-5 alkyl) (C 1-5 alkyl), -CONH 2、-CONH(C1-5 alkyl) and-CON (C 1-5 alkyl) (C 1-5 alkyl), preferably optionally substituted with C 1-5 alkyl, C 1-5 haloalkyl, -O (C 1-5 alkyl), -SH, -S (C 1-5 alkyl), more preferably optionally substituted with C 1-5 alkyl, C 1-5 haloalkyl, even more preferably optionally substituted with C 1-5 haloalkyl, preferably selected from-CH 2F、-CHF2 and CF 3, most preferably optionally substituted with-CHF 2.
36. A compound according to claim 1, selected from the group consisting of:
or a pharmaceutically acceptable salt, hydrate or solvate thereof.
37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
38. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 37, for use in therapy.
39. The compound for use or the pharmaceutical composition for use according to claim 38, for use in a method of treatment of a disease or disorder in which PARG activity is implicated.
40. The compound for use according to claim 38 or the pharmaceutical composition for use in a method of treating a proliferative disorder, preferably wherein the proliferative disorder is cancer, preferably human cancer.
CN202280067788.0A 2021-10-04 2022-10-03 PARG inhibitory compounds Pending CN118055934A (en)

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Publication number Priority date Publication date Assignee Title
CN118459452A (en) * 2024-07-10 2024-08-09 苏州国匡医药科技有限公司 PolyADP ribose hydrolase inhibitor and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118459452A (en) * 2024-07-10 2024-08-09 苏州国匡医药科技有限公司 PolyADP ribose hydrolase inhibitor and application thereof
CN118459452B (en) * 2024-07-10 2024-10-25 苏州国匡医药科技有限公司 PolyADP ribose hydrolase inhibitor and application thereof

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