RIP1 Inhibitory Compounds and Methods for Preparing and Using the Same

Abstract

The present disclosure relates to kinase inhibitory compounds, such as receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, and pharmaceutical compositions and combinations comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and / or combinations can be used to inhibit RIP1 kinase in vivo or ex vivo, and can also treat or prevent kinase-related diseases or disorders, particularly RIP1-related diseases or disorders.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of the earlier filing date of U.S. Provisional Application No. 62 / 666,452, filed May 3, 2018, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates to compounds, and methods for preparing and using the compounds, e.g., for inhibiting receptor - interacting protein - 1 kinase (“RIP1”) and for treating diseases and / or disorders associated with RIP1. Background Art

[0004] Receptor - interacting protein - 1 kinase (referred to herein as “RIP1”) belongs to the tyrosine kinase - like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling and its role in programmed cell death has been implicated in different inflammatory diseases such as inflammatory bowel disease, psoriasis, and other diseases and / or disorders associated with inflammation and / or necrotic cell death. Summary of the Invention

[0005] Compounds of formula I are provided herein:

[0006]

[0007] or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that, unless otherwise specified, compounds within the scope of formula I also include their stereoisomers, N - oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs.

[0008] Referring to formula I, ring B is a 5 - membered heteroaryl; L is a C 1-10 aliphatic linker; R 1 is R a or R b , where at least one R 1 is R b ; each of R 2 and R 3 is independently R a ; each R 4 and each R 5 is independently R a or R b ; for each occurrence, R a is independently H, D, C 1-10 aliphatic, or C 1-10 cycloaliphatic; for each occurrence, R b is independently a halogen or - NR d Rd , wherein (i) each R d is independently R a or R e ; or (ii) two R d groups together with the nitrogen to which they are attached provide a C 3-10 heterocyclic group; for each occurrence, R e is independently -OR a , -NR a , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, or two R e groups are linked together such that together with the R e group to which these two R b groups are attached provide a C 3-10 heterocyclic group; m is from 1 to 4, such as 1, 2, 3, or 4, where in a specific embodiment it is 1 or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5.

[0009] The disclosed compounds can have a structure satisfying the following formula:

[0010]

[0011] In any one or all of the above embodiments, ring B can have a structure satisfying the following formula:

[0012]

[0013] wherein at least one W is nitrogen, and each remaining W is selected from carbon, CH, oxygen, sulfur, nitrogen, or NH, where specific embodiments of ring B are triazole or oxazole. Suitable exemplary triazoles include any one of the following:

[0014]

[0015] Suitable exemplary oxazoles include any one of the following:

[0016]

[0017] Certain disclosed compounds contain an R 5 group, said R 5 group being an R a group, where R a is C 1 -C 4 aliphatic, or said R 5 group is an R b group, where R b is halogen, R 2is R a , wherein R a is C 1 -C 4 aliphatic, and R 3 is R a , wherein R a is hydrogen.

[0018] R 1 is R b , wherein R b is -NR d R d , wherein the two R d groups together with the nitrogen to which they are attached provide a C 3-10 heterocyclic group. In some embodiments, the C 3-10 heterocyclic group is substituted by one or more R e groups, and / or in certain embodiments has one or more additional heteroatoms in addition to the nitrogen to which the two R d groups are attached. In some embodiments, the C 3-10 heterocyclic group is substituted by two R e groups, the two R e groups being linked together so as to provide a C 3-10 heterocyclic group, and this C 3-10 heterocycle and the R b group can provide a spiro group or a bicyclic group. Certain disclosed spiro groups contain at least two rings, where each ring has a different number of atoms in the ring. In some embodiments, the spiro group contains at least two rings, where the first ring and the second ring of the spiro group have a different number of carbon atoms, a different number of heteroatoms, or both. In still further embodiments, each ring of the spiro group contains heteroatoms in the ring, and each ring of the spiro group can have different heteroatoms in the ring, or the same heteroatoms in the ring, such as at least one oxygen atom and at least one nitrogen atom. In some embodiments, the spiro group contains: a first ring containing a nitrogen atom and a second ring containing an oxygen atom. The spiro group contains a first ring coupled to a ring A phenyl group, where the first ring has from 3 to 7 atoms, and the second ring has from 3 to 7 atoms. Typically, the spiro group contains a total of greater than 7 atoms in the spiro system, and some embodiments have a spiro group that contains a total of 9 atoms in the spiro system.

[0019] The C e heterocycle formed by two R 3-10 groups, and the C b formed by two R d groups of R 3-10A heterocycle can provide a bicyclic group, such as a bicyclic containing one or more heteroatoms (such as nitrogen and / or oxygen) in the bicyclic group. The bicyclic group can be attached to the ring A phenyl group through the nitrogen atom of the bicyclic group. In some embodiments, the bicyclic group can be a fused bicyclic group or a bridged bicyclic group.

[0020] In any one or all of the above embodiments, R 1 is selected from:

[0021]

[0022]

[0023] where each n is independently an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; and R 6 is independently selected from hydrogen; aliphatic, such as C 1-10 aliphatic; aromatic, such as C 5-10 aromatic; or heteroaliphatic, such as C 1-10 heteroaliphatic. Exemplary compound embodiments are disclosed herein and can be selected from any one or more of Compounds I-1 to I-27.

[0024] Also disclosed herein are pharmaceutical composition embodiments that comprise a compound (or compounds) according to any one of the formulas and / or a species disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof), and at least one additional active agent and / or inactive agent, such as an excipient, therapeutic agent, adjuvant, or a combination thereof.

[0025] Also disclosed herein are methods for using the disclosed compounds. One such embodiment includes contacting receptor-interacting protein-1 (RIP1) kinase with: a compound according to any one of the formulas and / or a species disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof), or a pharmaceutical composition embodiment described herein. The contacting can occur ex vivo or in vivo.

[0026] Also disclosed is a method of treating a disease in a subject, the method comprising administering to the subject (i) a therapeutically effective amount of a compound according to any one of the formulas and / or a species disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof); or (ii) a therapeutically effective amount of a pharmaceutical composition of the compound; wherein the subject has or is suspected of having or developing the disease, the disease being related to receptor-interacting protein-1 (RIP1) kinase.

[0027] The foregoing and other objects, features, and advantages of the present disclosure will become apparent from the following detailed description. Detailed Description

[0028] I. Overview of Terms

[0029] The following explanations of terms and methods are provided to better describe the present disclosure and to guide one of ordinary skill in the art in practicing the present disclosure. The singular forms “a / an” and “the” refer to one or more than one, unless the context clearly indicates otherwise. The term “or” refers to a single element of the stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, “comprising” means “including.” Thus, “comprising A or B” means “including A, B, or A and B” without excluding additional elements. All references (including patents and patent applications) cited herein are incorporated by reference.

[0030] Unless otherwise specified, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, etc., as used in the specification or claims will be understood to be modified by the term “about.” Accordingly, unless explicitly or implicitly stated otherwise, the numerical parameters set forth are approximations that may depend upon the desired properties and / or the detection limits in standard test conditions / methods. When distinguishing embodiments directly or explicitly from the prior art being discussed, the number of embodiments is not approximate unless the term “about” is explicitly recited.

[0031] Unless otherwise interpreted, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the following describes suitable methods and materials. These materials, methods, and examples are illustrative only and not intended to be limiting.

[0032] When depicting or describing a chemical structure, unless otherwise clearly stated, it is assumed that all carbons include hydrogens such that each carbon conforms to a tetravalent valence. For example, in the structure on the left hand side of the following schematic, nine hydrogen atoms are implied. The nine hydrogen atoms are depicted in the left hand side structure.

[0033]

[0034] Sometimes a particular atom in a structure is described in the chemical formulas herein as having a hydrogen or hydrogen atoms, e.g., -CH 2 CH 2 -. One of ordinary skill in the art will understand that the techniques described above are common in the chemical arts to provide brevity and simplicity in the description of organic structures.

[0035] If R is depicted as "floating" on the ring system, such as R in the following groups, for example 1 :

[0036]

[0037] then unless otherwise defined, the substituent R (such as the above R 1 ) can be present on any atom of the fused bicyclic system, excluding the atom carrying the bond with the symbol, as long as a stable structure can be formed.

[0038] When the group R is depicted as being present on a ring system containing saturated carbon, such as in the following formula:

[0039]

[0040] wherein, in this example, y can be more than one, assuming the currently depicted, implied, or explicitly defined hydrogens on each alternative ring; then unless otherwise defined, two R's can be present on the same carbon. A simple example is when R is a methyl group. The depicted structure can exist as a gem - dimethyl on the carbon of the depicted ring ("annular" carbon). In another example, two R's (including the same carbon) on the same carbon can be included in the ring, thus generating a spiro ring ("spirocyclic" group) structure. For example, as shown below, in a spiro arrangement with a piperidine or azetidine ring, two Rs can form an oxetane or tetrahydropyran, such as:

[0041]

[0042] As used herein, the term "substituted" refers to all subsequent modifying portions of the term. For example, in the term "substituted aryl C 1-8 alkyl", substitution can occur on the "C 1-8 alkyl" portion, the "aryl" portion, or both portions of the aryl C 1-8 alkyl group.

[0043] When used to modify a specific group or moiety, "substituted" means that at least one, and perhaps two or more, hydrogen atoms of the designated group or moiety are independently replaced by the same or different substituent groups as defined below. In specific embodiments, a group, moiety, or substituent may be substituted or unsubstituted, unless explicitly defined as "unsubstituted" or "substituted". Thus, any of the groups designated herein may be unsubstituted or substituted, unless the context otherwise indicates or the specific structural formula excludes substitution. In specific embodiments, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" moiety may be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" is not substituted.

[0044] Unless otherwise specified, a "substituent" or "substituent group" used to replace one or more hydrogen atoms on a saturated carbon atom in a designated group or moiety may be -R 60 , halo, =O, -OR 70 , -SR 70 , -N(R 80 ) 2 , haloalkyl, perhaloalkyl, -CN, -NO 2 , =N 2 , -N 3 , -SO 2 R 70 , -SO 3 - M + , -SO 3 R 70 , -OSO 2 R 70 , -OSO 3 - M + , -OSO 3 R 70 , -P(O)(O - ) 2 (M + ) 2 , -P(O)(O - ) 2 M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 ) 2 , -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 - M + , -CO 2 R 70 、-C(S)OR 70 、-C(O)N(R 80 ) 2 、-C(NR 70 )(R 80 ) 2 、-OC(O)R 70 、-OC(S)R 70 、-OCO 2 - M + 、-OCO 2 R 70 、-OC(S)OR 70 、-NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO 2 - M + 、-NR 70 CO 2 R 70 、-NR 70 C(S)OR 70 、-NR 70 C(O)N(R 80 ) 2 、-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 ) 2 , where R 60 It is C 1-10 aliphatic, heteroaliphatic, or cycloaliphatic, typically C 1-6 Aliphatic, more typically C 1-6 Alkyl, where R 60 Optionally may be substituted; for each occurrence, each R 70 are independently hydrogen or R 60 ; For each occurrence, each R 80 Independently R 70 , or alternatively two R 80 The group together with the nitrogen atom to which it is attached forms a 3- to 7-membered heterocycloaliphatic group, which optionally includes from 1 to 4 identical or different additional heteroatoms selected from O, N and S, wherein N optionally has R 70is replaced, for example, by H or C 1 -C 3 is alkyl-substituted; and each M + is a counterion having a net single positive charge. Each M + is independently, in each occurrence, for example, an alkali metal ion such as K + 、Na + 、Li + ; an ammonium ion such as + N(R 60 ) 4 ; a protonated amino acid ion such as a lysine ion or an arginine ion; or an alkaline earth metal ion (such as [Ca 2+ 0.5 、[Mg 2+ 0.5 or [Ba 2+ 0.5 (the subscript “0.5” means that, for example, one of the counterions for such divalent alkaline earth ions can be the ionized form of the compound of the present invention, and other typical counterions (such as chloride) or two ionized compounds can act as the counterions for such divalent alkaline earth ions, or a doubly ionized compound can act as the counterion for such divalent alkaline earth ions). As a specific example, -N(R 80 ) 2 includes -NH 2 、-NH-alkyl、-NH-pyrrolidin-3-yl、N-pyrrolidinyl、N-piperazinyl、4N-methyl-piperazin-1-yl、N-morpholinyl, etc. For example, any two hydrogen atoms on a single carbon can also be replaced by, for example, =O、=NR 70 、=N-OR 70 、=N 2 or =S.

[0045] Unless otherwise specified, the substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbon are -R 60 、halo、-O - M + 、-OR 70 、-SR 70 、-S - M + 、-N(R 80 ) 2 、perhaloalkyl、-CN、-OCN、-SCN、-NO、-NO 2 、-N 3 、-SO 2 R 70 、-SO 3 - M + 、-SO 3 ​​​R 70 、 -OSO 2 R 70 、 -OSO 3 - M + 、 -OSO 3 R 70 、 -PO 3 -2 (M + ) 2 、 -PO 3 -2 M 2+ 、 -P(O)(OR 70 )O - M + 、 -P(O)(OR 70 ) 2 、 -C(O)R 70 、 -C(S)R 70 、 -C(NR 70 )R 70 、 -CO 2 - M + 、 -CO 2 R 70 、 -C(S)OR 70 、 -C(O)NR 80 R 80 、 -C(NR 70 )N(R 80 ) 2 、 -OC(O)R 70 、 -OC(S)R 70 、 -OCO 2 - M + 、 -OCO 2 R 70 、 -OC(S)OR 70 、 -NR 70 C(O)R 70 、 -NR 70 C(S)R 70 、 -NR 70 CO 2 - M + 、 -NR 70 CO 2 R 70 、 -NR 70 C(S)OR 70 、 -NR 70 C(O)N(R 80 ) 2 、 -NR 70 C(NR70 )R 70 and -NR 70 C(NR 70 )N(R 80 ) 2 , where R 60 , R 70 , R 80 and M + are as previously defined. In an independent embodiment, the substituent is not -O - M + , -OR 70 , -SR 70 , or -S - M + .

[0046] Unless otherwise specified, the substituent groups for replacing hydrogen atoms on the nitrogen atoms in groups containing such nitrogen atoms are -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 ) 2 , perhaloalkyl, -CN, -NO, -NO 2 , -S(O) 2 R 70 , -SO 3 - M + , -SO 3 R 70 , -OS(O) 2 R 70 , -OSO 3 - M + , -OSO 3 R 70 , -PO 3 2- (M + ) 2 , -PO 3 2- M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2 R 70 、-C(S)OR 70 、-C(O)NR 80 R 80 、-C(NR 70 )NR 80 R 80 、-OC(O)R 70 、-OC(S)R 70 、-OCO 2 R 70 、-OC(S)OR 70 、-NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO 2 R 70 、-NR 70 C(S)OR 70 、-NR 70 C(O)N(R 80 ) 2 、-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 ) 2 , where R 60 , R 70 , R 80 and M + is as defined previously.

[0047] In one embodiment, a substituted group has at least one substituent, up to as many substituents as possible for the particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

[0048] Additionally, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Therefore, in a group or moiety comprising a first group, the first group is a substituent on a second group, the second group itself is a substituent on a third group, the group or moiety is attached to the parent structure, and the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group comprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with a substituent that is not itself substituted.

[0049] As will be understood by one of ordinary skill in the art, any group or moiety defined herein can be attached to any other part of the disclosed structure (e.g., a parent or core structure), e.g., by considering valence rules, comparison with exemplary species, and / or consideration of functionality, unless the context clearly states or implies the connectivity of the group or moiety to the other part of the structure.

[0050] "Acyl" means the group -C(O)R, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C 1 -C 6 alkyl, -C(O)C 1 -C 6 haloalkyl -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl or -C(O)heterocycloalkyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et or -C(O)cyclopropyl.

[0051] "Aliphatic" means a group or moiety that is substantially hydrocarbon-based. Aliphatic groups or moieties can be acyclic, including alkyl, alkenyl, or alkynyl groups (and alkylene, alkenylene, or alkynylene groups), their cyclic forms, such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl or cycloalkynyl, and further include straight-chain and branched arrangements, as well as all stereoisomers and positional isomers. Unless otherwise expressly stated, aliphatic groups contain from one to twenty-five carbon atoms (C 1-25 ); for example, for acyclic aliphatic groups or moieties, from one to fifteen (C 1-15 ), from one to ten (C 1-10 ), from one to six (C 1-6 ), or from one to four carbon atoms (C 1-4 ), or for cycloaliphatic groups or moieties, from three to fifteen (C 3-15 ), from three to ten (C 3-10 ), from three to six (C 3-6 ), or from three to four (C 3-4 ) carbon atoms. Aliphatic groups can be substituted or unsubstituted, unless "unsubstituted aliphatic" or "substituted aliphatic" is expressly mentioned. Aliphatic groups can be substituted with one or more substituents (up to two substituents for each methylene carbon in the aliphatic chain, or up to one substituent for each carbon of a -C=C- double bond in the aliphatic chain, or up to one substituent for the carbon of a terminal methylene group).

[0052] "Lower aliphatic" means an aliphatic group containing from one to ten carbon atoms (C 1-10), for example from one to six (C 1-6 ), or from one to four (C 1-4 ) carbon atoms; or for lower cycloaliphatic groups, from three to ten (C 3-10 ), for example from three to six (C 3-6 ) carbon atoms.

[0053] "Alkoxy" means the group -OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group. In certain instances, R is a C 1-6 alkyl group or a C 3-6 cycloalkyl group. Methoxy (-OCH 3 ) and ethoxy (-OCH 2 CH 3 ) are exemplary alkoxy groups. In a substituted alkoxy, R is a substituted alkyl or a substituted cycloalkyl, and examples in the compounds of the present disclosure include haloalkoxy groups, such as -OCF 2 H.

[0054] "Alkoxyalkyl" means the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH 2 CH 2 -O-CH 2 CH 3 is an exemplary alkoxyalkyl group.

[0055] "Alkyl" means a saturated aliphatic hydrocarbon group having from 1 to at least 25 carbon atoms (C 1-25 ), more typically 1 to 10 carbon atoms (C 1-10 ), for example 1 to 6 carbon atoms (C 1-6 ). The alkyl moiety can be substituted or unsubstituted. By way of example, this term includes straight-chain or branched hydrocarbon groups such as methyl (CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 )) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), isobutyl (-CH 2 CH 2 (CH 3 )) 2 ), sec-butyl (-CH(CH 3)CH 2 CH 3 )、tert-butyl (-C(CH 3 ) 3 )、n-pentyl (-CH 2 CH 2 CH 2 CH 2 CH 3 )、and neopentyl (-CH 2 C(CH 3 ) 3 )。

[0056] "Amino" means the group -NH 2 -, -NHR, or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aromatic (including both aryl and heteroaryl), heterocycloaliphatic, or two R groups together with the attached nitrogen form a heterocycle. Examples of such heterocycles include those in which two R groups together with the attached nitrogen form a -(CH 2 ) 2-5 -ring, which ring is optionally interrupted by one or two heteroatom groups (such as -O- or -N(R g ))), for example in the group where R g is R 70 -, -C(O)R 70 -, -C(O)OR 60 or -C(O)N(R 80 ) 2 .

[0057] "Amide" means the group -N(R)acyl, where R is hydrogen, heteroaliphatic, or aliphatic, such as alkyl, especially C 1-6 alkyl.

[0058] Unless otherwise specified, "aromatic" means a cyclic conjugated group or moiety having from 5 to 15 ring atoms, having a single ring (such as phenyl, pyridyl, or pyrazolyl) or multiple fused rings, in which at least one ring is aromatic (such as naphthyl, indolyl, or pyrazolopyridyl), that is, at least one ring, and optionally multiple fused rings, having a continuous delocalized π electron system. Typically, the number of out-of-plane π electrons corresponds to Hückel's rule (4n + 2). The point of attachment of the parent structure is typically through the aromatic portion of the fused ring system. For example However, in certain instances, the context or the explicit disclosure may indicate that the point of attachment is through the non-aromatic portion of the fused ring system. For example An aromatic group or moiety may contain only carbon atoms in the ring, such as in an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms that contain lone electron pairs (such as S, O, N, P, or Si), such as in a heteroaryl group or moiety. Unless otherwise specified, an aromatic group may be substituted or unsubstituted.

[0059] Unless otherwise indicated, "aryl" refers to an aromatic carbocyclic group having from 6 to 15 carbon atoms, said aromatic carbocyclic group having a single ring (such as phenyl) or multiple fused rings in which at least one ring is aromatic (such as 1,2,3,4-tetrahydroquinoline, benzodifuran, etc.). If any aromatic ring contains a heteroatom, the group is heteroaryl and not aryl. For example, an aryl group may be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, an aryl group may be substituted or unsubstituted.

[0060] "Arylaliphatic" refers to an aryl group attached to a parent via an aliphatic moiety. Arylaliphatic includes aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0061] "Carboxyl" refers to -CO 2 H.

[0062] "Formamide" refers to -C(O)amino.

[0063] "Carboxyl ester" ("Carboxyl ester" or "carboxy ester") refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0064] "Carboxylate" refers to -C(O)O - or its salt.

[0065] "Cyano" refers to the group -CN.

[0066] "Cycloaliphatic" refers to a cycloaliphatic group having a single ring (such as cyclohexyl), or multiple rings (such as fused rings, bridged rings, or spiro ring systems where at least one of the rings in the ring or system is aliphatic). Typically, the point of attachment of the parent structure is through the aliphatic moiety of the polycyclic system. Cycloaliphatic includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. A cycloaliphatic group may contain from three to twenty-five carbon atoms; for example, from three to fifteen, from three to ten, or from three to six carbon atoms. Unless otherwise specified, a cycloaliphatic group may be substituted or unsubstituted. Exemplary cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0067] "Halogen", "halide", or "halogen element" means fluorine, chlorine, bromine, or iodine.

[0068] "Haloalkyl" means an alkyl moiety substituted with one or more halogen atoms. Exemplary haloalkyl moieties include -CH 2 F, -CHF 2 and -CF 3 .

[0069] "Heteroaliphatic" means an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., at least one carbon atom from an aliphatic compound or group containing at least two carbon atoms has been replaced by an atom having at least one lone pair of electrons (typically nitrogen, oxygen, phosphorus, silicon, or sulfur). Heteroaliphatic compounds or groups can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, such as heteroalicyclic groups.

[0070] Unless otherwise specified, "heteroaryl" means an aromatic group or moiety having from 5 to 15 ring atoms and containing at least one carbon atom and at least one heteroatom (such as N, S, O, P, or Si). Heteroaryl groups or moieties can contain a single ring (such as pyridyl, pyrimidinyl, or pyrazolyl) or multiple fused rings (such as indolyl, benzopyrazolyl, or pyrazolopyridyl). For example, heteroaryl groups or moieties can be monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, heteroaryl groups or moieties can be substituted or unsubstituted.

[0071] "Heterocyclic group", "heterocycle" ("heterocyclo" and "heterocycle") refers to both aromatic and non-aromatic ring systems, and more particularly to stable three- to fifteen-membered ring moieties containing at least one carbon atom (and typically multiple carbon atoms) and at least one (e.g., from one to five) heteroatom. The one or more heteroatoms can be one or more nitrogen, phosphorus, oxygen, silicon, or sulfur atoms. The heterocyclic group moiety can be a monocyclic moiety or can contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of these rings contains a heteroatom. Such polycyclic moieties can include fused or bridged ring systems as well as spiro ring systems; and any nitrogen, phosphorus, carbon, silicon, or sulfur atom in the heterocyclic group moiety can optionally be oxidized to various oxidation states. For convenience, particularly but not exclusively, those defined as cyclic aromatic nitrogens are not meant to include their corresponding N-oxide forms, although not explicitly defined as such in a particular instance. Thus, for a compound having, for example, a pyridyl ring; unless the context otherwise explicitly excludes or precludes, the corresponding pyridyl-N-oxide is included as another compound of the present disclosure. In addition, the cyclic nitrogen atom can optionally be quaternized. Heterocycles include heteroaryl moieties and heterocycloalkyl or heterocyclic aliphatic moieties, which are partially or fully saturated heterocyclic group rings. Examples of heterocyclic group moieties include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazole, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, tetrahydroisoquinolinyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridyl, tetrahydropyridyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolinyl, isoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furanyl, diazabicycloheptane, diazapane, diazepinyl, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothielyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

[0072] "Hydroxy" refers to the group -OH.

[0073] "Nitro" means the group -NO 2 .

[0074] "Phosphate ester" means the group -O-P(O)(OR'), 2 where each -OR' is independently -OH, -O-aliphatic (e.g., -O-alkyl or -O-cycloalkyl), -O-aromatic (including both -O-aryl and -O-heteroaryl), -O-arylalkyl, or -OR' is -O - M + where M + is a counterion having a single positive charge. Each M + can be a basic ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R") 4 , where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth metal ion, such as [Ca 2+ 0.5 , [Mg 2+ 0.5 or [Ba 2+ 0.5 . Phosphorylalkyl means the group -alkyl-phosphate ester, such as -CH 2 OP(O)(OH) 2 , or its salt, such as -CH 2 OP(O)(O - Na + ) 2 , and (((dialkoxyphosphoryl)oxy)alkyl) means a dialkyl ester of phosphorylalkyl, such as -CH 2 OP(O)(O-tert-butyl) 2 .

[0075] "Phosphonate ester" means the group -P(O)(OR'), 2 where each -OR' is independently -OH, -O-aliphatic (e.g., -O-alkyl or -O-cycloalkyl), -O-aromatic (including both -O-aryl and -O-heteroaryl), or -O-arylalkyl, or -OR' is -O - M + , and M + is a counterion having a single positive charge. By way of example, each M + is a positively charged counterion and can be an alkali metal ion, such as K + , Na + , Li + ; an ammonium ion, such as​​​+ N(R”) 4 , wherein R” is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth metal ion such as [Ca 2+ 0.5 、[Mg 2+ 0.5 or [Ba 2+ 0.5 . Phosphorylalkyl refers to the group -alkyl-phosphonate, such as -CH 2 P(O)(OH) 2 、or -CH 2 P(O)(O - Na + ) 2 , and ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of phosphorylalkyl, such as -CH 2 P(O)(O-tert-butyl) 2 .

[0076] "Patient" or "subject" generally can refer to any living being, but more typically refers to mammals and other animals, especially humans. Thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0077] ​​​"Pharmaceutically acceptable excipient" refers to a substance other than the active ingredient, which is included in the formulation of the active ingredient. As used herein, the excipient can be incorporated within the granules of the pharmaceutical composition, or it can be physically mixed with the granules of the pharmaceutical composition. For example, an excipient can be used to dilute the active agent and / or modify the properties of the pharmaceutical composition. Excipients can include, but are not limited to, anti-adhesives, binders, coatings, enteric coatings, disintegrants, flavoring agents, sweetening agents, coloring agents, lubricants, glidants, adsorbents, preservatives, carriers or vehicles. Excipients can be starches and modified starches, celluloses and cellulose derivatives, sugars and their derivatives (such as disaccharides, polysaccharides and sugar alcohols), proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS or TPGS), carboxymethyl cellulose, dipalmitoyl phosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugars, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

[0078] "Adjuvant" is a component that modifies the effect of other agents (typically the active ingredient). Adjuvants are usually pharmaceutical and / or immunological agents. Adjuvants can improve the action of the active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants (such as Freund's complete adjuvant or Freund's incomplete adjuvant).

[0079] "Pharmaceutically acceptable carrier" refers to an excipient that acts as a carrier or vehicle, such as a suspending aid, solubilizing aid or nebulizing aid. Remington: The Science and Practice of Pharmacy, Philadelphia College of Pharmacy, Editors: Lippincott, Williams, and Wilkins, Philadelphia, PA, 21st Edition (2005) (incorporated herein by reference), describes exemplary compositions and formulations suitable for the delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0080] Typically, the nature of the carrier will depend on the specific mode of administration employed. For example, parenteral formulations generally include injectable liquids that include pharmaceutically or physiologically acceptable liquids such as water, saline, balanced salt solutions, aqueous dextrose, glycerol, or the like such as vehicles. In some instances, the pharmaceutically acceptable carrier may be sterile to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to the biologically neutral carrier, the pharmaceutical composition to be administered may contain small amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents, etc., such as sodium acetate or sorbitan monolaurate.

[0081] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of compounds derived from a variety of organic and inorganic counterions as would be known to one of ordinary skill in the art, and by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, etc.; and when the molecule contains basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free base upon formation by an acid partner. Specifically, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid, etc. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases (such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc.). Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include but are not limited to primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and base ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.). Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977; 66:1-19, which is incorporated herein by reference). In a specific disclosed embodiment, the compound may be a formate, trifluoroacetate, hydrochloride, or sodium salt.

[0082] "Effective amount" of a compound or pharmaceutical composition means an amount of the compound or pharmaceutical composition sufficient to achieve a particular desired result, such as inhibition of a protein or enzyme. In a specific embodiment, the effective amount is an amount sufficient to inhibit RIP1; to elicit a desired biological or medical response in a tissue, system, subject or patient; to treat a particular disorder or disease; to ameliorate or eliminate one or more of its symptoms; and / or to prevent the occurrence of a disease or disorder. One of ordinary skill in the art will understand that the amount of the compound that constitutes an "effective amount" can vary depending on the compound, the desired result, the disease state and its severity, the size, age, and gender of the patient to be treated, etc.

[0083] A "prodrug" is a compound that is converted in vivo to yield a biologically active compound, or a compound that is more biologically active compared to the parent compound. For example, the in vivo conversion can occur by hydrolysis or enzymatic transformation. Common examples of prodrug moieties include, but are not limited to, the ester and amide forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present disclosure include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C 1-6 alkyl esters). Other prodrug moieties include phosphate esters, such as -CH 2 -O-P(O)(OR') 2 or its salts, where R' is H or C 1-6 alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present disclosure include, but are not limited to, primary, secondary, and tertiary alkyl amides (e.g., having between about one and about six carbons). The disclosed amides and esters of the compounds according to the invention can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in the following references: T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0084] "Solvate" refers to a complex formed by the combination of solvent molecules with the molecules or ions of a solute. The solvent can be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, and propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide, tetrahydrofuran, alkyl sulfoxides such as dimethyl sulfoxide, water, and combinations thereof. When combined with a pharmaceutically acceptable or unacceptable solvent (such as water, ethanol, etc.), the compounds described herein can exist in both non-solvated and solvated forms. The solvate forms of the compounds of the present disclosure are within the scope of the examples disclosed herein.

[0085] "Sulfonamide" refers to the group or moiety -SO 2 amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0086] "Thioalkyl" refers to the group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

[0087] "Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, or -S(O)aromatic (including both -S(O)aryl and -S(O)heteroaryl).

[0088] "Sulfonyl" refers to the group: -SO 2 H, -SO 2 aliphatic, -SO 2 heteroaliphatic, -SO 2 aromatic (including -SO 2 aryl and -SO 2 heteroaryl both).

[0089] As used herein, "treating" (Treating or treatment) involves treating a disease or disorder of interest in a patient and subject (particularly a human having a disease or disorder of interest), and includes, by way of example and not limitation:

[0090] (i) preventing the occurrence of a disease or disorder in a patient or subject, particularly when such patient or subject is predisposed to the disorder but has not yet been diagnosed as having it;

[0091] (ii) inhibiting the disease or disorder, such as preventing or slowing its development;

[0092] (iii) alleviating the disease or disorder, such as causing a reduction in symptoms or the regression of the disease or disorder or its symptoms; or

[0093] (iv) stabilizing the disease or disorder.

[0094] As used herein, the terms "disease" and "disorder" may be used interchangeably or may be different, since a particular malady or disorder may not have a known causative agent (so the etiology is not yet determined) and is thus not yet considered a disease but only an undesirable disorder or syndrome, in which a more or less specific set of symptoms is identified by a clinician.

[0095] The above definitions and the following general chemical formulas are not intended to include non-permissible substitution patterns (e.g., a methyl group substituted with five fluorine groups). Such non-permissible substitution patterns are readily recognizable to those of ordinary skill in the art.

[0096] Those of ordinary skill in the art will understand that a compound may exhibit tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may include one or more chiral centers and / or double bonds and may thus exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof (such as racemic mixtures). As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms and mixtures thereof. Since the various compound names, chemical formulas, and chemical structures within the specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, those of ordinary skill in the art will understand that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric forms of the compounds described herein, along with mixtures of these various different isomeric forms. Techniques known to those of ordinary skill in the art, particularly in light of this disclosure, may be used to separate mixtures of different isomeric forms (including mixtures of enantiomers and / or stereoisomers), thereby providing each individual enantiomer and / or stereoisomer. Atropisomers are also possible in the case of restricted rotation (e.g., around an amide bond or between two directly attached rings (such as a pyridyl ring, a biphenyl group, etc.)) and are specifically included in the compounds of the present invention.

[0097] In any embodiment, any or all of the hydrogens present in or within a particular group or moiety of the compound may be replaced by deuterium or tritium. Thus, the recitation of an alkyl group includes deuterium-containing alkyl groups in which from one to the maximum number of hydrogens present may be replaced by deuterium. For example, ethyl refers to C 2 H 5 or C 2 H 5 both (where from 1 to 5 hydrogens are replaced by deuterium, such as in C 2 D x H 5-x ).

[0098] II. RIP1 Active Compounds and Pharmaceutical Compositions Containing RIP1 Active Compounds

[0099] A. Compounds

[0100] Compounds and pharmaceutical compositions containing such compounds that can be used to inhibit RIP1 and / or for treating diseases and / or disorders associated with RIP1 are disclosed herein. In some embodiments, the compounds are selective kinase inhibitors. For example, relative to RIP2, RIP3, or both RIP2 and RIP3, the exemplary compounds are capable of selectively inhibiting RIP1. In some embodiments, the compounds of the present disclosure may have a structure that satisfies Formula I

[0101]

[0102] or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that within its scope, the disclosed general formula includes all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs of compounds that additionally have the structural features required by such formula.

[0103] Referring to Formula I:

[0104] Ring B is a 5-membered heteroaryl;

[0105] L is C 1-10 an aliphatic linker;

[0106] R 1 is R a or R b wherein at least one R 1 is R b ;

[0107] Each of R 2 and R 3 is independently R a ;

[0108] Each R 4 and each R 5 is independently R a or R b ;

[0109] For each occurrence, R a is independently H or D (except for embodiments where L and / or R 1 is R a ), C 1-10 aliphatic, or C 1-10 cycloaliphatic;

[0110] For each occurrence, R b is independently a halogen or -NR d Rd , wherein (i) each R d is independently R a or R e ; or (ii) two R d groups together with the nitrogen to which they are attached provide a C 3-10 heterocyclic group, and in some embodiments provide a C 3-10 heterocyclic group, the C 3-10 heterocyclic group being substituted by one or more R e and / or R g groups, and / or having one or more additional heteroatoms in addition to the nitrogen to which the two R d groups are attached;

[0111] For each occurrence, R e is independently -OR a , -NR a , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, or two R e groups are joined together such that together with the R e group to which these two R b groups are attached provide a C 3-10 heterocyclic group, and in some embodiments, the C 3-10 heterocyclic group is substituted by one or more R g groups;

[0112] R g is halogen, C 1-10 aliphatic-C 5-10 aromatic, or =O;

[0113] m is from 1 to 4, such as 1, 2, 3, or 4, and in specific embodiments is 1 or 2;

[0114] n is 0, 1, or 2; and

[0115] p is 0, 1, 2, 3, 4, or 5.

[0116] In a specific embodiment of formula I, the 5-membered heteroaryl may have a structure satisfying the formula , wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered heteroaryl group is a triazole or an oxazole. Exemplary triazoles include any one of the following:

[0117]

[0118] Exemplary oxazoles include any one of the following:

[0119]

[0120] In a specific embodiment of Formula I, L is C 1-10 an aliphatic linker, such as C 1- C 4 an alkylene linker (e.g., -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, or -CH 2 CH 2 CH 2 CH 2 -). In some embodiments, L is -CH 2 -.

[0121] R 1 can be located on any suitable one or more carbon atoms of benzene ring A, such as at positions 1, 2, 3, or 4, as illustrated in Formula I. In some embodiments, one R 1 is R a wherein R a is C 1- C 10 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, or decyl), and the second R 1 is R b wherein R b is a halogen (e.g., Br, F, I, or Cl) or -NR d R d wherein the two R d groups together with the nitrogen to which they are attached provide a C 4-9 heterocyclic group. In some embodiments, the C 4-9 heterocyclic group is substituted with one or more R e groups, and / or has one or more additional heteroatoms in addition to the nitrogen to which the two R d groups are attached. Some compound embodiments include an R b group that is an R 1 group wherein R b is -NR d R d wherein (i) each R d is independently R a or R e ; or (ii) the two R d groups together with the nitrogen to which they are attached provide a C 4-9 heterocyclic group. In some embodiments, R bis - NR d R d , wherein one R d is R a , wherein R a is H, and the other R d is R e , wherein R e is C 1-6 haloalkyl. In some embodiments, the heterocyclic group contains 1 or 2 heteroatoms (including the nitrogen atom of R b ). Certain heterocyclic groups contain the nitrogen atom of the R b group, as well as an oxygen atom or an additional nitrogen atom. In some compound embodiments, the heterocyclic group is attached to the benzene ring of ring A of formula I via the nitrogen atom of the R b group. In some embodiments, the heterocyclic group is substituted by two R e groups, where for each occurrence, R e is independently C 1-6 haloalkyl (e.g., -CH 2 Cl) or C 1-6 heteroalkyl (e.g., CH 2 OH). The heterocyclic group is a 6 - membered or 7 - membered heterocyclic group. In an exemplary embodiment, the heterocyclic group is:

[0122]

[0123] wherein each n is independently an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; and R 6 is selected from hydrogen; aliphatic, such as C 1-10 aliphatic; aromatic, such as C 5-10 aromatic; or heteroaliphatic, such as C 1-10 heteroaliphatic.

[0124] In some embodiments, R 1 is R b , wherein R b is - NR d R d and the two R d groups together with the nitrogen to which they are attached provide a C e heterocyclic group substituted by at least two R 4-9 groups, where the two R e groups are linked together such that together with the R b group to which they are attached provide a C 3-10 heterocyclic group. In such embodiments, the two R e groups can be linked together such that a bicyclic group or a spirocyclic group is provided (where one ring of the bicyclic group or spirocyclic group is provided by the R b group, and one ring of the bicyclic group or spirocyclic group is provided by the two Re The group provides another ring of a bicyclic group or a spiro group). In embodiments comprising a spiro group, each ring of the spiro group may have the same number of atoms or a different number of atoms. In a specific embodiment, the spiro group comprises at least two rings, wherein the first ring and the second ring of the spiro group have a different number of carbon atoms, a different number of heteroatoms, or both. In some embodiments, the two rings of the spiro group comprise the same number of carbon atoms, the same number of heteroatoms, or both. In some embodiments, each ring of the spiro group contains a heteroatom in the ring, and in each ring, the heteroatoms may be the same, or each ring of the spiro group may have different heteroatoms in the ring. The spiro group may comprise a first ring coupled to a carbon atom of the ring A phenyl group, wherein the first ring has from 3 to 7 atoms, and the second ring has from 3 to 7 atoms. In some embodiments, in addition to the nitrogen atom of R b , the spiro group further comprises at least one oxygen atom. The spiro group may contain a total of more than 7 atoms in the spiro system, wherein a specific embodiment contains a total of 9 atoms in the spiro system. In an exemplary embodiment, R b , together with two R e groups, may provide the following spiro rings:

[0125]

[0126] wherein R 6 is selected from hydrogen; aliphatic, such as C 1-10 aliphatic; aromatic, such as C 5-10 aromatic; or heteroaliphatic, such as C 1-10 heteroaliphatic.

[0127] A bicyclic group may be provided by the R b group and the two attached R e groups. The bicyclic group contains two or more heteroatoms in the bicyclic group. In such embodiments, the two or more heteroatoms are nitrogen and / or oxygen. In some embodiments, when R b is -NR d R d , the bicyclic group is attached to the carbon atom of the ring A phenyl group described in the general formula provided herein through the nitrogen atom of the R b group. The bicyclic group may be any bicyclic group, including a fused bicyclic group and a bridged bicyclic group, but for certain exemplary embodiments, the bicyclic group is a 2.2.1 bicyclic, 3.2.1 bicyclic, or 3.2.2 bicyclic. In an exemplary embodiment, when R b , together with two R e groups, provides a bicyclic group, the bicyclic group may be:

[0128]

[0129] where each n is independently an integer ranging from 0 to 4, such as 0, 1, 2, 3, or 4; and R 6 is independently selected from hydrogen; aliphatic, such as C 1-10 aliphatic; aromatic, such as C 5-10 aromatic; or heteroaliphatic, such as C 1-10 heteroaliphatic.

[0130] In some embodiments, each of R 2 and R 3 is independently R a where R a is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In a specific embodiment, each of R 2 and R 3 is independently hydrogen or methyl. In an exemplary embodiment, R 2 is methyl and R 3 is hydrogen.

[0131] In some embodiments, each R 4 independently and / or each R 5 independently is R a or R b where for each occurrence, R a is independently an alkyl, alkenyl, or alkynyl, and where R b is chlorine, bromine, iodine, or fluorine. In a specific embodiment, each R 4 and / or each R 5 is independently a lower alkyl or fluorine.

[0132] In some embodiments, m is 1; n is 0 or 1; and p is 0 or 1. In a specific embodiment, m is 1, n is 0, and p is 0 or 1.

[0133] The compound having formula I may also have a structure satisfying any one or more of formulas II and IIA - IIC.

[0134]

[0135] Referring to formulas II and IIA - IIC, each of R 1 and R 5 is as recited above for formula I. In a specific embodiment, R 1 is R b where R b is -NR dR d and two of the Rs d groups, together with the nitrogen to which they are attached, provide a heterocycle substituted by two Rs e groups, where for each occurrence, the R e group is independently haloalkyl or C 1-6 heteroalkyl, or where two of the R e groups are joined together such that, together with the R e group to which the two Rs b groups are attached, provide a C 3-10 heterocyclic group. In some embodiments, and two of the R e groups are bicyclic or spiro groups. In specific embodiments, R 5 is present and is fluorine. In other specific embodiments, R 5 is absent. Referring to Formulas IIA - IIC, each W is independently nitrogen or oxygen.

[0136] In some embodiments, a compound having Formula I may also have a structure that satisfies any one or more of Formulas III, where R 1 is a heterocyclic group; Formulas IVA or IVB, where R 1 is a heterocyclic group and is further a spiro group; or Formulas VA, VB or VC, where R 1 is a heterocyclic group and is further a bicyclic group.

[0137]

[0138]

[0139] Referring to Formula III, for each occurrence, each R e is independently C 1-6 haloalkyl (e.g., alkyl - Cl, alkyl - Br, alkyl - F, or alkyl - I) or C 1-6 heteroalkyl (e.g., alkyl - OH). In a specific embodiment of Formula III, one R e is - CH 2 OH, and the other R e is - CH 2 Cl. Referring to Formulas IVA and IVB, each Y is independently nitrogen, oxygen, or - C(R f ) 2 -, where for each occurrence, each R f is independently hydrogen or C 1 - C 6 alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In specific embodiments of Formulas IVA, IVB, VA and VB, at least one Y is oxygen and the remaining Y variables are all - CH 2- In specific embodiments of Formulas IVA, IVB, VA, and VB, at least one Y is oxygen, e.g., at least one Y is oxygen and all remaining Y variables are -CH 2 - In specific embodiments of Formula VC, Y is nitrogen or -CR f -, where R f is hydrogen or aliphatic, particularly C 1 -C 6 alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. In specific embodiments of Formula VC, X is nitrogen and Y is nitrogen. Referring to any one of Formulas III, IVA, IVB, and VA-VC, Ring B is:

[0140]

[0141] Certain disclosed exemplary compounds within the scope of one or more of Formulas I, II, IIA-IIC, III, IVA, IVB, or VA-VC include:

[0142]

[0143]

[0144] Exemplary compounds within the scope of one or more of Formulas I-V, VIA, VIB, or VIIA-VIIC include:

[0145] I-1: (S)-N-(7-(4-(Chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0146] I-2: (S)-1-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0147] I-3: (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;

[0148] I-4: (S)-1-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]non-7-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0149] I-5: (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0150] I-6: N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

[0151] I-7: N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0152] I-8: (S)-1-(4-Fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepin-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0153] I-9: (S)-5-Benzyl-N-(5-methyl-7-(1,4-oxazepin-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;

[0154] I-10: (S)-5-(4-Fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepin-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0155] I-11: (S)-5-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0156] I-12: (S)-5-Benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0157] I-13: N-((3S)-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

[0158] I-14: (S)-N-(7-(1,4-diazabicyclo[3.2.2]non-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

[0159] I-15: (S)-5-Benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0160] I-16: (S)-N-(7-(1,4-diazabicyclo[3.2.2]non-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0161] I-17: (S)-5-Benzyl-N-(7-((3-chloropropyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0162] I-18: (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0163] I-19: (S)-5-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]dec-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0164] I-20: (S)-N-(7-(azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0165] I-21: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]dec-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0166] I-22: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]dec-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0167] I-23: (S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]dec-8-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0168] I-24: (S)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undec-9-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0169] I-25: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0170] I-26; (S)-5-benzyl-N-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; and

[0171] I-27: (S)-5-benzyl-N-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0172] Additional exemplary compound classes contemplated by the present disclosure are described below.

[0173]

[0174]

[0175]

[0176] In some embodiments, one or more of the compounds may be included in a pharmaceutical composition or a medicament, and in some embodiments, the one or more compounds may be in the form of: a parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof. The pharmaceutical composition typically includes at least one additional component in addition to the one or more disclosed compounds, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described in the following sections), or any combination thereof.

[0177] Pharmaceutically acceptable excipients can be included within pharmaceutical compositions for various purposes, such as for diluting a pharmaceutical composition to be delivered to a subject, for facilitating formulation, for providing favorable material properties to a formulation, for facilitating dispersion of a delivery device, for stabilizing a formulation (such as antioxidants or buffers), for providing a satisfactory or palatable taste or consistency to a formulation, and the like. The one or more pharmaceutically acceptable excipients can include one or more pharmaceutically acceptable carriers. Exemplary excipients include, but are not limited to: monosaccharides, disaccharides, and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitol, dipalmitoyl phosphatidylcholine, and lecithin; swelling agents; buffers, such as phosphate and citrate buffers; anti-adhesion agents, such as magnesium stearate; binders, such as saccharides (including disaccharides, such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose esters (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavoring agents and sweetening agents (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla; lubricants (such as mineral oil, exemplified as talc or silica, fats (exemplified as vegetable stearin), magnesium stearate or stearic acid); preservatives (such as antioxidants, exemplified as vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium, amino acids (exemplified as cysteine and methionine), citric acid and sodium citrate, parabens (exemplified as methylparaben and propylparaben); coloring agents; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0178] B. Combinations of Therapeutic Agents

[0179] The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The one or more compounds or compositions comprising the one or more compounds can be administered once or administered multiple times. In some embodiments, the compounds of the invention can be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents can be administered simultaneously, sequentially in any order, by the same route of administration as the compounds of the present disclosure or by a different route. For sequential administration, the one or more compounds and the one or more therapeutic agents can be administered such that the effective time periods of at least one compound and therapeutic agent overlap with the effective time periods of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination comprising four components, the effective time period of the first component administered can overlap with the effective time periods of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components can independently overlap or not overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective time period of the first component administered overlaps with the effective time period of the second component, but not with the effective time periods of the third or fourth components; the effective time period of the second component overlaps with the effective time periods of the first and third components; and the effective time period of the fourth component overlaps only with the effective time period of the third component. In some embodiments, the effective time periods of all compounds and / or therapeutic agents overlap with each other.

[0180] In some embodiments, the compounds are administered with another therapeutic agent (e.g., an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylate cyclase C agonist, an incretin, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof). The anti-inflammatory agent can be a steroid or a non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, antilymphocyte globulin, antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0181] In some embodiments, the compounds of the invention can be used in combination with anti-cancer agents or cytotoxin agents. Various types of anti-cancer agents and anti-tumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureases, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents (e.g., DNMT inhibitors such as azacitidine and decitabine). Exemplary alkylating agents include, but are not limited to, nitrogen mustards, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, by way of example but not limitation, the folic acid analogue methotrexate; the pyrimidine analogues fluorouracil, cytarabine; the purine analogues mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkaloids include, by way of example but not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example but not limitation, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as anti-tumor agents include L-asparaginase. Exemplary coordination compounds include, by way of example but not limitation, cisplatin and carboplatin. Exemplary sex hormones and hormone-related compounds include, by way of example but not limitation, adrenocortical steroids (prednisone and dexamethasone); aromatase inhibitors (aminoglutethimide, formestane, and anastrozole); progesterone compounds (hydroxyprogesterone caproate, medroxyprogesterone); and anti-estrogen compounds tamoxifen.

[0182] These and other useful anti-cancer agent compounds are described in the Merck Index, 13th Edition, (edited by O'Neil M.J. et al.) Merck Publishing Group (2001); and Goodman and Gilman, The Pharmacological Basis of Therapeutics, 12th Edition, edited by Brunton L.L., Chapters 60 - 63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0183] Among CTLA 4 antibodies that can be used in combination with the inhibitors of the present disclosure is ipilimumab, sold by Bristol-Myers Squibb for sale.

[0184] Other chemotherapeutic agents for combination include immuno-oncology agents such as checkpoint pathway inhibitors, for example PD-1 inhibitors (such as nivolumab and lambrolizumab) and PD-L1 inhibitors (such as pembrolizumab, MEDI-4736, and MPDL3280A / RG7446). Additional checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

[0185] Other chemotherapeutic agents for combination with the inhibitors of the present disclosure include anti-SLAMF7 agents (such as the humanized monoclonal antibody elotuzumab (BMS-901608)), anti-KIR agents (such as the anti-KIR monoclonal antibody lirilumab (BMS-986015)), and anti-CD137 agents (such as the fully human monoclonal antibody urelumab (BMS-663513).

[0186] The compounds of the present disclosure can also be advantageously used in combination with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0187] Additional anti-proliferative compounds useful in combination with the compounds of the present invention include, by way of example but not limitation, antibodies against growth factor receptors (such as anti-Her2); and cytokines (such as interferon-α and interferon-γ, interleukin-2, and GM-CSF).

[0188] Other chemotherapeutic agents useful in combination with the compounds of the present invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, and the like.

[0189] Examples of kinase inhibitors useful in combination with the compounds of the present disclosure, particularly in the treatment of malignancies, include: Btk inhibitors such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib, and vandetinib; Mek inhibitors such as trametinib; Raf inhibitors such as dabrafenib, sorafenib, and vemurafenib; VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib; PI3 kinase inhibitors such as idelalisib; Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib.

[0190] In other embodiments, the second therapeutic agent may be selected from any of the following:

[0191] Analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, pethidine, pentazocine, dextromoramide, dipipanone;

[0192] Antibiotics - aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromomycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancin), lincosamides (e.g., clindamycin and lincomycin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oleandomycin, telithromycin, and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanic acid), polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilamide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim - sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), anti - mycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others (e.g., arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuprisin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and tinidazole);

[0193] Antibodies - anti - TNF - α antibodies, e.g., infliximab (Remicade TM) Adalimumab, golimumab, certolizumab; anti-B cell antibodies, such as rituximab; anti-IL-6 antibodies, such as tocilizumab; anti-IL-1 antibodies, such as anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, such as nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, crisaborole, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zilucoplan;

[0194] Anticoagulants - warfarin (Coumadin TM ), acenocoumarol, phenprocoumon, dicumarol, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatroban, dabigatran, ximelagatran, batroxobin, defibrase;

[0195] Anti-inflammatory agents - steroids (e.g., budesonide), non-steroidal anti-inflammatory agents (e.g., aminosalicylates (e.g., sulfasalazine, mesalazine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors, such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin);

[0196] Immunosuppressive agents - mercaptopurine, corticosteroids (such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone), alkylating agents (such as cyclophosphamide), calcineurin inhibitors (such as cyclosporine, sirolimus, and tacrolimus), inosine monophosphate dehydrogenase (IMPDH) inhibitors (such as mycophenolate mofetil, mycophenolic acid, and azathioprine), and agents designed to inhibit cellular immunity while leaving the recipient's humoral immune response intact, including various antibodies (such as antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibody (OKT3)), and radiation. Azathioprine is currently available under the trade name Azasan from Salix Pharmaceuticals; mercaptopurine is currently available under the trade name Purinethol from Gate Pharmaceuticals; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available under the trade name Rapamune from Wyeth-Ayerst; tacrolimus is currently available under the trade name Prograf from Fujisawa; cyclosporine is currently available under the trade names Sandimmune from Novartis and Gengraf from Abbott; IMPDH inhibitors (such as mycophenolate mofetil and mycophenolic acid) are currently available under the trade name Cellcept from Roche and under the trade name Myfortic from Novartis; azathioprine is currently available under the trade name Imuran from Glaxo Smith Kline; and antibodies are currently available under the trade name Orthoclone from Ortho Biotech, under the trade name Simulect (basiliximab) from Novartis, and under the trade name Zenapax (daclizumab) from Roche; and

[0197] Guanylate cyclase C receptor agonists or incretins - such as linaclotide sold under the name Linzess.

[0198] These different agents can be used according to their standard or conventional dosages, as specified in the prescription information accompanying the commercially available forms of these drugs (see also, the prescription information in the 2006 version of The Physician’s Desk Reference), the disclosure of which is incorporated herein by reference.

[0199] III. Method for Preparing Compounds

[0200] In the context of the benefits of the present disclosure, the disclosed compounds can be prepared by any acceptable synthetic method understood by those of ordinary skill in the art. The following exemplifies a suitable method, as illustrated for specific compounds in the examples. The exemplary method for preparing the compounds may include the following first reaction step according to Scheme 1.

[0201]

[0202] Referring to Scheme 1, using suitable metal-mediated cross-coupling conditions, starting compound 100 reacts with reagent 102 containing R 1 to provide R 1 -functionalized product 104. X is a group suitable for metal-mediated cross-coupling, such as a halogen or trifluoromethanesulfonate group, and PG is an amine protecting group, which can be selected from, but not limited to, 9-fluorenylmethoxycarbonyl (“Fmoc”) group, tert-butyloxycarbonyl (“Boc”) group, triphenylmethyl (“Tr”) group, allyloxycarbonyl (“Alloc”) group, benzyloxycarbonyl (“Cbz”) group, etc. In some embodiments, the metal-mediated cross-coupling conditions include using a transition metal catalyst, such as a Pd(0) catalyst (e.g., Pd 2 (dba) 3 2 2 3 3 ) 4 4

[0203] Representative examples of the method shown in Scheme 1 are provided below in Schemes 2A-2G.

[0204]

[0205]

[0206]

[0207] Examples of the method for preparing the compounds may further include additional steps for converting R 1The functionalized product 104 is converted to the desired compound within the scope of the present disclosure. In some embodiments, these additional steps can include a first deprotection step to provide an amine compound 300. The amine compound 300 is then converted to an amide compound 304 by reacting the amine compound with a suitable acid coupling partner 302, as illustrated in Scheme 3.

[0208]

[0209] Referring to Scheme 3, deprotection can involve using any suitable reagent capable of removing an amine protecting group (“PG” as shown in Schemes 1 and 3). In some embodiments, an acid, such as TFA, is used in the deprotection step. In still further embodiments, a base, such as piperidine, can be used in the deprotection step. In view of the benefits of the present disclosure, other acids and bases suitable for deprotection are readily recognized by those of ordinary skill in the art. The amide formation step can be carried out using a reagent capable of promoting amide formation between the free amine of the amine compound 300 and the acid functional group of the acid coupling partner 302. Suitable coupling partners can be synthesized using methods recognized by those of ordinary skill in the art in view of the benefits of the present disclosure, or can be purchased from commercial sources. In some embodiments, propylphosphonic anhydride can be used in combination with a base for amide formation, such as diisopropylethylamine; however, other reagents, such as 2-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethylammonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-N,N,N’,N’-hexafluorophosphate, 2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N’,N’-tetramethylammonium hexafluorophosphate, 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide·HCl, benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluoride, benzotriazol-1-yloxy-tris(pyrrolidino)-phosphonium hexafluoride, bromo-tris(pyrrolidino)-phosphonium hexafluoride, etc., can be used in combination with diisopropylethylamine, isopropylamine, etc. A suitable solvent, such as dichloromethane (“DCM”), can be used.

[0210] Representative examples of the method steps shown in Scheme 3 are provided below in Schemes 4A - 4N.

[0211]

[0212]

[0213]

[0214]

[0215] Referring to the above Schemes 4A - 4N, the acid - coupled chaperone 402 can be prepared using the following procedure: A solution of ethyl 5 - benzylisoxazole - 3 - carboxylate is dispersed into an NaOH solution in MeOH and water. After standing for a suitable time at 20 °C, the solvent is removed in vacuo. The residue is acidified with dilute HCl and then extracted with EtOAc. The organic phase is washed with water and saturated brine and then dried over sodium sulfate, followed by evaporation in vacuo. Other acid - coupled chaperones described in Schemes 4A - 4N can be prepared using a similar method starting with suitable starting materials (such as ethyl 5 - benzyl - 1H - 1,2,4 - triazole - 3 - carboxylate, ethyl 1 - benzyl - 1H - 1,2,4 - triazole - 3 - carboxylate, and their fluorinated versions).

[0216] IV. Methods of Using Compounds

[0217] A. Diseases / Disorders

[0218] The disclosed compounds, as well as their combinations and / or pharmaceutical compositions, can be used to inhibit RIP1 kinase by contacting a kinase in vivo or in vitro with one or more of the compounds of the present disclosure, or a composition comprising one or more of the compounds of the present disclosure. One or more of the disclosed compounds, or a composition comprising one or more of the disclosed compounds, can also be used to alleviate, treat, or prevent various diseases and / or disorders. In specific embodiments, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions can be used to treat conditions in which inhibiting RIP1 or involvement of the RIP1 pathway is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, erythrocyte deficiency, lung and brain injury (such as induced by ischemia - reperfusion or cisplatin and / or cerebrovascular accident), and bacterial and viral infections.

[0219] In some embodiments, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions can be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

[0220] The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be used to treat immunomodulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory or immunomodulatory disorders that can be treated with the compounds (or their pharmaceutical compositions or combinations) include, but are not limited to, transplantation of organs or tissues, graft-versus-host disease resulting from transplantation, autoimmune syndromes, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases (including rheumatic fever and post-infectious glomerulonephritis), inflammatory and proliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoma cornea, ocular pemphigus, corneal erosive ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway diseases, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or intractable asthma, late asthma, and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular injury caused by ischemic diseases and thrombosis, ischemic bowel disease, ischemic reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, polyneuropathy, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythrogenesis imperfecta, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy or myocardial infarction, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, obesity, eosinophilic fasciitis,Lesions of the gums, periodontal tissues, alveolar bone, and cementum (substantia ossea dentis), glomerulonephritis, male pattern hair loss or senile alopecia by preventing hair loss or providing hair growth and / or promoting hair generation and hair growth, muscular dystrophy, pyoderma, and Sézary's syndrome, Addison's disease, ischemia-reperfusion injury occurring after organ preservation, transplantation or ischemic diseases, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxicosis caused by pulmonary oxygen or drugs, lung cancer, pulmonary emphysema, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar, corneal alkali burn, dermatitis, erythema multiforme, linear IgA bullous dermatitis, and intractable dermatitis, gingivitis, periodontitis, septicemia, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, cancer metastasis, and hypobaropathy, diseases caused by the release of histamine or leukotriene-C4, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock, or anoxia, hepatitis B virus, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, "acute-on-chronic" liver failure, chronic kidney disease, kidney damage / injury (caused by, for example, nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, acute kidney injury), increased chemotherapy efficacy, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection.,

[0221] In certain embodiments, the compounds of the invention can be used to treat neuropathic pain, including pain caused by neuropathy and inflammation.

[0222] In certain embodiments, the compounds can be used to treat interleukin-1 converting enzyme-related fever syndromes, tumor necrosis factor receptor-associated periodic syndromes, NEMO deficiency syndromes, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndromes, lysosomal storage diseases (such as Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, sialidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

[0223] In certain embodiments, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat and / or prevent rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis (especially pustular psoriasis), type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout attacks, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of the Il-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0224] Proliferative diseases that can be treated by the pyrazole compound, a combination of pyrazole compounds, and / or a composition thereof include benign or malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, malignant glioma, neuroblastoma, multiple myeloma, gastrointestinal cancer (especially colon cancer or colorectal adenoma), head and neck tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorders, MyD88-driven disorders (such as ABC diffuse large B-cell lymphoma (DLBCL), Waldenström macroglobulinemia( macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or asymptomatic multiple myeloma, or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, or intravascular large B-cell lymphoma). Specifically, the compounds of the present disclosure can be used to treat drug-resistant malignancies, such as those resistant to the JAK inhibitor ibrutinib, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström macroglobulinemia.

[0225] Examples of allergic disorders that can be treated using the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., allergic asthma, atopic asthma, atopic bronchial IgE-mediated asthma, non-allergic asthma, bronchial asthma, non-atopic asthma, idiopathic wheezing, true asthma, intrinsic asthma caused by pathophysiological disorders, idiopathic wheezing of unknown or obscure origin, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational wheezing, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infections, early asthma, asthmatic infant syndrome, bronchiolitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, nasal discharge, purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis).

[0226] As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion, and tenderness of systemic target joints. RA is characterized by a chronically inflamed synovium with dense lymphocytes. The synovium, typically one cell layer thick, becomes hypercellular and assumes a form similar to lymphoid tissue (including dendritic cells, T cells, B cells, and NK cells, macrophages, and clusters of plasma cells). This process, along with numerous immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to destruction of the integrity of the joint, which results in deformity at or near the joint, permanent loss of function, and / or bone erosion. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat, alleviate, or prevent any one, several, or all of these RA symptoms. Thus, in the context of RA, a compound is considered to provide a therapeutic benefit when any symptom commonly associated with RA is reduced or alleviated, regardless of whether the treatment results in a reduction in the amount of circulating rheumatoid factor ("RF") and / or combination therapy for RA below.

[0227] The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. Once such parameters, the ACR20 (ACR criteria for 20% clinical improvement) requires a 20% improvement in both the tender and swollen joint counts, and a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain assessment, disability level, and acute phase reactant level. These criteria are increased to 50% and 70% in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and radiological progression (such as the Sharp score).

[0228] In some embodiments, patients suffering from RA obtain therapeutic benefits when they exhibit ACR20. In specific embodiments, an ACR improvement of ACR50 or even ACR70 can be achieved.

[0229] B. Formulation and Administration

[0230] The pharmaceutical compositions comprising one or more active compounds of the present invention can be manufactured by any suitable method, such as mixing, dissolving, granulating, sugar coating, grinding, emulsifying, encapsulating, entrapping, or lyophilization processes. These pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (such as diluents, carriers, or adjuvants), one or more adjuvants, or combinations thereof to provide pharmaceutically usable formulations.

[0231] One or more active compounds per se can be formulated as pharmaceutical compositions, or in the form of their pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts can also be formed that have lower solubility than the corresponding free acids and bases.

[0232] The pharmaceutical compositions of the present invention can take almost any mode suitable for administration, including, for example, topical, ocular, oral, buccal, systemic, intranasal, injection (such as intraperitoneal or intravenous), transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0233] For topical administration, the one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs can be formulated as solutions, gels, ointments, creams, suspensions, etc., as are well known in the art.

[0234] Systemic formulations include those designed for administration by injection (such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection), along with those designed for transdermal, transmucosal, oral, or pulmonary administration.

[0235] Useful injectable formulations include sterile suspensions, solutions, or emulsions of one or more active compounds in aqueous or oily vehicles. These pharmaceutical compositions can also contain formulating agents such as suspending agents, stabilizers, and / or dispersing agents. These formulations for injection can be in unit dosage forms, for example, in ampoules or in multi-dose containers, and can contain added preservatives.

[0236] Alternatively, before use, the injectable preparation can be provided in the form of a powder for reconstitution with a suitable vehicle, which includes but is not limited to sterile, pyrogen-free water, buffers, glucose solutions, etc. For this purpose, the one or more active compounds can be dried by any technique known in the art (such as lyophilization) and reconstituted before use.

[0237] For transmucosal administration, a penetrant suitable for the barrier to be penetrated is used in the preparation. Such penetrants are known in the art.

[0238] For oral administration, the pharmaceutical composition can take the form of, for example, lozenges, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients (such as binders (such as pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (such as lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (such as magnesium stearate, talc or silica); disintegrants (such as potato starch or sodium starch glycolate); and / or wetting agents (such as sodium lauryl sulfate)). These tablets can be coated by methods well known in the art, such as with sugar, film or enteric coatings.

[0239] Liquid preparations for oral administration can take the form of, for example, elixirs, solutions, syrups or suspensions, or they can exist as a dry product to be compounded with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable excipients (such as suspending agents (such as sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (such as lecithin or gum arabic); non-aqueous vehicles (such as almond oil, esters of fatty acids, ethanol, cremophore TM or fractionated vegetable oils); and preservatives (such as methyl paraben or propyl paraben or sorbic acid)). These preparations can also optionally contain buffer salts, preservatives, flavoring agents, coloring agents and sweetening agents.

[0240] As is well known, preparations for oral administration can be suitably formulated to give controlled release of the active compound.

[0241] For buccal administration, these pharmaceutical compositions can take the form of tablets or lozenges formulated in a conventional manner.

[0242] For rectal and vaginal routes of administration, the one or more active compounds can be formulated as solutions (for retention enemas), suppositories or ointments containing conventional suppository bases (such as cocoa butter or other glycerides).

[0243] For intranasal administration or administration by inhalation or insufflation, the one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs can be conveniently delivered in the form of a spray from a pressurized package or nebulizer using a suitable propellant, which is, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluorocarbons, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules or cartridges (e.g., capsules and cartridges comprising gelatin) can be formulated for use in an inhaler or insufflator, which contain a powder mixture of the compound and a suitable powder matrix (e.g., lactose or starch).

[0244] Specific examples of aqueous suspension formulations suitable for intranasal administration using commercially available intranasal spray devices include the following components: active compound (0.5 - 20 mg / ml); benzalkonium chloride (0.1 - 0.2 mg / mL); polysorbate 80( 0.5 - 5 mg / ml); sodium carboxymethylcellulose or microcrystalline cellulose (1 - 15 mg / ml); phenethyl alcohol (1 - 4 mg / ml); and glucose (20 - 50 mg / ml). The pH of the final suspension can be adjusted to a range from about pH 5 to pH 7, with a typical pH being about 5.5.

[0245] Another specific example of an aqueous suspension suitable for administering the compound by inhalation contains 20 mg / mL of one or more of the disclosed compounds, 1% (v / v) polysorbate 80 50 mM citric acid and / or 0.9% sodium chloride.

[0246] For ocular administration, the one or more active compounds can be formulated as solutions, emulsions, suspensions, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Patent Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporated herein by reference.

[0247] For extended delivery, the one or more active compounds may be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or be formulated as a sparingly soluble derivative, e.g., as a sparingly soluble salt. Alternatively, a transdermal delivery system may be used that is manufactured as an adhesive disk or patch for slow release of the one or more active compounds for transdermal absorption. For this purpose, a penetration enhancer may be used to facilitate the transdermal penetration of the one or more active compounds. Suitable transdermal patches are described, for example, in U.S. Patent Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

[0248] Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver the one or more active compounds. Certain organic solvents (such as dimethyl sulfoxide (DMSO)) may also be employed, although usually at the cost of greater toxicity.

[0249] If desired, the pharmaceutical composition may be presented in a package or dispenser device that may comprise one or more unit dosage forms containing the one or more active compounds. The package may, for example, comprise a metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration.

[0250] C. Dosage

[0251] The disclosed compounds, pharmaceutical compositions, or combinations of the disclosed compounds will generally be used in an amount effective to achieve the desired result, e.g., in an amount effective to inhibit RIP1 kinase and / or effective to treat, prevent, or alleviate a specific disorder. The one or more disclosed compounds or their pharmaceutical compositions may be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. A therapeutic benefit means the eradication or alleviation of the underlying disorder being treated and / or the eradication or alleviation of one or more symptoms associated with the underlying disorder such that, although the patient may still be afflicted with the underlying disorder, the patient reports a reduction in feeling or condition. For example, administration of a compound to a patient suffering from allergies provides a therapeutic benefit not only when the underlying allergic response is eradicated or alleviated, but also when the patient reports a reduction in the severity or duration of symptoms associated with the allergy upon exposure to an allergen. As another example, a therapeutic benefit in the context of asthma includes improvement in breathing after the onset of an asthma attack or a decrease in the frequency or severity of asthma attacks. Whether or not improvement is achieved, a therapeutic benefit also includes the arrest or slowing of the progression of the disease.

[0252] As is known to those of ordinary skill in the art, the preferred dosage of the disclosed compounds may depend on various factors, including the age, weight, general health, and severity of the disorder of the patient or subject being treated. When administered by inhalation, the dosage may also need to be adjusted to accommodate the gender of the individual and / or the lung capacity of the individual. The dosage may also be adjusted to accommodate an individual suffering from more than one disorder or having additional disorders (e.g., emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory infections) that affect lung capacity and normal breathing ability. The dosage and frequency of administration of the one or more disclosed compounds or their pharmaceutical compositions will also depend on whether the one or more disclosed compounds are formulated for the treatment of an acute episode of a disorder or for prophylactic treatment of a disorder. A person skilled in the art or one of ordinary skill will be able to determine the optimal dosage for a specific individual.

[0253] For prophylactic administration, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is not known whether a patient or subject is allergic to a particular drug, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered prior to administration of the drug to avoid or mitigate an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or mitigate the onset of symptoms in a patient diagnosed with the underlying disorder. For example, prior to an anticipated exposure to an allergen, one or more of the disclosed compounds, or pharmaceutical compositions thereof, can be administered to an allergy sufferer. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be administered prophylactically to a healthy individual to prevent the onset of the disorder, the healthy individual being repeatedly exposed to an agent known to cause one of the above diseases. For example, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a healthy individual who is repeatedly exposed to an allergen (such as latex) known to cause allergies, in an attempt to prevent the individual from developing allergies. Alternatively, the disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient with asthma prior to participating in an activity that triggers an asthma attack to reduce the severity of the asthma attack or to avoid the asthma attack altogether.

[0254] The effective dose can initially be estimated from in vitro assays. For example, an initial dose for a subject can be formulated to achieve a circulating blood or serum concentration of the active compound equal to or higher than the IC 50 or EC 50 of a particular compound as measured in an in vitro assay. Taking into account the bioavailability of the particular compound, the dose can be calculated to achieve such a circulating blood or serum concentration. Fingl and Woodbury, “General Principles”, in: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, Pergamon Press, and the references cited therein, provide additional guidance on effective doses.

[0255] In some embodiments, the disclosed compounds have an EC 50 from greater than 0 to 20 μM (such as from greater than 0 to 10 μM, from greater than 0 to 5 μM, from greater than 0 to 1 μM, from greater than 0 to 0.5 μM, from greater than 0 to 0.1 μM, or from greater than 0 to 0.05 μM).

[0256] Initial doses can also be estimated from in vivo data, such as animal models. Animal models for testing the efficacy of compounds in treating or preventing the various diseases described above are well known in the art. Suitable animal models for hypersensitivity or allergic reactions are described in: Foster, (1995) Allergy, 50 (Suppl 21): 6-9, Discussion 34-38; and Tumas et al., (2001), J. Allergy Clin. Immunol. 107(6):1025-1033. Suitable animal models for allergic rhinitis are described in: Szelenyi et al., (2000), Arzneimittelforschung 50(11):1037-42; Kawaguchi et al (1994), Clin. Exp. Allergy 24(3):238-244; and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7. A person of ordinary skill in the art can adjust such information to determine a dose suitable for human administration.

[0257] In some embodiments, assays suitable for determining RIP1 activity can be used. Such assay methods can be used to evaluate the efficacy of the compound embodiments disclosed herein, and / or can be used to determine the amount / dose of the compound embodiments that can provide the desired efficacy. In some embodiments, the assay can be an ADP-Glo TM assay for evaluating the ability of a compound embodiment to inhibit RIP1. In other embodiments, a whole cell assay using a necrosis assay of mouse and / or human cells (such as U937 and / or L929 cells) can be performed to determine the effective dose of a compound that can be used in human in vivo studies. Using a whole cell assay, the activity of a compound against human and / or murine RIP1 can be evaluated in an in vitro context, which then allows a person skilled in the art or a person of ordinary skill to determine a safe and effective dose for in vivo use. Yet another assay that can be used to evaluate the activity of the compound embodiments described herein in treating diseases or disorders involving RIP1 is the acute hypothermic mouse model, which evaluates the ability of the compound to inhibit TNF-α-induced hypothermia. Each of these assays, and the different results from using these assays, are described in detail in the Examples section of the present disclosure.

[0258] The dosage of the disclosed compounds will typically range from greater than 0 mg / kg / day (e.g., 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day) up to at least about 100 mg / kg / day. More typically, the dosage (or effective amount) can range from about 0.0025 mg / kg to about 1 mg / kg administered at least once a day, such as from 0.01 mg / kg to about 0.5 mg / kg, or from about 0.05 mg / kg to about 0.15 mg / kg. The total daily dosage typically ranges from about 0.1 mg / kg to about 5 mg / kg or up to about 20 mg / kg per day, such as from 0.5 mg / kg to about 10 mg / kg per day or from about 0.7 mg / kg to about 2.5 mg / kg per day. Among other factors, the dosage can be higher or lower, depending on the activity of the disclosed compound, its bioavailability, the mode of administration, and the various factors discussed above.

[0259] The dosage and dosage interval can be adjusted for an individual to provide a plasma level of the disclosed compound sufficient to maintain a therapeutic or prophylactic effect. For example, the compound can be administered once a day, multiple times a day, once a week, multiple times a week (e.g., every other day), once a month, multiple times a month, or once a year, among other things, depending on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician. Without undue experimentation, one of ordinary skill in the art can optimize an effective topical dosage.

[0260] A pharmaceutical composition comprising one or more of the disclosed compounds typically comprises from greater than 0 up to 99% of the one or more disclosed compounds, and / or other therapeutic agents (by weight percentage). More typically, a pharmaceutical composition comprising one or more of the disclosed compounds comprises from about 1 to about 20 total weight percentage of the disclosed compounds and other therapeutic agents, and from about 80 to about 99 weight percentage of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition can further comprise an adjuvant.

[0261] Preferably, the disclosed compounds, combinations of the disclosed compounds, or their pharmaceutical compositions will provide a therapeutic or prophylactic benefit without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxicity and therapeutic (or prophylactic) effect is the therapeutic index. Disclosed compounds exhibiting a high therapeutic index are preferred.

[0262] V. Examples

[0263] Example 1

[0264]

[0265] Step 1 - At 85 °C, a mixture of (S)-7-bromo-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 200 (which is prepared using the method described below; 0.25 g, 0.49 mmol), 7-oxa-2-azaspiro[3.5]nonane hydrochloride (0.10 g, 0.60 mmol), Pd 2 (dba) 3 (0.025 g, 0.027 mmol), racemic BINAP (0.05 g, 0.08 mmol) and NaO t Bu (0.12 g, 1.3 mmol) in toluene (5 mL) was stirred for 16 h. The reaction mixture was then concentrated under reduced pressure to give a residue, which was purified by chromatography (eluting with ethyl acetate / hexane (3 / 7)) to afford (S)-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 204 (0.26 g, 96%) as a brown solid.

[0266]

[0267] Exemplary method for preparing compound 200

[0268] Step 2 - Trifluoroacetic acid (15.7 mmol, 1.2 mL) was added to a mixture of (S)-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 204 (0.26 g, 0.46 mmol) in dichloromethane (6 mL). The resulting solution was stirred at room temperature for 0.5 h. The solution was then concentrated under reduced pressure. The residue was dissolved in methanol and then basified with 28% ammonium hydroxide solution. The resulting mixture was then reconcentrated under reduced pressure to give a residue, which was purified by chromatography (eluting with ethyl acetate to dichloromethane / MeOH (10 / 2)) to afford (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 205 (0.16 g, 91%) as a pale white solid. 1 H NMR(CD 3OD, 400 MHz) 6.96 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 2.8 Hz, 1H), 6.32 (dd, J = 8.8, 2.8 Hz, 1H), 4.30 (m, 1H), 3.98 (m, 1H), 3.72 (m, 1H), 3.64 (m, 8H), 3.33 (s, 3H), 1.81 (m, 4H) ppm; MS m / e: 318.2 (M + H) + 。

[0269] Step 3 - To a stirred mixture of (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 3 (0.025 g, 0.08 mmol) 205 and 5-benzyl-1H-1,2,4-triazole-3-carboxylic acid (0.018 mg, 0.09 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (0.05 ml, 0.3 mmol) and T 3 P (propylphosphonic anhydride solution (50% wt.%, in ethyl acetate). The reaction mixture was stirred at room temperature for 3 h and quenched with water. The organic layer was separated and concentrated under reduced pressure to give a residue which was purified by chromatography (eluting with ethyl acetate / hexane (3 / 7 to 9 / 1)) to afford (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide I-5 (0.02 g, 61%). 1 H NMR (CD 3 OD, 400 MHz) 7.26 (m, 5H), 7.01 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 2.8 Hz, 1H), 6.36 (dd, J = 9.0, 2.4 Hz, 1H), 4.96 (m, 1H), 4.47 (m, 1H), 4.25 (m, 1H), 4.13 (s, 2H), 3.64 (m, 8H), 3.35 (s, 3H), 1.82 (m, 4H) ppm; MS m / e: 503.3 (M + H) + 。

[0270] Example 2

[0271] As described herein, the above synthetic procedure was adapted to prepare the following compound I-1.

[0272]

[0273] (S)-N-(7-(4-(Chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 8.56 (s, 1H), 7.82 (m, 1H), 7.65 (m, 1H), 7.38 (m, 2H), 7.07 (m, 3H), 5.43 (s, 2H), 5.00 (m, 1H), 4.60 (m, 1H), 4.49 (m, 1H), 4.40 (m, 2H), 3.43 (s, 3H), 2.38 (m, 2H), 2.02 (m, 2H), 1.35 (m, 6H) ppm; MS m / e: 557.3 (M + H) + 。

[0274] Example 3

[0275] As described herein, the above synthetic procedure was adapted to prepare the following compound I-2.

[0276]

[0277] (S)-1-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CDCl 3 , 400 MHz) 8.01 (m, 2H), 7.26 (m, 2H), 7.05 (m, 3H), 6.26 (dd, J = 9.0, 2.8 Hz, 1H), 6.18 (d, J = 2.8 Hz, 1H), 5.33 (s, 2H), 5.08 (m, 1H), 4.65 (m, 1H), 4.13 (m, 1H), 3.65 (m, 8H), 3.38 (s, 3H), 1.85 (m, 4H) ppm; MS m / e: 521.3 (M + H) + 。

[0278] Example 4

[0279] As described herein, the above synthetic procedure was adapted to prepare the following compound I-3.

[0280]

[0281] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]non-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide 1 H NMR(CDCl 3 , 400 MHz) 7.69 (m, 1H), 7.26 (m, 5H), 7.01 (d, J = 8.8 Hz, 1H), 6.26 (m, 2H), 6.18 (d, J = 2.8 Hz, 1H), 5.00 (m, 1H), 4.61 (m, 1H), 4.13 (m, 1H), 4.08 (s, 2H), 3.64 (m, 8H), 3.38 (s, 3H), 1.84 (m, 4H) ppm; MS m / e: 503.3 (M + H) + 。

[0282] Example 5

[0283] As described herein, the above synthetic procedure was adapted to prepare the following compound I-4.

[0284]

[0285] (S)-1-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]non-7-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 8.56 (s, 1H), 7.40 (m, 2H), 7.09 (m, 3H), 6.96 (m, 1H), 6.90 (m, 1H), 5.45 (s, 2H), 4.97 (m, 1H), 4.51 (m, 1H), 4.49 (s, 4H), 4.31 (m, 1H), 3.38 (s, 3H), 3.12 (m, 4H), 2.01 (m, 4H) ppm; MS m / e: 521.3 (M + H) + 。

[0286] Example 6

[0287] As described herein, the above synthetic procedure was adapted to prepare the following compound I-6.

[0288]

[0289] N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 7.28 (m, 5H), 7.02 (d, J = 8.8 Hz, 1H), 6.58 (m, 1H), 6.53 (dd, J = 8.4, 2.8 Hz, 1H), 6.37 (s, 1H), 4.96 (m, 1H), 4.63 (m, 1H), 4.51 (m, 1H), 4.45 (m, 1H), 4.30 (m, 1H), 4.14 (s, 2H), 3.83 (m, 2H), 3.55 (m, 1H), 3.36 (s, 3H), 3.07 (m, 1H), 2.02 (m, 1H), 1.93 (m, 1H) ppm; MS m / e: 475.1 (M+H) + 。

[0290] Example 7

[0291] As described herein, the above synthetic procedure was adapted to prepare the following compound I-7.

[0292]

[0293] N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 8.54 (s, 1H), 7.38 (m, 2H), 7.06 (m, 3H), 6.59 (d, J = 2.8 Hz, 1H), 6.54 (dd, J = 8.4, 2.8 Hz, 1H), 5.43 (s, 2H), 4.97 (m, 1H), 4.63 (m, 1H), 4.49 (m, 2H), 4.26 (m, 1H), 3.83 (m, 2H), 3.55 (m, 1H), 3.36 (s, 3H), 3.07 (m, 1H), 2.01 (m, 1H), 1.94 (m, 1H) ppm; MS m / e: 493.3 (M+H) + 。

[0294] Example 8

[0295] As described herein, the above synthetic procedure was adapted to prepare the following compound I-8.

[0296]

[0297] (S)-1-(4-Fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) δ 8.55 (s, 1H), 7.37 (m, 2H), 7.08 (m, 3H), 6.72 (m, 2H), 5.43 (s, 2H), 4.98 (m, 1H), 4.49 (m, 1H), 4.26 (m, 1H), 3.83 (m, 2H), 3.70 (m, 2H), 3.64 (m, 4H), 3.37 (s, 3H), 2.01 (m, 2H) ppm; MS m / e: 495.3 (M+H) + 。

[0298] Example 9

[0299] As described herein, the above synthetic procedure was adapted to prepare the following compound I-9.

[0300]

[0301] (S)-5-Benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) δ 7.28 (m, 5H), 7.02 (d, J = 9.2 Hz, 1H), 6.69 (d, J = 2.8 Hz, 1H), 6.65 (dd, J = 9.0, 3.2 Hz, 1H), 6.36 (s, 1H), 4.97 (m, 1H), 4.44 (m, 1H), 4.29 (m, 1H), 4.14 (s, 2H), 3.80 (m, 2H), 3.68 (m, 2H), 3.63 (m, 4H), 3.36 (s, 3H), 1.99 (m, 2H) ppm; MS m / e: 477.3 (M+H) + 。

[0302] Example 10

[0303] As described herein, the above synthetic procedure was adapted to prepare the following compound I-10.

[0304]

[0305] (S)-5-(4-Fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 7.28 (m, 2H), 7.03 (m, 3H), 6.66 (m, 2H), 4.98 (m, 1H), 4.49 (m, 1H), 4.25 (m, 1H), 4.13 (s, 2H), 3.81 (m, 2H), 3.68 (m, 2H), 3.62 (m, 4H), 3.37 (s, 3H), 1.99 (m, 2H) ppm; MS m / e: 495.3 (M+H) + 。

[0306] Example 11

[0307] As described herein, the above synthetic procedure was adapted to prepare the following compound I-11.

[0308]

[0309] (S)-5-(4-Fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 7.27 (m, 2H), 7.03 (m, 3H), 6.43 (d, J = 2.4 Hz, 1H), 6.37 (dd, J = 8.8, 2.8 Hz, 1H), 4.96 (m, 1H), 4.48 (m, 1H), 4.25 (m, 1H), 4.13 (s, 2H), 3.65 (m, 8H), 3.36 (s, 3H), 1.83 (m, 4H) ppm; MS m / e: 519.3 (M-H) - 。

[0310] Example 12

[0311] As described herein, the above synthetic procedure was adapted to prepare the following compound I-12.

[0312]

[0313] (S)-5-Benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 7.26 (m, 4H), 7.02 (d, J = 9.2 Hz, 1H), 6.69 (d, J = 3.2 Hz, 1H), 6.66 (m, 1H), 4.99 (m, 1H), 4.49 (m, 1H), 4.25 (m, 1H), 4.14 (s, 2H), 3.82 (m, 2H), 3.69 (m, 2H), 3.62 (m, 4H), 3.37 (s, 3H), 1.99 (m, 2H) ppm; MS m / e: 475.3 (M - H) - 。

[0314] Example 13

[0315] As described herein, the above synthetic procedure was adapted to prepare the following compound I-13.

[0316]

[0317] N-((3S)-7-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide 1 H NMR(CD 3 OD, 400 MHz) 7.32 (m, 5H), 7.04 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 2.8 Hz, 1H), 6.76 (dd, J = 8.8, 2.8 Hz, 1H), 6.37 (s, 1H), 4.94 (m, 1H), 4.44 (m, 3H), 4.31 (m, 1H), 4.14 (s, 2H), 3.37 (m, 5H), 2.90 (m, 2H), 1.95 (m, 4H) ppm; MS m / e: 489.1 (M + H) + 。

[0318] Example 14

[0319] As described herein, the above synthetic procedure was adapted to prepare the following compound I-14.

[0320]

[0321] (S)-N-(7-(1,4-Diazabicyclo[3.2.2]non-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide MS m / e:502.3(M+H) + 。

[0322] Other exemplary compounds are described below.

[0323]

[0324] (S)-5-Benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[0325] 1 H nmr(400MHz,CDCl 3 )δ8.08(1H,d,J Hz,NH),7.29-7.19(5H,m,C 6 H 5 ),7.04(1H,d,J 9.0Hz,oxobenzoxazepine H-6),6.74(1H,dd,J 9.0,2.5Hz,oxobenzoxazepine H-7),6.68(1H,d,J 2.5Hz,oxobenzoxazepine H-9),5.06(1H,dt,J 11.0,7.5Hz,oxobenzoxazepine H-3),4.67(1H,dd,J 10.0,7.5Hz,1H of oxobenzoxazepine H-2),4.21(1H,dd,J 11.0,10.0Hz,1H of oxobenzoxazepine H-2),4.13(2H,s,CH 2 C 6 H 5 ),3.70,3.68(4H,2d AB system,J5.5Hz,pyran H-2,H-6),3.34(3H,s,NCH 3 ),3.20,3.18(4H,2d AB system,J 5.5Hz,piperidine H-2,H-6),1.70-1.68(4H,m,piperidine H-3,H-5),1.56-1.53(4H,m,pyran H-3,H-5);m / z:531[M+H] + (Found [M+H] + ,531.2711,C 29 H 34 N 6 O 4Claim [M+H] + 531.2714).

[0326]

[0327] (S)-5-Benzyl-N-(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]dec-8-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[0328] 1 H NMR (400 MHz, chloroform-d) δ 8.03 - 7.93 (m, 1H), 7.34 - 7.23 (m, 4H), 7.21 - 7.18 (m, 2H), 7.14 - 7.09 (m, 5H), 6.96 (br d, J = 8.8 Hz, 1H), 6.72 (br d, J = 8.9 Hz, 1H), 6.65 (br s, 1H), 4.94 (t, J = 9.2 Hz, 1H), 4.50 - 4.40 (m, 3H), 4.07 (t, J = 10.0 Hz, 1H), 3.94 (br s, 2H), 3.57 - 3.51 (m, 2H), 3.30 (s, 3H), 3.18 (t, J = 6.9 Hz, 2H), 2.86 - 2.79 (m, 2H), 2.13 - 2.06 (m, 2H), 1.93 (t, J = 6.9 Hz, 2H), 1.54 - 1.50 (m, 2H); LRMS (M+H) m / z 620.5.

[0329]

[0330] (S)-5-Benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undec-9-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide

[0331] 11H NMR (400 MHz, chloroform-d) δ 8.00 - 7.83 (m, 1H), 7.31 - 7.17 (m, 6H), 7.06 - 7.04 (m, 5H), 6.91 (br d, J = 8.8 Hz, 1H), 6.66 (br d, J = 9.0 Hz, 1H), 6.59 (br s, 1H), 4.93 - 4.87 (m, 1H), 4.54 (br s, 2H), 4.38 (br s, 1H), 4.08 - 3.98 (m, 1H), 3.86 (br s, 2H), 3.45 - 3.39 (m, 2H), 3.24 (br s, 2H), 3.19 (br s, 3H), 2.95 - 2.88 (m, 2H), 2.37 - 2.30 (m, 2H), 1.80 - 1.77 (m, 4H), 1.61 - 1.58 (m, 2H); LRMS (M+H) m / z 634.5。

[0332] Example 15

[0333] In this example, ADP-Glo TM technology was used, and biochemical assays were performed to evaluate the compounds of the present disclosure.

[0334] The ADP-Glo TM (Promega Corporation, Madison, Wisconsin, USA) reagent was thawed at ambient temperature. The kinase assay reagent was prepared by mixing the kinase assay buffer with the lyophilized kinase assay substrate.

[0335] A 5X reaction kinase buffer with a stock solution volume of 500 ml was prepared by mixing 1000 μl of 1M MgCl 2 , 500 μl of 1M Tris-HCL pH 7.4, 0.5 mg / ml (25 mg) of BSA, and 3475 μl of distilled H 2 2O. A 3 ml 2X working stock solution volume of the reaction kinase buffer was prepared to a final volume containing 100 μM DTT and 4 mM MnCl 2 .

[0336] On ice, the components of the RIPK1 enzyme (Igel Pharmaceuticals, South San Francisco, California, USA) were thawed. Diluted RIPK1 was prepared in 1X kinase reaction buffer (diluted from 2X buffer) to 31 ng / well. A 166 μM working stock ATP assay solution was prepared in 1X kinase reaction buffer (diluted from 2X buffer).

[0337] In a 96-well plate, the compound was serially diluted from 250 μM in DMSO in 4-fold dilutions and then diluted 1:5 in 2X reaction buffer. In duplicate, 1.0 μl of the diluted compound was added to a 384-well plate. 2 μl of the diluted active RIPK1 was added to the 384-well plate (not to column 1), and 2X rxn buffer was added to column 1. 150 nM of AKT (Anaspec, Fremont, CA, USA) was combined with an equal volume of the ATP working stock solution and added to the 384-well plate at 2 μl / well. The final reaction volume was 5.0 μl.

[0338] The plate was centrifuged briefly, and the reaction was incubated at 30 °C for 30 minutes. 5 μl of ADP-Glo TM , was added to terminate the reaction. The plate was centrifuged briefly and the reaction was incubated at room temperature for 40 minutes. Then the kinase detection reagent was added and the reaction was incubated at room temperature for 30 minutes. The relative light units (RLU) of the kinase reaction were determined by luminescence (fluorescence 0.1 s) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). Table 1 provides the IC 50 values obtained from this example.

[0339]

[0340]

[0341] Example 16

[0342] In this example, U937 and L929 cells were exposed to the compounds of the present disclosure and a cell necrosis assay was performed to evaluate the activity of the compounds against human RIP1 and murine RIP1.

[0343] U937 and L929 cells were obtained from the American Type Culture Collection (Manassas, VA, USA). At 37 °C, in 5% CO 2In this case, the two cell lines were maintained in logarithmic growth phase in RPMI 1640 medium (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, St. Louis, MO, USA). For the necrosis assay, L929 cells were seeded at 10K cells / well in 100 μL / well of medium in a Costar 96-well black clear-bottom plate (Fisher Scientific, Hampton, NH, USA) for 18 h; on the day of the assay, U937 cells were seeded at 50K cells / well in 50 μL / well of medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland). The medium was removed from the L929 cells in the 96-well plate and replaced with 50 μL / well of fresh medium containing 40 μM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted 4-fold from 2.5 mM in DMSO and then diluted 1:125 in complete medium. Then 50 μL / well of 2x the compound was added to the cells in the plate. The cells were pre-incubated with the compound at 37 °C in 5% CO 2 2 for 1 h, and then 10 μL / well of 11x TNFα (Peprotech, Rocky Hill, NJ, USA) was added to give a final concentration of TNFα of 2 ng / mL. At 37 °C in 5% CO 2 2, using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA), and the Luminescent Cell Viability Reagent Assay ( Promega, Madison, WI, USA), after 18 h of TNFα stimulation, added according to the manufacturer's instructions, the relative amount of necrotic cells was determined by luminescence. The results from this example are summarized in Table 2. This example demonstrated that the exemplified compounds described in the text have unexpectedly potent activity against human RIP1 and murine RIP1, an activity that permits their evaluation in in vivo murine models of disease. These results can be used to determine safe and effective doses for humans.

[0344]

[0345]

[0346] Example 17

[0347] In this example, an acute hypothermia mouse model assay was used to evaluate the ability of the compounds disclosed herein to inhibit TNF-α-induced hypothermia.

[0348] Female C57BL / 6 mice were randomly grouped and weighed on day -1. On the day of the study (day 0), the vehicle or test article was administered to the mice by oral gavage. Fifteen minutes after oral administration of the test reagent, each mouse was administered an intraperitoneal (IP) injection containing a solution of recombinant human tumor necrosis factor α (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at hour zero (before IP injection) and hourly via a rectal probe temperature measuring device. Three (3) hours after IP injection of TNF-α and zVAD / FMK, the mice were euthanized by CO 2 asphyxiation and blood was collected via cardiac puncture. Serum and plasma were harvested and used to determine cytokine and compound levels, respectively. Mice including a separate group (satellite mice) were used to determine the compound levels in plasma when TNFα / zVAD-FMK was administered.

[0349] (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014 / 125444) having the structure as described below was used as a comparative compound and examined using the same assay protocol. This comparative compound exhibited only 70% inhibition at 30 mg / kg. In contrast, Compound I-5 of the present disclosure achieved 81% inhibition at 15 mg / kg.

[0350]

[0351] Given the many possible embodiments to which the principles of the present disclosure may be applied, it should be recognized that the illustrated embodiments are only preferred examples and should not be considered limiting. On the contrary, the scope of the present disclosure is defined by the appended claims. Accordingly, we claim all of the invention falling within the scope and spirit of these claims.

Claims

1. A compound having the formula or a pharmaceutically acceptable salt thereof, wherein: Ring B has a structure that satisfies the formula where at least one W is nitrogen and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH; R 1 is -NR d R d , where two R d groups together with the nitrogen to which they are attached provide a non - aromatic 3 - 15 membered heterocyclic group having at least one heteroatom selected from nitrogen and oxygen, optionally substituted by one or more R e and / or R g groups, where R g is halogen, C 1-10 aliphatic -C 5-10 aromatic or =O; R 2 is C 1 -C 10 alkyl; R 3 is hydrogen; R 4 is hydrogen; R 5 is a halogen; For each occurrence, R a is independently H, D, C 1-10 aliphatic, or C 1-10 cycloaliphatic; For each occurrence, R e is independently -OR a 、-NR a 、C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, or two R e groups are joined together to provide a non-aromatic 3- to 15-membered heterocyclic group having at least one heteroatom selected from nitrogen and oxygen; n is 0; and p is 0 or 1.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is a triazole selected from the following: or an oxazole selected from the following:

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 1 is -NR d R d , where two R d groups together with the nitrogen to which they are attached provide a non-aromatic 3- to 15-membered heterocyclic group having at least one heteroatom selected from nitrogen and oxygen, said 3- to 15-membered heterocyclic group containing two R e groups, said two R e groups being linked together so as to provide a second non-aromatic 3- to 15-membered heterocyclic group having at least one heteroatom selected from nitrogen and oxygen.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the second 3- to 15-membered heterocycle formed by the two R e groups and the 3- to 15-membered heterocycle formed by the two R d groups provide a spiro group comprising at least two rings, wherein the spiro group comprises at least one oxygen atom and at least one nitrogen atom, wherein the spiro group comprises a first ring coupled to a carbon atom of the compound, the first ring having from 3 to 7 atoms, and the second ring having from 3 to 7 atoms.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 4, wherein the spiro group contains a total of more than 7 atoms in the spiro system.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the second 3- to 15-membered heterocyclic group formed by the two R e groups and the 3- to 15-membered heterocyclic group formed by the two R d groups provide a bicyclic group having two or more heteroatoms selected from nitrogen and oxygen, wherein the bicyclic group is a fused bicyclic group or a bridged bicyclic group, and wherein the bicyclic group is attached to the ring A phenyl group of formula I through a nitrogen atom of the bicyclic group.

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is where each n is independently an integer ranging from 0 to 4, and R 6 is independently selected from hydrogen, C 1-25 aliphatic, aromatic having 5 to 15 ring atoms, or C having at least one heteroatom selected from nitrogen and oxygen 1-25 heteroaliphatic.

8. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

9. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 10. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, an excipient, a therapeutic agent, an adjuvant, or a combination thereof.

11. Use of a compound or a pharmaceutical composition thereof for the preparation of a medicament for treating a disease in a subject, wherein the use comprises administering to the subject (i) a therapeutically effective amount of the compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof; or (ii) a therapeutically effective amount of the pharmaceutical composition according to claim 10; wherein the subject has or is suspected of having or is developing the disease, and wherein the disease is a disease involving receptor-interacting protein-1 (RIP1) kinase.

12. A method for preparing the compound according to any one of claims 1-9, the method comprising: Combine a starting material having formula A with an R 1 -H-containing R 1 reagent for coupling to form an R 1 functionalized product, which is carried out as follows: combining the starting material and the R 1 reagent with a transition metal catalyst, a ligand component, and a solvent; Deprotect the amino group of the product of the R 1 functionalization to provide an amine compound; and forming an amide bond between the amine compound and an acid-containing coupling partner; wherein formula A is: Said R 1 The functionalized product has a structure satisfying formula B: and the acid-containing coupling partner has a structure satisfying formula C: Formula C; and wherein X is halogen or trifluoromethanesulfonate; PG is an amine protecting group; And rings B, R 1 , R 2 , R 4 , R 5 , each of n and p is as described in claim 1.

13. The method according to claim 12, wherein the amide bond is formed by coupling the amine compound and the acid-containing coupling partner in the presence of propylphosphonic anhydride and diisopropylethylamine.

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