EA046406B1 - RIP1 INHIBITING COMPOUNDS AND METHODS OF THEIR PRODUCTION AND USE - Google Patents

Description

Cross reference to related application

This application claims the benefit of the earlier filing date of U.S. Provisional Patent Application No. 62/666,452, filed May 3, 2018, the entire contents of which are incorporated herein by reference.

Field of technology to which the invention relates

The present invention relates to compounds, as well as methods for preparing and using compounds, for example, intended for inhibiting receptor interacting protein kinase-1 (RIP1) and for treating diseases and/or conditions associated with RIP1.

Prerequisites for the creation of an invention

Receptor-interacting protein kinase 1 (hereinafter referred to as RIP1) belongs to the tyrosine kinase-like protein kinase family and is a serine/threonine protein kinase involved in innate immune receptor signaling. RIP1 plays a central role in the regulation of cell signaling, and its role in programmed cell death has been linked to various inflammatory diseases such as inflammatory bowel disease, psoriasis, and other diseases and/or conditions associated with inflammation and/or necroptotic cell death.

Brief description of the invention

This document discloses embodiments of a compound represented by formula I.

R ² °

Formula I, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroaryl containing at least one carbon atom and at least one N or O heteroatom; 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 independently represents R ^a ;

each R ⁴ and each R ⁵ independently represent halogen, R ^a or R ^b ;

R ^a independently for each occurrence represents H, D, C _1-10 aliphatic C _3-10 cycloaliphatic, wherein the C _1-10 aliphatic and C _3-10 cycloaliphatic are optionally substituted with one, two or three R ^e and/or R ^g ;

R ^b is independently for each occurrence -NR ^d R ^d , wherein the two R ^d groups together with the nitrogen atom bound thereto form a C _3-10 heterocyclic group comprising at least one carbon atom and one to five heteroatoms selected from nitrogen, phosphorus, oxygen, silicon or sulfur, wherein the C _3-10 heterocyclic group is optionally substituted with one, two or three R ^e and/or R ^g , each R ^e is independently for each occurrence -OR ^a , -N(R ^a )2, C 1-6 αalkyl, C 1-6 haloalkyl, C 1-6 hetero αalkyl comprising at least one heteroatom selected from nitrogen, oxygen, phosphorus, silicon or sulfur, C 3-6 cycloalkyl, or two R ^e groups are joined together to form a C 3-10 heterocyclic group with the R ^b group to which the two R ^e groups are bound, wherein the C _3-10 heterocyclic group optionally substituted with one, two or three R ^g ; and each R ^g is independently for each occurrence halogen, C _1-10 aliphatic-C _5-10 aromatic, or =O;

m is from 1 to 4;

n is 0, 1, or 2; and p is 0, 1, 2, 3, 4, or 5.

The disclosed compounds may have a structure corresponding to the formula below

In any or all of the above embodiments, ring B may have a structure corresponding to the formula

wherein at least one W is nitrogen and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen or NH, wherein particular embodiments of ring B

- 1 046406 are a triazole or oxazole. Suitable illustrative triazoles include any of the following:

Suitable illustrative oxazoles include any of the following:

Certain disclosed compounds comprise a group R ⁵ , which is a group R ^a , wherein R ^a is a C1-C4 aliphatic group, or R ⁵ is halogen; and/or wherein R ² is R ^a , wherein R ^a is a C1- _C4 aliphatic group, and R ³ is R ^a , wherein R ^a is hydrogen.

In some embodiments, R ⁵ is ^Ra , wherein ^Ra is C1-C4 aliphatic, or R ⁵ is halogen; and/or wherein R ² is ^Ra , wherein ^Ra is C1- _C4 aliphatic, and R ³ is ^Ra , wherein ^Ra is hydrogen.

In some embodiments, R ¹ is R ^b , wherein R ^b is NR ^d R ^d , wherein two R ^d groups, together with the nitrogen atom bonded thereto, form a first C3-10 heterocyclic group comprising two R ^e groups that are joined together to form a second C3-10 heterocyclic group, wherein the second C _3-10 heterocyclic group is optionally substituted with one, two, or three R ^g .

In some embodiments, the first C _3-10 heterocyclic group and the second C _3-10 heterocyclic group form a spirocyclic group or a bicyclic group.

In some embodiments, the spirocyclic group comprises at least two rings, wherein the first ring and the second ring of the spirocyclic group comprise a different number of carbon atoms, a different number of heteroatoms, or both, and wherein each ring of the spirocyclic group comprises a heteroatom in the ring.

In some embodiments, the spirocyclic group comprises at least one oxygen atom and at least one nitrogen atom.

In some embodiments, the spirocyclic group comprises a first ring and a second ring, wherein the first ring is bonded to a carbon atom of the compound and contains from 3 to 7 atoms, and the second ring contains from 3 to 7 atoms.

In some embodiments, the spirocyclic group contains a total of more than 7 atoms in the spirocyclic system.

In some embodiments, the C _3-10 heterocyclic group and the second C _3-10 heterocyclic group form a bicyclic group.

In some embodiments, the bicyclic group is a fused bicyclic group or a bridged bicyclic group, wherein the bicyclic group is attached to the compound via a nitrogen atom of said bicyclic group.

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In some embodiments, R ¹ is

where each n is independently an integer ranging from 0 to 4, and R ⁶ is independently selected from hydrogen, an aliphatic, a substituted aromatic, or a heteroaliphatic group.

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In some embodiments, the compound is selected from

- 4 046406

- 5 046406

In some embodiments, the compound is

Illustrative embodiments of the compounds are disclosed herein and may be selected from any one or more of compounds I-1 through I-27.

Also disclosed herein are embodiments of a pharmaceutical composition comprising a compound (or compounds) according to any of the formulas and/or species disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one additional active and/or inactive agent, such as an excipient, a therapeutic agent, an adjuvant, or a combination thereof. Also disclosed herein are embodiments of a method of using the disclosed compounds. One such embodiment involves contacting a receptor interacting protein kinase-1 (RIP1) with a compound according to any of the formulas and/or species disclosed herein, or a pharmaceutically acceptable salt thereof, or an embodiment of a pharmaceutical composition described herein. The contacting may occur ex vivo or in vivo.

Also disclosed is a method of treating a disease in a subject comprising administering to the subject (i) a therapeutically effective amount of a compound according to any of the formulas and/or variations disclosed herein, or a pharmaceutically acceptable salt thereof; and/or (ii) a therapeutically effective amount of an embodiment of the pharmaceutical composition described herein; wherein the subject has or is suspected of having or developing a disease involving receptor interacting protein kinase-1 (RIP1).

The above and other objects, features and advantages of the present invention will become more apparent from the following detailed description.

Detailed description of the invention

I. Review of terms.

The following explanations of terms and methods are provided to better describe the present disclosure and to provide those skilled in the art with guidance in practicing the present invention. The singular forms "a" or "an" refer to one or more than one unless the context clearly indicates otherwise. The term "or" refers to one element of specified alternative elements or a combination of two or more elements unless the context clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising" A or B means "including" A, B, or A and B without excluding additional elements.

All literature, including patents and patent applications, cited in this document are incorporated by reference.

Unless otherwise stated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, etc., which are used in the description or claims of the invention, are to be understood as being modified by the term approximately. Therefore, unless otherwise implicitly or explicitly stated, the numerical parameters set forth are approximate values that may depend on the desired properties being determined and/or detection limits under standard test/method conditions. In the case of direct and obvious

- 6 046406 distinct embodiments from the discussed prior art, the numbers of the embodiments do not represent approximations unless the word approximately is expressly stated.

Unless otherwise defined, 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 invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

When chemical structures are drawn or described, unless explicitly stated otherwise, all carbon atoms are assumed to contain a hydrogen atom, so that each carbon atom satisfies a valence of four. For example, the structure shown on the left in the diagram below is assumed to contain nine hydrogen atoms. The structure shown on the right is depicted with nine hydrogen atoms.

Sometimes a particular atom in a structure is described in the text formula as having a hydrogen atom or hydrogen atoms, for example, -CH2CH2-. One skilled in the art will appreciate that the above descriptive methods are common in various fields of chemistry to ensure brevity and simplicity in describing organic structures.

If the R group is shown floating in a ring system, as with R ¹ in the group:

then, unless otherwise specified, the substituent R (e.g. R ¹ above) may be located on any atom of the fused bicyclic ring system except the atom bearing the bond to com .~w, provided that a stable structure is formed.

When the R group is depicted as existing in a ring system containing saturated carbon atoms, as in the formula:

atoznaato-

where in this example y may be greater than one, given the fact that each replaces a hydrogen on the ring depicted, implied, or expressly stated herein; then, unless otherwise stated, two R may be on the same carbon atom. A simple example is when R is a methyl group. The structure depicted may exist as a geminal dimethyl on the carbon atom of the ring depicted (the ring carbon). In another example, two R on the same carbon atom, together with the carbon atom, may be incorporated into the ring, thus forming a spirocyclic ring structure (spirocyclyl group). For example, as shown below, two R may form an oxetane or tetrahydropyran ring in spirocyclic form with a piperidine or azetidine ring, as

As used herein, the term substituted refers to all subsequent modifiers in the term, for example, in the term substituted arylC _1-8 alkyl, the substitution may occur on the C _1-8 alkyl portion, the aryl portion, or both portions of the arylC _1-8 alkyl group.

The term substituted, when used to modify a specified group or moiety, means that at least one, and optionally two or more, hydrogen atoms of the specified group or moiety are independently replaced with the same or different substituent groups, as defined below. In a particular embodiment, a group, moiety or substituent may be substituted or unsubstituted unless expressly identified as unsubstituted or substituted. Accordingly, any of the groups specified herein may be unsubstituted or substituted unless the context dictates otherwise or the specific structural formula precludes substitution. In particular embodiments, a substituent may or may not be expressly identified as substituted, but is still considered optionally substituted. For example, an aliphatic or cyclic moiety may be unsubstituted or substituted, but an unsubstituted aliphatic or unsubstituted cyclic is unsubstituted.

Substituents or substituent groups for replacing one or more hydrogen atoms

- 7 046406 at saturated carbon atoms in the said group or fragment may represent, unless otherwise specified, -R ⁶⁰ , halogen, =O, -OR ⁷⁰ , -SR ⁷⁰ , -N(R ⁸⁰ )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R ⁷⁰ , -SO3'M ⁺ , -SO3R ⁷⁰ , -OSO2R ⁷⁰ , -OSO3'M ⁺ , -OSO3R ⁷⁰ , -P(O)(O')2(M ⁺ )2, -P(O)(O')2M 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 +. -CO2R ⁷⁰ , -C(S)OR ⁷⁰ , -C(O)N(R ⁸⁰ )2, -C(NR ⁷⁰ )(R ⁸⁰ );, -OC(O)R ⁷⁰ , -OC(S)R ⁷⁰ , -OCO; M'„ -OCO2R ⁷⁰ , -OC(S)OR ⁷⁰ , -NR ⁷⁰ C(O)R ⁷⁰ , -NR ⁷⁰ C(S)R ⁷⁰ , -NR ⁷⁰ CO2M ⁺ , -NR ⁷⁰ CO2R 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 is C1_10 aliphatic, heteroaliphatic or cycloaliphatic, typically C1_10 aliphatic, more often C1.6 alkyl, wherein R ⁶⁰ may be optionally substituted; each R ⁷⁰ independently for each occurrence is hydrogen or R ⁶⁰ ; each R ⁸⁰ is, independently for each occurrence, R ⁷⁰ , or alternatively two R ⁸⁰ groups taken together with the nitrogen atom to which they are bonded form a 3- to 7-membered heterocycloaliphatic group which optionally contains from 1 to 4, same or different, additional heteroatoms selected from O, N and S, of which N optionally has an R ⁷⁰ substitution such as H- or C1-C3- _alkyl substitution; and each M ⁺ is a counterion with a net single positive charge. Each M ⁺ is, independently for 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 [Ca2 ⁺ ] _0.5 , [Mg2 ⁺ ]0.5, or [Ba2 ⁺ ] _0.5 (the subscript 0.5 means, for example, that one of the counterions for these divalent alkaline earth metal ions may be an ionized form of the compound of the present invention, and the other is a typical counterion such as chloride, or two ionized compounds may serve as counterions for such divalent alkaline earth metal ions, or a doubly ionized compound may serve as a counterion for such divalent alkaline earth metal ions). As specific examples, -N( ^R80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methylpiperazin-1-yl, Nmorpholinyl, and the like. Any two hydrogen atoms on one carbon atom can also be replaced, for example, by =O, =NR ⁷⁰ , =N-OR ⁷⁰ , =N2 or =S.

Substituent groups for replacing hydrogen atoms at unsaturated carbon atoms in groups containing unsaturated carbon atoms are, unless otherwise specified, -R ⁶⁰ , halogen, -OM ⁺ , -OR ⁷⁰ , -SR ⁷⁰ , -SM', -N(R ⁸⁰ )2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R ⁷⁰ , -SO3 ^- M ⁺ , -SO3R ⁷⁰ , -OSO2R ⁷⁰ , -OSO3 ^- M ⁺ , -OSO3R ⁷⁰ , -PO3 ^-2 (M ⁺ )2, -PO3 ^-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 ⁺ , -CO2R 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 , -OCO2 ^- M ⁺ , -OCO2R ⁷⁰ , -OC(S)OR ⁷⁰ , -NR ⁷⁰ C(O)R ⁷⁰ , -NR ⁷⁰ C(S)R ⁷⁰ , -NR ⁷⁰ CO2 ^- M ⁺ , -NR ⁷⁰ CO2R 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, wherein R ⁶⁰ , R ⁷⁰ , R ⁸⁰ and M ⁺ are as previously defined. In an independent embodiment, the substituents are not -O'M ⁺ , -OR ⁷⁰ , -SR ⁷⁰ or -S'M ⁺ .

Substituent groups for replacing hydrogen atoms at nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise specified, -R ⁶⁰ , -O ^- M ⁺ , -OR ⁷⁰ , -SR ⁷⁰ , -S ^- M ⁺ , -N(R ⁸⁰ ) ₂ , perhaloalkyl, -CN, -NO, -NO2, -S(O)2R ⁷⁰ , -SO3 ^- M ⁺ , -SO3R ⁷⁰ , -OS(O)2R ⁷⁰ , -OSO3-M+, -OSO3R ⁷⁰ , -PO3 ^2- (M ⁺ )2, -PO3 ^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 , -CO2R 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 , -OCO2R ⁷⁰ , -OC(S)OR ⁷⁰ , -NR ⁷⁰ C(O)R ⁷⁰ , NR ⁷⁰ C(S)R ⁷⁰ , -NR ⁷⁰ CO2R 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 ⁺ are as defined previously.

In one embodiment, a group that is substituted contains from at least one substituent to the number of substituents possible for a particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

Furthermore, in embodiments wherein a group or moiety is substituted with a substituted substituent, the inclusion of such substituted substituents is limited to three, thereby preventing the formation of polymers. Thus, in a group or moiety comprising a first group that is a substituent for a second group, which itself is a substituent for a third group attached to the parent structure, the first (outer) 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 substituents that are themselves unsubstituted.

Any group or moiety defined herein may be bonded to any other part of the disclosed structure, such as the parent or base structure, as will be apparent to one skilled in the art, for example, by reference to valence rules, by comparison with illustrative elements, and/or by reference to reactivity of functional groups, unless the ability of the group or moiety to form a bond with another part of the structure is explicitly stated or is not required by context.

Acyl refers to the group -C(O)R, where R is H, an aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl) group. Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1- _C6 -alkyl, -C(O)C1- _C6- haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or

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-C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

An aliphatic group refers to a group or moiety predominantly based on a hydrocarbon. An aliphatic group or moiety may be an acyclic group, including alkyl, alkenyl or alkynyl groups (as well as alkylene, alkenylene or alkynylene), cyclic variants thereof such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl or cycloalkynyl, and further includes straight and branched chain forms, as well as all stereoisomers and positional isomers. Unless expressly stated otherwise, an aliphatic group contains from one to twenty-five carbon atoms ( _{C1_25} ); for example, from one to fifteen ( _C1-15 ), from one to ten ( _{C1_10} ), from one to six ( _{C1_6} ), or from one to four carbon atoms (Cm) for an acyclic aliphatic group or moiety, or from three to _fifteen ( _C3-15 ), from three to ten ( _{C3_10} ), from three to _six ( _{C3-6 )} , or from three to four carbon atoms ( _{C3-4 )} for a cycloaliphatic group or moiety. An aliphatic group may be substituted or unsubstituted unless an unsubstituted aliphatic or substituted aliphatic group is expressly mentioned. An aliphatic group may be substituted by one or more substituents (no more than two substituents for each methylene carbon atom in the aliphatic chain, or no more than one substituent for each carbon atom of the -C=C- double bond in the aliphatic chain, or no more than one substituent for the carbon atom of the terminal methine group).

The lower aliphatic group refers to an aliphatic group containing from one to ten carbon atoms (C _1-10 ), such as from one to six (C1_ ₆ ) or from one to four (C1_ ₄ ) carbon atoms; _{or from three to ten (C 3-10 ), such as from three to six (C 3-6 ) carbon} atoms for a lower cycloaliphatic group.

Alkoxy refers to the group -OR, wherein R is a substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl group. In certain examples, R is a C ₁ . ₆ alkyl group or a C ₃ . ₆ cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy, R is a substituted alkyl or substituted cycloalkyl, examples of which in the compounds disclosed herein include haloalkoxy groups such as -OCF2H.

Alkoxyalkyl refers to the group -alkyl-OR, where R is _a substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl group; _-CH2CH2 - _O - _CH2CH3 is an illustrative alkoxyalkyl group.

Alkyl refers to a saturated aliphatic hydrocarbyl group containing from 1 to at least 25 ( _{C1_25} ) carbon atoms, more typically from 1 to 10 ( _C1-10 ) carbon atoms, such as from 1 to 6 carbon atoms ( _{C1_6} ). The alkyl moiety may be substituted or unsubstituted. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3) and neopentyl (-CH2C(CH3)3).

Amino refers to a -NH2, -NHR, or -NRR group, wherein each R is independently selected from H, an aliphatic, a heteroaliphatic, an aromatic including both aryl and heteroaryl groups, or a heterocycloaliphatic group, or two R groups, together with the nitrogen atom to which they are attached, form a heterocyclic ring. Examples of such heterocyclic rings _include those wherein two R groups, together with the nitrogen atom to which they are attached, form a -( _CH2 ) _2-5- ring, optionally interrupted by one or two heteroatom-containing groups such as -O- or -N( ^Rg ), such as in the \—/ and \—/ groups, wherein ^Rg is ^R70 ,

-C(O)R ⁷⁰ , -C(O)OR ⁶⁰ or -C(O)N(R ⁸⁰ )2.

An amide refers to the group -N(R)acyl, where R is hydrogen, a heteroaliphatic, or an aliphatic group such as alkyl, particularly C ₁ . ₆ alkyl.

An aromatic group refers to a cyclic, conjugated group or moiety, unless otherwise noted, of 5 to 15 ring atoms, containing one ring (e.g., phenyl, pyridinyl, or pyrazolyl) or several fused rings of which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), i.e., at least one ring and optionally several fused rings have a continuous, delocalized π-electron system. Typically, the number of out-of-plane π-electrons follows the Huckel rule (4n+2). The point of attachment to the parent structure is usually at the aromatic portion of the fused ring system.

For example, O . However, in some examples, the context or direct disclosure may indicate that the point of attachment is at the non-aromatic portion of the fused ring

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systems. For example, . An aromatic group or moiety may contain only carbon atoms in a ring, such as in an aryl group or moiety, or it may contain one or more carbon atoms in a ring and one or more heteroatoms in a ring containing a lone pair of electrons (e.g., 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.

Aryl refers to an aromatic carbocyclic group, unless otherwise specified, of 6 to 15 carbon atoms containing a single ring (e.g., phenyl) or multiple fused rings of which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.). If any portion of the aromatic ring contains a heteroatom, the group is a heteroaryl rather than an aryl. Aryl groups may be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, an aryl group may be substituted or unsubstituted.

An araliphatic group refers to an aryl group attached to the parent structure through an aliphatic moiety. An araliphatic group includes aralkyl or arylalkyl groups such as benzyl and phenylethyl.

Carboxyl refers to _-CO2H .

Carboxamide refers to -C(O)amino.

A carboxylic acid ester or carboxy ester refers to a -C(O)OR group where R is an aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl) group.

Carboxylate refers to -C(O)O or its salts.

Cyano belongs to the -CN group.

A cycloaliphatic group refers to a cyclic aliphatic group containing one ring (e.g., cyclohexyl) or multiple rings, such as in a fused, bridged, or spirocyclic system, wherein the ring or at least one of the rings in the system is aliphatic. Typically, the point of attachment to the parent structure is at the aliphatic portion of the multi-ring system. A cycloaliphatic group includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. A cycloaliphatic group may contain from three to twenty-five carbon atoms, such as 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.

Halogen radical, halide or halogen refers to fluorine, chlorine, bromine or iodine.

Haloalkyl refers to an alkyl moiety substituted with one or more halogen atoms. Illustrative haloalkyl moieties include -CH2F, -CHF2, and _-CF3 .

Heteroaliphatic refers to an aliphatic compound or group containing at least one heteroatom and at least one carbon atom, i.e. at least one carbon atom of an aliphatic compound or group containing at least two carbon atoms that have been replaced by an atom having at least one lone pair of electrons, typically a nitrogen, oxygen, phosphorus, silicon or sulfur atom. Heteroaliphatic compounds or groups may be substituted or unsubstituted, branched or unbranched, chiral or achiral, and/or acyclic or cyclic, such as a heterocycloaliphatic group.

Heteroaryl refers to an aromatic group or moiety containing, unless otherwise specified, from 5 to 15 ring atoms, including at least one carbon atom and at least one heteroatom such as N, S, O, P or Si. A heteroaryl group or moiety may contain a single ring (e.g., pyridinyl, pyrimidinyl or pyrazolyl) or multiple fused rings (e.g., indolyl, benzopyrazolyl or pyrazolopyridinyl). Heteroaryl groups or moieties may be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise specified, a heteroaryl group or moiety may be substituted or unsubstituted.

Heterocyclyl, heterocyclo and heterocycle refer to both aromatic and non-aromatic ring systems and more particularly refer to a stable three- to fifteen-membered ring moiety containing at least one carbon atom, typically several carbon atoms, and at least one heteroatom, such as one to five heteroatoms. The heteroatom(s) may be nitrogen, phosphorus, oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be a monocyclic moiety or may contain several rings, such as in a bicyclic or tricyclic ring system, provided that

- 10 046406 at least one of the rings contains a heteroatom. Such a multi-ring moiety may include fused or bridged ring systems, as well as spirocyclic systems; wherein any nitrogen, phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, nitrogen atoms, particularly but not exclusively defined as nitrogen atoms, being in an aromatic ring are meant to include their corresponding N-oxide form, even if not explicitly defined as such in a particular example. Thus, for a compound containing, for example, a pyridinyl ring, the corresponding pyridinyl N-oxide is included as another compound of the present invention, unless expressly excluded or excluded by context. Furthermore, nitrogen atoms being in a ring may be optionally quaternized. The heterocycle includes heteroaryl moieties and heteroalicyclyl or heterocycloaliphatic moieties, which are heterocyclyl rings that are partially or completely saturated. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapan, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothielyyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl and oxadiazolyl.

Hydroxyl belongs to the -OH group.

Nitro belongs to the -NO2 group.

Phosphate refers to the group -OP(O)(OR') ₂ , where each -OR' is independently -OH, an O-aliphatic group such as -O-alkyl or -O-cycloalkyl, an -O-aromatic group including both -O-aryl and -O-heteroaryl, -O-aralkyl; or -OR' is -O ^- M ⁺ , where M ⁺ is a counterion with a single positive charge. Each M ⁺ can be an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; an ammonium ion such as +N(R)4, where R is H, an aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl) group; or an alkaline earth metal ion such as [Ca2 ⁺ ] _0.5 , [Mg2 ⁺ ]0.5 or [Ba2 ⁺ ] _0.5 . Phosphonooxyalkyl refers to an -alkyl phosphate group such as, for example, _-CH2OP (O)(OH) ₂ , or a salt thereof such as _-CH2OP (O)(O ^- Na ⁺ ) ₂ , and (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group such as, for example, -CH2OP(O)(O-tert-butyl)2.

Phosphonate refers to the group -P(O)(OR')2, where each -OR' is independently -OH, an -O-aliphatic group such as -O-alkyl or -O-cycloalkyl, an -O-aromatic group including both -O-aryl and -O-heteroaryl; or -O-aralkyl; or -OR' is -O ^- M ⁺ and M ⁺ is a counterion with a single positive charge. Each M ⁺ is a positively charged counterion and can be, for example, an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; an ammonium ion such as +N(R)4, where R is H, an aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl) group; or an alkaline earth metal ion such as [Ca2 ⁺ ] _0.5 , [Mg2 ⁺ ]0.5 or [Ba2 ⁺ ] _0.5 . Phosphonoalkyl refers to an -alkyl phosphonate group such as, for example, _-CH2P (O)(OH) ₂ or _-CH2P (O)(O ^- Na ⁺ ) ₂ , and ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of a phosphonoalkyl group such as, for example, -CH2P(O)(O-tert-butyl)2.

The patient or subject may generally refer to any living being, but most often refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human and veterinary therapy.

A pharmaceutically acceptable excipient refers to a substance other than the active ingredient that is formulated with the active ingredient. As used herein, the excipient may be embedded in the particles of the pharmaceutical composition or it may be physically mixed with the particles of the pharmaceutical composition. The excipient may be used, for example, to dilute the active substance and/or to modify the properties of the pharmaceutical composition. Excipients may include, but are not limited to, anti-adhesives, binders, coating agents, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, sorbents, preservatives, carriers, or vehicle vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, saccharides and derivatives thereof such as disaccharides, polysaccharides, and sugar alcohols, protein, synthetic polymers, cross-linked polymers,

- 11 046406 ry, antioxidants, amino acids or preservatives. Illustrative excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch varieties, hydroxypropyl cellulose, hydroxypropyl methylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol succinate 1000 (also known as vitamin E-TPGS or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silicon dioxide, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

An adjuvant is a component that modifies the effect of another agent, usually an active ingredient. Adjuvants are often pharmacological and/or immunological agents. An adjuvant may modify the effect of an active ingredient by enhancing the immune response. An adjuvant may also act as a stabilizing agent for the formulation. Illustrative 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.

A pharmaceutically acceptable carrier refers to an excipient that is a carrier or vehicle, such as a suspending agent, a solubilizing agent, or an aerosolizing agent. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, ^21st Edition (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for pharmaceutical delivery of one or more of the therapeutic compositions and additional pharmaceutical agents.

In general, the nature of the carrier will depend on the particular route of administration employed. For example, parenteral formulations typically provide injection fluids that include pharmaceutically and physiologically acceptable fluids such as water, saline, balanced salt solutions, aqueous dextrose, glycerol, or the like as a carrier medium. In some examples, the pharmaceutically acceptable carrier may be sterile so that it is suitable for administration to a subject (e.g., via parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, pH-adjusting buffering agents, and the like, for example, sodium acetate or sorbitan monolaurate.

A pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of a compound prepared from a variety of organic and inorganic counterions known to those skilled in the art and including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and in the case where the molecule contains a basic functional group, to salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. Pharmaceutically acceptable acid addition salts are a subset of pharmaceutically acceptable salts that retain the biological effectiveness of the free bases when formed by acidic components. In particular, 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 and the like, as well as 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, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like. Pharmaceutically acceptable base addition salts are a subgroup of pharmaceutically acceptable salts that are derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and cation 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, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Illustrative organic bases include

- 12 046406 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 certain disclosed embodiments, the compounds can be a formate, trifluoroacetate, hydrochloride, or sodium salt.

An effective amount, with respect to a compound or pharmaceutical composition, refers to an amount of the compound or pharmaceutical composition sufficient to achieve a specific desired result, such as inhibition of a protein or enzyme. In particular embodiments, an 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 the said disorder or disease; to reduce the intensity of the manifestation or elimination of one or more symptoms thereof; and/or to prevent the occurrence of the disease or disorder. The amount of the compound that constitutes an effective amount may vary depending on the compound, the desired result, the disease state and its severity, the weight, age and sex of the patient to be treated, etc., as will be understood by one of skill in the art.

A prodrug refers to compounds that are converted in vivo to produce a biologically active compound or a compound more biologically active than the parent compound. The in vivo conversion can occur, for example, by hydrolysis or enzymatic conversion. Representative examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound whose active form comprises a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present invention include, but are not limited to, esters formed between phosphate groups and carboxylic acids, such as aliphatic esters, in particular alkyl esters (e.g., C1 ₆ alkyl esters). Other prodrug moieties include phosphoric acid esters, such as -CH2-OP(O)(OR')2 or a salt thereof, wherein R' is H or _C1 . ₆ αalkyl. Suitable 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 invention include, but are not limited to, primary amides as well as secondary and tertiary alkyl amides (e.g., containing from about one to about six carbon atoms). Amides and esters of the disclosed illustrative embodiments of the compounds of the present invention can be prepared according to conventional methods. A detailed discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol 14 ACS Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

A solvate refers to a complex formed by combining solvent molecules with solute molecules or ions. The solvent may 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, propanol; amides such as N,N-dialiphatic amides, for example N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water, and combinations thereof. The compounds described herein can exist in both unsolvated and solvated forms when combined with solvents, whether pharmaceutically acceptable or not, such as water, ethanol, and the like. Solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

Sulfonamide refers to a _-SO2- amino or N(R)sulfonyl group or moiety, where R is H, an aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl) group.

Sulfanyl refers to a group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic group (including both S-aryl and -S-heteroaryl group).

Sulfinyl refers to a -S(O)H, -S(O)aliphatic, -S(O)heteroαliphatic, or -S(O)aromatic group or moiety (including both -S(O)aryl and -S(O)heteroaryl groups).

Sulfonyl refers to the group: -SO2H, -SO2 _- aliphatic, -SO2 _- heteroaliphatic, -SO2 _- aromatic (including both -SO2 _- aryl and -SO2 _- heteroaryl groups).

Treatment or treatment, as used herein, refers to the treatment of a disease or condition of interest in a patient or subject, particularly a human, having the disease or condition of interest, and includes by way of example and without limitation:

(i) preventing the occurrence of a disease or condition in a patient or subject, in particular where such patient or subject is susceptible to the condition but has not yet been diagnosed with it;

- 13 046406 (ii) suppression of a disease or condition, for example by delaying or slowing its progression;

(iii) alleviation of the disease or condition, such as resulting in relief of a symptom or regression of the disease or condition or its symptoms; or (iv) stabilization of the disease or condition.

As used in this document, the terms disease and condition may be used interchangeably or may be distinguished in that a particular disease or condition may have no known causative agent (and therefore the etiology has not yet been determined) and therefore has not yet been recognized as a disease, but only as an undesirable condition or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

The above definitions and the following general formulae are not intended to include invalid substitution patterns (e.g., methyl substituted with 5 groups representing fluorine atoms). Such invalid substitution patterns are readily recognized by one skilled in the art.

One skilled in the art will appreciate that the compounds may exhibit tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For example, certain disclosed compounds may contain one or more chiral centers and/or double bonds and, as a result, may exist as stereoisomers, such as isomers at the position of the double bond (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds may exist in multiple tautomeric forms, including an enol form, a keto form, and mixtures thereof. Since the various compound names, formulas and depictions of compounds in the specification and claims may represent only one of the possible tautomeric, conformational isomeric, optically isomeric or geometrically isomeric forms, it will be understood by one skilled in the art that the disclosed compounds encompass any tautomeric, conformational isomeric, optically isomeric and/or geometrically isomeric forms of the compounds described herein, as well as mixtures of such various distinct isomeric forms. Mixtures of various isomeric forms, including mixtures of enantiomers and/or stereoisomers, can be separated to obtain each individual enantiomer and/or stereoisomer using techniques known to those skilled in the art, particularly with the advantage of the present invention. In cases of limited rotation, such as about an amide bond or between two directly attached rings such as pyridinyl rings, biphenyl groups and the like, atropisomers are also possible and are also specifically included within the definition of the compounds of the present invention.

In any of the embodiments, any or all of the hydrogen atoms present in the compound or in a particular group or moiety of the compound may be replaced by deuterium or tritium atoms. Thus, the enumeration of alkyl includes a deuterated alkyl in which from one to the maximum number of hydrogen atoms present may be replaced by deuterium. For example, ethyl refers to both C2H5 and C2H5, where from 1 to 5 hydrogen atoms are replaced by deuterium, such as in C2D _x H _5-x .

II. RIP1-active compounds and pharmaceutical compositions containing RIP1-active compounds.

A. Connections.

Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that are useful for inhibiting RIP1 and/or for treating diseases and/or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds are capable of selectively inhibiting RIP1 over RIP2, RIP3, or both RIP2 and RIP3. In some embodiments, a compound of the present invention may have a structure corresponding to Formula I

Formula I, or a pharmaceutically acceptable salt thereof, wherein:

ring B is a 5-membered heteroaryl containing at least one carbon atom and at least one N or O heteroatom; L is a C _1-10 aliphatic linker; R ¹ is ^Ra or R ^b , where at least one R ¹ is R ^b ;

each of R ² and R ³ independently represents R ^a ;

each R ⁴ and each R ⁵ independently represent halogen, R ^a or R ^b ;

R ^a independently for each occurrence is H, D, C _1-10 aliphatic C _3-10 cycloaliphatic, wherein the C _1-10 aliphatic and C _3-10 cycloaliphatic are optionally substituted with one, two or three R ^e and/or R ^g ;

- 14 046406

R ^b is independently for each occurrence -NR ^d R ^d , wherein the two R ^d groups together with the nitrogen atom bound thereto form a C _3-10 heterocyclic group comprising at least one carbon atom and one to five heteroatoms selected from nitrogen, phosphorus, oxygen, silicon or sulfur, wherein the C _3-10 heterocyclic group is optionally substituted with one, two or three R ^e and/or R ^g , each R ^e is independently for each occurrence -OR ^a , -N(R ^a )2, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl comprising at least one heteroatom selected from nitrogen, oxygen, phosphorus, silicon or sulfur, C3-6 cycloalkyl, or two R ^e groups are joined together to form a C3-10 heterocyclic group with the R ^b group to which the two R ^e groups are bound, wherein the C _3-10 heterocyclic group is optionally substituted with one, two or three R ^g ; and each R ^g independently for each occurrence represents a halogen, a C _1-10 aliphatic-C _5-10 aromatic group, or =O;

m is from 1 to 4;

n is 0, 1, or 2; and p is 0, 1, 2, 3, 4, or 5.

In some embodiments, the compound has a structure corresponding to the formula

In some embodiments, ring B has a structure corresponding to the formula

Wr, where at least one W is nitrogen and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH.

In some embodiments, ring B is a triazole selected from or

oxazole selected from

In some embodiments, R ⁵ is ^Ra , wherein ^Ra is C1-C4 aliphatic, or R ⁵ is halogen; and/or wherein R ² is ^Ra , wherein ^Ra is C1- _C4 aliphatic, and R ³ is ^Ra , wherein ^Ra is hydrogen.

In some embodiments, R ¹ is R ^b , wherein R ^b is -NR ^d R ^d , wherein two R ^d groups, together with the nitrogen atom bonded thereto, form a first C3-10 heterocyclic group comprising two R ^e groups that are joined together to form a second C3-10 heterocyclic group, wherein the second C _3-10 heterocyclic group is optionally substituted with one, two, or three R ^g .

In some embodiments, the first C _3-10 heterocyclic group and the second C _3-10 heterocyclic group form a spirocyclic group or a bicyclic group.

In some embodiments, the spirocyclic group comprises at least two rings, wherein the first ring and the second ring of the spirocyclic group comprise a different number of carbon atoms, a different number of heteroatoms, or both, and wherein each ring of the spirocyclic group comprises a heteroatom in the ring.

In some embodiments, the spirocyclic group comprises at least one oxygen atom and at least one nitrogen atom.

In some embodiments, the spirocyclic group comprises a first ring and a second ring, wherein the first ring is bonded to a carbon atom of the compound and contains from 3 to 7 atoms, and the second ring contains from 3 to 7 atoms.

In some embodiments, the spirocyclic group contains a total of more than 7 atoms in the spirocyclic system.

In some embodiments, the C _3-10 heterocyclic group and the second C _3-10 heterocyclic group form a bicyclic group.

- 15 046406

In some embodiments, the bicyclic group is a fused bicyclic group or a bridged bicyclic group, wherein the bicyclic group is attached to the compound via a nitrogen atom of said bicyclic group.

In some embodiments, R ¹ is

where each n is independently an integer ranging from 0 to 4, and R ⁶ is independently selected from hydrogen, an aliphatic, a substituted aromatic, or a heteroaliphatic group.

- 16 046406

In some embodiments, the compound is selected from

- 17 046406

1-27

- 18 046406

In some embodiments, the compound is

Also disclosed is a pharmaceutical composition comprising any of the said compounds and one or more excipients or adjuvants.

Also disclosed is a method for treating a disease, wherein the disease is a disease involving receptor-interacting protein kinase-1 (RIP1), comprising contacting receptor-interacting protein kinase-1 (RIP1) with a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17.

Also disclosed is the use of any of the disclosed compounds or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing any of the said compounds for the treatment of a disease, wherein the disease is a disease involving receptor interacting protein kinase-1 (RIP1).

Also disclosed is a method for producing the disclosed compounds or pharmaceutically acceptable salts thereof, comprising providing a coupling reaction of a starting material characterized by formula A with an R ¹ -containing reagent characterized by formula R 1-H, by combining the starting material and the R ¹ -containing reagent with a transition metal catalyst, a ligand component and a solvent to form an R ¹ -functionalized product;

removing the protective group from the amino group of the ^R1 -functionalized product to obtain an amino compound and ensuring the formation of an amide bond between the amino compound and the coupling reaction participant containing an acidic group;

where formula A represents

NHPG

Formula A;

The R ¹ -functionalized product has a structure corresponding to formula B,

NHPG

Formula B;

and the coupling reaction participant containing the acid group has a structure corresponding to formula C,

p

Formula C;

and where X is a halogen or triflate;

PG is a protecting group for the amino group;

and each of the rings B, L, R ¹ , R ² , R ⁴ , R ⁵ , m, n and p is as specified in paragraph 1.

In some embodiments, the formation of the amide bond is achieved by coupling an amino compound and a coupling partner containing an acidic group in the presence of propylphosphonic anhydride and diisopropylethylamine.

- 19 046406

Certain disclosed illustrative compounds within the scope of one or more of Formulae I, II, IIA-IIC, III, IVA, IVB, or VA-VC include

- 20 046406

1-27

- 21 046406

Illustrative compounds within the scope of one or more of formulae IV, VIA, VIB, or VIIA-VIIC include

I-1: (5)-N-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperide in-1 -yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b ] [ 1,4]oxazepin-3 -yl)-1 -(4-fluorobenzyl)- 1H-1,2,4triazol-3-carboxamide;

1-2: (5)-1-(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;

1-3: (5)-5-benzyl-^-(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)isoxazole-3-carboxamide;

1-4: (5)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-5: (L')-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[L][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-6: K-((5)-7-((18,48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

1-7: K-((5)-7-((18,48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

1-8: (L')-1-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[L][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-9: (5)-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;

1-10: (L')-5-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[L][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-11: (5)-5-(4-fluorobenzyl)-H-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2yl)-2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3carboxamide;

1-12: (5)-5-benzyl-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b] [1, 4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-13: 18G-((35)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

1-14: (5)-18G-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

1-15: (8)-5-benzyl-A-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)2,3,4,5- tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide;

- 22 046406

1-16: (5)-X-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3carboxamide;

1-17: (5)-5-benzyl-M-(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;

1-18: (5)-5-benzyl-M-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5 · tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-19: (5)-5-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8 yl)-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3carboxamide;

1-20: (5)-X-(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;

1-21: (£)-5-benzyl-X-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5· tetrahydrobenzo[L][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

1-22: (£)-5-benzyl-X-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5· tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

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

1-24: (5)-5-benzyl-X-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5,5]undecan-9-yl)-5 methyl-4-oxo -2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3 carboxamide;

1-25: (5)-5-benzyl-X-(5-methyl-4-oxo-7-(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;

1-26: (5)-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

1-27: (5)-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.

- 23 046406

Additional illustrative variations of compounds contemplated by the present invention are presented below.

- 24 046406

- 25 046406

In some embodiments, one or more compounds may be included in a pharmaceutical composition or medicament, and in some embodiments, the compound or compounds may be in the form of the parent compound or a pharmaceutically acceptable salt thereof. The pharmaceutical composition typically includes at least one

- 26 046406 an additional component other than the compound or compounds described, such as a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent (described in the next section) or any combination thereof.

Pharmaceutically acceptable excipients can be included in pharmaceutical compositions for a variety of purposes, such as to dilute the pharmaceutical composition for delivery to a subject, to facilitate processing of the formulation, to impart preferred physical properties to the formulation, to facilitate dispersion from a delivery device, to stabilize the formulation (e.g., antioxidants or buffers), to impart a good or pleasant taste or texture to the formulation, or the like. The pharmaceutically acceptable excipient(s) can include pharmaceutically acceptable carrier(s). Illustrative excipients include, but are not limited to: mono-, di-, 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 sorbitols, diphosphatidylcholine, and lecithin; bulking agents; buffers such as phosphate and citrate buffers; anti-stick agents such as magnesium stearate; binding agents such as saccharides (including disaccharides such as sucrose and lactose), polysaccharides (such as starches, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coating agents (such as cellulose ethers including hydroxypropyl methylcellulose, shellac, zein, which is a protein from corn, and gelatin); release agents (such as enteric coatings); disintegrating agents (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); flavorings and sweetening agents (such as mint, cherry, anise, peach, apricot or liquorice, raspberry and vanilla); lubricants (such as minerals, examples of which are talc or silicon dioxide, fats, examples of which are vegetable stearin, magnesium stearate or stearic acid); preservatives (such as antioxidants, examples of which are vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium, amino acids, examples of which are cysteine and methionine, citric acid and sodium citrate, parabens, examples of which are methylparaben and propylparaben); colors; pressing aids; emulsifying agents; encapsulating agents; gums; granulating agents and combinations thereof.

B. Combinations of therapeutic agents.

The compounds described herein may be used alone, in combination with one another, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other conventional therapies. The compound or compounds, or a composition comprising the compound (or compounds), may be administered in a single or multiple administrations. In some embodiments, the compounds of the present invention may be used in combination with other therapeutic agents useful for the disorder or condition being treated. Such other therapeutic agents may be administered simultaneously, sequentially, in any order, via the same route of administration or via a different route than the compounds disclosed herein. For sequential administration, the compound(s) and therapeutic agent(s) may be administered such that the effective period of time of at least one compound and therapeutic agent overlaps the effective period of time of at least one other compound and/or therapeutic agent. In an exemplary embodiment of a combination comprising four components, the effective period of time of the first component administered may overlap with the effective periods of time of the second, third, and fourth components, but the effective periods of time of the second, third, and fourth components independently may overlap with each other or may not overlap. In another exemplary embodiment of a combination comprising four components, the effective period of time of the first component administered overlaps with the effective period of time of the second component, but does not overlap with the effective period of time of the third or fourth component; the effective period of time of the second component overlaps with the effective periods of time of the first and third components; and the effective period of time of the fourth component overlaps only with the effective period of time of the third component. In some embodiments, the effective periods of time of all compounds and/or therapeutic agents overlap with each other.

In some embodiments, the compounds are administered with another therapeutic agent, such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory, an immunosuppressant, a guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral, an anticancer, an antifungal, or a combination thereof. The anti-inflammatory agent may be a steroidal or non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent

- 27 046406 the agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotodine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, 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, an antilymphocyte globulin, an antimyocyte globulin, an antibody to T-cell antigens, or a combination thereof. In one embodiment, the antibody is infliximab.

In some embodiments, the compounds of the present invention can be used with anticancer or cytotoxic agents. Various classes of anticancer and antitumor compounds include, but are not limited to, alkylating agents, metabolic inhibitors, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, such as DNMT inhibitors such as azacitidine and decitabine. Exemplary alkylating agents include, but are not limited to, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan), and carmustine. Illustrative metabolic inhibitors include, by way of example and not limitation, the folate analog methotrexate; the pyrimidine analog fluorouracil, cytosine arbinoside; and the purine analogs mercaptopurine, thioguanine, and azathioprine. Illustrative vinca alkaloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Illustrative antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. Illustrative enzyme effective as an antineoplastic agent includes L-asparaginase. Illustrative coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Illustrative hormones and hormone-related compounds include, by way of example and not limitation, the adrenocorticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the estrogen antagonist compound tamoxifen.

These and other useful anticancer compounds are described in Merck Index, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton L.L. ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

Among the CTLA 4 antibodies that may be used in combination with the inhibitors disclosed herein is ipilimumab, marketed as YERVOY® by BristolMyers Squibb.

Other chemotherapeutic agents for combination include immuno-oncology agents such as immune checkpoint 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 BMS986016 (MDX-1408).

Additional chemotherapeutic agents for combination with the inhibitors disclosed herein 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).

The compounds disclosed herein may also be advantageously used with CAR-T therapies. Examples of currently available CAR-T therapies include axicabtagene, ciloleucel, and tisagenleucel.

Additional antiproliferative compounds useful in combination with the compounds of the present invention include, by way of example and not limitation, antibodies directed against growth factor receptors (e.g., Her ₂ ) and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

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

Examples of kinase inhibitors that may be used in combination with the compounds described herein, 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,

- 28 046406 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 and fedratinib.

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

pain relievers - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

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

antibodies - anti-TNF-α antibodies, such as infliximab (Remicade™), adalimumab, golimumab, certolizumab; antibodies to B cell antigens, 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, clenoliximab, clasakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants - warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, gementin;

anti-inflammatory drugs - steroids such as budesonide, non-steroidal anti-inflammatory drugs such as aminosalicylates (eg sulfasalazine, mesalamine, olsalazine and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

immunosuppressants such as 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, mycophenolate mofetil, and azathioprine, and agents designed to suppress cellular immunity while leaving the patient's humoral immune response intact, including various antibodies (e.g., antilymphocyte globulin (ALG), antimycotic globulin (ATG), monoclonal antibodies to specific T-cell antigens (OKT3)) and radiation exposure. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratoire

- 29 046406 ries, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name

Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the trade name Imuran and the antibodies are currently available from Ortho Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab) and from Roche under the trade name Zenapax (daclizumab); and

Guanylate cyclase-C receptor agonists or intestinal secretagogues such as linaclotide are sold under the name Linzess.

These various agents may be administered according to their standard or usual dosages as directed in the prescribing information accompanying the commercially available forms of the drug (see also the prescribing information in the 2006 edition of the Physician's Desk Reference), the disclosure of which is incorporated herein by reference.

III. Methods for obtaining compounds.

The disclosed compounds may be prepared by any suitable synthetic method, as will be apparent to one skilled in the art in view of the advantages of the present invention. One suitable method is illustrated by way of example below, as shown for specific compounds in the examples. An illustrative method for preparing the compounds may include the following first reaction step according to Scheme 1.

Scheme 1

Referring to Scheme 1, starting compound 100 is reacted with R ¹ -containing reagent 102 using suitable metal-mediated cross-coupling conditions to yield R ¹ -functionalized product 104. X is a suitable group for metal-mediated cross-coupling, such as a halogen or a triflate group, and PG is a protecting group for an amino group that can be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl (Fmoc) group, a tert-butyloxycarbonyl (Boc) group, a trityl (Tr) group, an allyloxycarbonyl (Alloc) group, a benzyloxycarbonyl (Cbz) group, and the like. In some embodiments, the metal-mediated cross-coupling conditions comprise using a transition metal catalyst, such as a Pd(0)-based catalyst (e.g., _Pd2 (dba) ₃ , Pd(dba) ₂ , _Pd2 ( _PPh3 ) ₄ , and the like) in combination with a ligand component, such as a ligand capable of generating Pd(II) from the Pd(0)-based catalyst (e.g., a BINAP ligand, a BINOL ligand, and the like), a base (e.g., t-BuONa), and a solvent. In some embodiments, the cross-coupling step comprises heating the reaction mixture at a suitable temperature (e.g., 60°C or higher, such as from 70 to 140°C, or from 80 to 120°C, or from 85 to 100°C).

Illustrative examples of the method shown in Scheme 1 are shown below in Schemes 2A-2G.

Scheme 2A

- 30 046406

Scheme 2B

NH HCI

Vg

NHTr

200

Br

NHTr

200

Br

200 'NHTr

Br

•NHTr

200

Br

200 'NHTr

Br

200 'NHTr

Pd ₂ (dba) ₃ , BINAP, f-BuONa toluene, 85°C, overnight

Scheme 2C

HCI HN

Pd ₂ (dba) ₃ , BINAP,t-BuONa toluene, 85 °C, overnight

2D diagram

N

H

HCI

Pd ₂ (dba) ₃ , BINAP.t-BuONa toluene, 85 C, overnight

Scheme 2E

NH ^НС|

Pd ₂ (dba) ₃ , ΒΙΝΑΡ,ί-BuONa toluene, 85°C, overnight

Scheme 2F

HCI

Pd ₂ (dba) ₃ , ΒΙΝΑΡ,ί-BuONa toluene, 85°C, overnight

Scheme 2G n^ НС)

IVa NH

Pd ₂ (dba) ₃ , BINAPT-BuONa toluene, 85 °C, overnight

204 'NHTr

NHTr

206

NHTr

H

208

210 'NHTr

212 'NHTr

214 'NHTr

Embodiments of the method for preparing compounds may further include additional steps used to convert the R ¹ -functionalized product 104 into the desired compounds within the scope of the present invention. In some embodiments, such additional steps may include a first step of removing the protecting group to obtain the amino compound 300.

The amino compound 300 is then converted to the amide compound 304 by reacting the amino compound with a suitable coupling partner 302, which is an acid, as shown in Scheme 3.

- 31 046406

Scheme 3

Referring to Scheme 3, the deprotection may involve the use of any suitable reagent that can remove the protecting group of an amino group (PG, as shown in Schemes 1 and 3). In some embodiments, an acid such as TFA is used in the deprotection step. In further embodiments, a base such as piperidine can be used in the deprotection step. Other acids and bases suitable for deprotection are known to those skilled in the art given the benefits of the present invention. The amide formation step can be accomplished using reagents that can facilitate the formation of an amide from the free amine of the amino compound 300 and the acidic functionality of the coupling partner 302, which is an acid. Suitable coupling partners can be synthesized using methods known to those skilled in the art given the benefits of the present invention, or can be purchased from commercial sources. In some embodiments, propylphosphonic anhydride can be used in combination with a base, such as diisopropylethylamine, to form an amide; however, other reagents such as 2-(7-aza-1H-benzotriazol-1-yl)N,N,N',N'-tetramethylaminium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-N,N,N',N'-hexafluorophosphate, 2(6-chloro-1H-benzotriazol-1-yl-N,N,N',N'-tetramethylaminium hexafluorophosphate, 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl, benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate and the like, in combination with diisopropylethylamine, isopropylamine and the like. A suitable solvent such as dichloromethane (DCM) is also used.

Illustrative examples of the steps of the method shown in Scheme 3 are shown below in Schemes 4A-4N.

Scheme 4A

Scheme 4B

- 32 046406

Scheme 4C

4D diagram

Scheme 4E

Scheme 4F

4G Scheme

- 33 046406

Scheme 4H

Scheme 4I

Scheme 4J

4K Scheme

Scheme 4L

- 34 046406

Scheme 4M

Scheme 4N

Referring to Schemes 4A-4N above, the acidic coupling participant 402 can be prepared using the following procedure. A solution of ethyl 5-benzylisoxazole-3-carboxylate was added to a solution of NaOH in MeOH and water. After a suitable time at 20°C, the solvent was removed in vacuo. The residue was acidified with dilute HCl and then extracted with EtOAc. The organic phase was washed with water and brine and dried over sodium sulfate, followed by evaporation in vacuo. Other acid coupling partners described in Schemes 4A-4N can be prepared using a similar method and from a suitable starting material (e.g., ethyl 5-benzyl-1H-1,2,4-triazole-3-carboxylate, ethyl 1-benzyl-1H-1,2,4-triazole-3-carboxylate and its fluorinated species).

IV. Methods of using compounds.

A. Diseases/disorders.

The disclosed compounds, as well as combinations thereof and/or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase either in vivo or ex vivo with a compound or compounds of the present invention, or a composition comprising a compound or compounds of the present invention. The disclosed compound or compounds, or compositions comprising the disclosed compound or compounds, can also be used to ameliorate, treat, or prevent a number of diseases and/or disorders. In particular embodiments, a disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be useful for treating conditions in which inhibition of RIP1 or a pathway involving RIP1 is therapeutically beneficial. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds are useful for treating autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancers, ischemic conditions, red blood cell deficiency, lung and brain injury (e.g., caused by ischemia-reperfusion or cisplatin and/or cerebrovascular accident), and bacterial and viral infections.

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

The disclosed compound, combinations of the disclosed compounds or pharmaceutical compositions based on it(them) may also be useful for the treatment of immunoregulatory disorders associated with bone marrow or organ transplant rejection or graft versus host disease. Examples of inflammatory disorders and immunoregulatory disorders that can be treated with

- 35 046406 by the power of the compounds (or pharmaceutical compositions based on them or combinations thereof), include, without limitation, reactions arising from organ or tissue transplantation, graft-versus-host reactions arising from transplantation, autoimmune syndromes, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, severe myasthenia, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, including acute rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, pruritic dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema forms, vasculitis, erythema, eosinophilia associated with skin diseases, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, pemphigus of the eye, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible airway obstruction, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, asthma, dust-induced, chronic or intractable asthma, late asthma and airway hyperresponsiveness, bronchitis, gastric ulcers, vascular injury caused by ischemic disease and thrombosis, ischemic bowel injury, ischemia/reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, bowel injury associated with thermal burns, forms of celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red blood cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, allergic photosensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis, polyarteritis nodosa, myocardosis or myocardial infarction, scleroderma (including systemic sclerosis), antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, adiposis, eosinophilic fasciitis, gingival lesions, periodontal disease, alveolar bone, root cementum, glomerulonephritis, androgenetic alopecia or senile alopecia that can be avoided by preventing hair removal along with the hair follicles or by allowing new hair follicles to germinate and/or by promoting the generation of new hair follicles and hair growth, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs arising from preservation, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, drug-induced or radiation-induced colitis, acute renal failure due to ischemia, chronic renal failure, intoxication caused by the presence of high levels of oxygen in the lungs or by drugs, lung cancer, pulmonary emphysema, cataracts, siderosis, pigmentary retinal dystrophy, retinal degeneration, retinal detachment, senile macular degeneration, vitreous scarring, corneal alkali burn, dermatitis, erythema multiforme, linear IgA bullous dermatosis and cement contact dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, oncogenesis, metastasis of carcinoma and altitude sickness, histamine or leukotriene C4 release disease, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, reactions occurring after partial liver resection, acute liver necrosis, necrosis due to toxins, viral hepatitis, shock or anoxia, viral hepatitis B, hepatitis other than hepatitis A/hepatitis B, liver cirrhosis, alcoholic liver disease including alcoholic liver cirrhosis, alcoholic steatohepatitis, nonalcoholic steatohepatitis (NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, acute liver failure due to chronic liver failure, chronic kidney disease, kidney injury/damage (e.g., due to nephritis, kidney transplant, surgery, nephrotoxic drugs, acute kidney injury), enhancement of chemotherapy effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

In certain embodiments, the compounds of the present invention are useful for the treatment of neuralgia, including neuropathic pain and pain caused by inflammation.

In certain embodiments, the compounds are useful for treating interleukin-1 converting enzyme associated fever syndrome, periodic syndrome,

- 36 046406 tumor necrosis factor receptor-related disease, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., 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, free sialic acid storage disease of childhood, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease and Wolman disease).

In certain embodiments, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof are useful for the treatment and/or prevention of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, in particular pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, acute gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Parkinson's disease.

Proliferative diseases that can be treated with the disclosed compound, a combination of the disclosed compounds or pharmaceutical compositions based on it(them) include benign or malignant tumors, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testicles, urogenital tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastoma forms, neuroblastoma forms, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, head and neck tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial origin, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, forms of Hodgkin's lymphoma and forms of non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 mediated disorders, MyD88 mediated disorder (such as diffuse large B cell lymphoma ABC (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, or chronic lymphocytic leukemia), smoldering or indolent multiple myeloma, or hematologic malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, DLBCL ABC, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds disclosed herein are useful in the treatment of malignancies refractory to drug therapy, such as malignancies refractory to JAK inhibitors, malignancies refractory to ibrutinib, including hematological malignancies refractory to ibrutinib, such as ibrutinib-refractory CLL and ibrutinib-refractory Waldenstrom's macroglobulinemia.

Examples of allergy-related disorders that can be treated using the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, IgE-mediated atopic bronchial asthma, non-atopic asthma, bronchial asthma, non-allergenic asthma, idiopathic asthma, true asthma, endogenous asthma caused by pathophysiological abnormalities, idiopathic asthma of unknown or non-obvious cause, emphysematous asthma, exercise-induced asthma, emotionally induced asthma, exogenous asthma caused by environmental factors, cold-air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal or viral infection, early asthma, childhood obstructive pulmonary syndrome, bronchiolitis, cough-variant asthma or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip

- 37 046406 sinusitis, purulent and non-purulent sinusitis, acute or chronic sinusitis and ethmoiditis, frontal sinusitis, maxillary sinusitis or sphenoid sinusitis.

As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion, and stiffness in affected joints throughout the body. RA is characterized by a chronically inflamed synovial membrane that is densely surrounded by lymphocytes. The synovial membrane, which is normally one cell layer thick, becomes cellular and takes on a lymphoid-like appearance, including dendritic cells, T, B, and NK cells, macrophages, and plasma cell clusters. This process, as well as a variety of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, ultimately leads to a breakdown of joint integrity, resulting in deformity, eventual failure, and/or destruction of bone near or adjacent to the joint. The disclosed compound, combinations of the disclosed compounds or pharmaceutical compositions thereof can be used to treat, ameliorate or prevent any one, several or all of these symptoms of RA. Thus, in the context of RA, the compounds are considered to provide a therapeutic effect when a reduction or amelioration of any of the symptoms commonly associated with RA is achieved, regardless of whether the treatment is a consequence of concomitant treatment of the underlying RA disease and/or a reduction in the amount of circulating rheumatoid factor (RF).

The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. One such parameter, ACR20 (ACR criterion for 20% clinical improvement), requires a 20% improvement in the number of tender and swollen joints and a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain score, disability, and acute phase proteins. These criteria have been expanded to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include the Paulus criteria and radiographic progression (eg, Sharp score).

In some embodiments, a therapeutic effect in patients suffering from RA is achieved when the patient has an ACR20. In specific embodiments, improvements according to ACR criteria corresponding to ACRC50 or even ACR70 can be achieved.

B. Composition and introduction.

Pharmaceutical compositions containing one or more active compounds of the present invention can be prepared by any suitable method, such as mixing, dissolving, granulating, pelletizing, triturating, emulsifying, encapsulating, entrapping or lyophilizing processes. The pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers or excipients), one or more adjuvants or combinations thereof to obtain preparations that can be used in pharmaceuticals.

The active compound(s) can be formulated into pharmaceutical compositions per se or in the form of a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug thereof. As a rule, such salts are more soluble in aqueous solutions than their corresponding free acids and bases, but salts having lower solubility than the corresponding free acids and bases can also be formed.

The pharmaceutical compositions of the present invention can be formulated for virtually any route of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection such as i. v. or i. p., transdermal, rectal, vaginal, etc., or formulated for administration by inhalation or insufflation.

For topical administration, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug may be formulated as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

Formulations for systemic administration include those formulated for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those formulated for transdermal, transmucosal, oral or inhalation administration.

Suitable injectable preparations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily carrier media. The pharmaceutical compositions may also contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, and may contain added preservatives.

Alternatively, the injection formulation may be provided in the form of a powder that needs to be

- 38 046406 dissolved with a suitable carrier medium, including but not limited to sterile, pyrogen-free water, buffer, dextrose solution, etc., prior to use. In this regard, the active compound(s) may be dried by any technique known in the art, such as lyophilization, and dissolved prior to use.

For transmucosal administration, penetration enhancing substances are used in the composition, which are capable of overcoming this barrier. Such penetration enhancing substances are known from the state of the art.

For oral administration, the pharmaceutical compositions can be presented in the form of, for example, lozenges, tablets or capsules prepared by conventional methods using pharmaceutically acceptable excipients such as binders (e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silicon dioxide); disintegrants (e.g. potato starch or sodium starch glycolate) and/or wetting agents (e.g. sodium lauryl sulfate). The tablets can be coated by methods well known in the art, for example with sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, for example, strong infusions, solutions, syrups or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable excipients such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous carrier vehicles (e.g. almond oil, fatty esters, ethyl alcohol, Cremophore™ or fractionated vegetable oils) and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). If desired, the preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents and sweetening agents.

It is well known that oral preparations can be suitably formulated to provide controlled release of the active compound.

For buccal administration, the pharmaceutical compositions may be in the form of tablets or lozenges formulated in the conventional manner.

For rectal and vaginal administration, the active compound(s) may be formulated as solutions (for retention enemas), suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

For nasal administration or administration by inhalation or insufflation, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug may conveniently be delivered in the form of a spray aerosol from pressurized packs or a nebulizer using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a metered amount. Capsules and cartridges for use in an inhaler or insufflator (e.g., capsules and cartridges containing gelatin) can be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

A specific example of an aqueous suspension formulation suitable for nasal administration using commercially available nasal spray devices comprises the following ingredients: active compound (0.5-20 mg/mL); benzalkonium chloride (0.1-0.2 mg/mL); polysorbate 80 (TWEEN® 80; 0.5-5 mg/mL); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg/mL); phenylethanol (1-4 mg/mL) and dextrose (20-50 mg/mL). The pH of the final suspension can be adjusted to a value in the range of about pH 5 to pH 7, with a typical pH value being about pH 5.5.

Another specific example of an aqueous suspension suitable for administration of the compounds by inhalation comprises 20 mg/mL of the disclosed compound(s), 1% (v/v) polysorbate 80 (TWEEN® 80), 50 mM citrate and/or 0.9% sodium chloride.

For ocular administration, the active compound(s) may be formulated as a solution, emulsion, suspension, etc., suitable for administration to the eye. A number of carrier media suitable for administration of 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.

For prolonged delivery, the active compound(s) may be formulated as depot preparations for administration by implantation or intramuscular injection. The active ingredient may be formulated using suitable polymeric or hydrophobic materials (e.g., emulsions)

- 39 046 406 sic in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example as a sparingly soluble salt. Alternatively, transdermal delivery systems in the form of an adhesive disk or patch which slowly release the active compound(s) can be used for absorption through the skin. In this connection, penetration enhancing agents can be used to facilitate the penetration of the active compound(s) through the skin. 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; 5008110 and 4921475, which are incorporated herein by reference.

Alternatively, other pharmaceutical delivery systems may be used. Well-known examples of carrier media that may be used to deliver the active compound(s) are liposomes and emulsions. Certain organic solvents such as dimethyl sulfoxide (DMSO) may also be used, although usually at the cost of greater toxicity.

The pharmaceutical compositions may optionally be present in a package or dosing device which may contain one or more unit dosage forms containing the active compound(s). The package may comprise, for example, metal foil or polymer film, such as in a blister pack. The package or dosing device may be accompanied by instructions for administration.

C. Dosages.

The disclosed compound, pharmaceutical compositions or combinations of the disclosed compounds will generally be administered in an amount effective to achieve the desired result, for example, in an amount effective to inhibit RIP1 kinase and/or to treat, prevent or ameliorate a particular condition. The disclosed compound(s) or pharmaceutical compositions thereof may be administered as a therapy to achieve a therapeutic effect or as a prophylaxis to achieve a prophylactic effect. Therapeutic effect means the elimination or amelioration of the underlying disorder being treated and/or the elimination or amelioration of one or more symptoms associated with the underlying disorder, such that the patient reports an improvement in well-being or condition, although the patient may still be affected by the underlying disorder. For example, administration of the compound to a patient suffering from an allergy provides a therapeutic effect not only when the underlying allergic reaction is eliminated or ameliorated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the allergy after exposure to the allergen. As another example, a therapeutic effect in the context of asthma includes improvement in breathing after an asthma attack or a reduction in the frequency or severity of asthmatic episodes. A therapeutic effect also includes stopping or slowing the progression of the disease, whether or not improvement is achieved.

As is known to those skilled 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 condition of the patient or subject being treated. Dosage adjustments may also be necessary based on the sex of the individual and/or the lung capacity of the individual when administered by inhalation. The dosage may also be adjusted for individuals suffering from more than one condition, or for those individuals who have additional conditions that affect lung capacity and the ability to breathe normally, such as emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and upper respiratory tract infections. The dosage and frequency of administration of the disclosed compound(s) or pharmaceutical compositions thereof will also depend on whether the disclosed compound(s) is/are formulated to treat acute episodes of the condition or to prophylactically treat the disorder. One skilled in the art will be able to determine the optimal dosage for a particular individual.

For prophylactic administration, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered to a patient or subject at risk of developing one of the conditions described above. For example, if it is unknown whether the patient or subject is allergic to a particular drug, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be administered prior to administration of the drug to avoid or reduce the intensity of an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or reduce the intensity of symptoms in a patient diagnosed with an underlying disorder. For example, the disclosed compound(s) or pharmaceutical composition(s) thereof can be administered to an individual suffering from an allergy prior to expected exposure to the allergen. The disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can also be prophylactically administered to healthy individuals who are systematically exposed to agents known to cause one of the diseases described above to prevent the occurrence of the disorder. For example, disclosure

- 40 046406 the compound, combinations of the disclosed compounds or pharmaceutical compositions based on it(them) can be administered to a healthy individual who is systematically exposed to an allergen that is known to cause various forms of allergy, for example latex, in order to prevent the individual from developing an allergy. Alternatively, the disclosed compound, combinations of the disclosed compounds or pharmaceutical compositions based on it(them) can be administered to a patient suffering from asthma before engaging in an activity that causes asthma attacks in order to reduce the severity of an asthmatic episode or to avoid it altogether.

Effective dosages can be initially estimated from in vitro assays. For example, the initial dosage for administration to subjects can be formulated to achieve a circulating blood or serum concentration of the active compound that is equal to or greater than the IC ₅₀ or EC5 ₀ of the particular compound as measured in an in vitro assay. Dosages can be calculated to achieve such circulating blood or serum concentrations taking into account the bioavailability of the particular compound. Fingl & Woodbury, General Principles in: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Section 1, pp. 1-46, Pergamon Press, and references cited therein, provide additional guidance on effective dosages.

In some embodiments, the disclosed compounds have an EC ₅₀ value of greater than 0 to 20 μM, such as greater than 0 to 10 μM, greater than 0 to 5 μM, greater than 0 to 1 μM, greater than 0 to 0.5 μM, greater than 0 to 0.1 μM, or greater than 0 to 0.05 μM.

Initial dosages can also be estimated based on in vivo data obtained, for example, using animal models. Animal models suitable for testing the efficacy of compounds for the treatment or prevention of the various diseases described above are well known in the art. Suitable animal models of hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50(21Suppl):6-9, discussion 34-38, and Tumas et al., (2001), J. Allergy Clin. Immunol. 107(6): 1025-1033. Suitable animal models of 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. Those skilled in the art will be able to use this information to determine dosages appropriate for administration to humans.

In some embodiments, assays suitable for determining RIP1 activity can be used. Such assay methods can be used to evaluate the efficacy of embodiments of the compounds disclosed herein and/or can be used to determine amounts/dosages of embodiments of the compounds that can provide the desired efficacy. In some embodiments, the assay can be an ADP-Glo™ assay, which determines the ability of an embodiment of the compound to inhibit RIP1. In other embodiments, whole cell assays using mouse and/or human cells, such as U937 and/or L929 cell necroptosis assays, can be conducted to determine safe and effective doses of compounds that can be used in human studies in vivo. When conducted in such whole cell assays, the activity of the compound against human and/or mouse RIP1 can be assessed in an in vitro context, which then allows one of skill in the art to determine safe and effective doses for use in vivo. Another assay that can be used to evaluate the activity of the embodiments of the compounds described herein for treating a disease or condition involving RIP1 is performed in a mouse model of acute hypothermia, which evaluates the ability of the compound to inhibit TNF-alpha-induced hypothermia. Each of these assays and the various results obtained from performing such assays are described in detail in the Examples section of this disclosure.

Dosage amounts of the disclosed compounds will typically range from greater than 0 mg/kg/day, such as 0.0001 mg/kg/day, or 0.001 mg/kg/day, or 0.01 mg/kg/day, 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 when administered at least once per 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 is typically in the range of 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 per day to about 2.5 mg/kg/day. Dosage amounts may be higher or lower depending on, among other factors, the activity of the disclosed compound, its bioavailability, the route of administration, and various factors discussed above.

The dosage amount and the interval between dosing can be adjusted for individual individuals to provide plasma levels of the disclosed compound that are sufficient to maintain a therapeutic or prophylactic effect. For example, the compounds can be administered once daily, several times daily, once weekly, several times weekly (e.g., every other day), once monthly, several times monthly, or once annually, depending, among other things, on the route of administration, the specific indication for treatment, and the

- 41 046406 decisions of the attending physician. Specialists in this field will be able to optimize effective dosages for local use without unnecessary experiments.

Pharmaceutical compositions comprising one or more disclosed compounds typically comprise from greater than 0 to 99% of the disclosed compound or compounds and/or another therapeutic agent by percentage of total weight. More typically, pharmaceutical compositions comprising one or more disclosed compounds comprise from about 1 to about 20% of the disclosed compound and another therapeutic agent by total weight and from about 80 to about 99% by weight of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

Preferably, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions based on it(them) will provide a therapeutic or prophylactic effect without causing significant toxicity. The toxicity of the disclosed compound can be determined using standard pharmaceutical procedures. The ratio of doses providing a toxic and therapeutic (or prophylactic) effect is the therapeutic index. Disclosed compounds characterized by high therapeutic indices are preferred. V.

Example 1.

Examples

Step 1. A mixture of (S)-7-bromo-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 200 (which was prepared using the method illustrated below; 0.25 g, 0.49 mmol), 7-oxa-2-azaspiro[3.5]nonane hydrochloride (0.10 g, 0.60 mmol), _Pd2 (dba) ₃ (0.025 g, 0.027 mmol), racBINAP (0.05 g, 0.08 mmol), and NaOtBu (0.12 g, 1.3 mmol) in toluene (5 mL) was stirred at 85 °C 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/hexanes (3/7) to give (S)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(tritylamino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 204 as a brown solid (0.26 g, 96%).

Illustrative method for preparing compound 200.

200

Step 2. To a mixture of (S)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(tritylαmino)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 204 (0.26 g, 0.46 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (15.7 mmol, 1.2 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 re-concentrated under reduced pressure to give a residue which was purified by chromatography eluting with ethyl acetate-dichloromethane/MeOH (10/2) to give (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 205 as a pale white solid (0.16 g, 91%).

- 42 046406

1H NMR (CD3OD, 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 mass/charge: 318.2 (M+H)+.

Step 3. To a stirred mixture of (S)-3-amino-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 3 (0.025 g, 0.08 mmol) 205 and 5-benzyl-III-1,2,4-triazole-3-carboxylic acid (0.018 mg, 0.09 mmol) in dichloromethane (1 mL) were added N,N-diisopropylethylamine (0.05 mL, 0.3 mmol) and _T3P (propylphosphonic anhydride solution (50% by weight 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 at reduced pressure to give a residue which was purified by chromatography eluting with ethyl acetate/hexanes (3/7 to 9/1) to give (S)-5-benzyl-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 1-5 as a white solid (0.02 g, 61%).

1H NMR (CD3OD, 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 mass/charge: 503.3 (M+H) ⁺ .

Example 2.

The above synthetic procedure was adapted as described herein to provide compound I-1 below.

O

1-1 (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)-1 H-1,2,4-triazol-3-carboxamide.

1H NMR (CD3OD, 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 mass/charge: 557.3 (M+H) ⁺ .

Example 3.

The above synthetic procedure was adapted as described herein to provide compound I-2 below.

1-2 (S)-1-(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.

1H NMR (CDCl3, 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 mass/charge: 521.3 (M+H) ⁺ .

Example 4.

The above synthetic procedure was adapted as described herein to provide compound I-3 below.

1-3 (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-αzaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide.

1H NMR ( _CDCl3 , 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 mass/charge: 503.3 (M+H) ⁺ .

- 43 046406

Example 5.

The above synthetic procedure was adapted as described herein to provide compound I-4 below.

(S)-1 -(4-Fluorobenzyl)-M-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

^1H NMR (CD3OD, 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 mass/charge: 521.3 (M+H) ⁺ .

Example 6.

The above synthetic procedure was adapted as described herein to provide compound I-6 below.

N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide.

^1H NMR (CD3OD, 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 mass/charge: 475.1 (M+H) ⁺ .

Example 7.

The above synthetic procedure was adapted as described herein to provide compound I-7 below.

N-((S)-7-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 -(4-fluorobenzyl)-1H-1,2,4-triazol-3 -carboxamide.

1H NMR (CD3OD, 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 mass/charge: 493.3 (M+H)+.

Example 8.

The above synthetic procedure was adapted as described herein to provide compound I-8 below.

(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.

1H NMR (CD3OD, 400 MHz) 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 mass/charge: 495.3 (M+H) ⁺ .

- 44 046406

Example 9.

The above synthesis procedure was adapted to yield compound I-9 below.

as described in this document, to obtain

(S)-5-Benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3yl)isoxazole-3-carboxamide.

1H NMR (CD ₃ OD, 400 MHz) 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 mass/charge: 477.3 (M+H)+.

Example 10.

The above synthetic procedure was adapted as described herein to provide compound I-10 below.

(S)-5-(4-Fluorobenzyl)-N-(5-methyl-7-(1,4-oxαzepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxαzepin-3yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (CD3OD, 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/z: 495.3 (M+H) ⁺ .

Example 11.

The above synthetic procedure was adapted as described herein to provide compound I-11 below.

(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-triazol-3-carboxamide.

^1H 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 mass/charge: 519.3 (M-N)-.

Example 12.

The above synthetic procedure was adapted as described herein to provide compound I-12 below.

(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.

1H NMR (CD3OD, 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 mass/charge: 475.3 (M-N)-.

- 45 046406

Example 13.

The above described synthesis procedure was adapted to yield compound I-13 below.

as described in this document, to obtain

N-((3 S)-7-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide.

^1H NMR (CD3OD, 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 mass/charge: 489.1 (M+H)+.

Example 14.

The above synthetic procedure was adapted as described herein to provide compound I-14 below.

(S)-N-(7-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide.

MS mass/charge: 502.3 (M+H)+.

Other illustrative connections are described below.

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

1H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J Hz, NH), 7.29-7.19 (5H, m, CH5), 7.04 (1H, d, J=9, 0 Hz, H-6 oxobenzoxazapine), 6.74 (1H, dd, J=9.0, 2.5 Hz, H-7 oxobenzoxazapine), 6.68 (1H, d, J=2.5 Hz, H-9 oxobenzoxazapine), 5.06 (1H, dt, J=11.0, 7.5 Hz, H-3 oxobenzoxazapine ), 4.67 (1H, dd, J=10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.21 (1H, dd, J=11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.13 (2H, s, CH ₂ C ₆ H ₅ ), 3.70, 3.68 (4H, 2d AB systems, J=5.5 Hz, H-2, H-6 pyran), 3.34 (3H, s, NCH ₃ ), 3.20, 3.18 (4H, 2d AB systems, J=5.5 Hz, H-2, H-6 piperidine), 1.70-1.68 (4H, m, H-3 , H-5 piperidine), 1.56-1.53 (4H, m, H-3, H-5 pyran); mass/charge: 531 [M+H]+ (the found value of [M+H]+ 531.2711, C ₂₉ H ₃₄ N ₆ O ₄ provides [M+H]+ 531.2714).

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

1H NMR (400 MHz, Chloroform-d) δ 8.03-.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) mass/charge 620.5.

- 46 046406

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

1H 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), 4.083.98 (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) mass/charge 634.5.

Example 15.

In this example, compounds of the present invention were evaluated using a biochemical assay using ADP-Glo™ technology.

ADP-Glo™ reagents (Promega, Madison, WI, USA) were thawed at ambient temperature. Kinase detection reagent was prepared by mixing kinase detection buffer with lyophilized kinase detection substrate.

A stock volume of 500 ml of 5X kinase reaction buffer was prepared by mixing 1000 µl _of 1 M MgCl2, 500 µl of 1 M Tris-HCL pH 7.4, 0.5 mg/ml (25 mg) BSA and 3475 µl of distilled H2O. A 2X working stock solution of kinase reaction buffer was prepared in a volume of 3 ml with a final concentration of 100 µM DTT and ₄ mM MnCl2.

RIPK1 enzyme components (Rigel Pharmaceuticals, South San Francisco, CA, USA) were thawed on ice. Diluted RIPK1 was prepared in 1X kinase reaction buffer (diluted from 2X buffer) to 31 ng/well. A working stock solution for the ATP assay with a concentration of 166 μM was prepared in 1X kinase reaction buffer (diluted from 2X buffer).

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

The plate was quickly centrifuged and the reaction mixture was incubated at 30°C for 30 min. The addition of 5 μl of ADP-Glo™ ensured completion of the reaction. The plate was quickly centrifuged and the reaction mixture was incubated at room temperature for 40 min. The kinase detection reagent was then added and the mixture was incubated at room temperature for 30 min. The relative light unit (RLU) of the kinase reaction was determined by luminescence (0.1 s luminescence) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). The IC ₅₀ values obtained from this example are listed in Table 1.

- 47 046406

Table 1

Connection RIP1 ADP-Glo™ Kinase (ICso) 1-1 0,1977 1-2 0,0522 1-3 0,0374 1-4 0,0601 1-5 0,0678 1-6 0,0609 1-7 0,1075 1-8 0,2546 1-9 0,0392 1-10 0.3547 1-11 0,0394 1-12 0,0146 1-13 0,0145 1-14 0,4857 1-15 0,0425 1-16 0,2219 1-17 0,0404 1-18 0,088 1-19 0,0623 1-20 0,0482 1-21 0,0377 1-22 0,0236 1-23 0,0697 1-24 0,0745 1-25 0,082 1-26 0,0164 1-27 0,0432

Example 16.

In this example, U937 and L929 cells were exposed to compounds of the present invention and a cell necroptosis assay was performed to evaluate the activity of the compounds against human RIP 1 and mouse RIP 1.

U937 and L929 cells were obtained from the American Type Culture Collection (Manassas, VA, USA). Both cell types were maintained at logarithmic growth phase in complete RPMI 1640 medium (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, St. Louis, MO, USA) at 37°C with 5% CO ₂ . For necroptosis assays, L929 cells were seeded for 18 h in 100 μl/well medium at 10K cells/well in 96-well black Costar clear-bottom plates (Fisher Scientific, Hampton, NH, USA); U937 cells were seeded on the day of the assay in 50 μl/well of medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland) at 50K cells/well. The medium from the 96-well plates was removed from the L929 cells and replaced with new 50 μl/well medium containing 40 μM zVAD-fmk. Each compound of the invention evaluated in this example was serially diluted in DMSO, starting at 2.5 mM, in 4-fold dilutions and then diluted 1:125 in complete medium. Compound was then added to the cells in duplicate at 50 μl/well in the plates. Cells were pre-incubated with compound for 1 h at 37°C with 5% _CO2 before addition of 10 μl/well 11x TNFa (Peprotech, Rocky Hill, NJ, USA) to give a final concentration of 2 ng/ml for TNFa. The relative amount of necroptotic cells was determined by luminescence assay using a Wallac Victor2 luminometer (PerkinElmer, Worcester, WA, USA).

- 48 046406 Ltem, MA, USA) and by means of a fluorescent cell viability assay using the CellTiter-Glo® reagent (Promega, Madison, WI, USA) added according to the manufacturer's instructions after 18 h of TNFa stimulation at 37°C with 5% CO2. The results of this example are summarized in Table 2. This example confirms that embodiments of the compounds described herein have unexpectedly potent activity against human RIP 1 and mouse RIP1, allowing their evaluation in mouse models of the disease in vivo. Such results are applicable to the determination of safe and effective doses in humans.

Example 17.

In this example, an assay was performed in a mouse model of acute hypothermia to evaluate the ability of the compounds disclosed herein to inhibit TNF-alpha-induced hypothermia.

Female C57BL/6 mice were randomly grouped and weighed on day 1. On the day of the study (day 0), mice were administered vehicle or test drug via gavage. Fifteen minutes after oral administration of test drugs, each mouse received an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-a, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at zero hours (before IP

- 49 046406 injections) and hourly using a rectal probe temperature measurement device. Three (3) hours after IP injections of TNF-α and zVAD/FMK, mice were sacrificed by CO2 asphyxiation and blood was collected by cardiac puncture. Serum and plasma were collected for cytokine and compound levels, respectively. Separate groups of mice (satellite mice) were included for determination of plasma compound levels during TNFa/zVAD-FMK administration.

(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 illustrated below was used as a reference compound and tested using the same assay protocol. This reference compound showed only 70% inhibition at 30 mg/kg. In comparison, compound I-5 of the present invention achieved 81% inhibition at 15 mg/kg.

Comparative connection.

/ O

In view of the many possible embodiments to which the principles of the present invention may be applied, it should be understood that the illustrative embodiments are merely preferred examples and should not be considered limiting. Rather, the scope of the present invention is defined by the claims set forth below. Accordingly, the inventors of the present invention claim as their invention everything that falls within the scope and spirit of these claims.

Claims (21)

1. A compound characterized by the formula or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroaryl containing at least one carbon atom and at least one N or O heteroatom; 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 independently represents R ^a ; each R ⁴ and each R ⁵ independently represent halogen, R ^a or R ^b ; R ^a independently for each occurrence is H, D, C _1-10 aliphatic C _3-10 cycloaliphatic, wherein the C _1-10 aliphatic and C _3-10 cycloaliphatic are optionally substituted with one, two or three R ^e and/or R ^g ; R ^b independently for each occurrence is -NR ^d R ^d , wherein two R ^d groups together with the nitrogen atom bound thereto form a C _3-10 heterocyclic group containing at least one carbon atom and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen, silicon or sulfur, wherein the C _3-10 heterocyclic group is optionally substituted with one, two or three R ^e and/or R ^g ; each R ^e is, independently for each occurrence, -OR ^a , -N(R ^a )2, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl containing at least one heteroatom selected from nitrogen, oxygen, phosphorus, silicon or sulfur, C 3-6 cycloalkyl, or two R ^e groups are joined together to form a C 3-10 heterocyclic group with a R ^b group to which the two R ^e groups are bonded, the C _3-10 heterocyclic group being optionally substituted with one, two or three R ^g ; and each R ^g is, independently for each occurrence, halogen, C _1-10 aliphatic-C _5-10 aromatic, or =O; m is from 1 to 4; n is 0, 1, or 2 and p is 0, 1, 2, 3, 4, or 5. 2. The compound according to claim 1, wherein the compound has a structure corresponding to the formula - 50 046406 3. A compound according to claim 1 or 2, wherein ring B has a structure corresponding to the formula ^w *', wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. 4. A compound according to any one of claims 1 to 3, wherein ring B is a triazole selected from 5. A compound according to any one of claims 1 to 4, wherein R ⁵ is ^Ra , wherein ^Ra is a C1-C4 aliphatic group, or R ⁵ is halogen; and/or wherein R ² is ^Ra , wherein ^Ra is a C1- _C4 aliphatic group, and R ³ is ^Ra , wherein ^Ra is hydrogen. 6. A compound according to any one of claims 1 to 5, wherein R ¹ is R ^b , wherein R ^b is -NR ^d R ^d , wherein two R ^d groups together with the nitrogen atom bound thereto form a first C 3-10 heterocyclic group containing two ^Re groups that are joined together to form a second -N-N heterocyclic group, wherein the second C 3-10 heterocyclic group is optionally substituted with one, two or three R ^g . 7. The compound according to claim 6, wherein the first ^-^heterocyclic group and the second ^-^heterocyclic group form a spirocyclic group or a bicyclic group. 8. The compound of claim 7, wherein the spirocyclic group comprises at least two rings, wherein the first ring and the second ring of the spirocyclic group contain a different number of carbon atoms, a different number of heteroatoms, or both, and wherein each ring of the spirocyclic group contains a heteroatom in the ring. 9. A compound according to any one of claims 6 to 8, wherein the spirocyclic group contains at least one oxygen atom and at least one nitrogen atom. 10. A compound according to any one of claims 6 to 9, wherein the spirocyclic group comprises a first ring and a second ring, wherein the first ring is bonded to a carbon atom of the compound and contains from 3 to 7 atoms, and the second ring contains from 3 to 7 atoms. 11. A compound according to any one of claims 6 to 10, wherein the spirocyclic group contains a total of more than 7 atoms in the spirocyclic system. 12. A compound according to any one of claims 6 to 11, wherein the C 3-10 heterocyclic group and the second C _3-10 heterocyclic group form a bicyclic group. 13. The compound of claim 12, wherein the bicyclic group is a fused bicyclic group or a bridged bicyclic group, wherein the bicyclic group is attached to the compound via a nitrogen atom of said bicyclic group. - 51 046406 14. The compound 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, an aliphatic, a substituted aromatic, or a heteroaliphatic group. - 52 046406 15. A compound according to any one of claims 1 to 14, wherein the compound is selected from 1-2; 1-3; 1-4; n 1-5; 1-6; 1-7; 1-8; - 53 046406 - 54 046406 16. A compound according to any one of claims 1 to 15, wherein the compound is 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and one or more excipients or adjuvants. 18. A method for treating a disease, wherein the disease is a disease involving receptor-interacting protein kinase-1 (RIP1), comprising contacting receptor-interacting protein kinase-1 (RIP1) with a compound according to any one of claims 1 to 16 or a pharmaceutical composition according to claim 17. 19. The use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 17 for the treatment of a disease, wherein the disease is a disease involving receptor interacting protein kinase-1 (RIP1). 20. A method for producing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, comprising providing a coupling reaction of a starting material characterized by formula A with an R1-containing reagent characterized by formula R1-H by combining the starting material and the ^R1 -containing reagent with a transition metal catalyst, a ligand component and a solvent to form an R1 ^- functionalized product; removing the protective group from the amino group of the ^R1 -functionalized product to obtain an amino compound and ensuring the formation of an amide bond between the amino compound and the coupling reaction participant containing an acidic group; where formula A represents NHPG Formula A; The R ¹ -functionalized product has a structure corresponding to formula B NHPG Formula B; and the participant in the coupling reaction containing the acid group has a structure corresponding to the formula C r Formula C; - 55 046406 and where X is halogen or triflate; PG is a protecting group for the amino group; and each of the rings B, L, R ¹ , R ² , R ⁴ , R ⁵ , m, η and p is as specified in paragraph 1. 21. The method according to claim 20, wherein the formation of the amide bond is achieved by a coupling reaction of an amino compound and a coupling reaction participant containing an acid group in the presence of propylphosphonic anhydride and diisopropylethylamine.