EA045207B1 - COMPOUNDS INHIBITING RIP1, AS WELL AS METHODS OF THEIR PREPARATION AND APPLICATION - Google Patents

Description

Cross reference to related application

This application claims priority to the earlier filing date of U.S. Provisional Patent Application No. 62/666,462, 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, for inhibiting receptor-interacting protein kinase 1 (RIP1) and for treating diseases and/or conditions associated with RIP1.

Prerequisites for creating the 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 signaling from innate immune receptors. RIP1 plays a central role in the regulation of cell signaling, and its role in programmed cell death has been associated with 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 invention discloses embodiments of the compound represented by Formula I

or a pharmaceutically acceptable salt thereof. One skilled in the art will appreciate that compounds within the scope of Formula I also include their stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes and/or prodrugs thereof.

With reference to formula I, ring B is a 5- or 6-membered heteroaryl;

L represents a heteroatom or R ^a with the proviso that R ^a does not represent H or D;

Z represents a C _1-10 aliphatic group (such as C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _3-6 cycloalkyl) or

R ¹ is halogen, -C^CH or a -linker-R ⁶ group, wherein the linker is R ^a provided that R ^a is not H or D, and R ⁶ is R ^b , -C(R ^f ) ₃ or -C(R ^f )=C(R ^f )2;

R ² and R ³ are independently R ^a ;

R ⁴ and R ⁵ are independently R ^e ;

R ^a independently in each case represents H, D, C _1-10 aliphatic, C _1-10 haloaliphatic, C _5-10 aromatic or C _3-6 heterocyclic group;

R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a ) ₃ , -C(O)OH, -C(O)OR ^c or -C(O)NR ^d R ^d ;

^Rc is independently in each case a C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-6cycloalkyl (which may be substituted with 1, 2 or 3 ^Re ) or a C5-10aromatic group (which may be substituted with 1, 2 or 3 R ^e );

R ^d is independently in each case H, a C1-6 alkyl (which may be substituted with 1, 2 or 3 R ^e ), a C3-6 cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ), a C3-6 heterocyclic group (which may be substituted with 1, 2 or 3 R ^e ), C5-10 aryl (which may be substituted with 1, 2 or 3 R ^b ), C5-10 heteroaryl (which may be substituted with 1, 2 or 3 R ^b ), or two R groups ^d together with the associated nitrogen atom form a C3-9 heterocyclic group (which may be substituted by one or more ^Re ) or a C _5-10 heteroaryl (which may be substituted by one or more ^Re );

R ^e is independently in each case halogen, C _1-6 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _5-10 heteroaryl or -OR ^a ;

R ^f is independently in each case R ^a , R ^b or R ^e , or two R ^f groups together with their associated carbon atom form a C3-6 cycloalkyl group (which may be substituted by one or more R ^e ) or a C3-10 heterocyclic group (which may be replaced by one or more R ^e );

m is from 1 to 4;

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

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

R ² °

In any or all of the above embodiments, ring B may be characterized by 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 N, wherein particular embodiments the B rings are diazole, triazole, oxadiazole, oxazole or pyridinyl. Suitable exemplary triazoles include any of the following:

Suitable exemplary oxadiazoles include any of the following:

Suitable exemplary oxazoles include any of the following:

Λ

Ν; X ; Π ; N OR

Certain disclosed compounds contain an R ⁵ group, which is a R ^e group, where R ^e is a C1-C4 aliphatic group or halogen, R ² is R ^a , where R ^a is a C1-C4 aliphatic group, and R ³ is R ^a , where R ^a represents hydrogen.

For certain disclosed embodiments, R ¹ is a linker-R ⁶ group, wherein the linker is R ^a and R ^a is a Cp, C2, C3, or C4 aliphatic group. The C2 aliphatic group may be an alkyl, alkenyl or alkynyl group. The group R ⁶ may represent R ^b , where R ^b represents -C(R ^f )3, where one R ^f represents R ^e , in particular -OR ^a , where R ^a represents H; and each of the remaining R ^f independently for each case represents R ^a , where R ^a represents C1. ₄ alkyl, in particular methyl. In certain embodiments, the C ₂ group is an alkyne. In any or all of the above embodiments, ring B may be selected from

In some embodiments, R ⁶ may be R ^b , where R ^b is -C(O)OEt; or R ^b may be -C(O)NR ^d R ^d , where each R ^d is independently in each case H, C5.juheteroaryl (which may be substituted with 1, 2 or 3 R ^e ), C1.6 alkyl (which may be substituted with 1, 2 or 3 R ^e ), or two R ^d groups together with the associated nitrogen atom form a C3.9 heterocyclic group (which can be substituted with one or more R ^e ) or a C5.yuheteroaryl group (which can be substituted with one or several R ^e ). More specifically, one R ^d is H and the other R ^d is an aromatic group such as

Certain compounds may contain an ^R6 group, which is ^Rb , where Rb ^is pre

-2045207 represents -OH; OR ^c , where R ^c is C1.10 alkyl (which may be substituted with 1, 2 or 3 R ^e ), _C2-10 alkenyl (which may be substituted with 1, 2 or 3 R ^e ), C2.10 alkynyl (which may be substituted with 1, 2 or 3 R ^e ) or C5. ₁₀ aromatic group (which may be substituted with 1, 2 or 3 R ^e ); or NR ^d R ^d , wherein one R ^d is H and the other R ^d is a C5.10 aromatic group (which may be substituted with 1, 2 or 3 R ^e ). In some embodiments, R ^b is OR ^c , where R ^c is C2 alkyl substituted with pyridinyl. In some other embodiments, R ^b may be -NR ^d R ^d where one R ^d is H and the other R ^d is pyridinyl.

The linker group in the linker-R ⁶ group may be a ^-group, and the corresponding R ⁶ group is R ^b , where R ^b is -NR ^d R ^d , where the two R ^d groups together with the associated nitrogen atom form a ^ ^heterocyclic group (which may be substituted by one or more ^Re ) or C5.10heteroaryl (which may be substituted by one or more ^Re ), in particular the two ^Rd groups together with the nitrogen atom attached to them form C3. ₉ heterocyclic group substituted with one R ^e . In such embodiments, R ^e may be a C510 heteroaryl such as pyridinyl. In other embodiments, two R ^d groups, together with the nitrogen to which they are associated, can form C5. ₁₀ heteroaryl, which may optionally be substituted by one or more ^Re . From ₅ . ₁₀ heteroaryl without substituents R ^e can represent < ^Ν ΥΊ

In some embodiments, R ⁵ is R ^e , where R ^e is halogen or methyl. In some embodiments, the linker in the linker-R ⁶ group is R ^a , where R ^a is a C1-, C2-, C3-, or C4-aliphatic group providing an alkyl, alkenyl, or alkynyl group. In some such embodiments, the C2 group is an alkyne, wherein ^R6 is ^Rb , wherein ^Rb is -C( ^Rf )3, wherein one ^Rf is ^Re , and each of the other ^Rfs is independently in each case is R ^a where R ^a is C _1-4 alkyl. In certain embodiments, R ^e is -OR ^a where R ^a is H. In some such embodiments, R ^a is methyl and ring B is

R ¹ may be located at any suitable carbon atom(s) of the phenyl ring A, for example, at the 1, 2, 3 or 4 position as shown in Formula I. Exemplary R ¹ groups are as follows:

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Exemplary types of compounds are presented in this invention.

This invention also discloses embodiments of a pharmaceutical composition containing a compound (or compounds) according to any of the formulas and/or varieties disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug based thereon), and at least one additional active and/or inactive agent, such as an excipient, therapeutic agent, adjuvant, or combinations thereof.

The present invention also discloses embodiments of a method of using the disclosed compounds. One such embodiment involves contacting receptor-interacting protein kinase-1 (RIP1) with a compound according to any of the formulas and/or variations disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate thereof) , solvate, isotope or prodrug based thereon), or an embodiment of the pharmaceutical composition described in this invention. 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 varieties disclosed herein (or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug based on it); 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).

Also described are embodiments of a method for producing embodiments of the compound disclosed in this invention. In some embodiments, the method may include allowing the coupling of a starting material of Formula A with an R1-co containing reagent by combining the starting material and an R ¹ containing reagent, wherein R ¹ contains a linker-R ⁶ group, with a transition catalyst metal, base and solvent to form a functionalized product; removing the protecting group from the amino group of the functionalized product to obtain an amino compound and forming an amide bond between the amino compound and a coupling agent containing an acid group to obtain an amide group-containing compound; wherein formula A is

NHPG formula A;

the functionalized product is characterized by a structure corresponding to formula B

NHPG (I ⁶ -Linker) _t J2 Ό Gx formula B;

- 4 045207 and the coupling agent containing an acid group has a structure corresponding to formula C

formula C;

wherein X represents halogen or triflate;

PG represents a protecting group for an amino group; and each of ring B, L, R ¹ , R ² , R ⁴ , R ⁵ , m, n and p is as specified for any one or more of the above embodiments of the compound.

The foregoing and other objects and features 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 guidance to those skilled in the art in the practice of the present invention. Singular forms refer to one or more than one, unless the context clearly indicates otherwise. The term or refers to one element of certain alternative elements or a combination of two or more elements, unless the context clearly requires otherwise. As used herein, contains means includes. Thus, containing A or B means including A, B, or A and B without excluding additional elements. All literature, including patents and patent applications, cited herein are incorporated by reference.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, etc., which are used in the specification or claims are to be understood as modified by the term approximately. Therefore, unless otherwise implicitly or explicitly stated, the stated numerical parameters 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 directly and clearly distinguishable embodiments from the discussed prior art, the numbers from the embodiments do not represent approximate values unless the word approximate is expressly stated.

Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one skilled in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described in the present invention may 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 depicted or described, unless explicitly stated otherwise, all carbon atoms are assumed to contain a hydrogen atom, so that each carbon atom has a valency of four. For example, the structure shown on the left in the diagram below assumes nine hydrogen atoms. The structure shown on the right shows nine hydrogen atoms.

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

If the R group is depicted as floating in a ring system, such as with R ¹ in the group

then, unless otherwise specified, the substituent R (eg, R ¹ above) can be located on any atom of the fused bicyclic ring system, with the exception of the atom bearing a bond with the */vw sign, 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

wherein in this example, y may be greater than one, taking into account the fact that each replaces the hydrogen shown, implied, or expressly defined herein on the ring; then, unless otherwise stated, two R's 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 at the carbon atom of the depicted ring (ring carbon). In another example, two R's on the same carbon atom together with that carbon atom can be included in a ring, thereby forming a spirocyclic ring structure (spirocyclyl group).

As used herein, the term substituted refers to all subsequent modifiers in the term, for example, in the term substituted αryl-C ₁ .8 αlkyl substitution may occur at the C ₁ part. ₈ alkyl, parts aryl or both parts aryl-C ₁ . ₈ alkyl group.

The term substituted, when used to modify a specified group or moiety, means that at least one and possibly two or more hydrogen atoms of the specified group or moiety are independently replaced by the same or different substituent groups as defined below. In a particular embodiment, a group, moiety, or substituent may be substituted or unsubstituted unless specifically designated as unsubstituted or substituted. Accordingly, any of the groups specified in this invention may be unsubstituted or substituted, unless the context indicates otherwise or the specific structural formula excludes substitution. In certain embodiments, the substituent may or may not be explicitly defined as substituted, but it is still considered optionally substituted. For example, an aliphatic or cyclic moiety may be unsubstituted or substituted, but an unsubstituted aliphatic or unsubstituted cyclic moiety is unsubstituted.

Substituents or substituent groups for replacing one or more hydrogen atoms on saturated carbon atoms in said group or moiety may be, unless otherwise indicated, -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 , -OSO3M ⁺ , -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 , -СО2М', -CO2R ⁷⁰ , -C(S)OR ⁷⁰ , -C(O)N(R ⁸⁰ )2, -C(NR ⁷⁰ )(R ⁸⁰ )2, -OC(O)R ⁷⁰ , -OC(S)R ⁷⁰ , -OCO;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, where R ⁶⁰ represents a C1.10 aliphatic, heteroaliphatic or cycloaliphatic group, usually C1 .6aliphatic, more often C1.6alkyl, and R ⁶⁰ may optionally be substituted; each R ⁷⁰ is independently for each case hydrogen or R ⁶⁰ ; each R ⁸⁰ is independently in each case an R ⁷⁰ , or alternatively two R ⁸⁰ groups, taken together with the nitrogen atom to which they are bonded, form a 3-7 membered heterocycloaliphatic group, which optionally contains from 1 to 4 identical or different additional heteroatoms selected from O, N and S, among which N optionally has an R ⁷⁰ substitution such as H or C 1 -C ₃ alkyl substitution; and each M ⁺ represents a counterion with a net unit positive charge. Each M ⁺ independently for each case represents, for example, an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; ammonium ion such as +N(R ⁶⁰ )4; a protonated amino acid ion such as a lysine ion or an arginine ion; or an alkaline earth metal ion such as [Ca ²⁺ ] _0.5 , [Mg ²⁺ ]0.5 or [Ba ²⁺ ] _0.5 (the subscript 0.5 means, for example, that one of the counterions for of these divalent alkaline earth metal ions may be an ionized form of the compound of the present invention and the other a typical counterion such as a 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(R ⁸⁰ ) ₂ includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methylpiperazin-1-yl, N-morpholinyl, etc. .P. Any two hydrogen atoms at 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 on unsaturated carbon atoms in groups containing unsaturated carbon atoms are, unless otherwise indicated, -R ⁶⁰ , halogen, -OM', -OR ⁷⁰ , -SR ⁷⁰ , -SM', - N(R ⁸⁰ );, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO;, -N3, -SO;R 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 , -С(С 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 , -OCO;M ⁺ , -OCO2R ⁷⁰ , -OC(S)OR ⁷⁰ , -NR ⁷⁰ C(O)R ⁷⁰ , -NR ⁷⁰ C(S)R ⁷⁰ , -NR'CO;M'„ -NR ⁷⁰ CO2R ⁷ ° -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 such as previously defined In an independent embodiment, the substituents are not -O ^- M ⁺ , -OR ⁷⁰ , -SR ⁷⁰ or -S'M ⁺ .

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Substituent groups for replacing hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise indicated, -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 , -OSO3M+, -OSO3R ⁷⁰ , -ROz ^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 previously defined.

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

Additionally, in embodiments where 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 that is itself 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 containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are themselves unsubstituted.

Any group or fragment defined in this invention may be associated with any other part of the disclosed structure, such as the parent or main structure, as will be understood by one skilled in the art, for example, taking into account the rules of valency, when compared with illustrative elements and/ or taking into account the reactivity of functional groups, unless the ability of the group or fragment to form a bond with another part of the structure is clearly indicated or not required by the context.

Acyl refers to the group -C(O)R, where R represents 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 -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 predominantly hydrocarbon-based group or moiety. The aliphatic group or moiety may be an acyclic group, including alkyl, alkenyl, or alkynyl groups (as well as alkylene, alkenylene, or alkynylene), cyclic species thereof, such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, and further include forms with straight and branched chain, as well as all stereoisomers and positional isomers. Unless otherwise explicitly stated, an aliphatic group contains from one to twenty-five carbon atoms (C1_ ₂₅ ); for example, one to fifteen ( _C1-15 ), one to ten ( _C1-10 ), one to six ( _C1-6 ) or one to four carbon atoms (C1.4) for an acyclic aliphatic group or moiety , or three to _fifteen ( _{C3_15} ), three to ten ( _{C3_10} ), three _{to six} ( _{C3_6} ) or three to _four carbon atoms ( _{C3_4} ) for cycloaliphatic groups or fragment. An aliphatic group may be substituted or unsubstituted unless unsubstituted aliphatic or substituted aliphatic is specifically 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).

A lower aliphatic group refers to an aliphatic group containing one to ten carbon atoms ( _C1-10 ), such as one to six ( _C1-6 ) or one to four (Cm) carbon atoms; or three to ten (C ₃ - ₁₀ ), for example, three to six (C _3-6 ) carbon atoms for the lower cycloaliphatic group.

Alkoxy refers to the group -OR, where R represents a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group. In certain examples, R is C ₁ . ₆ alkyl group or C ₃ . ₆ cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH ₂ CH ₃ ) are exemplary alkoxy groups. In substituted alkoxy, R is 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 represents a substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl group; -CH ₂ CH ₂ -O-CH ₂ CH ₃ is an exemplary 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 (CH ₃ ), ethyl (-CH ₂ CH ₃ ), n-propyl (-CH ₂ CH ₂ CH ₃ ), isopropyl (-CH(CH ₃ ) ₂ ), n-butyl (-CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl

- 7 045207 (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3) and neopentyl (-CH ₂ C(CH ₃ ) ₃ ).

Amino refers to a -NH ₂ , -NHR or -NRR group, where each R is independently selected from an H, aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, group or a heterocycloaliphatic group, or two R groups together with a nitrogen atom, to which they are attached form a heterocyclic ring. Examples of such heterocyclic rings include those where the two R groups together with the nitrogen atom to which they are attached form a -(CH ₂ ) _2-5 - ring, optionally interrupted by one or two heteroatom containing groups such as -O- or - N(R ^g ), as, for example, in groups

-^-N^ \|—R ⁹ \---/ and \, where R ^g represents R ⁷⁰ , -C(O)R ⁷⁰ , -C(O)OR ⁶⁰ or -C(O)N(R ⁸⁰ )2.

Amide refers to the group -N(R)acyl, where R represents hydrogen, a heteroaliphatic or aliphatic group such as alkyl, in particular C _1-6 alkyl.

An aromatic group refers to a cyclic, conjugated group or moiety, unless otherwise noted, of 5-15 ring atoms containing a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings, of which at least one ring is aromatic (for example, naphthyl, indolyl or pyrazolopyridinyl), i.e. at least one ring and optionally more than one fused ring has a continuous delocalized π electron system. As a rule, the number of out-of-plane π electrons corresponds to Hückel's rule (4n+2). The point of attachment to the parent structure is usually in the aromatic part of the fused ring system.

For example,

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

An aromatic group or moiety may contain only ring carbon atoms, such as an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms containing a lone pair of electrons (e.g., S, O, N , P or Si), for example in a heteroaryl group or fragment. Unless otherwise specified, an aromatic group may be substituted or unsubstituted.

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

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

Carboxyl refers to -CO2H.

Carboxamide belongs to -C(O)amino.

A carboxylic acid ester or carboxyester refers to the group -C(O)OR, where R represents 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 (eg cyclohexyl) or multiple rings, for example 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 original structure is located in the aliphatic part of the multiring system. The cycloaliphatic group includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl and cycloalkynyl. The cycloaliphatic group can contain from three to twenty-five carbon atoms, for example from three to fifteen, from three to ten or from three to six carbon atoms. Unless otherwise specified, a cycloaliphatic group may be substituted or unsubstituted. Exemplary cycloaliphatic groups include

- 8 045207 does not include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl or cyclohexenyl.

A 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. Exemplary haloalkyl moieties include -CH2F, -CHF2 and -CF ₃ .

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 from an aliphatic compound or group containing at least two carbon atoms that has 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. The heteroaryl group or moiety may contain a single ring (eg, pyridinyl, pyrimidinyl, or pyrazolyl) or multiple fused rings (eg, indolyl, benzopyrazolyl, or pyrazolopyridinyl). The heteroaryl group or moiety 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 moiety in the form of a three-membered fifteen-membered ring containing at least one carbon atom, typically several carbon atoms, and at least one heteroatom, e.g. from 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 multiple rings, such as in a bicyclic or tricyclic ring system, provided that 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 optionally be oxidized to various oxidation states. For convenience, nitrogen atoms, particularly but not exclusively those defined as nitrogen atoms located on an aromatic ring, are meant to include their corresponding N-oxide form, even if it is 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. In addition, the nitrogen atoms present in the ring may optionally be quaternized. The heterocycle includes heteroaryl moieties and heteroalicyclyl or heterocycloaliphatic moieties, which are heterocyclyl rings that are partially or fully 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, imidazolidine yl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroin dolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazabicycloheptane, diazapane, 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 belongs to the group -OP(O)(OR')2, where each -OR' independently represents -OH, -O-aliphatic group such as -O-alkyl or -O-cycloalkyl, -O-aromatic group, including both -O-aryl and -O-heteroaryl, -O-aralkyl; or -OR' is -O ^- M ⁺ , where M ⁺ is a counterion with a unit positive charge. Each M ⁺ may 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 [Ca ²⁺ ] _0.5 , [Mg ²⁺ ]0.5 or [Ba ²⁺ ] _0.5 . Phosphonook

- 9 045207 sialkyl refers to an -alkyl phosphate group, such as, for example, -CH ₂ OP(O)(OH) ₂ , or a salt thereof, such as -CH ₂ OP(O)(O ^- Na ⁺ ) ₂ , and ( ((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group, such as, for example, -CH ₂ OP(O)(O-tert-butyl) ₂ .

Phosphonate belongs to the group -P(O)(OR')2, where each -OR' independently represents -OH, -O-aliphatic group such as -O-alkyl or -O-cycloalkyl, -O-aromatic group, including both -O-aryl and -O-heteroaryl; or -O-aralkyl; or -OR' represents -O ^- M ⁺ and M ⁺ represents a counterion with a unit 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 [Ca ²⁺ ] _0.5 , [Mg ²⁺ ]0.5 or [Ba ²⁺ ] _0.5 . Phosphonoalkyl refers to an -alkylphosphonate group, such as, for example, -CH ₂ P(O)(OH) ₂ or -CH ₂ P(O)(O ^- Na ⁺ ) ₂ , and ((dialkoxyphosphoryl)alkyl) refers to a complex dialkyl an ester of a phosphonoalkyl group, such as, for example, -CH2P(O)(Otretbutyl)2.

Patient or subject can generally refer to any living creature, but more often refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable in both human and veterinary medicine.

A pharmaceutically acceptable excipient refers to a substance other than the active ingredient that is included in a composition containing the active ingredient. As used in this invention, the excipient may be included in the particles of the pharmaceutical composition or it may be physically mixed with the particles of the pharmaceutical composition. The excipient can be used, for example, to dilute the active substance and/or to modify the properties of the pharmaceutical composition. Excipients may include, without limitation, release agents, binders, coating agents, enteric coatings, disintegrants, flavoring agents, sweeteners, colorants, lubricants, lubricants, sorbents, preservatives, carriers or carrier media. Fillers may be starch varieties and modified starch varieties, cellulose and cellulose derivatives, saccharides and their derivatives such as disaccharides, polysaccharides and sugar alcohols, protein, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starches, hydroxypropylcellulose, hydroxypropylmethylcellulose, 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 other agents, usually the active ingredient. Adjuvants are often pharmacological and/or immunological agents. An adjuvant can modify the effect of an active ingredient by enhancing the immune response. The adjuvant may also act as a stabilizing agent for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete adjuvant or Freund's incomplete adjuvant.

A pharmaceutically acceptable carrier refers to an excipient that is a carrier or carrier medium, 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 illustrative compositions and formulations , suitable for pharmaceutical delivery of one or more of therapeutic compositions and additional pharmaceutical agents.

In general, the nature of the carrier will depend on the particular route of administration used. For example, formulations for parenteral administration typically provide injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, saline, balanced salt solutions, aqueous dextrose, glycerol, or the like as the carrier medium. In some examples, the pharmaceutically acceptable carrier may be sterile such that it is suitable for administration to a subject (eg, by 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 agents such as wetting or emulsifying agents, preservatives, pH adjusting buffers and the like, for example sodium acetate or sorbitan monolaurate.

- 10 045207

Pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of a compound derived from a variety of organic and inorganic counterions known to one skilled in the art and including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and the like; and in case 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 formed by acidic moieties. 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 acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, xinafoic acid and the like. Pharmaceutically acceptable base addition salts are a subset 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. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, for example, S. M. Berge et al., Pharmaceutical Salts, J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein by reference). In specific disclosed embodiments, the compounds may be a formic acid, trifluoroacetate, hydrochloride, or sodium salt.

An effective amount, with respect to a compound or pharmaceutical composition, refers to an amount of a compound or pharmaceutical composition sufficient to achieve a particular desired result, such as inhibition of a protein or enzyme. In specific embodiments, the effective amount is an amount sufficient to inhibit RIP1; to induce a desired biological or medical response in a tissue, system, subject or patient; for the treatment of a specified disorder or disease; to reduce the intensity of manifestation or eliminate one or more of its symptoms; and/or to prevent the occurrence of a disease or disorder. The amount of 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 being treated, and the like, as will be appreciated by one skilled in the art.

Prodrug refers to compounds that are converted in vivo to produce a biologically active compound or a compound that is more biologically active than the parent compound. In vivo conversion may occur, for example, by hydrolysis or enzymatic conversion. Typical examples of prodrug moieties include, but are not limited to, the ester and amide forms of a compound whose active form contains a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present invention include, but are not limited to, esters formed by phosphate groups and carboxylic acids, such as aliphatic esters, in particular alkyl esters (eg, C ₁ . ₆ alkyl esters). Other prodrug moieties include phosphoric acid esters, such as -CH ₂ -OP(O)(OR') ₂ or a salt thereof, where R' is H or C ₁ . ₆ alkyl. Suitable esters also include cycloalkyl esters and arylalkyl esters, such as, but not limited to, benzyl esters. 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 alkylamides (eg, those containing from about one to about six carbon atoms). The 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

- 11 045207

Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

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 K,K-dialiphatic amides, for example K,K-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water and their combinations. The compounds described in this invention may 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 the group or moiety -SO ₂ amino or -N(R)sulfonyl, where R is H, an aliphatic, heteroaliphatic or aromatic (including both aryl and heteroaryl) group.

Sulfanyl refers to the 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 group).

Sulfonyl belongs to the group: -SO2H, -SO ₂ aliphatic, -SO ₂ heteroaliphatic, -SO ₂ aromatic (including both -SO ₂ aryl and -SO ₂ heteroaryl group).

The administration of a treatment or treatment as used in this invention relates to the treatment of a disease or condition of interest in a patient or subject, particularly a person having a 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, particularly if such patient or subject is susceptible to the condition but has not yet been diagnosed;

(ii) suppressing a disease or condition, for example, by delaying or slowing its progression;

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

As used herein, the terms disease and condition may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (hence 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 clinicians have identified a more or less specific set of symptoms.

The above definitions and the following general formulas are not intended to include unacceptable substitution schemes (eg, methyl substituted with 5 groups representing fluorine atoms). Such unacceptable substitution patterns are easily recognized by one skilled in the art.

One skilled in the art will appreciate that 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 double bond position isomers (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 enol form, keto form, and mixtures thereof. Since the various compound names, formulas, and illustrations of compounds in the specification and claims may represent only one of the possible tautomeric, conformationally isomeric, optically isomeric, or geometrically isomeric forms, one skilled in the art will recognize that the disclosed compounds include any tautomeric, conformationally isomeric, optically isomeric and/or geometrically isomeric forms of the compounds described in this invention, as well as mixtures of such various different isomeric forms. Mixtures of different isomeric forms, including mixtures of enantiomers and/or stereoisomers, can be separated to obtain each individual enantiomer and/or stereoisomer using methods known to those skilled in the art, in particular with the advantages of the present invention. In cases of limited rotation, for example around an amide bond or between two directly attached rings, such as pyridinyl rings, biphenyl groups, etc., it is also possible for atropisomers to exist, which are also specifically included in the definition of the compounds of the present invention.

- 12 045207

In any embodiment, any or all of the hydrogen atoms present in a compound or a particular group or fragment of a compound may be replaced by deuterium or tritium atoms. Thus, the enumeration of alkyl includes 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 1 to 5 hydrogen atoms are replaced by deuterium, such as in C ₂ D _x H ₅ - _x .

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

A. Connections.

The present invention discloses compounds and pharmaceutical compositions containing 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. One skilled in the art will appreciate that the general formulas disclosed include within their scope all stereoisomers, Noxides, tautomers, hydrates, solvates, isotopes of compounds and/or prodrugs based on compounds otherwise having the structural features contemplated by such formulas.

With reference to formula I, ring B is a 5-membered or 6-membered heteroaryl;

L represents a heteroatom or R ^a , with the proviso that R ^a does not represent H or D;

Z represents C ₁ . _{a 10} aliphatic group (such as _C1.10alkyl , _{C2.10alkenyl , C2.10alkynyl} or _{C3.6cycloalkyl ) or}

R ¹ is halogen, -C^CH or a -linker-R ⁶ group, where the linker is R ^a , provided that R ^a is not H or D, and R ⁶ is R ^b , -C(R ^f ) ₃ or C(R ^f )=C(R ^f )2;

R ² and R ³ are independently R ^a ;

R ⁴ and R ⁵ are independently R ^e ;

R ^a is independently in each case H or D (except for embodiments where L is R ^a ), C ₁ . ₁₀ aliphatic group (such as C ₁ . ₁₀ alkyl, C ₂ . ₁₀ alkenyl, C ₂ . ₁₀ alkynyl or C ₃ . ₆ cycloalkyl), C ₁ . ₁₀ halogenαliphatic group, C ₅ . ₁₀ aromatic group or ^^heterocyclic group;

R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a ) ₃ , -C(O)OH, -C(O)OR ^c or -C(O)NR ^d R ^d ;

^Rc is independently in each case a C1.10alkyl (which may be substituted with 1, 2 or 3 ^Re ), C2. ₁₀ alkenyl (which may be substituted with 1, 2 or 3 R ^e ), C2.10 alkynyl (which may be substituted with 1, 2 or 3 R ^e ), C3. ₆ cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ) or C ₅ . ₁₀ aromatic group (which may be substituted with 1, 2 or 3 R ^e );

R ^d is independently for each case H; C1.6alkyl (which may be substituted with 1, 2 or 3 R ^e ); C3. ₆ cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ); a C3.6 heterocyclic group (which may be substituted with 1, 2 or 3 R ^e ); C5. ₁₀ aryl (which may be substituted with 1, 2 or 3 R ^b ); C5.10heteroaryl (which may be substituted with 1, 2 or 3 R ^e ); or two R ^d groups together with the nitrogen atom attached to them form C3. ₉ heterocyclic group (which may be substituted by one or more R ^e ) or C ₅ . ₁₀ heteroaryl (which may be substituted by one or more ^Re );

R ^e is independently in each case a halogen, C ₁ . ₆ alkyl, C ₂ . ₁₀ alkenyl, C ₂ . ₁₀ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, C ₅ . ₁₀ heteroaryl or -OR ^a ; And

R ^f is independently in each case R ^a , R ^b or R ^e , or two R ^f groups together with their associated carbon atom form a C3.6 cycloalkyl group (which may be substituted by one or more R ^e ) or C3 . ₁₀ heterocyclic group (which may be substituted by one or more ^Re );

m is from 1 to 4, for example 1, 2, 3 or 4, and in certain embodiments is 1 or 2;

- 13 045207 n equals 0, 1 or 2; and p equals 0, 1, 2, 3, 4 or 5.

In some embodiments, a compound of the present invention may have a structure corresponding to Formula IA

R2 ⁰ formula IA, or its corresponding pharmaceutically acceptable salt. One skilled in the art will appreciate that the general formulas disclosed include within their scope all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes of compounds and/or prodrugs based on compounds otherwise having the structural features contemplated by such formulas.

With reference to formula IA, ring B is a 5-membered or 6-membered heteroaryl;

L represents a heteroatom or R ^a , with the proviso that R ^a does not represent H or D;

R ¹ is halogen, -C'-CH or a -linker-R ⁶ group, where the linker is R ^a , provided that R ^a is not H or D, and R ⁶ is R ^b , -C( R ^f )3 or -C(R ^f )=C(R ^f )2;

R ² and R ³ are independently R ^a ;

R ⁴ and R ⁵ are independently R ^e ;

R ^a is independently in each case H or D (except in embodiments where L is R ^a ), a C _1-10 aliphatic group (such as C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or C _3-6 cycloalkyl), C _1-10 haloaliphatic group, C _5-10 aromatic group or C _3-6 heterocyclic group;

R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a ) ₃ , -C(O)OH, -C(O)OR ^c or -C(O)NR ^d R ^d ;

^Rc is independently in each case C1-10alkyl (which may be substituted with 1, 2 or 3 ^Re ), C2-10alkenyl (which may be substituted with 1, 2 or 3 ^Re ), C2-10alkynyl (which may be substituted 1, 2 or 3 R ^e ), a C3-6 cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ) or a C _5-10 aromatic group (which may be substituted with 1, 2 or 3 R ^e );

R ^d is independently for each case H; C1-6alkyl (which may be substituted with 1, 2 or 3 R ^e ); C3-6cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ); a C3-6 heterocyclic group (which may be substituted with 1, 2 or 3 R ^e ); C5-10aryl (which may be substituted with 1, 2 or 3 R ^b ); C5-10heteroaryl (which may be substituted with 1, 2 or 3 R ^e ); or two R ^d groups together with the associated nitrogen atom form a C3-9 heterocyclic group (which may be substituted by one or more ^Re ) or a C _5-10 heteroaryl (which may be substituted by one or more ^Re );

R ^e is independently in each case halogen, C _1-6 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _5-10 heteroaryl or -OR ^a ; And

R ^f is independently in each case R ^a , R ^b , or R ^e , or two R ^f groups together with their associated carbon atom form a C3-6 cycloalkyl group (and in some embodiments, the C 3-6 cycloalkyl group is substituted with one or more R ^e ) or a C3-10 heterocyclic group (and in some embodiments, the _C3-10 heterocyclic group is substituted with one or more ^Re );

m is from 1 to 4, for example 1, 2, 3 or 4, and in certain embodiments is 1 or 2;

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

In specific embodiments of Formulas I or IA, the 5-membered heteroaryl group 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. In some embodiments, the 5-membered heteroaryl group is a diazole, triazole, oxadiazole, or oxazole. Exemplary triazoles include any of the following:

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Exemplary diazoles are selected from any of the following:

Exemplary oxazoles are selected from any of the following:

Exemplary oxadiazoles are selected from any of the following:

In specific embodiments of formulas I or IA, L is oxygen or ^Ra , wherein R ^a is a C ₁ -C ₄ alkyl such as -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-. In some embodiments, L is -CH2- or oxygen.

The linker group in R ¹ groups, where R ¹ is a linker-R ⁶ , is a C1-, C2-, C3- or C4 aliphatic group, such as a C2 alkyl group, an alkenyl group or an alkynyl group, or a C1-, a C2-, C3- or C4-haloaliphatic group, such as a C2-haloalkyl group or a haloalkenyl group. In some embodiments, the linker group in R ¹ is R ^a where R ^a is a C1-C ₄ alkyl such as -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-; or the linker group is a C ₂ -C ₄ alkenyl such as -CH=CH-, -CH=CHCH ₂ -, -CH ₂ CH=CH- or -CH ₂ CH=CHCH ₂ -; or the linker group is a C ₂ -C ₄ -alkynyl such as -C=C-, -C=CCH2-, -CH ₂ C^C- or -CHC=C-CH ₂ -. In some embodiments, the linker group is a C ₂ -C ₄ haloalkenyl such as -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF =CF-or -CCl=CF-, -CF=CCl-. In some embodiments, the linker group is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CC1=€H-, -CH=CC1-, or -C=C-.

In some embodiments, the R ⁶ group in R ¹ is C(R ^f ) 3 , where one R ^f is R ^e , where R ^e is -OR ^a (eg, hydroxyl or OMe), and each of the other R ^f independently represents R ^a where R ^a represents a C1-4 aliphatic group, and preferably each of the remaining R ^f represents R ^a where R ^a is independently in each case a C1-4 alkyl. In specific embodiments, each of the remaining R ^f is R ^a where R ^a is methyl or CD3. In still further embodiments, ^R6 is -C( ^Rf )3, wherein each ^Rf is ^Ra , wherein ^Ra is methyl or H, or wherein each ^Rf is ^Ra , wherein ^Ra is methyl or R ^b where R ^b is -C(O)OR ^c . In some additional embodiments, one R ^f is R ^e which is -OR ^a (e.g., hydroxyl or OMe), and two other R ^f groups are joined together to form an alicyclic group (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane) or a heterocyclic group (eg, epoxy, oxetane, tetrahydrofuran, tetrahydropyran or hexahydrofuro[3,2-b]furan) with the carbon atom to which they are bonded. In some such embodiments, the alicyclic and/or heterocyclic group may be substituted, and in some particular embodiments, substituted with one or more hydroxyl groups or benzylcarbonyl groups.

Some embodiments of the compound contain a linker group that is a C _2-4 group, which may include an alkyne. In specific embodiments, R ¹ is a -linker-R ⁶ group, and the linker is R ^a , where R ^a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or -S S-. or -CH-C C-, and R ⁶ is R ^b , where R ^b is -C(O)OEt, or -C(O)NR ^d R ^d , or -NR ^d R ^d , wherein each R ^d is independently in each case hydrogen, C5-10heteroaryl, C3-6cycloalkyl, or both ^Rd groups are joined together to form a heterocyclic group with the nitrogen atom to which they are bonded, which may further contain one or more additional heteroatoms in addition to the nitrogen atom, with which the groups R ^d are associated. In some embodiments, one R ^d is hydrogen and the other R ^d is C5-10 heteroaryl, which may be substituted

- 15 045207 one or more R ^e , for example, one of the following:

^R6 may also be ^Rb , wherein ^Rb is -OH or ^-ORc (wherein ^Rc is C1.6alkyl, and in some embodiments, C1.6alkyl is substituted with C5.10heteroaryl, such as pyridinyl; or wherein R ^c is a _C5.10 heteroaryl such as quinolinyl), or R ^b may be -NR ^d R ^d , wherein R ^d is independently in each case H, a C5.10 heteroaryl group (and in some embodiments a C5.10 heteroaryl group substituted with one or more R ^e groups, or two R ^d groups together with the associated nitrogen atom form a ^heterocyclic group (and in some embodiments, the ^heterocyclic group is substituted with one or more R ^e groups) or C5. ₁₀ heteroaryl (and in some embodiments, the C ₅ . ₁₀ heteroaryl is substituted with one or more R ^e groups). In substitution embodiments, R ^e R ^e is independently, in each case, C5.10heteroaryl or -OR ^a , wherein R ^a is _C1-10 alkyl.

Some compounds contain a linker, which is a ^ group, and an R ⁶ group, which is R ^b , where R ^b is -NR ^d R ^d , where one R ^d is H and the other R ^d is pyridinyl, or both ^Rd groups together with the nitrogen atom associated with them form C5.10heteroaryl; or R ^b is OR ^c where R ^c is C1. ₄ alkyl substituted with a pyridinyl group. In some embodiments, R ^b is

In some embodiments, R ¹ can be selected from any of the following:

- 16 045207

In some embodiments, R ² and R ³ are each independently R ^a , wherein R ^a is independently, for each occurrence, hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. In specific embodiments, R ² and R ³ are each independently R ^a , which is independently hydrogen, methyl, or ethyl in each case. In illustrative embodiments, R ² is methyl and R ³ is hydrogen.

In some embodiments, each R ⁴ independently and/or each R ⁵ independently represents R ^e , where R ^e is alkyl, alkenyl, alkynyl, chlorine, bromine, iodo, or fluorine. In specific embodiments, each R ⁴ and/or each R ⁵ independently represents R ^e , where R ^e represents a lower aliphatic group (eg, methyl), fluorine, or chlorine.

In some embodiments, m is 1; n is 0 or 1; and p is 0, 1, or 2. In particular embodiments, m is 1, n is 0; and p equals 0, 1 or 2.

Compounds of formulas I or IA may also have structures corresponding to any one or more of formulas II and IIA-IIF:

formula II

/o PA formula

PV formula

PS formula

- 17 045207

I o formula IID

I o formula NOT

formula IIF

With reference to formulas II and IIA-IIF, each of R ¹ and R ⁵ is as defined above for formulas I and/or IA. In certain embodiments, 0, 1, or 2 R ⁵ groups are present. R ⁵ may be R ^e where R ^e represents fluorine or chlorine. In other specific embodiments, R ⁵ is absent. With reference to formulas IIA-IIF, each W independently represents nitrogen or oxygen, and in particular nitrogen.

In some embodiments, compounds of Formulas I or IA may also have structures corresponding to any one or more of Formulas III-VI:

R ⁶

R ⁶

formula IV

R formula VI

With reference to Formulas III-VI, each R ⁵ independently can be as defined above, and in some specific embodiments, it is a lower aliphatic group (eg, methyl) or a halogen such as chlorine or fluorine. Also, ring B is as defined above, and in some embodiments selected from

- 18 045207

R ⁶ as shown in Formulas III-VI is as defined above, and in some embodiments is selected from the following:

Certain disclosed exemplary compounds falling within the scope of one or more of Formulas I, IA, II, IIA-IIF, and III-VI include

- 19 045207

1-25;

- 20 045207

- 21 045207

1-53; 1-54;

- 22 045207

- 23 045207

1-69;

D ₃ C CD ₃

1-71;

1-73;

1-75;

1-76;

1-77;

1-78;

1-79;

1-80;

1-81;

1-82;

-24045207

1-97.

- 25 045207

Exemplary compounds falling within the scope of one or more of Formulas I, IA, II, IIA-IIF, and III-VI include

I-1: ethyl-(5)-3 -(3 -(5-benzyl-\H-1,2,4-triazol-3-carboxamido)-5-methyl-4-oxo2,3,4,5 - tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate;

1-2: (S)-N-(7-(3 -((1R-indazol-5-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo [b][1,4]oxazepin-3-yl)-5-benzyl-1//-1,2,4-triazole-3carboxamide;

1-3: (S)-N-(l-(3 -((1R-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5 tetrahydrobenzo [b][1,4]oxazepin-3-yl)-5-benzyl-1R-1,2,4-triazole-3carboxamide;

1-4: (S)-5-benzyl-A-(7-(3 -((6,7-dimethoxyquinazolin-4-yl)amino)-3-oxopropyl)-5methyl-4-oxo-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-5: ethyl-($)-3-(3-(1-(2-fluorobenzyl)-1R-1,2,4-triazol-3-carboxamido)-5-methyl-4oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-7-yl)propanoate;

1-6: (S)-3-(3-(1 -(2-fluorobenzyl)-1R-1,2,4-triazol-3-carboxamide o)-5-methyl-4-oxo2,3,4, 5-tetrahydrobenzo[/>][1,4]oxazepin-7-yl)propanoic acid;

1-7: (5)-7U-(7-(3-((1R-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ />] [1,4]oxazepin-3-yl)-1 -(2-fluorobenzyl)-1H-1,2,4-triazol-3 carboxamide;

1-8: ethyl-(5)-3 -(3 -(1 -(2,6-dichlorobenzyl)-1H-1,2,4-triazol-3-carboxamido)-5methyl-4-oxo-2,3 ,4,5-tetrahydrobenzo[/>][1,4]oxazepin-7-yl)propanoate;

1-9: (5)-3 -(3 -(5-benzyl-1 Η-1,2,4-triazol-3-carboxamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ />][1,4]oxazepin-7-yl)propanoic acid;

1-10: (5)-5-benzyl-A-(5 -methyl-4-oxo-7-(3 -oxo-3 -(pyrrolidin-1 -yl)propyl)2,3,4,5 - tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3-carboxamide;

1-11: (5)-5-benzyl-A-(5-methyl-7-(3-morpholino-3-oxopropyl)-4-oxo-2,3,4,5tetrahydrobenzo[/>] [ 1,4 ]oxazepin-3-yl)-IА-1,2,4-triazol-3-carboxamide;

- 26 045207

1-12: (5)-5 -benz yl-R-(5 -methyl-4-oxo-7-(3 -oxo-3 -(quinolin-7-ylamino)propyl)2,3,4,5 - tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1 R-1,2,4-triazol-3-carboxamide;

1-13: (5)-5-benzyl-R-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[/>] [1 ,4] oxazepin-3 -yl)-\H-1,2,4-triazol-3-carboxamide;

1-14: (5)-5-benzyl-R-(7-(3-hydroxypropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepine-3 -yl)-\H-1,2,4-triazol-3-carboxamide;

1-15: (5)-5-benzyl-R-(7-(4-hydroxybutyl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepine-3 -yl)-1H-1,2,4-triazol-3-carboxamide;

1-16: (5)-5-benzyl-R-(5-methyl-4-oxo-7-(4-(pyridin-2-ylmethoxy)butyl)-2,3,4,5tetrahydrobenzo[/>] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-17: (5)-5-benzyl-R-(5-methyl-4-oxo-7-(4-(pyridin-2-ylamino)butyl)-2,3,4,5tetrahydrobenzo[/>] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-18: (5)-1 -(2,6-dichlorobenzyl)-R-(5 -methyl-4-oxo-7-(3 -oxo-3 -(pyrrolidin-1 yl)propyl)-2,3 ,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazole-3 carboxamide;

1-19: (S)-N-(l-(3 -(cyclopropylamino)-3-oxopropyl)-5 -methyl-4-oxo-2,3,4,5 tetrahydrobenzo[/>] [1,4] oxazepin-3-yl)-1 -(2,6-dichlorobenzyl)-1H-1,2,4-triazol-3 carboxamide;

1-20: (5)-5-benzyl-R-(5 -methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin-1 -yl)methyl)2,3,4, 5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-21: (S)-1 -(2,6-dichlorobenzyl)-R-(5-methyl-4-oxo-7-((4-(pyridin-4-yl)piperazin1-yl)methyl)-2 ,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-1,2,4-triazole-3carboxamide;

1-22: (5, R)-5 -benz yl-L-(5 -methyl-4-oxo-7-(3 -oxo-3 -(pyrrolidin-1 -yl)prop-1 -en-

-yl)-2,3,4,5-tetrahydrobenzo[/>] [1,4]oxazepin-3 -yl)-\H-1,2,4-triazol-3 carboxamide;

1-23: (5,E)-5-benzyl-R-(7-(3-(cyclopropylamino)-3-oxoprop-1-ey-1-yl)-5-methyl4-oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3 carboxamide;

1-24: (5)-5-benzyl-R-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8R)yl)methyl) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo|7>][1,4]oxazepin-3-yl)-1R-

1,2,4-triazole-3-carboxamide;

- 27 045207

1-25: (£)-1-benzyl-A-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8R)yl)methyl) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[/?][1,4]oxazepin-3-yl)-1/ΤΙ, 2,4-triazole-3-carboxamide;

1-26: (5)-1-benzyl-A-p-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[/>] [1, 4] oxazepin-3-yl)-1 R-1,2,4-triazol-3-carboxamide;

1-27: (5)-R-(7-(3-(cyclopropylamino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepine -3-yl)-5-(2,4-difluorobenzyl)-1H-1,2,4-triazol-3 carboxamide;

1-28: (5)-5-benzyl-R-(7-(3-hydroxy-3-methylbutyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [ 1,4 ]oxazepin-3 -yl)-1H-1,2,4-triazol-3-carboxamide;

1-29: (5)-1-benzyl-M-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-30: (5)-5-benzyl-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-31: (5)-M-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepine-3 - yl)-5-benzyl-1H-1,2,4-triazole-3 carboxamide;

1-32: (5)-N-(7-(3-amino-3-oxopropyl)-5 -methyl-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepine-3 -yl)-1-benzyl-1H-1,2,4-triazol-3 carboxamide;

1-33: (5)-1 -benzyl-M-(5 -methyl-4-oxo-7-(3 -oxo-3 -(pyrrolidin-1 -yl)propyl)2,3,4,5 -tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1 N-1,2,4-triazol-3-carboxamide;

1-34: (5)-5 -(2,4-difluorobenzyl)-M-(5 -methyl-4-oxo-7-(3 -oxo-3 -(pyrrolidin-1 yl)propyl)-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3 carboxamide;

1-35: (S)-5-benzyl-M-(7-(5-hydroxypent-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-36: (S)-5 -benzyl-3 -((7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5 -methyl-4-oxo2,3,4,5 - tetrahydrobenzo[/>][1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide;

1-3 7: (S)-1-benzyl-R-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-in-1-yl)2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-38: (5)-5-benzyl-R-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-in-1-yl)2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

- 28 045207

1-39: (5)-1-benzyl-A-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 -a]pyrazin-7(8R)-yl)methyl)-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide ;

1-40: (0)-5-benzyl-R-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 - "]pyrazin-7(8R)-yl)methyl)-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3 -yl)- 1H-1,2,4-triazol-3 - carboxamide;

1-41: (5)-5 -benzyl-LC5 -methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1 -in-1 -yl)2,3,4,5 -tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-42: (5)-1-benzyl-R-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-in-1-yl)2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-43: (5)-5 -(2,4-difluorobenzyl)-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1R-1,2,4-triazole-3carboxamide;

1-44: (5)-1-benzyl-R-(5 -methyl-4-oxo-7-(4-(quinolin-5 -yloxy)but-1 -in-1 -yl)2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-45: (5)-5 -benzyl-R-(5 -methyl-4-oxo-7-(4-(quinolin-5 -yloxy)but-1 -in-1 -yl)2,3,4 ,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-46: (5)-1-benzyl-R-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-d ihydro-

[1,2,4]tr iazolo[4,3-a]pyrazin-7(8R)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl )- 1R-1,2,4-triazole-3-carboxamide;

1-47: (5)-5-benzyl-R-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-

[1,2,4]tr iazolo[4,3-a]pyrazin-7(8R)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl )- 1R-1,2,4-triazole-3-carboxamide;

1-48: (5)-1-benzyl-A-(7-(3,3-d immethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-49: (5)-5-benzyl-R-(7-(3,3-d immethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-50: (5)-1-benzyl-R-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-51: (5)-5-benzyl-R-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-52: (5)-1-benzyl-R-(7-((1 - hydroxycycle opentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4] oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

- 29 045207

1-5 3: (5)-5-benzyl-R-(7-((1 - hydroxycycle opentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-54: (5)-1-benzyl-R-(7-((4-hydroxytetrahydro-2R-pyran-4-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-17/-1,2,4-triazole-3-carboxamide;

1-55: (5)-5-benzyl-R-(7-((4-hydroxytetrahydro-2R-pyran-4-yl)ethynyl)-5-methyl-4oxo-2,3,4,5-tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1 R-1,2,4-triazole-3-carboxamide;

1-56: (5)-iso-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-57: (5)-5-benzyl-R-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-58: (5)-1-benzyl-R-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1 ,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-59: (5)-5-benzyl-A-(5-methyl-7-(3-methylbut-3-ey-1-in-1-yl)-4-oxo-2,3,4, 5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-60: (5)-5-benzyl-R-(7-isopentyl-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1R -1,2,4-triazole-3-carboxamide;

1-61: (5)-5-benzyl-R-(7-(3-methoxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-62: (5)-1-benzyl-R-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-63: (5)-5-benzyl-R-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-64: (5)-R-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-65: (5)-5 -(2,6-dichlorobenzyl)-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1R-1,2,4-triazole-3carboxamide;

1-66: (5)-5-benzyl-R-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 - "]pyrazin-7(877)-yl)methyl)-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3 -yl)- 1R-1,2,4-triazol-3 - carboxamide;

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1-67: (5)-1-benzyl-77-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[1,5 -a]pyrazin-7(877)-yl)methyl)-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3 -yl)-\H-1,2,4-triazol-3 -carboxamide;

1-68: (5)-R-(7-(3 -hydroxy-3 -(methylY3)but-1 -in-1 -yl-4,4,4-<73 )-5 -methyl-4-oxo2 ,3,4,5-tetrahydrobenzo[#][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-69: (5)-5-benzyl-R-(7-(3-hydroxy-3-(methyl-J3)but-1-in-1-yl-4,4,4-eI)-5 - methyl4-oxo-2,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3 carboxamide;

1-70: (7?)-5-benzyl-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4, 5tetrahydrobenzo[#][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-71: (5)-5-benzyl-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [#][1,4]oxazepin-3-yl)-1,3,4-oxadiazol-2-carboxamide;

1-72: (5)-77-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4] oxazepin-3-yl)-4-phenoxypicolinamide;

1-73: (5)-5-benzyl-77-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-74: (35',Za7?,67?,6a5)-6-(((5)-3-(5-benzyl-1R-1,2,4-triazole-3-carboxamido)-5methyl-4 -oxo-2,3,4,5-tetrahydrobenzo[#][1,4]oxazepin-7-yl)ethynyl)-6hydroxyhexahydrofuro[3,2-#]furan-3-ylbenzoate;

1-7 5: 5-benzyl-77-((5)-7-(((37?,3a5,65,6a7?)-3,6-dihydroxyhexahydrofuro[3,20]furan-3-yl)ethynyl) -5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[0][1,4]oxazepin-3yl)-1R-1,2,4-triazol-3-carboxamide;

1-76: methyl-(5)-4-(3-(5-benzyl-1R-1,2,4-triazol-3-carboxamido)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo [/>] [1,4]oxazepin-7-yl)-2,2-d imethylbut-3-inoate;

1-77: (5)-1-benzyl-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)-1R-pyrazol-3-carboxamide;

1-78: (5)-5-(3-fluorobenzyl)-77-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3 ,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-1,2,4-triazole-3 carboxamide;

1-79: (5)- 5 -(4-fluorobenzyl)-77-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3 carboxamide;

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1-80: (5)-5-(2-fluorobenzyl)-LC7-(3-hydrocty-3-methylbut-1-in-1-yl)-5-methyl-4oxo-2,3,4,5- tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3 carboxamide;

1-81: (0)-5-benzyl-R-(7-ethynyl-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][1,4]oxazepin-3-yl)- 1H-1,2,4-triazole-3-carboxamide;

1-82: ($)-Ν-(Ί-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1 -(2-methylbenzyl)-1H-1,2,4-triazol-3 carboxamide;

1-83: (5)-1 -([ 1,1 '-biphenyl]-4-ylmethyl)-R-(7-(3 -hydroxy-3-methylbut-1 -in-1 -yl)-5methyl- 4-oxo-2,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3 carboxamide;

1-84: (5)-1 -(2,6-dimethylbenzyl)-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl4-oxo-2, 3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3 carboxamide;

1-85: (S)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[th] [ 1,4]oxazepin-3-yl)-1-isobutyl-1H-1,2,4-triazol-3 carboxamide;

1-86: (5)-5-benzyl-R-ethyl-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3-carboxamide;

1-87: (A)-5-benzyl-R-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)isoxazol-3-carboxamide;

1-88: (5)-5-benzyl-R-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7yl)ethynyl)-2,3,4,5- tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-1,2,4-triazole-3carboxamide;

1-89: (S)-N-(l-(3,3-d imethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[/>][ 1,4]oxazepin-3-yl)-5-(2-fluorobenzyl)-1R-1,2,4-triazol-3carboxamide;

1-90: (5)-1 -(2,6-d and methyl benzyl)-L-(7-(3,3-dimethylbut-1-in-1-yl)-5 -methyl-4-oxo2 ,3,4,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-\H-1,2,4-triazole-3-carboxamide;

1-91: (5)-5-benzyl-R-(5-ethyl-7-(3-hydroxy-3-methylbut-1-in-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo [/>] [1,4]oxazepin-3-yl)-\H-1,2,4-triazol-3-carboxamide;

1-92: (5)-R-(5-ethyl-7-(3-hydroxy-3-methylbut-1-in-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo[th][ 1,4]oxazepin-3-yl)-5-(3-fluorobenzyl)-1R-1,2,4-triazol-3carboxamide;

1-93: (5)- 5-benzyl-R-(7-(3-methylbut-3-en-1-in-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-94: (A, 2)-5-benzyl-b1-(7-(2-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-5-methyl-4oxo-2,3 ,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3carboxamide;

1-95: (5)-5-benzyl-R-(5-methyl-4-oxo-7-(3-(pyrrolidin-1 -yl)prop-1 -yn-1 -yl)2,3,4 ,5-tetrahydrobenzo[/>][1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide;

1-96: (8)-5-benzyl-R-(5-methyl-7-(3-morpholinoprop-1-in-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepin-3-yl)-1R-1,2,4-triazol-3-carboxamide or

1-97: (5)-5-benzyl-R-(5-methyl-4-oxo-7-((trimethylsilyl)ethynyl)-2,3,4,5tetrahydrobenzo[/>] [1,4]oxazepine- 3-yl)-1R-1,2,4-triazol-3-carboxamide.

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In some embodiments, one or more compounds may be included in a pharmaceutical composition or drug product, and in some embodiments, the compound or compounds may be in the form of the parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate thereof , isotope or prodrug based on it. The pharmaceutical composition typically includes at least one additional component other than the compound or compounds described, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described in the next section), or any combination thereof.

Pharmaceutically acceptable excipients may be included in pharmaceutical compositions for various purposes, for example, 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 the delivery device, to stabilize the formulation (e.g. antioxidants or buffers), to give the composition a good or pleasant taste or consistency or the like

- 41 045207 no. The pharmaceutically acceptable excipient(s) may include pharmaceutically acceptable carrier(s). Exemplary excipients include, without limitation: mono-, di- and polysaccharides, sugar alcohols and other polyols such as lactose, glucose, raffinose, melecitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch or combinations thereof; surfactants such as sorbitol, diphosphatidylcholine and lecithin; volume-forming agents; buffers such as phosphate and citrate buffers; anti-blocking agents such as magnesium stearate; binders such as saccharides (including disaccharides such as sucrose and lactose), polysaccharides (such as starches, cellulose, microcrystalline cellulose), cellulose ethers (such as hydroxypropylcellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols ); coating agents (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, zein, a corn protein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, cross-linked sodium carboxymethylcellulose and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate); flavorings and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, 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); dyes; additives for pressing; emulsifying agents; means for encapsulation; gum; granulation agents and their combinations.

B. Combinations of therapeutic agents.

The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an addition to or in combination with other conventional treatments. The compound or compounds, or a composition containing the compound (or compounds), can be administered in a single dose or over 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, by the same route of administration or by a different route as the compounds disclosed herein. For sequential administration, the compound(s) and therapeutic agent(s) may be administered such that the effective time period of at least one compound and therapeutic agent overlaps with the effective time period of at least one other compound and/or therapeutic agent. In an exemplary embodiment of a combination containing four components, the effective time period of administration of the first component may overlap with the effective time periods of the second, third and fourth components, but the effective time periods of the second, third and fourth components may independently overlap with each other or may not overlap. In another illustrative embodiment of a combination containing four components, the effective time period of the first component administered overlaps with the effective time period of the second component, but does not overlap with the effective time period of the third or fourth component; the effective time period of the second component overlaps with the effective time periods of the first and third components; and the effective time period of the fourth component overlaps only with the effective time period of the third component. In some embodiments, the effective time periods of all compounds and/or therapeutic agents overlap with each other.

In some embodiments, the compounds are administered with another therapeutic agent, such as an analgesic, antibiotic, anticoagulant, antibody, anti-inflammatory agent, immunosuppressant, guanylate cyclase-C agonist, gut secretagogue, antiviral agent, anticancer agent, antifungal agent, or a combination thereof . The anti-inflammatory agent may be a steroidal or non-steroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotodine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, pir oxicam, salsalate, sulindac , tolmetin or combinations thereof. In some embodiments, the immunosuppressant is a 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.

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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, ethylene imines, methylmelamines, alkyl sulfonates (eg, busulfan), and carmustine. Exemplary metabolic inhibitors include, by way of example and not limitation, the folic acid analogue methotrexate; pyrimidine analogue - fluorouracil, cytosine arbinoside; purine analogs are mercaptopurine, thioguanine and azathioprine. Exemplary vinca alkaloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. An exemplary enzyme effective as an antitumor agent includes L-asparaginase. Exemplary coordination compounds include, by way of example and not by way of limitation, cisplatin and carboplatin. Illustrative hormones and hormone-related compounds include, by way of example and not limitation, the adrenocorticosteroids prednisone and dexamethasone; aromatase inhibitors - aminoglutethimide, formestane and anastrozole; progestin compounds - hydroxyprogesterone caproate, medroxyprogesterone; and the estrogen antagonist compound tamoxifen.

Such 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 can 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, such as 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 agents directed against LAG-3, such as BMS-986016 (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 agents directed against CD137, such as the fully human monoclonal antibody urelumab (BMS-663513).

The compounds disclosed herein can also be used successfully with CAR-T therapies. Examples of currently available CAR T therapies are axicabtagene, ciloleucel, and tisagenleucelucel.

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., against Her2) 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 can be used in combination with the compounds described herein, especially in the treatment of cancer, include: Btk inhibitors, such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors such as afatinib, erlotinib, gefitinib, lapatinib, osimertinib and vandetinib; Mek inhibitors such as trametinib; Raf inhibitors such as dabrafenib, sorafenib and vemurafenib; VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib, PI3-kinase inhibitors such as idelalisib, Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

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

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

- 43 045207 antibiotics - aminoglycosides (for example, amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin and paromycin), carbapenems (for example, ertapenem, doripenem, imipenem, cilastatin and meropenem), cephalosporins (for example, cefadroxil, cefazo lin, cephalothin, cephalexin , cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibutene, ceftizoxime, ceftriaxone, cefepime and ceftobiprole), glycopeptide ov (for example, 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), penicillium new ( e.g. amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin and ticarcillin), combinations with penicillins (e.g. amoxicillin/clavulanate, ampicillin/sulbactam , piperacillin/tazobactam and ticarcillin/clavulanate), polypeptides (for example, bacitracin, colistin and polymyxin B), quinolones (for example, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin and temafloxacin), sulfonamides (for example, mafenide, sulfonamidochryzoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim and trimethoprim-sulfamethoxazole), tetracyclines (for example, Demec locycline, doxycycline, minocycline, oxytetracycline and tetracycline) , antimycobacterial compounds (eg, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine and streptomycin) and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronida angry , mupirocin, platensimicin, quinuprisin/dalfopristin, rifaximin, thiamphenicol, tigecycline and timidazole;

antibodies - antibodies directed against TNF-α, for example, infliximab (Remicade™), adalimumab, golimumab, certolizumab; antibodies to B cell antigens, such as rituximab; antibodies directed against IL-6, for example, tocilizumab; anti-IL-1 antibodies, such as anakinra; anti-PD-1 and/or anti-PD-L1 antibodies, for example, nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fleticumab, 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, hementin;

anti-inflammatory drugs - steroids, for example, budesonide, non-steroidal anti-inflammatory drugs, for example, aminosalicylates (for example, 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 - 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 mo fetyl and azathioprine, and agents designed to suppress cellular immunity while leaving the patient's humoral immune response unchanged, including various antibodies (eg, antilymphocyte globulin (ALG), antimycytic globulin (ATG), monoclonal antibodies to T-cell antigens (OKT3 )) and exposure to radiation. 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 Laboratories, 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 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

- 44 045207 Guanylate cyclase-C receptor agonists or intestinal secretagogues such as linaclotide are sold under the name Linzess.

These various agents may be administered in accordance with their standard or usual dosages as specified in the prescribing information provided with the commercially available dosage forms (see also prescribing information in the 2006 edition of the Physician's Desk Reference), the disclosure of which is included into this document by reference.

III. Methods for obtaining compounds.

The compounds can be prepared using any suitable method, as will be appreciated by one skilled in the art. One illustrative suitable method is presented below with reference to the specific compounds in the examples and may include the following first reaction step according to Scheme 1.

Scheme 1

With reference to Scheme 1, the amino-protected precursor 100 can be coupled with an R ¹ group 102 that contains an R ⁶ linker group as shown in Scheme 1 using a metal-mediated cross-coupling reaction to produce the cross-coupled product 104 In some embodiments, the metal-mediated cross-coupling reaction can be carried out using a transition metal catalyst, such as a palladium catalyst. Exemplary palladium catalysts include, but are not limited to, Pd(0) based catalysts (eg, Pd ₂ (dba) ₃ , Pd(dba) ₂ , Pd(PPh ₃ ) ₄ and the like) or Pd(II) based catalyst (eg, XPhos Pd 2nd generation or 3rd generation, PdCl ₂ , Pd(OAc) ₂ and the like). In some embodiments, a palladium catalyst may be used in combination with another cocatalyst, such as CuI, to promote a cross-coupling reaction, such as in the Sonogashira reaction. Metal-mediated cross-coupling may also involve the use of a base, such as an amine base (eg Et ₃ N) or an inorganic base (eg Cs ₂ CO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ or the like), and solvent (for example dimethylformamide). With reference to Scheme 1, X is a suitable group for metal-mediated cross-coupling, such as a halogen or triflate group, and PG is a protecting group for an amino group, which can be selected without limitation from 9-fluorenylmethoxycarbonyl (Fmoc) group, tert-butyloxycarbonyl (Boc ) group, trityl (Tr) group, allyloxycarbonyl (Alloc) group, benzyloxycarbonyl (Cbz) group and the like.

Illustrative examples of the process steps shown in Scheme 1 are presented below in Schemes 2A-2F. A method similar to that shown in Scheme 2A can be used to prepare compounds I-14-I-17 and I-35 by replacing the propargyl alcohol in Scheme 2A with the corresponding alkyne group, providing each of compounds I-14-I-17 and I-35; Additional modifications that can be applied to obtain the final structure of compounds I-14-I-17 are discussed below.

Scheme 2A

Scheme 2B

Scheme 2C

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2D diagram

Scheme 2E

Scheme 2F

Once the cross-coupled product 104 is obtained, it can be subjected to an optional linker group reduction step, wherein linker groups containing one or more centers of unsaturation can be reduced to saturated linker groups and/or linker groups with lower degrees of unsaturation. If a linker group reduction step is used, this may be followed by a deprotection step and then an amide formation step as shown in Scheme 3. Alternatively, if a linker group reduction step is not used, then the cross-coupling product may be deprotected 104 and convert it into amide compound 302.

Optional reduction of linkerθ _NHpG Removal of protective troupe (K ^b -Linker)t r ^N 2 o 'ri °

104 ( ^R4 ) _n 3θθ\302

Amide formation

Scheme 3

With reference to Scheme 3, the optional linker reduction step can be carried out. For example, if the linker contains a center of unsaturation (for example, a double or triple bond), the center of unsaturation can be reduced so that it becomes fully saturated (such as by reducing a double bond and/or triple bond to a single bond) or that it has lower degrees of unsaturation (such as by reducing a triple bond to a double bond). Suitable reagents for performing such an optional linker reduction step will be familiar to those skilled in the art in light of the present disclosure; however, one exemplary set of conditions involves exposing the cross-coupled product 104 to H ₂ in the presence of Pd on carbon. Since these steps are optional, they do not need to be performed in all embodiments. Conversely, in some embodiments, the cross-coupling product 104 can be deprotected to produce an amine, which is then converted to the amide compound 302 by reacting the amine with a suitable acid coupling agent 300 as shown in Scheme 3.

Illustrative examples of the process steps shown in Scheme 3 are presented below in Schemes 4A-4M. A method similar to that described in Scheme 4A can be used to prepare compounds I-14-I-17. Compounds I-16 and I-17 can be further functionalized as described below.

- 46 045207

NHTr

'NHTr

NHTr

BUT

204'NHTr

Scheme 4A

HC1, dioxane, grade, 6 hours.

Scheme 4B

HC1, dioxane, grade, 6 hours.

BUT, dioxane,

1) H ₂ , Pd/C. EY Ac K. t., 14 h.

2) HC1, CH ₂ CH, k. t, 14 hours.

iPr ₂ NEt, HATU DMF, k.t., 4 h.

iPr ₂ NEt, HATU DMF, k.t., 4 h.

lrr ₂ NEt, HATU DMF, room, 4 hours.

Scheme 4C

iPr ₂ NEt, NATU DMF, k.t., 4 h.

4D diagram

- 47 045207

EY

, 1) H ₂ , Pd/C, EtOAc ) NHBoc K. T., 14 4. _Eto b 2) HC1, CH ₂ C1 ₂ , K. t., 14 h.

208

EY

208

EY

1) H ₂ , Pd/C, EtOAc NHBoc K. t., 14 hours _Eto

2) HC1, CH,C1 ₂ , room τ' 14 hours.

Scheme 4E

EtO

Scheme 4F

1)H ₂ , Pd/C, EtOAc 'NHBoc k. T., 14 4. _Et0

2) HC1, CH ₂ C1 ₂ , k. τ., 14 hours.

iPr ₂ NEt, HATU DMF, 0°C, 1 4., then to.

iPr ₂ NEt, HATU DMF, 0°C, 1 4., then to.

208

410

iPr ₂ NEt, HATU DMF, 0°C, 1 4., then k. τ., 1 h.

4G scheme

Scheme 4H

- 48 045207

Scheme 4I

Scheme 4J

1-25

4K circuit

Scheme 4L

- 49 045207

Scheme 4M

In some embodiments, the method may further include providing one or more additional modifications to amide compound 302 to produce amide compound 500, such as modifications of an ^R6 group to form another ^R6 group, as shown in Scheme 5.

302 ⁵⁰⁰

Scheme 5

With reference to Scheme 5, one or more modifications of the R ⁶ group can be made. For example, if R ⁶ is an ester group, it can be converted to a carboxylic acid or a primary alcohol. Suitable reagents for carrying out such an optional modification step will be familiar to those skilled in the art in light of the present disclosure; however, one exemplary set of conditions involves exposing the R ⁶ ester group to LiOH to produce the corresponding acid, as, for example, shown in Schemes 6A-6E below. The resulting acid can even be further modified to produce an amide group-containing product by applying suitable coupling conditions to form an amide bond (such as those described above) in combination with an amine coupling agent, for example, as shown in Schemes 6A-6E. Similar methods can be used to prepare compounds I-10, I-11, I-13, I18, I-19, I-26, I-27, I-33, I-34 and I-22 and I-23 (where the double bond of the linker group is not first reduced before coupling). In yet further embodiments, compounds I-16 and I-17 can be prepared by converting the terminal alcohol produced in the above-described methods into a functionalized alcohol, such as for compound I-16, or an amine, such as for compound I-17.

1-9

1H-Indazol-5-amine, DMF, EtN(i-Pr) ₂ , HATU, from 0°C to room temperature.

1-2

Scheme 6A

Sh-Indazol-5-amine, DMF, EtN(i-Pr) ₂ , HATU, from 0°C to room temperature.

ABOUT

1-3

Circuit 6B

- 50 045207

6,7-Dimethoxyquinazolin-4-amine, DMF, EtN(i-Pr) ₂ , HATU, 0°C to room temperature.

Scheme 6C

Scheme 6D

Quinoline-7-amine, DMF,

EtN(i-Pr) ₂ , HATU, from 0°С to room temperature.

1-12

Scheme 6E

IV. Methods of using compounds.

A. Diseases/disorders.

The disclosed compounds, as well as combinations thereof and/or pharmaceutical compositions based thereon, can be used to inhibit RIP 1 kinase by contacting the kinase either in vivo or ex vivo with a compound or compounds of the present invention, or a composition containing a compound or compounds of the present invention. the present invention. The disclosed compound or compounds, or compositions containing the disclosed compound or compounds, can also be used to alleviate, treat, or prevent a number of diseases and/or disorders. In specific embodiments, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof may 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 the treatment of autoimmune diseases, inflammatory disorders, cardiovascular diseases, nervous disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancers, ischemic conditions, red blood cell deficiencies, lung and brain injuries ( for example, those caused by ischemia-reperfusion or cisplatin and/or cerebrovascular accident), as well as bacterial and viral infections.

In some embodiments, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used for the treatment or prevention of 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, endocrine Graves' ophthalmopathy or asthma.

The disclosed compound, combinations of disclosed compounds or pharmaceutical compositions on

- 51 045207 basis thereof 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 the compounds (or pharmaceutical compositions based thereon or combinations thereof) include, but are not limited to, organ or tissue transplant reactions, graft-versus-host disease, transplant-associated diseases, autoimmune syndromes, etc. including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, including acute rheumatic fever and post -infectious glomerulonephritis, inflammatory and hyperproliferative diseases of the skin, psoriasis, atopic dermatitis, contact dermatitis, itchy dermatitis, seborrheic dermatitis, red flat lichen, bullet permfigoid, bullet epidermolysis, angiite, forms Yu against the background of skin diseases , lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, epithelial corneal dystrophy, corneal cataract, pemphigus, Moray's ulcer, scleritis, Graves' ophthalmopathy, Fog syndrome ta-Koyanagi -Harada, sarcoidosis, pollen allergy, reversible airway obstruction, bronchial asthma, allergic asthma, endogenous asthma, exogenous asthma, dust-induced asthma, chronic or intractable asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcers, vascular damage, caused by ischemic diseases and thrombosis, ischemic intestinal lesions, ischemia/reperfusion injuries, inflammatory bowel diseases, necrotizing enterocolitis, intestinal injuries 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, hemolyticouremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves'ism, true erythrocyte aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytosis penic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, allergic photosensitivity, T-cell lymphoma of the skin, chronic lymph ocytic leukemia, arteriosclerosis, atherosclerosis , aortitis, polyarteritis nodosa, myocardosis or myocardial infarction, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, adiposis, eosinophilic fasciitis, damage to the gums, periodontium, alveolar bone, root cementum, glomerulonephritis, androgenetic alopecia or aging chelic alopecia , which can be avoided by preventing hair removal along with the hair follicles, or allowing the generation of new hair follicles, and/or promoting the generation of new hair follicles and hair growth, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs that occur during conservation, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, drug or radiation colitis, acute renal failure due to ischemia, chronic renal failure, intoxication caused by the presence of high levels of oxygen in the lungs or drugs, lung cancer, pulmonary emphysema, cataract, siderosis, retinal pigmentary degeneration, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, alkali burn of the cornea, dermatitis, erythema multiforme, linear IgA-dependent bullous dermatosis and cementum dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, tumorigenesis, carcinoma metastasis and altitude sickness, histamine or leukotriene C4 release disease, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, reactions occurring with partial liver resection, acute liver necrosis, toxin-induced necrosis, viral hepatitis, shock or anoxia, viral hepatitis B, hepatitis other than hepatitis A/hepatitis B, liver cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune hepatobiliary diseases, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, acute liver failure secondary to chronic liver failure, chronic kidney disease, kidney injury/damage (caused by, e.g., nephritis, kidney transplant, surgery, nephrotoxic drugs, acute kidney injury), increased 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

- 52 045207 treatment of neuralgia, including neuropathic pain and pain caused by inflammation.

In certain embodiments, the compounds are useful for the treatment of interleukin-1-converting enzyme-associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage disease (eg, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartyl glucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, childhood free sialic acid storage disease , 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, cryopyrine-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, disease Still's disease manifesting in adulthood, gout, acute gout, pseudogout, SAPHO syndrome, Castleman's 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 thereon include benign or malignant tumors, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, tumors of the stomach, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testes, urogenital tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, forms of glioblastoma, forms of neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, neck and head tumor, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial origin, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell carcinoma lung, forms of lymphoma

Hodgkin's lymphoma and forms of non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 disorder, MyD88 disorder (such as diffuse large B cell lymphoma type ABC (DLBCL), Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary T-cell lymphoma of the skin or chronic lymphocytic leukemia), smoldering or smoldering multiple myeloma or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, DLBCL type 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, Walden macroglobulinemia stroma (WM), lymphoma marginal zone of the spleen, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds disclosed herein are useful in the treatment of drug-resistant cancers, such as JAK inhibitor-resistant cancers, ibrutinib-resistant cancers, including ibrutinib-resistant hematological malignancies , such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia.

Examples of allergy-related disorders that can be treated with the use of 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 asthma, non-atopic asthma, bronchial asthma, non-allergenic asthma, idiopathic asthma, true asthma, endogenous asthma caused by pathophysiological abnormalities, idiopathic asthma with an unknown or not obvious cause, emphysematous form of asthma, asthma induced by physical activity, asthma induced by emotional disorders, exogenous asthma caused by environmental factors environment, asthma induced by inhalation of cold air, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal or viral infection, early stage asthma,

- 53 045207 bronchial obstruction syndrome in children, bronchiolitis, cough asthma or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent and non-purulent sinus it, acute or chronic sinusitis and ethmoiditis, frontal sinusitis, sinusitis or sphenoidal sinusitis.

As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of mobility, and stiffness in affected joints throughout the body. RA is characterized by a chronically inflamed synovium that is densely surrounded by lymphocytes. The synovial membrane, which is typically one layer of cells thick, becomes saturated with cells and takes on a form similar to lymphoid tissue, including dendritic cells, T, B, and NK cells, macrophages, and clusters of plasma cells. This process, as well as a variety of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, ultimately leads to disruption of the integrity of the joint, resulting in deformation, permanent cessation of function and/or destruction of bone at or in the immediate vicinity of the joint . The disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof can be used to treat, ameliorate, or prevent any one, more, or all of these symptoms of RA. Thus, in the context of RA, compounds are believed to provide a therapeutic effect when a reduction or amelioration of the intensity of any of the symptoms typically associated with RA is achieved, regardless of whether the treatment results from concomitant treatment of the underlying RA disorder 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 of these parameters, ACR20 (ACR criterion for clinical improvement of 20%), requires a 20% improvement in the number of tender and swollen joints, as well as a 20% improvement in 3 of the following 5 parameters: patient-reported global score , general assessment according to the physician, assessment of pain intensity according to the patient, degree of disability and level of acute phase proteins. These criteria were expanded to 50 and 70% improvement in ACR50 and ACR70, respectively. Other criteria include the Paulus criteria and radiographic progression (eg, Sharpe score).

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

B. Compositions 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, drageeing, trituration, emulsification, encapsulation, entrapment or lyophilization processes. Pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (eg, diluents, carriers or excipients), one or more adjuvants, or combinations thereof to produce pharmaceutically usable formulations.

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

The pharmaceutical compositions of the present invention can be formulated to be suitable 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 administration, etc., or a form suitable 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 vehicles. Pharmaceutical compositions may also contain formulation agents such as a suspending, stabilizing and/or dispersing agent. Injectable formulations may be presented in unit dosage form

- 54 045207 form, for example in ampoules or multi-dose containers, and may contain added preservatives.

Alternatively, the injectable formulation may be provided in powder form, which must be dissolved using 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) can be dried using any technique known in the art, such as lyophilization, and dissolved before use.

For transmucosal administration, the composition contains substances that promote penetration and are able to overcome this barrier. Such penetration promoting substances are known in the art.

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

Liquid preparations for oral administration may be in the form of, for example, infusions, solutions, syrups or suspensions, or they may be presented as a dry product to be reconstituted with water or other suitable carrier medium before use. Such liquid preparations can be prepared by conventional methods using pharmaceutically acceptable excipients such as suspending agents (eg sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous carrier media (eg, almond oil, fat esters, ethyl alcohol, Cremophore™ or fractionated vegetable oils) and preservatives (eg, methyl or propyl p-hydroxybenzoates or sorbic acid). If necessary, the preparations may also contain buffer salts, preservatives, flavorings, dyes and sweeteners.

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

For buccal administration, the pharmaceutical compositions can be formulated into tablets or lozenges formulated in a conventional manner.

For the rectal and vaginal routes of administration, the active compound(s) can 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 be conveniently delivered in the form of a spray aerosol from packages under pressure or nebulizer with a suitable propellant gas, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be specified by providing a valve for delivering a metered amount. Capsules and cartridges for use in an inhaler or insufflator (eg, capsules and cartridges containing gelatin) can be formulated to contain a powder mixture 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 includes 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 finished 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 compounds by inhalation contains 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 are known in the art that are suitable for administering compounds to the eye. Specific non-limiting examples are described in US Pat. No. 6,261,547; 6197934; 6056950; 5800807; 5776445; 5698219; 5521222; 5403841; 5077033; 4882150; and 4738851, which are incorporated herein by reference.

- 55 045207

For sustained delivery, the active compound(s) can be formulated as depot preparations for administration by implantation or intramuscular injection. The active ingredient can be formulated using suitable polymeric or hydrophobic materials (eg, an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, eg, as a sparingly soluble salt. Alternatively, transdermal delivery systems can be used, formulated as an adhesive disc or patch that slowly releases the active compound(s) for absorption through the skin. In this regard, 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 US patent No. 5407713; 5352456; 5332213; 5336168; 5290561; 5254346; 5164189; 5163899; 5088977;5087240;5008110;and 4921475, which are incorporated herein by reference.

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

Pharmaceutical compositions, if desired, may be present in a package or dosing device, which may contain one or more unit dosage forms containing the active compound(s). The packaging may contain, for example, metal foil or plastic film, such as in a blister pack. Instructions for administration may be included with the package or dosing device.

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 RJP1 kinase and/or to treat, prevent, or ameliorate a particular condition. The disclosed compound(s) or pharmaceutical compositions based thereon may be administered as therapy to achieve a therapeutic effect or as prophylaxis to achieve a prophylactic effect. Therapeutic effect means the elimination or attenuation of the underlying disorder being treated and/or the elimination or attenuation of one or more symptoms associated with the underlying disorder, such that the patient reports an improvement in health or condition, although the patient may -still be affected by the underlying disorder. For example, administration of a compound to a patient suffering from an allergy provides a therapeutic benefit not only when the underlying allergic reaction is eliminated or reduced in severity, but also when the patient reports a decrease in the severity or duration of symptoms associated with the allergy following exposure to the allergen. As another example, a therapeutic effect in the context of asthma includes improving breathing after the onset of an asthma attack or reducing the frequency or severity of asthmatic episodes. The therapeutic effect also includes stopping or slowing the progression of the disease, whether improvement is achieved or not.

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. Dosage may also be adjusted for individuals suffering from more than one condition, or those individuals who have additional conditions affecting lung capacity and 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 based thereon will also depend on whether the disclosed compound(s) are formulated for the treatment of acute episodes of a condition or for the prophylactic treatment of a 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 may be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions based thereon(s) may be administered prior to administration of the drug to avoid or reduce the severity of the allergic reaction to the drug. Alternatively, prophylactic administration may be used to avoid or reduce the severity of symptoms in a patient diagnosed with an underlying disorder. For example, the disclosed compound(s) or a pharmaceutical composition based thereon may be administered to a person suffering from an allergy prior to anticipated exposure to the allergen. The disclosed compound, combinations of disclosed compounds or pharmaceutical

- 56 045207 compositions based thereon(s) can also be administered prophylactically to healthy individuals who are systematically exposed to agents known to cause one of the above-described diseases to prevent the occurrence of the disorder. For example, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions thereof may be administered to a healthy individual who is systematically exposed to an allergen known to cause various forms of allergy, such as latex, to prevent the individual from developing an allergy. Alternatively, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions based thereon(s) may be administered to a patient suffering from asthma before engaging in an activity that triggers asthma attacks to reduce the severity of an asthmatic episode or avoid it altogether.

Effective dosages can be initially assessed based on in vitro assays. For example, the initial dosage for use in subjects may be formulated to achieve a circulating blood or serum concentration of the active compound that is equal to or greater than the _IC50 or _EC50 of the particular compound measured in an in vitro assay. Dosages may be calculated to achieve such concentrations in circulating blood or serum, 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, p. 1-46, Pergamon Press, and references cited therein, provide additional guidance regarding 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 , from more than 0 to 0.1 µM or from more 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 effectiveness of compounds for the treatment or prevention of 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(21 Suppl):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 suitable 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 effectiveness of embodiments of the compounds disclosed in this invention and/or which can be used to determine amounts/dosages of embodiments of the compounds that can provide the desired effectiveness. In some embodiments, the assay may be an ADP-Glo™ assay that determines the ability of an embodiment of a compound to inhibit RIP1. In other embodiments, whole cell assays can be performed using mouse and/or human cells, such as U937 and/or L929 cell necroptosis assays, to determine safe and effective doses of compounds that can be used in in vivo human studies. By performing such whole cell assays, the activity of a compound against human and/or mouse RIP1 can be assessed in an in vitro context, which then allows one skilled in the art to determine safe and effective dosages for in vivo use. Another assay that can be used to evaluate the activity of embodiments of compounds described herein for treating a disease or condition involving RIP1 is performed in a mouse model of acute hypothermia, which evaluates the compound's ability to inhibit TNF-alpha-induced hypothermia. Each of such assays and the various results obtained by performing such assays are described in detail in the Examples section of this disclosure.

Dosage levels of the disclosed compounds will generally range from greater than 0 mg/kg/day, such as 0.0001 or 0.001 or 0.01 mg/kg/day, to at least about 100 mg/kg/day. day. More typically, the dosage (or effective amount) may range from about 0.0025 mg/kg to about 1 mg/kg when administered at least once daily, 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. Total daily dosage typically ranges from about 0.1 mg/kg to about 5 mg/kg or up to about 20 mg/kg per day, such as from 0.5 mg/kg to about 10 mg/kg per day or from about 0.7 mg/kg per day to about 2.5 mg/kg/day. Dosage levels may be higher or lower depending on, among other factors, the activity of the disclosed compound, its bioavailability, route of administration and various factors discussed above.

The dosage amount and dosage interval may be adjusted for individual individuals to provide plasma levels of the disclosed compound that are sufficient to maintain a therapeutic or prophylactic effect. On

- 57 045207 example, compounds can be administered once a day, several times a day, once a week, several times a week (for example, every other day), once a month, several times a month or once a year, in depending on, among other things, the route of administration, the specific indication for treatment and the judgment of the attending physician. Those skilled in the art will be able to optimize effective dosages for topical use without undue experimentation.

Pharmaceutical compositions containing one or more disclosed compounds typically contain from greater than 0 to 99% of the disclosed compound or compounds and/or other therapeutic agent as a percentage of total weight. More typically, pharmaceutical compositions containing one or more of the disclosed compounds contain from about 1% to about 20% by weight of the disclosed compound and other therapeutic agent 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 thereon(s) will provide a therapeutic or prophylactic effect without causing significant toxicity. The toxicity of the disclosed compound can be determined using procedures standard in the pharmaceutical field. The ratio of doses providing toxic and therapeutic (or prophylactic) effects is the therapeutic index. The disclosed compounds having high therapeutic indices are preferred.

V. Examples.

Example 1.

The compounds of the present invention can be prepared using a suitable starting compound, such as compound 200 or compound 206 shown in the diagrams above. An exemplary method for preparing compound 200 is shown in Scheme 7A, and an exemplary method for preparing compound 206 is shown in Scheme 7B.

iPr ₂ NEt, HATU

DMF, from 0°C to room temperature, 16 hours.

Scheme 7A

Mel, CS2CO3

DMF, k.t., 16 h.

HC1, dioxane grade, 3 days

Vg

NHTr Sz ₂ COz, DMF x Bg about 50°C, 1.5 days

200

Circuit 7B

NHBoc

HE

NaH, DMF,

NHBoc

HE

EYUN-N ₂ O Br 80°C, 1 hour.

Fe, NH4CI,

NHBoc

HE

HATU, iPr ₂ NEt, DMSO, room t„ 18 h.

'2

-D NHBoc ^ ^e| ' Cs ₂ CO ₃ , NHBoc

DMF, k. t„ 14 h. ^Вг Ν-Λ /О nor

206

Determination of spectral characteristics for 3-(S)-N-tritylamino-7-bromo-5-methyl-4oxobenzoxazapine (200):

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.38 (6H, m, 6H C(C ₆ H ₅ ) ₃ ), 7.25-7.15 (10H, m, H-8 oxobenzoxazapine , 9Н С(С _{6 Н5} ) ₃ ), 7.00 (1H, d, J 2.5 Hz, Н-6 oxobenzoxazapine), 6.91 (1H, d, J 8.5 Hz, Н-9 oxobenzoxazapine ), 4.50 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H in H-2 oxobenzoxazapine ), 3.53 (1H, dd, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH3).

These characterizations and specific methods for preparing the illustrative compounds disclosed in this invention are presented below.

- 58 045207

Example 2.

Synthesis of (S)-7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-3-(tritylamino)-2,3dihydrobenzo[6][1,4]oxazepine-4( 5H)-she. A mixture of bromoxazapine (0.210 g, 0.410 mmol, 1.0 eq.), potassium carbonate (0.566 g, 4.101 mmol, 10.0 eq.) and copper(I) iodide (0.008 g, 0.041 mmol, 0.1 eq.) in dimethylformamide (3.0 ml) was degassed by bubbling argon for five minutes. 2-Methyl-2hydroxybut-3-yne (0.052 g, 0.060 mL, 0.615 mmol, 1.5 eq.) and tetrakis(triphenylphosphine) palladium (0.024 g, 0.021 mmol, 0.05 eq.) were added and the reaction mixture was sealed before by heating in a microwave oven to 120°C for 1 hour. The reaction mixture was partitioned between EtOAc (80 ml) and water (80 ml). The organics were washed with brine (80 ml), water (80 ml) and brine (80 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. MPLC (10^80% EtOAchexane) provided the starting material (0.091 g) and the title compound (0.079 g) as a colorless oil;

^1H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.38 (6H, m, 6H C(C ₆ H ₅ ) ₃ ), 7.24-7.7.14 (9H, m, 9H C (C ₆ H ₅ ) ₃ ), 7.13 (1H, dd, J 8.0, 2.0 Hz, H-8 oxobenzoxazapine), 6.96 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 6.95 (1H, d, J 2.5 Hz, H-6 oxobenzoxazapine), 4.48 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4 .37 (1H, dd, J 11.5, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.55 (1H, dd, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 2 .78 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH ₃ ) ₂ );

mass/charge: 555 [M+K]+, 243 [C(C ₆ H ₅ ) ₃ ] ⁺ .

Removal of the trityl protecting group. To a solution of trityl-protected amine (0.079 g, 0.153 g, 1.0 eq.) in dioxane (2.0 ml) was added a solution of hydrogen chloride (0.15 ml of a 4 M solution in dioxane, 0.614 mmol, 4.0 eq. .). The reaction mixture was stirred at room temperature for 6 hours before concentration to dryness to obtain a white solid, which was used without purification;

mass/charge: 275 [M+H]+.

Synthesis of (S)-5-benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. To a solution of aminooxobenzoxazapine hydrochloride (0.076 mmol, 1.0 eq.) and benzyltriazolecarboxylic acid (0.017 g, 0.084 mmol, 1.1 eq.) in dimethylformamide (1.0 ml) was added diisopropylamine (0.025 g, 0.033 ml, 0.190 mmol, 2.5 eq) followed by the addition of HATU (0.032 g, 0.084 mmol, 1.1 eq). The reaction mixture was stirred at room temperature for 4 hours and partitioned between EtOAc-CH ₂ Cl ₂ (5:1, 60 ml) and NaHCO3 (60 ml). The organics were washed with brine (50 ml), water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. MPLC (0^10% MeOH-CH ₂ Cl ₂ ) gave the title compound as a white solid;

1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30-7.22 (7H, m, 7 x ArH), 7.11 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.02 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.68 (1H, dd, J 10.0 , 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.14 (2H, s, CCH ₂ C ₆ H ₅ ), 3.40 (3H, s, NCH ₃ ), 1.63 (6H, s, C(CH ₃ ) ₂ OH);

mass/charge: 442 [M+H-H ₂ O]+.

Steps similar to those described above for Example 2 can be used to prepare compounds I14 - I-17 and I-35.

Example 3.

Synthesis of ethyl-(S,E)-3-(3-((tert-butoxycarbonyl)amino)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine-7- yl)acrylate. Suspension of tert-butyl-(S)-(7-bromo-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)carbamate (0.500 g, 1. 35 mmol, 1.0 eq.) in dimethyl form

- 59 045207 mide (8 ml) was degassed by bubbling argon for five minutes. Ethyl acrylate (0.270 g, 0.29 mL, 2.70 mmol, 2.0 eq.) and triethylamine (0.272 g, 0.37 mL, 2.0 eq.) were added followed by tetrakis(triphenylphosphine) (0.156 g, 0.14 mmol, 0.1 eq.). The reaction mixture was sealed and heated in a microwave oven to 100°C for 1 hour and to 120°C for 1 hour. The reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The organics were washed with brine (70 ml), water (100 ml) and brine (70 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Column chromatography (10 >40% EtOAc-hexane) gave the title compound (0.250 g, %) as a yellow foam;

^1H NMR (400 MHz, CDCl ₃ ) δ 7.62 (1H, d, J 16.0 Hz, ArCH=CHCO), 7.35 (1H, dd, J 8.0, 2.0 Hz, H- 8 oxobenzoxazepine), 7.33 (1H, d, J 2.0 Hz, H-6 oxobenzoxazepine), 7.14 (1H, d, J 8.0 Hz, H-9 oxobenzoxazepine), 6.37 (1H, d, J 16.0 Hz, AgCH=CHCO), 5.49 (1H, d, J 7.0 Hz, NH), 4.65 (1H, dt, J 11.0, 7.0 Hz, H- 3 oxobenzoxazepine), 4.57 (1H, dd, J 9.5, 7.0 Hz, 1H in H-2 oxobenzoxazepine), 4.27 (2H, q, J 7.0 Hz, OCH ₂ CH ₃ ), 4.19 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 of oxobenzoxazepine), 3.41 (3H, s, NCH3), 1.39 (9H, s, C(CH ₃ ) ₃ ), 1.34 (3H, t, J 7.0 Hz, OCH ₂ CH ₃ );

mass/charge: 291 [M+H-CO ₂ -C ₄ H ₈ ]+.

Synthesis of ethyl (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)propanoate. To a solution of the α,β-unsaturated ester (0.25 g, 0.64 mmol, 1.0 eq.) in ethyl acetate (20 ml) was added palladium on carbon (0.23 g). The reaction mixture was purged with hydrogen and stirred under hydrogen for 14 hours. The reaction mixture was purged with nitrogen and filtered through Celite® eluting with ethyl acetate (2x20 ml). The filtrate was concentrated under reduced pressure;

^1H NMR (400 MHz, CDCl3) δ 7.04-6.82 (3H, m, H-6, H-8, H-9 oxobenzoxazepine), 5.50 (1H, d, J 7.5 Hz, NH), 4.61 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazepine), 4.52 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazepine), 4.14-4.07 (1H, m, 1H in H-2 oxobenzoxazepine), 4.12 (2H, q, J 7.0 Hz, OCH ₂ CH ₃ ), 3.36 (3H, s , NCH3), 2.91 (2H, t, J 7.5 Hz, 2H ArCH ₂ CH ₂ CO), 2.59 (2H, t, J 7.5 Hz, 2H ArCH ₂ CH ₂ CO), 1, 37 (9H, s, C(CH ₃ ) ₃ ), 1.23 (3H, t, J 7.0 Hz, OCH ₂ CH ₃ );

mass/charge: 337 [M+H-C ₄ H ₈ ] ⁺ , 293 [M+H-CO ₂ -C ₄ H ₈ ] ⁺ . The crude material was dissolved in dichloromethane (10 ml). Hydrogen chloride (0.80 mL of 4 M dioxane, 3.21 mmol, 5.0 eq.) was added. The reaction mixture was stirred at room temperature for 14 hours before adding more hydrogen chloride solution (0.8 mL, 5.0 eq.). After stirring for an additional 2 hours, the reaction mixture was concentrated under reduced pressure and dried under vacuum to obtain a brown solid. The crude material was used without further purification;

mass/charge: 293 [M+N] ⁺ .

F

Synthesis of ethyl-(S)-3 -(3 -(1 -(2-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamido)-5-methyl-4-oxo-2,3,4, 5tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate.

Fluorobenzyltriazole (0.116 g, 0.525 mmol, 1.1 eq.) was added to a solution of ethyl-(S)-3-(3-(1-(2fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)- 5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)propanoate (0.140 g, 0.477 mmol, 1.0 eq.) and diisopropylethylamine (0.154 g, 0 .21 mmol, 2.5 eq.) in dimethylformamide (5.0 eq.). HATU (0.199 g, 0.525 mmol, 1.1 eq.) was added and the reaction mixture was stirred at 0°C for 1 hour and at room temperature for 1 hour. The reaction mixture was partitioned between EtOAc (120 ml) and NaHCO ₃ -water (1:1, 120 ml). The organics were washed with brine (100 ml), water (100 ml) and brine (100 ml), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (40 >80% EtOAc-hexane) provided the title compound (0.138 mg) as a white solid;

^1H NMR (400 MHz, CDCl ₃ ) δ 8.11 (1H, s, H-5 triazole), 8.05 (1H, d, 7.0 Hz, NH), 7.38-7.30 (2H , m, 2H C6H4F), 7.26-7.07 (6H, m, 2H C6H4F, H-6, H-7, H-8, H-9 oxobenzoxazapine), 5.42 (2H, s, CH ₂ C ₆ H ₄ F), 5.08 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 of oxobenzoxazapine), 3.42 (3H, s, NCH3);

¹³ C NMR (100 MHz, CDCl3) δ 168.9, 160.6 (d, J 248.5 Hz), 158.3, 156.7, 150.1, 144.1 (d, J 2.0 Hz ), 136.0, 131.1 (d, J 8.5 Hz), 130.9 (d, J 2.5 Hz), 127.6, 125.7, 124.9 (d, J Hz), 123.3, 123.1, 121.2 (d, J 14.0 Hz), 115.8 (d, J 21.5 Hz), 77.3, 49.2, 47.9 (d, J 4 ,0 Hz), 35.5; ¹⁹ F NMR (380 MHz, CDCl3) δ -118.1;

mass/charge: 518 [M+Na] ⁺ , 496 [M+H] ⁺ (found value of [M+H] ⁺ , 496.1991, C ₂₅ H ₂₆ FN ₅ O ₅ provides [M+H] ⁺ 496, 1973).

- 60 045207

Steps similar to those described above for Example 3 and below for Examples 4 and 5 can be used to prepare compounds I-10, I-11, I-13, I-18, I-19, I-26, I-27, I -33, I-34 and I-22 and I-23 (where the double bond of the linker group is not first reduced before coupling).

Example 4.

F F

Synthesis of (S)-3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-7-yl)propanoic acid. To a solution of ethyl ester (0.103 g, 0.208 mmol, 1.0 eq.) in tetrahydrofuran (3 ml) was added an aqueous solution of lithium hydroxide (0.017 g, 0.416 mmol, 2.0 eq. in 1 ml of water). The reaction mixture was stirred at room temperature for 3 hours before partitioning between EtOAc (80 ml) and NH ₄ Cl (80 ml). The aqueous phase was extracted with EtOAc (2x60 ml). The combined organics were washed with brine (80 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Column chromatography (0 > 10% MeOH-CH ₂ Cl ₂ ) gave the title compound (0.054 g, %) as a white solid;

Ή NMR (400 MHz, CDCl ₃ ) δ 8.12 (1H, s, H-5 triazole), 8.04 (1H, d, J 7.5 Hz, NH), 7.40-7.30 (2H , m, 2 x ArH), 7.16 (1H, dd, J 7.5, 1.0 Hz, 1 x ArH), 7.14-7.10 (2H, m, 2 x ArH), 7, 07 (2H, m, 2 x ArH), 5.43 (2H, s, NCH ₂ C ₆ H ₅ F), 5.07 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazepine ), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazepine), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H in H- 2 oxobenzoxazepine), 3.41 (3H, s, NCH ₃ ), 2.96 (2H, t, J 7.5 Hz, 2H ArCH2CH2CO), 2.70 (2H, t, J 7.5 Hz, 2H ArCH2CH2CO );

¹⁹ F NMR (CDCl ₃ ) δ -118.1 (dd, J 16.5, 7.0 Hz);

mass/charge: 468 [M+H]+ (the found value of [M+H] ⁺ , 468.1688, C ₂₃ H ₂₂ FN ₅ O ₅ provides [M+H]+ 468.1678).

Example 5.

Synthesis of (S)-N-(7-(3-((1H-indazol-6-yl)amino)-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide. Solution of (S)3-(3-(1-(2-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b ][1,4]oxazepin-7-yl)propanoic acid (0.049 g, 0.105 mmol, 1.0 eq.) and 6-aminoindazole (0.017 g, 0.126 mmol, 1.2 eq.) in dimethylformamide (10 ml) cooled to 0°C. Diisopropylethylamine (0.027 g, 0.036 mL, 0.210 mmol, 2.0 eq.) was added followed by HATU (0.048 g, 0.126 mmol, 1.2 eq.) and the reaction mixture was stirred at 0°C for 1 h and room temperature for 2 hours. The reaction mixture was partitioned between EtOAc (50 ml) and NaHCO ₃ (50 ml). Organics were washed with saline (50 ml). The combined aqueous phase was extracted with EtOAc (20 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. Column chromatography (0>10% MeOH-CH ₂ Cl ₂ ) gave the title compound (0.xx g), the title compound was obtained as a white solid;

Ή NMR (400 MHz, CDCl ₃ ) δ 8.12 (1H, s, H-5 triazole), 8.00 (1H, d, J 7.5 Hz, NH), 7.94 (1H, d, J 0.5 Hz, H-3 indazole), 7.90 (1H, s, NH), 7.83 (1H, m, H-7 indazole), 7.57 (1H, d, J 9.0 Hz, H-4 indazole), 7.37-7.30 (2H, m, 2H C6H ₄ F), 7.13 (1H, td, J 7.5, 1.0 Hz, 1H C6H4F), 7.09- 7.00 (5H, m, H-5 indazole, 1H C6H4F, H-6, H-7, H-9 oxobenzoxazepine), 5.40 (2H, s, NCH2C6H4F), 5.02 (1H, td, J 11.5, 7.5 Hz, H-3 oxobenzoxazepine), 4.63 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazepine), 4.23 (1H, dd, J 11.5, 9.5 Hz, 1H in H-2 oxobenzoxazepine), 3.29 (3H, s, NCH ₃ ), 3.03 (2H, t, J 7.0 Hz, Ar^^CON), 2 .68 (2H, m, Ar^^CON);

¹³ C NMR (CDCl ₃ ) δ 170.6, 168.7, 160.7 (d, J 248.5 Hz), 158.8, 156.4, 148.4, 144.4, 140.6, 138 .5, 136.3, 135.9, 134.3, 131.2 (d, J 8.5 Hz), 131.0 (d, J 3.0 Hz), 127.5, 124.9 (d , J 4.0 Hz), 123.4, 122.9, 121.1, 121.0, 120.3, 115.8 (d, J 20.5 Hz), 115.3, 101.1, 77 ,2, 49.1, 48.0 (d, J 4.0 Hz), 39.3, 35.3, 31.1;

¹⁹ F NMR (CDCl ₃ ) δ -118.0;

mass/charge: 583 [M+H]+ (found value of [M+H] ⁺ , 583.2205, C ₃₀ H ₂₇ FN ₈ O ₄ provides [M+H]+ 583.2212).

- 61 045207

Example 6.

Cl

Ethyl-(S)-3-(3-(1-(2,6-dichlorobenzyl)-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanoate.

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.96 (1H, s, H-5 triazole), 7.42 (2H, m, 2 x ArH), 7.32 (1H, dd, J 9.0, 7.0 Hz, 1 x ArH), 7.10 (1H, m, 1 x ArH), 7.06 (2H, dd, J 6 ,0, 2.0 Hz, 2 x ArH), 5.70 (2H, s, CH2C6H3OD, 5.07 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazepine), 4.74 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazepine), 4.21 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazepine), 4 .14 (2H, q, J 7.0 Hz, OCH ₂ CH ₃ ), 3.41 (3H, s, NCH3), 2.95 (2H, t, J 7.5 Hz, 2H ArC^C^CO ), 2.63 (2H, t, J 7.5 Hz, 2H ArC^C^CO), 1.24 (3H, t, J 7.0 Hz, OCH2CH3);

¹³ C NMR (100 MHz, CDCl3) δ 172.5, 168.9, 158.3, 156.5, 148.4, 143.9, 138.4, 136.9, 135.8, 131.4, 129.1, 128.9, 127.5, 123.2, 122.9, 77.2, 60.6, 49.4, 49.3, 35.7, 35.5, 30.3, 14, 2;

mass/charge: 548.546 [M+H]+ (the found value of [M+H] ⁺ , 546.1291, C ₂₅ H ₂₅ Cl ₂ N ₅ O ₅ provides [M+H]+ 546.1306).

Example 7.

(8)-3-(3-(5-Benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1, 4]oxazepin-7-yl)propanoic acid.

1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (1H, d, J 7.5 Hz, NH), 7.32-7.22 (5H, m, 5 x ArH), 7.08-7, 06 (3H, m, 3 x ArH), 4.97 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.62 (1H, dd, J 9.5, 7, 5 Hz, 1H in H-2 oxobenzoxazapine), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.13 (2H, s, CH2C6H5), 3, 38 (3H, s, NCH3), 2.94 (2H, m, 2H ACH2CH2CO2H), 2.70 (2H, m, 2H ArCHCHzCOzH);

¹⁹ F NMR (CDCl ₃ ) δ -118.1;

mass/charge: 450 [M+H]+ (the found value of [M+H] ⁺ , 450.1760, C ₂₃ H ₂₃ N ₅ O ₅ provides [M+H]+ 450.1772).

Example 8.

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-(3-oxo-3-(pyrrolidin-1-yl)propyl)-2,3,4,5tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.29-7.21 (5H, m, 5 x ArH), 7.10-7, 07 (3H, m, 3 x ArH), 5.05 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7, 5 Hz, 1H in H-2 oxobenzoxazapine), 4.22 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.15 (2H, s, CH ₂ Ph), 3.45 (2H, t, J 7.0 Hz, 2H pyrrolidine), 3.38 (3H, s, NCH3), 3.35 (2H, m, 2H pyrrolidine), 2.97 (2H, t, J 7.5 Hz, 2H ArCH ₂ CH ₂ CO), 2.57 (2H, t, J 7.5 Hz, 2H ArCH ₂ CH ₂ CO), 1.92 (2H, m, 2H pyrrolidine), 1.83 (2H, m, 2H pyrrolidine);

¹³ C NMR (100 MHz, CDCl3) δ 170.4, 168.9, 158.5, 148.2, 139.5, 135.9, 135.7, 128.9, 128.8, 127.6, 127.1, 123.5, 122.7, 77.1. 49.2, 46.6, 45.8, 36.6, 35.5, 33.2, 30.4, 26.0, 24.4;

mass/charge: 503 [M+H]+ (the found value of [M+H] ⁺ , 503.2403, C ₂₇ H ₃₀ N ₆ O ₄ provides [M+H]+ 503.2401).

Example 9.

Synthesis of (S,E)-3-(5-methyl-4-oxo-3-(tritylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7yl)acrylamide. Dimethylformamide (5 ml) was added to a mixture of bromoxobenzoxazapine (0.300 g, 0.586 mmol, 1.0 eq) and acrylamide (0.062 g, 0.879 mmol, 1.5 eq) and the mixture was degassed by bubbling argon for five minutes. Triethylamine (0.178 g, 0.24 mL, 1.758 mmol, 3.0 eq) was added followed by X-PhosPd G2 (0.046 g, 0.059 mmol, 0.1 eq) and the reaction mixture was sealed and heated to 120°C in the microwave for 1 hour. The reaction mixture was divided between

- 62 045207

EtOAc (100 ml) and NaHCO ₃ (100 ml). The organics were washed with brine (80 ml), water (100 ml) and brine (80 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. MPLC (0 > 10% MeOH-CH ₂ Cl ₂ ) gave the title compound (0.267 g, 91%) as a pale yellow solid;

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.55 (1H, d, J 15.5 Hz, AgCH=CHCO), 7.39-7.36 (7H, m, 6H C(C ₆ H ₅ ) ₃ , H-8 oxobenzoxazapine), 7.25-7.13 (9H, m, 9H C(C ₆ H ₅ ) ₃ ), 7.01 (1H, d, J 8.5 Hz, H-9 oxobenzoxazepine) , 6.97 (1H, d, J 2.0 Hz, H-6 oxobenzoxazepine), 6.39 (1H, d, J 15.5 Hz, AgCH=CHCO), 5.95 (2H, br s, NH2 ), 4.51 (1H, dd, J 9.5, 7.0 Hz, 1H in H-2 oxobenzoxazepine), 4.39 (1H, dd, J 11.5, 9.5 Hz, 1H in H- 2 oxobenzoxazepine), 3.54 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazepine), 3.31 (1H, d, J 8.5 Hz, NH), 2.94 (3H , s, NCH ₃ );

mass/charge: 526 [M+Na]+, 243 [C(C ₆ H ₅ ) ₃ ] ⁺ .

Synthesis of (S)-3-(3-amino-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)propanamide. A solution of α,β-unsaturated carboxamide (0.267 g, 0.532 mmol, 1.0 eq.) in ethyl acetate-methanol (5:2, 7 ml) was purged with nitrogen and palladium on carbon (0.100 g) was added. The reaction mixture was purged with hydrogen and stirred under hydrogen for 2 hours. The reaction mixture was purged with nitrogen and filtered through Celite eluting with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in dioxane (5 ml) and hydrogen chloride (0.66 ml of 4 M dioxane solution, 2.659 mmol, 5.0 eq.) was added. The reaction mixture was stirred at room temperature for 6 hours, a white solid formed. The reaction mixture was concentrated to dryness and used without purification;

mass/charge: 265 [M+H]+.

Synthesis of (S)-N-(7-(3-amino-3-oxopropyl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin3-yl)- 5-benzyl-1H-1,2,4-triazole-3-carboxamide. To a mixture of aminooxobenzoxazapine hydrochloride (0.134 mmol, 1.0 eq.) and benzyltriazolecarboxylic acid (0.033 g, 0.161 mmol, 1.2 eq.) in dimethylformamide (1.0 ml) was added diisopropylethylamine (0.043 g, 0.058 ml, 0.335 mmol, 2.5 eq) followed by the addition of HATU (0.102 g, 0.268 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 4 hours and partitioned between EtOAc-CH ₂ Cl ₂ (5:1, 60 ml) and water (60 ml). The organics were washed with saline (50 ml), water (60 ml) and saline (50 ml). Organic matter was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. MPLC (0>10% MeOH-CH ₂ Cl ₂ ) gave the title compound as a white solid;

^1H NMR (400 MHz, CDCl ₃ ) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.36-7.28 (5H, m, 5 x ArH), 7.11-7 .06 (3H, m, 3 x ArH), 5.44 (2H, br s, CONH2), 5.02 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4, 68 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.17 (2H, s, CH ₂ C ₆ H5), 3.41 (3H, s, NCH3), 2.99 (2H, t, J 7.5 Hz, 2H ArCH2CH2CO), 2.54 (2H, t, J 7.5 Hz, 2H ArCH2CH2CO);

mass/charge: 449 [M+H]+.

Example 10.

Formation of (S)-7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-5-methyl-3(tritylamino) -2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one. Dioxane (4 ml) and water (2 ml) were added to a mixture of bromobenzoxazapine (0.270 g, 0.527 mmol, 1.0 eq.), 7-((trifluoro-λ ⁴ -boraneyl)methyl)5,6,7 potassium salt 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (0.180 g, 0.738 mmol, 1.4 eq.) and cesium carbonate (0.515 g, 1.581 mmol, 3.0 eq.). The reaction mixture was degassed by bubbling argon for ten minutes. X-PhosPd G2 (0.021 g, 0.026 mmol, 0.05 eq) was added and the reaction mixture was sealed and microwaved to 140°C for 45 min. The reaction mixture was partitioned between EtOAc (80 ml) and NaHCO ₃ (80 ml). The organics were washed with brine (80 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. MPLC (0>10% MeOH [2 M NH ₃ ]-CH ₂ Cl ₂ ) gave the title compound (0.255 g, %) as a yellow oil;

^1H NMR (400 MHz, CDCl3) δ 7.88 (1H, s, H-3 triazole), 7.38-7.35 (6H, m, 6H C(C ₆ H5)z), 7.21- 7.11 (9H, m, 9H C(C ₆ H ₅ ) ₃ ), 7.02 (1H, dd, J 8.0, 2.0 Hz, H-8 oxobenzoxazapine), 6.97 (1H, d , J 8.0 Hz, N-9 oxobene

- 63 045207 zoxazapine), 6.87 (1H, d, J 2.0 Hz, H-6 oxobenzoxazapine), 4.50 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine ), 4.36 (1H, dd, J 11.5, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.16 (2H, t, J 5.5 Hz, 2H in NCH2CH2N), 3.82 (2H, s, ArCH2N or NCH2CN), 3.69 (2H, s, ArC^N or NCH2CN), 3.51 (1H, dd, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 2 .91 (2H, t, J 5.5 Hz, 2H ArC^C^N), 2.88 (3H, s, NCH3);

mass/charge: 593 [M+Na]+, 243 [С(С6Н5)з] ⁺ .

Removal of the trityl protecting group. To a solution of trityl-protected amine (0.255 g, 0.447 mmol, 1.0 eq.) in dioxane (4.0 ml) was added hydrogen chloride (0.56 ml of a 4 M solution in dioxane, 2.237 mmol, 5.0 eq. ). A white precipitate formed. The reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated to dryness and used without purification;

mass/charge: 329 [M+H]+.

Formation of (S)-5-benzyl-N-(7-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8//)-yl)methyl) -5methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide. To a solution of aminooxobenzoxazapine hydrochloride (0.377 mmol, 1.0 eq.) and benzyltriazolecarboxylic acid (0.077 g, 0.377 mmol, 1.0 eq.) in dimethylformamide (4.0 ml) was added diisopropylethylamine (0.122 g, 0.16 ml, 0.943 mmol, 2.5 eq.). The reaction mixture was cooled to 0°C and HATU (0.143 g, 0.377 mmol, 1.0 eq.) was added. The reaction mixture was stirred at 0°C for 2 hours and at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc-CH ₂ Cl ₂ (9:1, 60 ml) and NaHCO ₃ water (1:1, 60 ml) . Organics were washed with saline (60 ml). The combined aqueous phase was re-extracted with EtOAc (30 ml). The combined organics were washed with water (90 ml) and brine (90 ml), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. MPLC (0^8% MeOH-CH ₂ Cl ₂ ) gave the title compound as a white solid;

1H NMR (400 MHz, CDCl ₃ ) δ 7.90 (1H, br m, NH), 7.75 (1H, s, H-3 triazole), 7.29-7.21 (7H, m, 7 x ArH), 7.16 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.10 (1H, H-3 oxobenzoxazapine), 4.74 (1H, dd, J 9.5, 7, 5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 (1H, t, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.21 (2H, t, J 5.5 Hz, 2H NCH2CH2N), 4.15 (2H, s, NCH2C6H5), 3.84, 3.78 (2H, 2d AB systems, J 15.5 Hz, ArC^N or NCH2C), 3.77, 3.73 (2H, 2d AB systems, J 13.5 Hz, ArC^N or NCH2C), 3.40 (3H, s, NCH3), 3.02 (2H, t, J 5.5 Hz, 2H NCH2CH2N);

mass/charge: 514 [M+H]+ (found value of [M+H]+, 514.2324, C ₂₆ H ₂₇ N ₉ O ₃ provides [M+H]+ 514.2310).

Additional illustrative embodiments of the connections are described below.

(S)-5 -Benzyl-3 -((7-(3 -hydroxy-3 -methylbut-1 -in-1 -yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)carbamoyl)-1,2,4-triazol-1-ide.

1H NMR (400 MHz, D ₆ DMSO) δ 7.83 (1H, d, J 8.0 Hz, NH), 7.45 (1H, d, J 2.0 Hz, H-6 oxobenzoxazapine), 7, 25 (1H, dd, J 8.0, 2.0 Hz, H-8 oxobenzoxazapine), 7.20-7.15 (5H, m, H-9 oxobenzoxazapine, 4H C6H5), 7.09-7.04 (1H, m, 1H 0.¾) 5.47 (1H, br s, OH), 4.81-4.74 (1H, m, H-3 oxobenzoxazapine), 4.39-4.36 (2H, m, 2H in H-2 of oxobenzoxazapine), 3.84 (2H, s, CH2C6H5), 3.28 (3H, s, NCH3), 1.44 (6H, s, C(CH3) ₂ OH);

mass/charge: 442 [M+H]+.

(S)-1-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-yn-1-yl)-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.76 (1H, dd, J 4.0, 1.5 Hz, H-2 quinoline), 8.03 (2H, m, NH, H-4 quinoline), 8.01 (1H, d, J 9.5 Hz, H-8 quinoline), 7.99 (1H, s, H-5 triazole), 7.40 (1H, dd, J 9.0, 3.0 Hz, H-7 quinoline), 7.37-7.7.33 (4H, m, 4H C6H5, H-6, H-8 oxobenzoxazapine), 7.28-7.24 (3H, m, 3H C6H5, H-6, H-8 oxobenzoxazapine), 7.12 (1H, d, J 2.5 Hz, H-5 quinoline), 7.10 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.36

- 64 045207 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.75 (1H, dd, J 10.0, 7, 5 Hz, 1H in H-2 oxobenzoxazapine), 4.30 (2H, t, J 7.0 Hz, CCH2CH2O), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H in H- 2 oxobenzoxazapine), 3.39 (3H, s, NCH ₃ ), 2.98 (2H, t, J 7.0 Hz, CCH2CH2O);

mass/charge: 573 [M+H]+ (found value of [M+H] ⁺ , 573.2244, C ₃₃ H ₂₈ N ₆ O ₄ provides [M+H]+ 573.2245).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-6-yloxy)but-1-un-1-ul)-2,3,4,5tetrahydrobenzo [ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.73 (1H, dd, J 4.0, 1.5 Hz, H-2 quinoline), 8.05 (2H, m, NH, H-4 quinoline) , 8.00 (1H, d, J 9.5 Hz, H-8 quinoline), 7.40 (1H, dd, J 9.5, 3.0 Hz, H-7 quinoline), 7.34 (1H , m, H-3 quinoline), 7.25 (1H, dd, J 8.0, 2.0 Hz, H-8 oxobenzoxazapine), 7.25-7.20 (6H, m, C ₆ H ₅ , H-7 oxobenzoxazapine), 7.11 (1H, d, J 3.0 Hz, H-5 quinoline), 7.09 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.02 ( 1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.29 ( 2H, t, J 7.0 Hz, CCH2CH2O), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.14 (2H, s, CH2C6H5), 3.37 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, CCH2CH2O);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 156.6, 149.7, 148.0, 144.3, 136.0, 134.9, 131.0, 130.8, 129.2 , 128.8 (2C), 128.6, 127.1, 126.5, 123.1, 122.4, 121.4, 121.0, 106.3, 86.6, 80.7, 77, 2, 66.2, 49.1, 35.4, 33.4, 20.4;

mass/charge: 573 [M+H]+ (the found value of [M+H] ⁺ , 573.2262, C ₃₃ H ₂₈ N ₆ O ₄ provides [M+H]+ 573.2245).

(S)-1-Benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a] pyrazin7(8I)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.04 (1H, d, J 7.5 Hz, NH), 8.00 (1H, s, H-5 triazole), 7.38-7.33 (3H , m, 3H C6H5), 7.27-7.24 (2H, m, 2H C6H5), 7.19 (2H, m, H-6, H-8 oxobenzoxazapine), 7.15 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.35 (2H, s, NCH ₂ C _{6 H5} ), 5.09 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine) , 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26-4.21 (3H, m, 1H in H-2 oxobenzoxazapine, 2H NCH2CH2N), 3.87 (2H, s, 2H ArCH ₂ NCH ₂ C), 3.75 (2H, s, 2H ArCH ₂ NCH ₂ C), 3.40 (3H, s, NCH ₃ ), 3.01 (2H, td, J 5.0, 1.5 Hz, 2H NCH2CH2N);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 158.4, 156.6, 153.5 (q, J 39.5 Hz), 152.2, 149.6, 143.9, 136, 4, 134.5, 133.7, 129.2, 129.0, 128.2, 127.8, 123.4, 123.3, 119.2 (q, J 270.5 Hz), 77.2 , 60.6, 54.3, 50.7, 49.2, 48.4, 47.1, 35.6;

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -65.4;

mass/charge: 582 [M+H]+ (the found value of [M+H] ⁺ , 582.2188, C ₂₇ H ₂₆ F ₃ N ₉ O ₃ provides [M+H] + 582.2183).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a] pyrazin7(8H)-ul)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.27-7.21 (6H, m, C ₆ H ₅ , H-8 oxobenzoxazapine), 7.21 (1H, dd, J 7.5, 2.0 Hz, H-8 oxobenzoxazapine), 7.15 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.07 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.29-4, 23 (3H, m, 1H in H-2 of oxobenzoxazapine, 2H NCH2CH2N), 4.12 (2H, s, CH2C6H5), 3.86 (2H, s, 2H ArCH ₂ NCH ₂ C), 3.76 (2H, s, 2H ArCH ₂ NCH ₂ C), 3.39 (3H, s, NCH ₃ ), 3.03 (2H, t, J 5.5 Hz, 2H NCH2CH2N);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 158.7, 153.4 (q, J 39.5 Hz), 152.2, 149.6, 136.3, 135.7, 134, 6, 128.8, 128.7, 127.9, 127.1, 123.4, 123.2, 123.1, 119.2 (q, J 269.5 Hz), 77.1, 60.7 , 50.4, 49.4, 48.6, 47.1, 35.6, 33.0;

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -65.3;

mass/charge: 582 [M+H]+ (found value of [M+H] ⁺ , 582.2167, C ₂₇ H ₂₆ F ₃ N ₉ O ₃ provides [M+H]+ 582.2183).

- 65 045207

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.75 (1H, dd, J 4.5, 2.0 Hz, H-2 quinoline), 8.09-8.06 (2H, m, NH, H-4 quinoline), 7.70 (1H, d, J 9.0 Hz, H-5 quinoline), 7.50 (1H, d, J 2.5 Hz, H-8 quinoline), 7.27-7.17 (9H, m, H-3, H-6 quinoline, H-6, H-8 oxobenzoxazapine, C6H5), 7.07 (1H, d, J 8.5 Hz, H-9 oxobenzoxazapine), 5.00 ( 1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.31 ( 2H, td, J 7.0, 2.5 Hz, OCH2CH2C), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.13 (2H, s , CH2C6H5), 3.36 (3H, s, NCH ₃ ), 2.97 (2H, t, J 7.0 Hz, OCH2CH2C);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 159.6, 158.6, 150.3, 149.6, 149.5, 136.0 (2C), 135.9, 131.0, 128.9, 128.8, 128.7, 127.0, 126.5, 123.7, 123.0, 121.0, 120.1, 119.1, 107.9, 86.8, 80, 6, 77.2, 66.1, 49.2, 35.5, 33.2, 20.3;

mass/charge: 573 [M+H]+ (found value of [M+H] ⁺ , 573.2269, C ₃₃ H ₂₈ N ₆ O ₄ provides [M+H]+ 573.2245).

(S)-1-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-7-yloxy)but-1-yn-1-yl)-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.20 (1H, dd, J 4.5, 2.0 Hz, H-2 quinoline), 8.06 (1H, dd, J 8.0, 1.5 Hz , H-4 quinoline), 8.03 (1H, d, J 7.0 Hz, NH), 7.99 (1H, s, H-5 triazole), 7.70 (1H, d, J 9.0 Hz, H-5 quinoline), 7.45 (1H, d, J 2.5 Hz, H-8 quinoline), 7.37-7.33 (3H, m, 3H C ₆ H ₅ , H-6 oxobenzoxazapine ), 7.27-7.22 (6H, m, H6, H-3 quinoline, H-8 oxobenzoxazapine, 3H C _{6 H5} , H-6 oxobenzoxazapine), 7.09 (1H, dd, J 8.0 , 0.5 Hz, H-9 oxobenzoxazapine), 5.35 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.33 (2H, t, J 7.0 Hz, OCH2CH2C), 4.23 (1H, dd, J 9 .5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 3.39 (3H, s, NCH3), 2.98 (2H, t, J 7.0 Hz, OCH2CH2C);

¹³ C NMR (100 MHz, CDCl3) δ 168.8, 159.4, 158.4, 156.6, 150.6, 149.8, 149.7, 143.9, 135.9, 135.7, 133.7, 130.9, 129.2, 128.9, 128.2, 126.5, 123.7, 123.1, 121.0, 119.9, 119.1, 108.2, 86, 6, 80.7, 77.1, 66.1, 54.3, 49.1, 38.6, 35.5, 20.3;

mass/charge: 573 [M+H]+ (found value of [M+H] ⁺ , 573.2249, C ₃₃ H ₂₈ N ₆ O ₄ provides [M+H]+ 573.2245).

(S)-5-(2,4-Difluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.27-7.20 (3H, m, H-6, H-8 oxobenzoxazapine, 1H C6H3F2 ), 7.10 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 6.82-6.74 (2H, m, 2H C6H3F2), 4.99 (1H, dt, J 11.0 , 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, dd, J 11.0 , 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.12 (2H, s, CH2C6H3F2), 3.39 (3H, s, NCH ₃ ), 1.61 (6H, s, C(CH ₃ ) _2OH );

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -111.2; -113.2;

mass/charge: 478 [M+HH ₂ O]+ (the found value of [M+H] ⁺ , 496.1795, C ₂₅ H ₂₃ F ₂ N ₅ O ₄ provides [M+H]+ 496.1791).

(S)-1-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5 -yloxy)but-1 -in-1 -yl)-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.89 (1H, dd, J 4.0, 2.0 Hz, H-2 quinoline), 8.63 (1H, ddd, J 8.5, 2.0 , 1.0 Hz, H-4 quinoline), 8.02 (1H, d, J 7.5 Hz, NH), 7.99 (1H, s, H-5 triazole), 7.70 (1H, d , J 8.5 Hz, H-8 quinoline), 7.59 (1H, dd, J 8.5, 7.5 Hz, H-7 quinoline), 7.38-7.33 (4H, m, H -3 quinoline, 3H C6H5, H-6 oxobenzoxase

- 66 045207 pin), 7.26-7.22 (4H, m, H-8 oxobenzoxazapine, 3H C6H5, H-6 oxobenzoxazapine), 7.09 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine ), 6.89 (1H, dd, J 7.5, 0.5 Hz, H-6 quinoline), 5.35 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.73 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.35 (2H, t, J 7.0 Hz , OCH2CH2C), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.37 (3H, s, NCH3), 3.03 (2H, t, J 7.0 Hz, OCH2CH2C);

mass/charge: 573 [M+H]+ (found value of [M+H] ⁺ , 573.2251, C ₃₃ H ₂₈ N ₆ O ₄ provides [M+H]+ 573.2245).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-(4-(quinolin-5-yloxy)but-1-yn-1-yl)-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.85 (1H, dd, J 4.0, 2.0 Hz, H-2 quinoline), 8.64 (1H, ddd, J 8.5, 2.0, 1.0 Hz, H-4 quinoline), 8.07 (1H, d, J 7.5 Hz, NH), 7.69 (1H, d, J 8.5 Hz, H-8 quinoline), 7. 59 (1H, dd, J 8.5, 7.5 Hz, H-3 quinoline), 7.26-7.17 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine), 7.08 ( 1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 6.90 (1H, dd, J 8.0, 0.5 Hz, H-6 quinoline), 5.02 (1H, dt, J 11 ,0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.36 (2H, t, J 7 ,0 Hz, OCH2CH2C), 4.25 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.13 (2H, s, CH ₂ C ₆ H ₅ ), 3 .36 (3H, s, NCH3), 3.04 (2H, t, J 7.0 Hz, OCH2CH2C);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 158.5, 153.9, 150.6, 149.7, 148.9, 136.0, 131.0, 130.9, 129.4 , 128.8, 128.7, 127.0, 126.5, 123.1, 121.8, 121.0, 120.9, 120.3, 105.4, 86.7, 80.7, 77 ,2, 49.1, 35.5, 33.2, 20.5;

mass/charge: 573 [M+H]+ (the found value of [M+H] ⁺ , 573.2266, C ₃₃ H ₂₈ N ₆ O ₄ provides [M+H]+ 573.2245).

(S)-1-Benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (1H, d, J 7.5 Hz, NH), 8.02 (1H, s, H-5 triazole), 7.39-7.35 ( 3H, m, 3 x ArH), 7.29-7.7.26 (2H, m, 2 x ArH), 7.20 (2H, m, 2 x ArH), 7.17 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.38 (2H, s, NCH ₂ C _{6 H5} ), 5.12 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine) , 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.15 (2H, t, J 5.5 Hz, 2H NCH2CH2N), 3.98, 3.93 (2H, 2d AB systems, J 15.5 Hz, 2H ArCH ₂ NCH ₂ ), 3 .76 (2H, s, 2H ArCH2NCH2), 3.42 (3H, s, NCH3), 2.96 (2H, dt, J 4.0, 5.5 Hz, 2H NCH2CH2N);

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -63.2;

mass/charge: 582 [M+H]+ (found value of [M+H] ⁺ , 582.2173, C ₂₇ H ₂₆ F ₃ N ₉ O ₃ provides [M+H]+ 582.2183).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a] pyrazin7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.01 (1H, d, J 7.0 Hz, NH), 7.27-7.19 (7H, m, C ₆ H ₅ , H-6, H- 8 oxobenzoxazapine), 7.16 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.09 (1H, dt, J 10.5, 7.5 Hz, H-3 oxobenzoxazapine), 4, 70 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 (1H, dd, J 10.5, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.14 (4H, m, 2H NCH2CH2N), 2H ArCH ₂ NCH ₂ or CH ₂ C ₆ H ₅ ), 3.93 (2H, s, 2H ArCH ₂ NCH ₂ or CH ₂ C ₆ H ₅ ), 3, 78, 3.74 (2H, 2d AB systems, J 13.5 Hz, 2H ArCH ₂ NCH ₂ ), 3.40 (3H, s, NCH ₃ ), 2.97 (2H, t, J 5.5 Hz, 2H NCH2CH2N);

¹³ C NMR (100 MHz, CDCl3) δ 168.8, 158.6, 152.0, 149.6, 143.4 (q, J 40.0 Hz), 136.4, 135.8, 134.3 , 128.8, 128.7, 127.9, 127.1, 126.9, 123.4, 123.2, 118.3 (q, J 270.5 Hz), 77.2, 60.8, 49.5, 49.4, 43.6, 35.6, 33.1;

¹⁹ F NMR (380 MHz, CDCl3) δ -63.2;

mass/charge: 582 [M+H]+ (found value of [M+H] ⁺ , 582.2208, C ₂₇ H ₂₆ F ₃ N ₉ O ₃ provides [M+H]+ 582.2183).

- 67 045207

(S)-1-Benzyl-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzoI [1,4 ]oxazepin3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCI3) δ 8.04 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s, H-5 triazole), 7.40-7.36 (3H, m, 3H C ₆ H ₅ ), 7.29-7.23 (4H, m, 2H C ₆ H ₅ , H-6, H-8 oxobenzoxazapine), 7.09 (1H, d, J 9.0 Hz , H-9 oxobenzoxazapine), 5.38 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.76 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3);

mass/charge: 458 [M+H]+ (the found value of [M+H] ⁺ , 458.2205, C ₂₆ H ₂₇ N ₅ O ₃ provides [M+H]+ 458.2187).

(S)-5-Benzyl-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][ 1,4]oxazepin3 -yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.21 (7H, m, C ₆ H ₅ , H-6, H- 8 oxobenzoxazapine), 7.07 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.02 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4, 66 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J Hz, 1H in H-2 oxobenzoxazapine), 4.15 (2H, s , CH2C6H5), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)s);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 158.5, 149.2, 135.9, 135.8, 130.9, 128.8, 128.7, 127.0, 126.4 , 122.8, 121.8, 99.4, 77.6, 77.2, 49.1, 35.5, 33.2, 30.9, 27.9;

mass/charge: 458 [M+H]+ (the found value of [M+H] ⁺ , 458.2200, C ₂₆ H ₂₇ N ₅ O ₃ provides [M+H]+ 458.2187).

VCO G J\NH hr (S)-1-Benzyl-N-(7-((1-hydroxycyclobutyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4 ]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.99 (1H, s, H-5 triazole), 7.38-7.34 (3H, m, 3H C6H5), 7.29-7.25 (4H, m, 2H C6H5, H-6, H-8 oxobenzoxazapine), 7.11 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine) , 5.36 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.75 (1H, dd, J 9.5, 7 .5 Hz, 1H in H-2 oxobenzoxazapine), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.40 (3H, s, NCH3), 2 .55-2.49 (2H, m, 2H H-2, H-4 cBu), 2.33 (2H, m, 2H H-2, H-4 cBu), 1.87 (2H, m, H -3 cBu);

mass/charge: 472 [M+H]+, 454 [M+HH ₂ O]+ (found value of [M+H]+, 472.1994, C ₂₆ H ₂₅ N ₅ O ₄ provides [M+H]+ 472.1979).

(S)-5 -Benzyl-N-(7-((1 -hydroxycyclobutyl)ethynyl)-5 -methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3 -yl )-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.10 (1H, d, J 7.5 Hz, NH), 7.29-7.20 (7H, m, C ₆ H ₅ , 2H in H-6, H-8, H-9 oxobenzoxazapine), 7.10 (1H, dd, J 7.5, 1.0 Hz, 1H in H-6, H-8, H-9 oxobenzoxazapine), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.15, 4.11 (2H, 2d AB systems, J 16.0 Hz, CH2C6H5), 3.39 (3H, s, NCH3), 2.57-2.50 (2H, m, 2H in H-2, H-4 cBu), 2.35 (2H, m, 2H in H-2, H-4 cBu), 1 .92-1.84 (2H, m, H-3 cBu);

¹³ C (100 MHz, CDCl ₃ ) δ 168.7, 158.7, 149.9, 136.0, 135.8, 131.0, 128.8, 128.7, 127.0, 126.5, 123.0, 120.4, 93.4, 81.9, 76.9, 68.2, 49.1, 38.5, 35.5, 33.0, 13.0;

mass/charge: 454 [M+HH ₂ O]+ (the found value of [M+H]+, 472.1999, C ₂₆ H ₂₅ N ₅ O ₄ provides

- 68 045207

[M+H]+ 472.1979).

(S)-1-Benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl )-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.99 (1H, s, H-5 triazole), 7.38-7.34 (3H , m, 3H from C6H5), 7.28-7.26 (4H, m, 2H from C6H5, H-6, H-8 oxobenzoxazapine), 7.10 (1H, d, J 9.0 Hz, H- 9 oxobenzoxazapine), 5.36 (2H, s, NCH2C6H5), 5.06 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.75 (1H, dd, J 9, 5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.24 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.40 (3H, s, NCH3 ), 2.08-1.99 (4H, m, H-2, H-5 cyclopentane), 1.90-1.84 (2H, m, 2H in H-3, H-4 cyclopentane), 1, 83-1.76 (2H, m, 2H in H-3, H-4 cyclopentane);

mass/charge: 486 [M+H] ⁺ , 468 [M+H-H2O] ⁺ (the found value of [M+H] ⁺ , 486.2122, C27H ₂₇ N ₅ O ₄ provides [M+H] ⁺ 486, 2136).

(S)-5-Benzyl-N-(7-((1-hydroxycyclopentyl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl )-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCls) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m, C6H5, H-6, H-7 oxobenzoxazapine), 7.10 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.14 ( 2H, s, CH2C6H5), 3.39 (3H, s, NCH3), 2.08-1.97 (4H, m, H-2, H-5 cyclopentane), 1.90-1.85 (2H, m, 2H in H-3, H-4 cyclopentane), 1.82-1.76 (2H, m, 2H in H-3, H-4 cyclopentane);

mass/charge: 468 [M+H-H2O] ⁺ (found value of [M+H] ⁺ , 486.2154, C27H27N5O4 provides [M+H] ⁺ 486.2136).

(S)-1-Benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.02 (1H, s, H-5 triazole), 7.39-7.35 (3H, m, 3H C6H5), 7.31-7.27 (4H, m, 2H C6H5, H-6, H-8 oxobenzoxazapine), 7.14 (1H, dd, J 8.0, 1.0 Hz, H -9 oxobenzoxazapine), 5.37 (2H, s, NCH2C6H5), 5.08 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.76 (1H, dd, J 9 .5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.95 (2H, dt, J 12.0, 4.5 Hz, 2H in H-2, H-6 pyran), 3.72 (2H, ddd, J 12.0, 9.0, 3.0 Hz, 2H in H-2, H-6 pyran), 3.42 (3H, s, NCH3), 2.07-2.02 (2H, m, 2H in H-3, H-5 pyran), 1.89 (2H, ddd, J 13.0, 9.0, 4.0 Hz, 2H in H-3, H-5 pirana);

mass/charge: 502 [M+H] ⁺ , 484 [M+H-H2O] ⁺ (found value of [M+H] ⁺ , 502.2105, C27H27N5O5 provides [M+H] ⁺ 502.2085).

(S)-5-Benzyl-N-(7-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1 ,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

^1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 6.5 Hz, NH), 7.28-7.19 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine) , 7.09 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.00 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.64 (1H , dd, J 9.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, t, J 10.5 Hz, 1H in H-2 oxobenzoxazapine), 4.12 (2H, s , CH2C6H5), 3.93 (2H, dt, J 12.0, 4.5 Hz, 2H in H-2, H-6 pyran), 3.70 (2H, ddd, J 11.5, 9.0 , 2.5 Hz, 2H in H-2, H-6 pyran), 3.37 (3H, s, NCH3), 2.03 (2H, m, 2H in H-3, H-5 pyran), 1 .88 (2H,

- 69 045207 ddd, J 13.0, 9.0, 4.0 Hz, 2H in H-3, H-5 pirana);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.6, 158.7, 150.1, 136.1, 135.7, 131.1, 128.9, 128.8, 127.1, 126.6 , 123.2, 120.0, 92.3, 83.4, 77.3, 66.1, 64.8, 49.1, 39.9, 35.6, 33.1;

mass/charge: 484 [M+HH ₂ O]+ (found value of [M+H]+, 502.2080, C ₂₇ H ₂₇ N ₅ O ₅ provides [M+H]+ 502.2085).

(S)-Iso-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin3-yl)-4-phenoxypicolinamide.

'H NMR (400 MHz, CDC13) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5 Hz, H-6 pyridine), 7.60 (1H, d, J 2.5 Hz, H-3 pyridine), 7.40 (2H, m, 2H C ₆ H ₅ ), 7.27-7.22 (3H, m, H-6, H- 8 oxobenzoxazapine, 1H C6H5), 7.10 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 7.05 (2H, m, 2H from C6H5), 6.93 (1H, dd, J 5 .5, 2.5 Hz, H-5 pyridine), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.70 (1H, dd, J 9.5 , 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.41 (3H, s, NCH ₃ ), 1.61 (6H, s, C(CH3)2OH);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 150.0, 136.2, 130.8, 130.3, 126 ,4, 125.6, '23.0, 120.7, 120.3, 114.4, 110.6, 94.4, 80.7, 77.2, 65.6, 49.3, 35, 4, 31.4;

mass/charge: 472 [M+H]+ (found value of [M+H]+, 472.1891, C ₂₇ H ₂₅ N ₃ O ₅ provides [M+H]+ 472.1867).

ίΓχ )-nh ⁿ ' ^nh o

(S)-5-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazol-3-carboxamide.

'H NMR (400 MHz, CDCl ₃ ) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine ), 7.14 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.03 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.93 ( 2Н, d, J 7.0 Hz, 2Н in Н-2, Н-4 oxetane), 4.80 (2Н, d, J 7.0 Hz, 2Н in Н-2, Н-4 oxetane), 4, 70 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.30 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.16 (2H, s, CH2C6H5), 3.41 (3H, s, NCH3), 2.98 (1H, br s, OH);

mass/charge: 474 [M+H]+ (the found value of [M+H] ⁺ , 474.1789, C ₂₅ H ₂₃ N ₅ O ₅ provides [M+H]+ 474.1772).

О 1 ii 2 ^{nh n} о

(S)-1-Benzyl-N-(7-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazol-3-carboxamide.

'H NMR (400 MHz, CDCI3) δ 8.03 (1H, d, J 7.0 Hz, NH), 8.01 (1H, s, H-5 triazole), 7.37 (3H, m, 3H C ₆ H ₅ ), 7.28-7.25 (4H, m, 2H C ₆ H ₅ , H-6, H-8 oxobenzoxazapine), 7.12 (1H, d, J 8.5 Hz, H- 9 oxobenzoxazapine), 5.35 (2H, s, NCH ₂ C ₆ H ₅ ), 5.04 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.89 (2H, dd, J 7.0, 1.0 Hz, 2H in H-2, H-4 oxetane), 4.78 (2H, ddd, J 6.5, 2.0, 1.0 Hz, 2H in H- 2, H-4 oxobenzoxazapine), 4.72 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.5, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.53 (1H, s, OH), 3.38 (3H, s, NCH3);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 158.4, 156.5, 150.4, 144.0, 136.1, 133.7, 130.9, 129.2, 129.0 , 128.2, 126.6, 123.4, 119.5, 88.9, 84.5, 77.1, 67.3, 54.4, 53.4, 49.1, 35.5;

mass/charge: 474 [M+N] ⁺ .

(S)-5 -Benzyl-N-(5 -methyl-7-(3 -methylbut-3 -en-1 - in-1 -yl)-4-oxo-2,3,4,5-tetrahydrobenzo [b ][1,4]oxazepin3 -yl)-1H-1,2,4-triazol-3-carboxamide.

'H NMR (400 MHz, CDCI3) δ 8.09 (1, d, J 7.5 Hz, NH), 7.27 (2H, t, J 7.0 Hz, 2H C6H5), 7.20-7 .15 (5H, m, 3H C ₆ H ₅ , H-6, H-8 oxobenzoxazapine), 7.09 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.41 (1H, q , J 1.0 Hz, Ш=СШ), 5.32 (1H, m, 1H=СН2), 5.01 (1H, dt, J 11.0, 7.5 Hz, Н-3 oxobenzoxazapine), 4 .63 (1H,

- 70 045207 dd, J 9.5, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 of oxobenzoxazapine), 4 .12 (2H, s, CH2C6H5), 3.38 (3H, s, NCH3), 1.98 (3H, t, J Hz, C(CH3)=CH2);

¹³ C NMR (100 MHz, CDCl3) δ 168.7, 158.7, 154.6, 149.8, 136.0, 135.9, 130.9, 128.8, 128.7, 127.0, 126.4 (2C), 123.1, 122.6, 121.0, 91.3, 86.7, 77.2, 49.2, 35.5, 33.0, 23.3;

mass/charge: 464 [M+Na] ⁺ , 442 [M+H] ⁺ (the found value of [M+H] ⁺ , 442.1869, C ₂₅ H ₂₃ N ₅ O ₃ provides [M+H] ⁺ 442, 1874).

(S)-5-Benzyl-N-(7-uzonentyl-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H1,2 ,4-triazole-3-carboxamide

1H NMR (400 MHz, CDCI3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.29-7.19 (5H, m, SbH ₅ ), 7.06 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 7.03 (1H, d, J 2.0 Hz, H-6 oxobenzoxazapine), 7.00 (1H, m, H-8 oxobenzoxazapine), 5.04 ( 1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.22 ( 1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.14 (2H, s, CH ₂ C ₆ H ₅ ), 3.39 (3H, s, NCH3), 2 .60 (2H, m, CH2CH2CH(CH3)2), 1.60 (1H, m, ODODSSCHSNzM 1.52-1.46 (2H, m, CH2CH2CH(CH3)2), 0.94 (6H, d, J 6.5 Hz, ODS^SSCHSN3M mass/charge: 448 [M+H]+ (found value [M+H] ⁺ , 448.2335, C ₂₅ H ₂₉ N ₅ O ₃ provides [M+H] ⁺ 448 ,2343).

(S)-5-Benzyl-N-(7-(3-methoxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzoI [1,4 ]oxazepin-3 -yl)- 1H-1,2,4-triazol-3-carboxamide

1H NMR (400 MHz, CDCl ₃ ) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.25 (2H, m, 2H C ₆ H ₅ ), 7.19 ( 5H, m, 3H C _{6 H5} , H-6, H-8 oxobenzoxazapine), 7.09 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.01 (1H, dt, J 11 ,0, 7.5 Hz, H-3 oxobenzoxazapine), 4.63 (1H, dd, J 9.0, 8.0 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 10 .5, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.12 (2H, s, CH ₂ C ₆ H ₅ ), 3.43 (3H, s, NCH ₃ or OCH ₃ ), 3.39 (3H, s, NCH3 or OCH3), 1.54 (6H, s, C(CH3)2OCH3);

mass/charge: 474 [M+H] ⁺ , 442 [M+H-CH3OH] ⁺ (the found value of [M+H] ⁺ , 474.2138, C26H ₂₇ N ₅ O ₄ provides [M+H] ⁺ 474, 2136).

(S)-1-Benzyl-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.01 (1H, d, J 7.5 Hz, NH), 8.00 (1H, s, triazole H-5), 7.39-7.34 (3H, m, 3H C ₆ H ₅ ), 7.27-7.23 (4H, m, 2H C ₆ H ₅ , H-8, H-9 oxobenzoxazapine), 7.12 (1H, d, J 8.0 Hz , H-6 oxobenzoxazapine), 5.36 (2H, s, NCH2C6H5), 5.05 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.23 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.39 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH);

mass/charge: 460 [M+H] ⁺ , 442 [M+H-H2O] ⁺ (found value of [M+H] ⁺ , 460.1968, C25H ₂₅ N ₅ O ₄ provides [M+H] ⁺ 460, 1979).

(S)-5-Benzyl-N-(8-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.18 (7H, m, C6H5, H-7, H-9 oxobenzoxazapine), 7.11 (1H, d, J 8.0 Hz, H-6 oxobenzoxazapine), 5.00 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.62 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.24 (1H, dd, J 11.5, 9.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.14, 4.10 (2H, 2d, J 16.0 Hz, CH2C6H5), 3.37 (3H, s, NCH3), 1.61 (6H, s, C(CH3)2OH);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 158.7, 149.5, 136.1, 135.9, 129.0, 128.8, 128.7, 127.0, 126.0 , 123.1,

- 71 045207

122.2, 95.1, 80.6, 76.9, 65.5, 49.2, 35.4, 33.0, 31.4 (2C);

mass/charge: 442 [M+HH ₂ O]+ (the found value of [M+H]+, 460.1972, C ₂₅ H ₂₅ N ₅ O ₄ provides [M+H]+ 460.1979).

(S)-N-(8-(3-Hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3yl)-4-phenoxypicolinamide.

1H NMR (400 MHz, CDCl3) δ 8.83 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5 Hz, H-3 pyridine), 7.60 ( 1H, d, J 2.5 Hz, H-6 pyridine), 7.42-7.38 (2H, m, 2H from C ₆ H ₅ ), 7.28-7.22 (3H, m, 1H C ₆ H ₅ , H-7, H-9 oxobenzoxazapine), 7.13 (1H, d, J 8.0 Hz, H-6 oxobenzoxazapine), 7.07-7.04 (2H, m, 2H C ₆ H ₅ ), 6.93 (1H, dd, J 5.5, 2.5 Hz, H-4 pyridine), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine) , 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.40 (3H, s, NCH ₃ ), 1.61 (6H, s, C(CH3)2OH);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 169.0, 166.1, 163.6, 153.7, 151.3, 150.1, 149.6, 136.4, 130.3, 128.9 , 126.0, 125.7, 123.0, 122.0, 120.7, 114.4, 110.6, 94.9, 80.6, 77.2, 65.6, 49.4, 35 ,3, 31.4;

mass/charge: 472 [M+H]+ (found value of [M+H] ⁺ , 472.1873, C ₂₇ H ₂₅ N ₃ O ₅ provides [M+H]+ 472.1867).

C.I.

(S)-5-(2,6-Dichlorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide.

Ή NMR (400 MHz, CDCl ₃ ) δ 8.05 (1H, d, J 7.5 Hz, NH), 7.33-7.29 (3H, m, 3H C ₆ H ₃ Cl ₂ , H-6 oxobenzoxazapine), 7.226-7.24 (1H, m, 1H C6H3Cl2, H-6 oxobenzoxazapine), 7.18-7.15 (1H, m, H-8 oxobenzoxazapine)), 7.10 (1H, d, J 8.5 Hz, H-9 oxobenzoxazapine), 5.00 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.67 (1H, dd, J 10.0, 7, 5 Hz, 1H in H-2 oxobenzoxazapine), 4.48 (2H, s, CH ₂ C ₆ H ₃ Cl ₂ ), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H in H -2 oxobenzoxazapine), 3.39 (3H, s, NCH3), 1.61 (6H, s, QCH3M mass/charge: 532, 530, 528 [M+H]+ 514, 512, 510 [M+HH ₂ O]+ (the found value of [M+H] ⁺ , 528.1201, C ₂₅ H ₂₃ Cl ₂ N ₅ O ₄ provides [M+H]+ 528.1200).

(S)-5-Benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a] pyrazin7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

Ή NMR (400 MHz, CDCl ₃ ) δ 8.04 (1H, d, J 7.5 Hz, NH), 7.30-7.17 (8H, m, C ₆ H ₅ , H-6, H- 7, H-9 oxobenzoxazapine), 5.08 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.30-4.25 (3H, m, 1H in H-2 of oxobenzoxazapine, NCH2CH2N), 4.14 (2H, s, CH ₂ C ₆ H ₅ ), 3.88, 3.83 (2H, 2d AB systems, J 16.0 Hz, 2H ArCHNCH), 3.76 (2H, s, ArCHNCH), 3.40 (3H, s, NCH3), 3.09-3.02 (2H, m, NCH2CH2N);

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -65.3;

mass/charge: 604 [M+Na]+ 582 [M+H] ⁺ .

(S)-1-Benzyl-N-(5-methyl-4-oxo-8-((2-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[1,5-a] pyrazin7(8H)-yl)methyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

Ή NMR (400 MHz, CDCl3) δ 8.05 (1H, d, J 7.0 Hz, NH), 8.00 (1H, s, H-5 triazole), 7.39-7.35 (3H, m, 3H C6H5, H-6, H-7, H-9 oxobenzoxazapine), 7.28-7.25 (2H, m, 2H C6H5, H-6, H-7, H-9 oxobenzoxazapine), 7, 23-7.17 (3H, m, 3H С6Н5, Н-6, Н-7, Н-9 oxobenzoxazapine), 5.37 (2Н, s, NCH2C6H5), 5.11 (1H, dt, J 11.0 , 7.5 Hz, H-3 oxobenzoxazapine), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28-4.23 (3H, m, 1H in H-2 oxobenzoxazapine, 2H NCH2CH2N), 3.90, 3.86 (2H, 2d AB systems, J 16.0 Hz, 2H ArCH2NCH2), 3.79, 3.75 (2H, 2d AB systems , J 13.5 Hz, 2H ArCHNCH), 3.42 (3H, s, NCH3), 3.10-3.02 (2H, m, 2H NCH2CH2N);

- 72 045207 ¹⁹ F NMR (380 MHz, CDCI3) δ -65.4; mass/charge: 604 [M+Na]+, 582 [M+H] ⁺ .

(S)-N-(7-(3-Hydroxy-3-(methyl-d3)but-1-in-1-yl-4,4,4-d3)-5-methyl-4-oxo-2, 3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide

1H NMR (400 MHz, CDCI3) δ 8.85 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, H-3 pyridine), 7.60 ( 1H, d, J 2.5 Hz, H-4 pyridine), 7.42-7.38 (2H, m, 2H C6H5), 7.27-7.22 (3H, m, 3H C6H5, H-6 , H-8 oxobenzoxazapine), 7.11 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 7.10-7.05 (2H, m, 2H C ₆ H ₅ , H-6, H -8 oxobenzoxazapine), 6.93 (1H, dd, J 5.5, 2.5 Hz, H-6 pyridine), 5.01 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.70 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 (1H, dd, J 11.5, 10.0 Hz, 1H in H -2 oxobenzoxazapine), 3.41 (3H, s, NCH3);

mass/charge: 478 [M+H] ⁺ , 460 [M+H-H2O]+ (found value of [M+H] ⁺ , 478.2255, C27H ₁₉ D ₆ N ₃ O ₄ provides [M+H]+ 478.2244).

o _h nuVY\ ^nh n' ^nh

D3C CD3 (S)-5-Benzyl-N-(7-(3-hydroxy-3-(methyl-d3)but-1-in-1-yl-4,4,4-d3)-5-methyl- 4-oxo-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1 H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCI3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.28-7.21 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine), 7.10 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.14 ( 2H, s, CH2C6H5), 3.39 (3H, s, NCH3);

¹³ C NMR (100 MHz, CDCI3) δ 168.6, 158.5, 149.9, 136.0, 135.8, 131.0, 128.8 (2C), 127.1 (2C), 126, 5, 123.1, 120.5, 94.6, 80.6, 77.2, 65.3, 49.1, 35.5, 33.2, 30.5 (m);

mass/charge: 466 [M+H] ⁺ , 448 [M+H-H2O]+ (found value of [M+H] ⁺ , 466.2356, C25H ₁₉ D ₆ N ₅ O ₄ provides [M+H]+ 466.2356).

(R)-5-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-robenzo tetrahydride [ b][1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide.

[α]589 ^20.2 +135.9 (СНС1з, с 0.54);

1H NMR (400 MHz, CDCI3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.30-7.23 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine), 7.11 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.02 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.68 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H oxobenzoxazapineH-2), 4.15 (2H, s, CH2C6H5), 3.40 (3H, s, NCH3), 1.63 (6H, s, C(CH3OH);

mass/charge: 460 [M+H] ⁺ , 442 [M+H-H2O]+ (found value of [M+H] ⁺ , 460.1985, C25H ₂₅ N ₅ O ₄ provides [M+H]+ 460, 1979).

(S)-5-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1,3,4-oxadiazol-2-carboxamide.

1H NMR (400 MHz, CDCI3) δ 7.99 (1H, d, J 6.5 Hz, NH), 7.36-7.29 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine), 7.13 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 4.97 (1H, ddd, J 11.0, 7.5, 7.0 Hz, H-3 oxobenzoxazapine), 4. 72 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, m, 1H in H-2 oxobenzoxazapine), 4.26 (2H, s, CH2C6H5) , 3.43 (3H, s, NCH3), 1.63 (6H, s, C(CH3M mass/charge: 484 [M+Na]+, 443 [M+HH ₂ O]+ (found value [M+ H] ⁺ , 443.1727, C ₂₅ H ₂₄ N ₄ O ₅ provides [M+HH ₂ O]+ 443.1714).

- 73 045207

(S)-N-(8-((3-Hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl )-4-phenoxypicolinamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.43 (1H, d, J 5.5 Hz, ruH-6), 7.60 ( 1H, d, J 2.5 Hz, H-3 pyridine), 7.42-7.39 (2H, m, 2H C ₆ H ₅ ), 7.31 (1H, dd, J 8.0, 2, 0 Hz, H-7 oxobenzoxazapine),

7.27-7.22 (2H, m, 1H C ₆ H ₅ , H-9 oxobenzoxazapine), 7.17 (1H, d, J 8.0 Hz, H-6 oxobenzoxazapine), 7.07-7, 05 (2H, m, 2H C6H5), 6.93 (1H, dd, J 5.5, 2.5 Hz, H-5 pyridine), 5.02 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.93 (2H, d, J 7.0 Hz, 2H in H-2, H-4 oxetane), 4.79 (2H, d, J 7.0 Hz, 2H in H-2, H-4 oxetane), 4.69 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.29 (1H, dd, J 11.0, 9 .5 Hz, 1H in H-2 oxo benzoxazapine), 3.42 (3H, s, NCH3);

mass/charge: 486 [M+H]+, (the found value of [M+H] ⁺ , 486.1674, C ₂₃ H ₂₃ N ₃ O ₆ provides [M+H] ⁺ 486.1660).

(S)-5-Benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepine -3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.97 (1H, s, OH), 7.32-7.22 (6H, m, C ₆ H ₅ , H-7 oxobenzoxazapine), 7.20 (1H, d, J 2.0 Hz, H-9 oxobenzoxazapine), 7.14 (1H, d, J 8.5 Hz, 1H in H-6 oxobenzoxazapine), 4.99 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.92 (2H, d, J 7.0 Hz, 2H in H-2, H-4 oxetane), 4.79 (2H, d, J 6.5 Hz, 2H in H-2, H-4 oxetane), 4.64 (1H, dd, J 9.5, 7.5 Hz, 1H in H -2 oxobenzoxazapine), 4.25 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.14 (2H, s, CH2C6H5), 3.40 (3H, s, NCH3);

mass/charge: 474 [M+H] ⁺ , 456 [M+H-H2O] ⁺ (found value of [M+H] ⁺ , 474.1784, C25H ₂₃ N ₅ O ₅ provides [M+H] ⁺ 474, 1772).

(3S,3aR,6R,6aS)-6-(((S)-3-(5-Benzyl-1H-1,2,4-triazol-3-carboxamido)-5-methyl-4-oxo-2, 3,4,5tetrahydrobenzo[b][1,4]oxazepin-7-yl)ethynyl)-6-hydroxyhexahydrofuro[3,2-b]furan-3-ylbenzoate.

1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (1H, d, J 7.5 Hz, NH), 8.03 (2H, m, 2H COC6H5), 7.59 (1H, tt, J 7, 5, 1.0 Hz, 1H COC6H5), 7.45 (2H, t, J 7.5 Hz, 2H COC6H5), 7.32-7.23 (7H, m, CH2C6H5, H-6, H-8 oxobenzoxazapine), 7.12 (1H, d, J 8.5 Hz, H-9 oxobenzoxazapine), 5.23 (1H, d, J 3.0 Hz, H-6 isosorbate), 5.02 (1H, dt , J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.87, 4.83 (2H, 2d AB systems, J 4.5 Hz, H-3a, H-6l isosorbate), 4, 69 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.28 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 of oxobenzoxazapine), 4.25-4.20 (2H, m, H-5 isosorbate), 4.15 (2H, s, CH2C6H5), 4.04, 3.95 (2H, 2d AB systems, J 9.5 Hz, H-2 isosorbate), 3.40 (3H, s, NCH3);

mass/charge: 650 [M+H] ⁺ (found value of [M+H] ⁺ , 650.2283, C ₃₅ H ₃₁ N ₅ O ₈ provides [M+H] ⁺ 650.2245).

5-Benzyl-N-((S)-7-(((3R,3aS,6S,6aR)-3,6-dihydroxyhexahydrofuro[3,2-6]furan-3-yl)ethynyl)-5methyl-4- oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CD3OD) δ 7.51 (1H, d, J 2.0 Hz, H-6 oxobenzoxazapine), 7.36 (1H, dd, J 8.0, 2.0 Hz, H-8 oxobenzoxazapine), 7.33-7.23 (5H, m, C ₆ H ₅ ), 7.19 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.01 (1H, dd, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.65, 4.54 (2H, 2d AB systems, J 4.5 Hz, H-3a, H-6a isosorbate), 4.60 ( 1H, dd, J 10.0, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.41 (1H, dd, J 11.5, 10.0 Hz, 1H in H-2 of oxobenzoxazapine), 4, 24 (1H, d, J 2.5 Hz, H-6 isosorbate), 4.15 (2H, s, CH2C6H5), 3.99-3.91 (2H, m, 2H in H-5 isosorbate), 3 .93, 3.71 (2H, 2d AB systems, J 8.5 Hz, H-2 isosorbate), 3.40 (3H, s, NCH3);

- 74 045207 ¹³ C NMR (100 MHz, CD3OD) δ 169.1, 150.3, 136.5, 130.7, 128.4, 128.3, 126.8, 126.6, 122.7, 119 ,9, 110.0, 89.5, 88.6, 87.1, 83.7, 78.1, 77.8, 77.5, 74.4, 49.1, 34.4, 33.2 ;

mass/charge: 546 [M+H]+ (the found value of [M+H] ⁺ , 546.2007, C ₂₈ H ₂₇ N ₅ O ₇ provides [M+H]+ 546.1983).

Methyl-(S)-4-(3-(5-benzyl-1H-1,2,4-triazole-3-carboxamido)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-7-yl)-2,2-dimethylbut-3-inoate.

1H NMR (400 MHz, CDCl3) δ 8.06 (1H, d, J 7.5 Hz, NH), 7.31-7.23 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine), 7.10 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.02 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.68 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.16 ( 2H, s, CH ₂ C ₆ H ₅ ), 3.78 (3H, s, OCH ₃ ), 3.41 (3H, s, NCH ₃ ), 1.58 (6H, s, C(CH ₃ ) ₂ );

mass/charge: 502 [M+H]+ (the found value of [M+H] ⁺ is 502.2107, C ₂₇ H ₂₇ N ₅ O ₄ provides [M+H]+ 502.2085).

(S)-1-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 7.79 (1H, d, J 7.0 Hz, NH), 7.38-7.32 (4H, m, 4H or C6H5, H-4 or H-5 pyrazole , H-6, H-8 oxobenzoxazapine), 7.28-7.21 (4H, m, 4H from C _{6 H5} , H-4 or H-5 pyrazole, H-6 or H-8 oxobenzoxazapine), 7 .12 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 6.74 (1H, d, J 2.5 Hz, H-4 or H-5 pyrazole), 5.31 (2H, s , NCH2C6H5), 5.05 (1H, dt, J 11.0, 7.0 Hz, H-3 oxobenzoxazapine), 4.73 (1H, dd, J 9.5, 7.5 Hz, 1H in H- 2 oxobenzoxazapine), 4.28 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.42 (3H, s, NCH3), 1.62 (6H, s, C (CH3)2OH);

mass/charge: 459 [M+H] ⁺ , 441 [M+H-H2O]+ (found value of [M+H] ⁺ , 459.2040, C26H ₂₆ N ₄ O ₄ provides [M+H]+ 459, 2027).

ΛΝΗ N' ^NH (S)-5-(3-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.10 (1H, d, J 7.0 Hz, NH), 7.28 (2H, m, H-6, H-8 oxobenzoxazapine), 7.21 (1H, m, 1H C6H ₄ F), 7.10 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 7.01 (1H, br d, J 8.0 Hz, 1H C6H ₄ F), 6 .96 (1H, br d, J 9.5 Hz, 1H C6H4F), 6.90 (1H, td, J 8.5, 2.5 Hz, 1H C6H4F), 5.00 (1H, dt, J 11 ,0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.29 (1H, dd, J 11 ,0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.15 (2H, s, CH2C6H4F), 3.40 (3H, s, NCH3), 1.62 (6H, s, C(CH3OH) ;

¹³ C NMR (100 MHz, CD3OD) δ 168.5, 164.0, 161.6, 149.9, 138.5, 135.9, 131.0, 130.2 (d, J 8.5 Hz) , 128.8, 126.5, 124.5 (d, J 2.5 Hz), 123.0, 120.5, 115.8 (d, J 22.0 Hz), 113.9 (d, J 21.5 Hz), 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 32.9, 31.4;

¹⁹ F NMR (380 MHz, CDCl3) δ -112.6;

mass/charge: 460 [M+HH ₂ O]+ (found value of [M+H]+, 478.1901, C ₂₅ H ₂₄ FN ₅ O ₄ provides [M+H]+478.1885).

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

1H NMR (400 MHz, CDCl3) δ 8.11 (1H, d, J 7.5 Hz, NH), 7.27-7.25 (2H, m, H-6, H-8 oxobenzoxazapine), 7, 17 (2H, dd, J 8.5, 5.5 Hz, 2H C6H4F), 7.09 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 6.90 (2H, t, J 8 .5 Hz, 2H from C6H4F), 4.99 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.64 (1H, dd, J 10.0, 7.5 Hz , 1H in H-2 oxobenzoxazapine), 4.29 (1H, dd, J 11.5, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.09 (2H, s,

- 75 045207

CH2C6H4F), 3.39 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH);

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -115.6;

mass/charge: 478 [M+H]+ 460 [M+HH ₂ O] ⁺ (found value of [M+H] ⁺ , 478.1902, C ₂₅ H ₂₄ FN ₅ O ₄ provides [M+H] ⁺ 478 ,1885).

(S)-5-(2-Fluorobenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b] [1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDQ3) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.26-7.16 (3H, m, H-6, H-8 oxobenzoxazapine, 1H C ₆ H ₄ F), 7.09 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 7.01 (1H, td, J 7.5, 1.0 Hz, 1H C ₆ H ₄ F) , 7.00-6.96 (1H, m, 1H C ₆ H ₄ F), 5.00 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.65 (1H , dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.17 (2H, s, CH ₂ C ₆ H ₄ F), 3.38 (3H, s, NCH3), 1.62 (6H, s, C(CH3)2OH);

¹³ C NMR (100 MHz, CDCl3) δ 168.7, 160.7 (d, J 246.3 Hz), 158.5, 149.9, 136.0, 131.0 (d, J 4.0 Hz ), 131.0, 129.1, 129.0 (d, J 8.5 Hz), 126.5, 126.3, 124.4 (d, J 4.0 Hz), 123.1, 120, 4, 115.4 (d, J 12.0 Hz), 94.6, 80.6, 76.9, 65.6, 49.1, 35.5, 31.4, 26.3;

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -117.5;

mass/charge: 460 [M+HH ₂ O] ⁺ (found value of [M+H] ⁺ , 478.1895, C ₂₅ H ₂₄ FN ₅ O ₄ provides [M+H] ⁺ 478.1885).

OS) (S)-7-(3-G hydroxy-3-methylbut-1-in-1-yl)-5-methyl-3-(tritylamino)-2,3-dihydrobenzo[b] [1,4] Oxazepine4(5H)-one.

1H NMR (400 MHz, CDCl3) δ 7.40-7.38 (6H, m, 3 x 2H C5H5), 7.24-7.20 (6H, m, 3 x 2H C6H5), 7.18-7 .12 (4H, m, 3 x 1H C6H5, 1H in H-6, H-8, H-9 oxobenzoxazapine), 6.97-6.95 (2H, m, 2H in H-6, H-8, H-9 oxobenzoxazapine), 4.48 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.37 (1H, dd, J 11.5, 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.55 (1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 3.28 (1H, d, J 8.5 Hz, NH), 2 .88 (3H, s, NCH3), 1.63 (6H, s, C(CH3)2OH);

mass/charge: 561 [M-H+HCO2H] ^- .

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-((Ίrimethylsilyl)ethynyl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3 yl) -1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.33-7.31 (2H, m, H-8, H-9 oxobenzoxazapine), 7, 25-7.20 (5H, m, C6H5), 7.09 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.01 (1H, dt, J 11.0, 7.5 Hz , H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, dd, J 11.0, 10.0 Hz , 1H in H-2 of oxobenzoxazapine), 4.15 (2H, s, CH2C6H5), 3.40 (3H, s, NCH3), 0.26 (9H, s, Si(CH3^);

mass/charge: 474 [M+H] ⁺ (found value of [M+H] ⁺ , 474.1981, C ₂₅ H ₂₇ N ₅ O ₃ Si provides [M+H] ⁺ 474.1956).

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

1H NMR (400 MHz, CDQ3) δ 8.06 (1H, d, J Hz, NH), 7.36 (1H, dd, J Hz, H-8 oxobenzoxazapine), 7.35-7.26 (6H, m, C ₆ H ₅ , H-6 oxobenzoxazapine), 7.14 (1H, d, J 8.5 Hz, H-9 oxobenzoxazapine), 5.04 (1H, dt, J 11.0, 7.5 Hz , H-3 oxobenzoxazapine), 4.71 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.29 (1H, dd, J 11.0, 9.5 Hz , 1H in H-2 oxobenzoxazapine), 4.17 (2H, s, CH2C6H5), 3.42 (3H, s, NCH3), 3.12 (1H,

- 76 045207 s, HCC);

¹³ C NMR (100 MHz, CDCI3) δ 168.6, 150.4, 136.1, 131.5, 128.9 (2C), 127.3, 127.0, 123.3, 119.8, 82 ,0,

78.1, 77.2, 49.1, 35.5, 33.5;

mass/charge: 402 [M+H]+ (the found value of [M+H] ⁺ , 402.1561, C ₂₂ H ₁₉ N ₅ O ₃ provides [M+H]+ 402.1576).

(S)-3-Amino-7-(3-hydroxy-3-me'Iulbut-1-in-1-yl)-5-methyl-2,3-dihydrobenzo[b][1,4]oxαzepine4(5H )-He.

1H NMR (400 MHz, CDCl ₃ ) δ 7.24 (1H, d, J 2.0 Hz, H-6 oxobenzoxazapine), 7.22 (1H, dd, J 8.0, 2.0 Hz, H- 8 oxobenzoxazapine), 7.06 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 4.41 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.12 (1H, dd, J 11.5, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.72 (1H, dd, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine);

mass/charge: 275 [M+H]+ (the found value of [M+H]+ is 275.1390, C ₁₅ H ₁₈ N ₂ O ₃ provides [M+H]+ 275.1404).

(S)-N-(7-(3-Hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4] Oxazepin-3-yl)-1-(2-methylbenzyl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.03 (1H, d, J 7.0 Hz, NH), 7.83 (1H, s, H-5 triazole), 7.32-7.21 (5H, m, 5H C ₆ H ₄ , H-6 oxobenzoxazapine), 7.16 (1H, dd, J 9.0, 2.0 Hz, H-8 oxobenzoxazapine), 7.12 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.37 (2H, s, NCH ₂ C ₆ H ₄ CH ₃ ), 5.07 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 9.5 Hz, 1H in H-2 of oxobenzoxazapine ), 3.41 (3H, s, NCH3), 2.27 (3H, s, C6H4CH3), 1.62 (6H, s, SCHH3CH3);

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.8, 158.4, 156.5, 149.9, 143.8, 136.8, 136.0, 131.4, 131.1, 130.9 , 129.7, 129.4, 126.8, 126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 52.6, 49.1, 35 .5, 31.4, 19.0;

mass/charge: 474 [M+H] ⁺ , 456 [M+HH ₂ O]+.

(S)-1-([1,1'-Biphenyl]-4-ylmethyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4- oxo-2,3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.07 (1H, s, H-5 triazole), 8.06 (1H, d, J 7.0 Hz, NH), 7.60-7.55 (4H , m, 4H CeHAHs), 7.45-7.42 (2H, m, 2H QH4C6H5), 7.38-7.34 (3H, m, 3H C ₆ H4C6H5), 7.28-7.26 (2H , m, H-6, H-8 oxobenzoxazapine), 7.11 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.41 (2H, s, NCH ₂ C ₆ H ₄ Ph), 5.07 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 of oxobenzoxazapine), 3.41 (3H, s, NCH ₃ ), 1.62 (6H, s, C(CH ₃ ) _2OH );

¹³ C NMR (100 MHz, CDCl3) δ 169.1, 158.7, 157.0, 150.3, 144.3, 142.3, 140.4, 136.3, 132.9, 131.2, 129.2, 129.0, 128.2, 128.0, 127.4, 126.8, 123.5, 120.7, 94.9, 80.9, 77.5, 65.9, 54, 4, 49.4, 35.8, 31.7;

mass/charge: 536 [M+H] ⁺ , 518 [M+HH ₂ O]+.

(S)-1-(2,6-Dimethylbenzyl)-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.02 (1H, d, J 7.0 Hz, NH), 7.59 (1H, s, H-5 triazole), 7.28-7.21 (3H , m, 3H in H-6, H-8, H-9 oxobenzoxazapine, C ₆ H ₃ (CH ₃ ) ₂ ), 7.13-7.10 (3H, m, 3H in H-6, H-8 , H-9 oxobenzoxazapine, C ₆ H ₃ (CH ₃ ) ₂ ), 5.41 (2H, s, NCH ₂ C ₆ H ₃ (CH ₃ ) ₂ ), 5.06 (1H, dt, J 11.0 , 7.5 Hz, H-3 oxobenzoxazapine), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.0 , 9.5 Hz, 1H in H-2 oxobenzoxazapine), 3.41 (3H, s, NCH ₃ ), 2.30 (6H, s, C ₆ H ₃ (CH ₃ ) ₂ ), 1.62 (6H , s, C(CH ₃ ) ₂ OH);

¹³ C NMR (100 MHz, CDCl3) δ 168.8, 158.5, 156.5, 149.9, 143.1, 138.1, 136.0, 130.9, 129.6, 129.0 ( 2C),

- 77 045207

126.5, 123.2, 120.4, 94.5, 80.6, 77.1, 65.5, 49.1, 49.0, 35.5, 31.4, 19.6;

mass/charge: 488 [M+H]+, 470 [M+HH ₂ O]+ (found value of [M+H]+, 488.2292, C ₂₇ H ₂₉ N ₅ O ₄ provides [M+H]+ 488.2292).

(S)-N-(7-(3-Hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin3 -yl)-1-isobutyl-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDC|) δ 8.04 (1H, s, H-5 triazole), 8.03 (1H, d, J 7.0 Hz, NH), 7.29-7.26 (2H , m, H-6, H-8 oxobenzoxazapine), 7.12 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.06 (1H, ddd, J 11.0, 7.5, 7.0 Hz, H-3 oxobenzoxazapine), 4.75 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.98 (2H, d, J 7.0 Hz, JH ₂ CH(CH3) ₂ ), 3.41 (3H, s, NCH3), 2.30 -2.23 (1H, m, CH(CH ₃ ) ₂ ), 1.62 (6H, s, C(CH ₃ ) ₂ OH), 0.91 (6H, dd, J 6.5, 1.0 Hz, CH(CH ₃ ) ₂ );

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.9, 158.5, 156.5, 149.9, 144.3, 136.0, 130.9, 126.5, 123.2, 120.4 , 94.5, 80.6, 77.1, 65.5, 57.6, 49.1, 35.5, 31.4, 29.0, 19.7;

mass/charge: 426 [M+H]+, 408 [M+HH ₂ O]+ (found value of [M+H]+, 426.2126, C ₂₂ H ₂₇ N ₅ O ₄ provides [M+H]+ 426.2136).

(S)-5-Benzyl-N-ethyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b] [1,4]oxazepin-3-yl)-1 H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 7.30-7.18 (5H, m, 5H C6H5, H-6, H-8, H-9 oxobenzoxazapine), 7.13-7.06 (3H, m , 3H C ₆ H ₅ , H-6, H-8, H-9 oxobenzoxazapine), 6.85-6.77 (0.66H, m, main, H-3 oxobenzoxazapine), 5.34-5.27 (0.33H, m, side, H-3 oxobenzoxazapine), 4.94 (0.33H, dd, J 12.0, 10.5 Hz, side, H-3 oxobenzoxazapine), 4.84 (0.66H , dd, J 12.0, 9.5 Hz, main, H-3 oxobenzoxazapine), 4.55 (0.66H, dd, J 9.5, 7.5 Hz, 1H, main, H-2 oxobenzoxazapine) , 4.50 (0.33H, m, 1H, side, H-2 oxobenzoxazapine), 4.11 (0.66H, s, side, CH2C6H5), 4.05 (1.32H, q, J 7.0 Hz, basic, NCH2CH3), 3.91, 3.84 (1.32H, 2d AB systems, J 15.5 Hz, basic, CH^^), 3.50 (0.66H, q, J 7, 0 Hz, side, NCH2CH3), 3.28 (1H, s, side, NCH3), 3.25 (2H, s, main, NCH3), 1.61 (2H, s, side, C(CH3) ₂ OH ), 1.57 (4H, s, basic, C(CH ₃ ) ₂ OH), 1.20 (3H, t, J 7.0 Hz, NCH2CH3);

mass/charge: 488 [M+H]+, 470 [M+H-H ₂ O]+ (found value of [M+H]+, 488.2291, C ₂₇ H ₂₉ N ₅ O ₄ provides [M+H ]+ 488.2292).

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

^1H NMR (400 MHz, CDCl3) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m, H-6 oxobenzoxazapine), 7.31 (1H, dd, J 8.0 , 2.5 Hz, H-8 oxobenzoxazapine), 7.15 (5H, br s, C ₆ H ₅ ), 7.02 (1H, dd, J 8.0, 1.0 Hz, H-9 oxobenzoxazapine) , 4.10 (2H, s, CH ₂ C6H5), 3.36 (3H, s, NCH3);

¹³ C (100 MHz, 100 MHz) δ 168.7, 158.9, 149.1, 137.4, 135.8, 130.6, 128.8, 128.7, 127.1, 126.4, 118.1, 77.2, 49.2, 35.5, 32.9;

mass/charge: 458.456 [M+H]+ (the found value of [M+H]+, 458.0651, C ₁₀ H ₁₈ BrN ₅ O ₃ provides [M+H]+ 458.0645).

(S)-5-Benzyl-N-(7-(3-hydroxy-3-methylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)isoxαzol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 7.72 (1H, d, J 7.0 Hz, NH), 7.36-7.21 (7H, m, C6H5, H-6, H-8 oxobenzoxazapine), 7.11 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 6.30 (1H, br s, H-5 isoxazole), 4.99 (1H, dt, J 11.0, 7, 0 Hz, H-3 oxobenzoxazapine), 4.70 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 10, 0 Hz, 1H in H-2 oxobenzoxazapine), 4.10 (2H, s, CH^^), 3.41 (3H, s, NCH3), 1.62 (6H, s,

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C(CH3)2OH);

¹³ C NMR (100 MHz, CDCI3) δ 174.1, 168.4, 158.5, 157.9, 149.9, 136.0, 135.2, 130.9, 128.9, 128.7, 127.4, 126.5, 123.1, 120.4, 101.6, 94.6, 80.6, 76.9, 65.6, 49.2, 35.5, 33.2, 31, 4;

mass/charge: 460 [M+H]+, 442 [M+H-H ₂ 0] ⁺ (the found value of [M+H] ⁺ , 460.1884, C ₂₆ H ₂₅ N ₃ O ₅ provides [M+H ] ⁺ 460.1867).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-((1,2,3,4-tetrahydroisoquinolin-7-yl)ethynyl)-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CD3OD) δ 7.71 (1H, dd, J 5.5, 3.0 Hz, 1 x ArH), 7.20 (1H, dd, J 5.5, 3.0 Hz, 1 x ArH), 7.59 (1H, d, J 2.0 Hz, 1 x ArH), 7.44 (1H, td, J 8.5, 2.0 Hz, 1 x ArH), 7.41 (1H, br s, 1 x ArH), 7.33-7.23 (6H, m, 6 x ArH), 5.03 (1H, dd, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine ), 4.60 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.45 (1H, dd, J 11.5, 9.5 Hz, 1H in H- 2 oxobenzoxazapine), 4.35 (2H, s, H-1 isoquinoline), 4.16 (2H, s CH2C6H5), 3.50 (2H, t, J 6.5 Hz, H-3 or H-4 isoquinoline ), 3.42 (3H, s, NCH3), 3.13 (2H, dd, J 7.0, 6.0 Hz, H-3 or H-4 isoquinoline);

mass/charge: 533 [M+H] ⁺ (found value of [M+H] ⁺ , 533.2296, C ₃₁ H ₂₈ N ₆ O ₃ provides [M+H] ⁺ 533.2296).

F

(S)-N-(7-(3,3-Dimethylbut-1-yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo [b] [1,4] Oxazepin-3 yl)-5-(2-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.0 Hz, NH), 7.26-7.19 (4H, m, H-6, H-7 oxobenzoxazapine, 2H C6H4F) , 7.08 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 7.06-7.02 (1H, m, 1H C6H4F), 7.03-6.99 (1H, m, 1H C ₆ H ₄ F), 5.01 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 10.0, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.25 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.19 (2H, s, CH ₂ C ₆ H ₄ F), 3.40 (3H, s, NCH3), 1.32 (9H, s, C(CH3)3);

¹³ C NMR (100 MHz, CDCl3) δ 168.8, 160.7 (d, J 245.5 Hz), 158.5, 149.2, 135.8, 131.0 (d, J 4.0 Hz ), 130.9, 128.9 (d, J 8.5 Hz), 126.4, 124.3 (d, J 4.0 Hz), 123.1 (d, J 15.0 Hz), 122 ,8, 121.8, 115.3 (d, J 21.5 Hz), 99.4, 77.6, 77.0, 49.2, 35.5, 30.9, 27.9, 26, 3;

mass/charge: 476 [M+H] ⁺ (found value of [M+H] ⁺ , 476.2100, C ₂₅ H ₂₆ FN ₅ O ₃ provides [M+H] ⁺ 476.2092).

(S)-1-(2,6-Dimethylbenzyl)-N-(7-(3,3-dimethylbut-1-in-1-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J 7.5 Hz, NH), 7.59 (1H, s, H-5 triazole), 7.26-7.22 (3H, m, H-6, H-8 oxobenzoxazapine, H-4 C ₆ H ₃ (CH ₃ ) ₂ ), 7.12 (2H, d, J 7.5 Hz, H-3, H-5 C ₆ H ₃ (CH ₃ ) ₂ ), 7.09 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.42 (2H, s, N^CeftCC^h), 5.06 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.76 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.24 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 3.42 (3H, s, NCH3), 2.31 (6H, s, C6H3(CH3)2, 1.32 (9H, s , С(СНз)з);

mass/charge: 486 [M+H] ⁺ (found value of [M+H] ⁺ , 486.2506, C ₂₈ H ₃₁ N ₅ O ₃ provides [M+H] ⁺ 486.2500).

(S)-5-Benzyl-N-(5-ethyl-7-(3-hydroxy-3-methylbut-1-in-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

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1H NMR (400 MHz, CDCl ₃ ) δ 8.08 (1H, d, J 7.5 Hz, NH), 7.33-7.26 (7H, m, C ₆ H ₅ , H-6, H- 8 oxobenzoxazapine), 7.12 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 4.99 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4. 66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 of oxobenzoxazapine), 4.21-4.11 (1H, m, 1H in NCH2CH3), 4.16 (2H, s, NCH2C6H5), 3.66 (1H, heptet, J 7.0 Hz, 1H NCH2CH3), 1.63 ( 6H, s, C(CH3)2OH), 1.19 (3H, t, J 7.0 Hz, NCH2CH3);

mass/charge: 456 [M+HH ₂ O]+ (found value of [M+H] ⁺ , 474.2143, C ₂₆ H ₂₇ N5O ₄ provides [M+H] ⁺ 474.2136).

(S)-N-(5-Ethyl-7-(3 -hydroxy-3-methylbut-1 -in-1 -yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4] Oxazepin-3-yl)-5-(3-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.30-7.28 (2H, m, H-6, H-8 oxobenzoxazapine), 7 ,26-7.21 (1H, m, 1H C6H4F), 7.12 (1H, d, J 8.5 Hz, H-9 oxobenzoxazapine), 7.03 (1H, br d, J 7.5 Hz, 1H C6H4F), 6.98 (1H, br d, J 9.5 Hz, 1H C6H4F), 6.92 (1H, td, J 8.5, 2.5 Hz, 1H C6H4F), 4.97 (1H , dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H , dd, J 11.0, 10.5 Hz, 1H in H-2 oxobenzoxazapine), 4.22-4.10 (1H, m, 1H NCH2CH3), 4.14 (2H, s, CH2C6H4F), 3, 66 (1H, heptet, J 7.0 Hz, 1H NCH2CH3), 1.63 (6H, s, C(CH3) ₂ OH), 1.19 (3H, t, J 7.0 Hz, NCH2CH3);

¹⁹ F NMR (380 MHz, CDCl ₃ ) δ -112.6;

mass/charge: 474 [M+HH ₂ O] ⁺ (found value of [M+H] ⁺ , 492.2047, C ₂₆ H ₂₆ FN ₅ O ₄ provides [M+H] ⁺ 492.2042).

(S)-5-Benzyl-N-(7-(3-methylbut-3-en-1-in-1-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1, 4]oxazepin-3yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.01 (1H, d, J 7.0 Hz, 1 x NH), 7.54 (1H, s, 1 x NH), 7.35-7.24 ( 6H, m, C ₅ H ₅ , H-8 oxobenzoxazapine), 7.10 (1H, d, J 8.5 Hz, H-9 oxobenzoxazapine), 7.09 (1H, m, H-6 oxobenzoxazapine), 5 .40 (1H, br s, 1H C=CH ₂ ), 5.32 (1H, br s, 1H C=CH ₂ ), 5.08 (1H, m, H-3 oxobenzoxazapine), 4.76 (1H , dd, J 10.0, 6.0 Hz, 1H in H-2 oxobenzoxazapine), 4.33 (1H, t, J 10.5 Hz, 1H in H-2 oxobenzoxazapine), 4.18 (2H, s , CH2C6H5), 1.98 (3H, s, CCH ₃ );

mass/charge: 428 [M+H] ⁺ (found value of [M+H] ⁺ , 428.1709, C ₂₄ H ₂₁ N ₅ O ₃ provides [M+H] ⁺ 428.1717).

(S)-5-Benzyl-N-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4 -triazole-3carboxamide.

1H NMR (400 MHz, CD3OD) δ 7.32-7.21 (7H, m, C ₆ H ₅ , H-6, H-8 oxobenzoxazapine), 7.06 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.00 (1H, dd, J 10.5, 6.5 Hz, H-3 oxobenzoxazapine), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H in H-2 oxobenzoxazapine), 4.40 (1H, t, J 9.5 Hz, 1H in H-2 oxobenzoxazapine), 4.15 (2H, s, CH2C6H5);

mass/charge: 444.442 [M+H] ⁺ (found value of [M+H] ⁺ , 444.0492, C ₁₉ H ₁₆ BrN ₅ O ₃ provides [M+H] ⁺ 444.0489).

(S,Z)-5 -Benzyl-N-(7-(2-chloro-3-hydroxy-3-methylbut-1-en-1-yl)-5-methyl-4-oxo-2,3,4 ,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.09 (1H, d, J 7.5 Hz, NH), 7.41-7.39 (2H, m, H-6, H-8 oxobenzoxazapine), 7, 29-7.22 (5H, m, C6H5), 7.15 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 6.31 (1H, s, CH=CCl), 5.05 ( 1H, dt, J 11.5, 7.5 Hz, H-3 oxobenzoxazapine), 4.67 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.28 ( 1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4.14 (2H, s, CH2C6H5), 3.43 (3H, s, NCH3), 1.57 (6H, s, C(CH3)2OH);

- 80 045207 ¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.7, 158.9, 158.4, 154.3, 150.2, 136.5, 135.9, 135.7, 135.7, 130.1, 128.9, 128.8, 127.2, 125.8, 122.8, 121.8, 77.2, 71.2, 49.1, 35.6, 33.2, 29, 4;

mass/charge: 480, 478 [M+HH ₂ O]+; mass/charge: 496.494 [M-H] ^- (the found value of [M+H] ⁺ , 496.1743, C2 ₅ H2 ₆ ClN ₅ O4 provides [M+H]+ 496.1746).

(S)-5-Benzyl-N-(5-methyl-4-oxo-7-(3 -(pyrrolidin-1 -yl)prop-1 -yn-1 -yl)-2,3,4,5tetrahydrobenzo[ b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.07 (1H, d, J 7.5 Hz, NH), 7.28-7.20 (7H, m, H-6, H-8 oxobenzoxazapine, C ₆ H ₅ ), 7.09 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.02 (1H, dt, J 11.0, 7.5 Hz, H-3 oxobenzoxazapine), 4.66 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.26 (1H, dd, J 11.0, 10.0 Hz, 1H in H-2 oxobenzoxazapine), 4 .14 (2H, s, CH2C6H5), 3.62 (2H, s, CCH2N), 3.38 (3H, s, NCH3), 2.73-2.70 (4H, m, 4H from pyrrolidine), 1 .86-1.82 (4H, m, 4H from pyrrolidine);

mass/charge: 485 [M+H]+ (the found value of [M+H] ⁺ , 485.2322, C ₂₇ H ₂₈ N ₆ O ₃ provides [M+H]+ 485.2296).

(S)-5-Benzyl-N-(5-methyl-7-(3-morpholinoprop-1-in-1-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1,4] Oxazepin-3-yl)-1H-1,2,4-triazol-3-carboxamide.

1H NMR (400 MHz, CDCl3) δ 8.08 (1H, d, J 7.0 Hz, NH), 7.29-7.27 (2H, m, H-6, H-8 oxobenzoxazapine), 7, 25-7.18 (5H, m, C ₆ H ₅ ), 7.10 (1H, d, J 9.0 Hz, H-9 oxobenzoxazapine), 5.02 (1H, dt, J 11.0, 7 .0 Hz, H-3 oxobenzoxazapine), 4.65 (1H, dd, J 9.5, 7.5 Hz, 1H in H-2 oxobenzoxazapine), 4.27 (1H, t, J 10.5 Hz, 1H in H-2 of oxobenzoxazapine), 4.13 (2H, s, CH ₂ C ₆ H ₅ ), 3.78, 3.76 (4H, 2d AB systems, J 4.5 Hz, 4H from morpholine), 3.50 (2H, s, CCH2N), 3.39 (3H, s, NCH ₃ ), 2.65, 2.63 (4H, 2d AB systems, J 4.5 Hz, 4H from morpholine);

mass/charge: 501 [M+H]+ (found value of [M+H] ⁺ , 501.2245, C ₂₇ H ₂₈ N ₆ O ₄ provides [M+H]+501.2245).

Example 11.

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

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

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

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. ACT (Anaspec, Fremont, CA, USA) at a concentration of 150 nM was combined with an equal volume of ATP working solution 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™ completed the reaction. The plate was quickly centrifuged and the reaction mixture was incubated at room temperature for 40 min. 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 the luminescence method (0.1 s luminescence) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). The IC ₅₀ values obtained from this example are given in table. 1.

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Table 1

Compound RIPK1 ADP-Glo kinase (IC50) 1-1 0.019 1-2 0.0157 1-3 0.0402 1-4 0.0568 1-5 0.0197 1-6 0.0724 1-7 0.021 1-8 0.0529 1-9 0.1892 1-10 0.0429 1-11 0.0571 1-12 0.052 1-13 0.0539 1-14 0.073 1-15 0.1359 1-16 1.633 1-17 0.4906 1-18 0.1645 1-19 0.1455 1-20 0.1528 1-21 0.077 1-22 0.048 1-23 0.0352 1-24 0.0592 1-25 0.051 1-26 0.0656 1-27 0.1583 1-28 0.0375 1-29 0.0124 1-30 0.0402 1-31 0.0334 1-32 0.0219 1-33 0.0145 1-34 0.0492 1-35 0.0223 1-36 0.0338 1-37 0.0565 1-38 0.068 1-39 0.0364 1-40 0.0887 1-41 0.08 1-42 0.0477 1-43 0.0854 1-44 0.034

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1-45 0.0825 1-46 0.0437 1-47 0.0683 1-48 0.0624 1-49 0.0604 1-50 0.0234 1-51 0.0317 1-52 0.0249 1-53 0.034 1-54 0.0269 1-55 0.0337 1-57 0.0215 1-58 0.011 1-59 0.0579 1-60 0.0644 1-61 0.0654 1-62 0.0355 1-63 0.0303 1-64 0.019 1-65 0.0639 1-66 0.0794 1-67 0.0415 1-68 0.0222 1-69 0.0286 1-70 1.155 1-71 0.0217 1-73 0.0429 1-74 0.0518 1-75 0.0546 1-76 0.0449

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1-77 0.0327 1-78 0.0334 1-79 0.0347 1-80 0.0206 1-81 0.019 1-82 0.0255 1-83 0.0664 1-84 0.0441 1-85 0.0423 1-86 0.6161 1-87 0.0187 1-88 0.0738 1-89 0.0527 1-90 0.3649 1-91 0.3879 1-92 0.9325 1-93 0.0641 1-94 0.0333 1-95 0.0271 1-96 0.0317 1-97 0.0858

Example 12.

In this example, U937 and L929 cells were exposed to the 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 in 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% CO2 . For the necroptosis assay, L929 cells were seeded for 18 h in 100 μl/well medium at 10 K cells/well in Costar 96-well black 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 a rate of 50 K cells/well. Media from 96-well plates was removed from L929 cells and replaced with new media 50 μl/well containing 40 μM zVAD-fmk. Each compound of the present 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. Then 50 μl/well of the compound was added to the cells in the plates in duplicate. Cells were preincubated with compound for 1 h at 37°C with 5% CO ₂ and before adding 10 μl/well 11 x TNFa (Peprotech, Rocky Hill, NJ, USA) to obtain a final concentration of 2 ng/ml for TNFa. The relative number of necroptotic cells was determined by the luminescent method using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA) and by a luminescent cell viability assay using CellTiter-Glo® reagent (Promega, Madison, WI, USA) added according to the manufacturer's instructions after 18 h TNFa stimulation at 37°C with 5% CO2. The results of this example are summarized in table. 2. This example confirmed that embodiments of the compounds described in this invention have unexpectedly potent activity against human RIP1 and mouse RIP1, allowing their evaluation in mouse models of disease in vivo. Such results are applicable in determining safe and effective doses for humans.

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- 85 045207

- 86 045207

Example 13.

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 the test agents, each mouse was given an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at 0 hours (before IP injections) and every hour using a temperature measuring device, which was a rectal probe. Three (3) hours after IP injections of TNF-α and zVAD/FMK, mice were sacrificed by CO2 asphyxia and blood was collected by cardiac puncture. Serum and plasma were collected to determine cytokine and compound levels, respectively. Separate groups of mice (satellite mice) were included to determine plasma levels of the compound during TNFa/zVAD-FMK administration.

The reference compound used was (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5

-

Claims (19)

tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014/125444), characterized by the structure shown below, and was studied using a protocol similar to that described in WO 2014/125444. This comparative compound had 93% inhibition at a dose of 30 mg/kg according to WO 2014/125444. In comparison, Compound I-30 of the present invention achieved greater than 85% inhibition at a dose of only 5 mg/kg using an assay protocol similar to that described above. Comparative connection. Because there are many possible embodiments to which the principles of the present invention may be applied, it should be understood that the illustrative embodiments are preferred examples only and should not be construed as limiting. More precisely, the scope of the present invention is defined by the following claims. Therefore, the inventors of the present invention claim as their invention everything that falls within the scope and spirit of the present claims. CLAIM 1. A compound characterized by the formula or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- or 6-membered heteroaryl; L represents CH2; R ¹ is -C-C11 or a -linker-R ⁶ group, where the linker is R ^a , provided that R ^a is not H or D and R ⁶ is R ^b , -C(R ^f )3 or -C(R ^f )=C(R ^f )2; R ² and R ³ are independently R ^a ; R ⁴ and R ⁵ are independently R ^e ; R ^a independently in each case represents H, D, C _1-10 aliphatic, C _1-10 haloaliphatic, C _5-10 aromatic or C _3-6 heterocyclic group; R ^b independently for each case represents -OH, -SH, -OR ^c , -SR ^c , -NR ^d R ^d , -Si(R ^a ) ₃ , -C(O)OH, -C(O)OR ^c or -C(O)NR ^d R ^d ; R ^c independently in each case represents a C _1-10 alkyl, a C _2-10 alkenyl, a C _2-10 alkynyl, a C _3-6 cycloalkyl or a C _5-10 aromatic group; ^Rd is independently in each case H, C1-6alkyl, C3-6cycloalkyl, C3-6heterocyclic group, C5-10aryl, C5-10heteroaryl, or two ^Rd groups together with the associated nitrogen atom form a C3-9heterocyclic group or C _5-10 heteroaryl; R ^e is independently in each case halogen, C _1-6 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, C _5-10 heteroaryl or -OR ^a ; R ^f is independently in each case R ^a , R ^b or R ^e , or two R ^f groups together with the associated carbon atom form a C _3-6 cycloalkyl group or a C _3-10 heterocyclic group; n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5, wherein each C _3-6 heterocyclic group, C _5-10 heteroaryl, C _3-9 heterocyclic group and C _3-10 heterocyclic group contains 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. 2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein ring B is characterized by 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. 3. A compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring B is a diazole, triazole, oxadiazole, oxazole or pyridinyl. - 88 045207 4. A compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein a triazole is diazole is oxadiazole is oxazole is 5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ⁵ represents R ^e , where R ^e represents halogen or methyl. 6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein the linker in the linker-R ⁶ group is R ^a , where R ^a is C ₁ -, C ₂ -, C ₃ - or C ₄ aliphatic a group comprising an alkyl, alkenyl or alkynyl group. 7. The compound or pharmaceutically acceptable salt thereof according to claim 6, wherein the C ₂ group is an alkyne, and wherein R ⁶ is -C(R ^f )3, wherein one R ^f is R ^e and each of the remaining R ^f independently for each case represents R ^a , where R ^a represents C1. ₄ alkyl. 8. A compound according to claim 7, where R ^e represents -OR ^a , where R ^a represents H. 9. A compound according to claim 7 or 8, where R ^a represents methyl. 10. The connection according to any one of claims 7-9, where the ring B is XX X _N H ^Ν , , Ν OR \ . 11. The connection according to any one of claims 1 to 10, where R ¹ represents - 89 045207 12. The connection according to any one of claims 1 to 11, where the connection is - 90 045207 - 91 045207 - 92 045207 - 93 045207 - 94 045207 1-97, - 95 045207 13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, where the compound is 14. A pharmaceutical composition containing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 and an excipient. 15. A method of inhibiting receptor-interacting protein kinase 1 (RIP1) in a patient in need thereof, comprising contacting the RIP1 kinase with a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14. 16. Use of (i) a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof; or (ii) a pharmaceutical composition according to claim 14 for treating a disease, wherein the disease is a disease involving receptor-interacting protein kinase-1 (RIP1). 17. The method according to claim 15, where the compound or a pharmaceutically acceptable salt thereof is 18. Use according to claim 16, wherein the compound or a pharmaceutically acceptable salt thereof is 19. A method for producing a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, where R ¹ contains -C^CH or a linker-R ⁶ group, including providing a coupling reaction of the starting material characterized by formula A with R ¹ -containing a reagent by combining the starting material and R ¹ -containing reagent with a transition metal catalyst, base and solvent to produce a functionalized product; removing the protecting group from the amino group of the functionalized product to obtain an amino compound; and causing the formation of an amide bond between the amino compound and the acid group-containing coupling agent to produce an amide group-containing compound, wherein formula A is NHPG formula A; the functionalized product is characterized by a structure corresponding to formula B - 96 045207 NHPG formula B; and the coupling agent containing an acidic group is characterized by a structure corresponding to formula C formula C; wherein X represents halogen or triflate; PG represents a protecting group for an amino group; and each of ring B, L, R ¹ , R ² , R ⁴ , R ⁵ , m, η and p is as specified in any one of claims 1 to 15. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2