WO2019224774A1

WO2019224774A1 - Heterocyclic amides as rip1 kinase inhibitors

Info

Publication number: WO2019224774A1
Application number: PCT/IB2019/054287
Authority: WO
Inventors: Ryan Michael Fox; Philip Anthony Harris; Mark Andrew Seefeld; Ding Zhou
Original assignee: GlaxoSmithKline Intellectual Property Development Ltd
Current assignee: GlaxoSmithKline Intellectual Property Development Ltd
Priority date: 2018-05-23
Filing date: 2019-05-23
Publication date: 2019-11-28
Anticipated expiration: 2020-11-23

Abstract

Disclosed are compounds having the formula: (I) wherein R1, R2, R3, R4, R5, and R6 are as defined herein, and methods of making and using the same.

Description

HETEROCYCLIC AMIDES AS RIP1 KINASE INHIBITORS

FIELD OF THE INVENTION

The present invention relates to heterocyclic amides that inhibit RIP1 kinase and methods of making and using the same.

BACKGROUND OF THE INVENTION

Receptor-interacting protein-1 (RJP1) kinase, originally referred to as RIP, is a TKL family serine/threonine protein kinase involved in innate immune signaling. RIP1 kinase is a RHIM domain containing protein, with an N-terminal kinase domain and a C-terminal death domain (Trends Biodiem. Sri., 30, 151-159 (2005)). The death domain of RIP1 mediates interaction with other death domain containing proteins including Fas and TNFR-1 (Cell, 81 513-523 (1995)), TRA1L-R1 and TRAIL-R2 (Immunity, 7, 821-830 (1997)), and TRADD (Immunity, 4, 387-396 (1996)), while the RHIM domain is crucial for binding other RHIM domain containing proteins such as TRIP (Nat. Immunol., 5, 503-507 (2004)), DAI (EMBO Rep. 10, 916-922 (2009)) and RIP3 (J. Biol. Chem., 274, 16871-16875 (1999)); Curr. Biol.,

9, 539-542 (1999)) and exerts many of its effects through these interactions. RIP1 is a central regulator of cell signaling, and is involved in mediating both pro-survival and programmed cell death pathways which will be discussed below.

The role for RIP1 in cell signaling has been assessed under various conditions

[including TLR3 (Nat Immunol., 5, 503-507 (2004)), TLR4 (J. Biol. Chem., 280, 36560- 6566 (2005)), TRAIL (Cell Signal., 27(2), 306 -314 (2015)), FAS (J. Biol. Chem., 279, 7925-7933 (2004))], but is best understood in the context of mediating signals downstream of the death receptor TNFR1 (Cell, 114, 181-190 (2003)). Engagement of the TNFR by TNF leads to its oligomerization, and the recruitment of multiple proteins, including linear K63- linked polyubiquitinated RIP1 (Mol. Cell, 22, 245-257 (2006)), TRAF2/5 (J. Mol. Biol., 396, 528-539 (2010)), TRADD (Nat. Immunol., 9, 1037-1046 (2008)), and cIAPs (Proc. Natl. Acad. Sci. USA, 105, 11778-11783 (2008)), to the cytoplasmic tail of the receptor. This complex which is dependent on RIP1 as a scaffolding protein (i.e. kinase independent), termed complex I, provides a platform for pro-survival signaling through the activation of the NFKB and MAP kinases pathways (Sci. Signal., 115, re4 (2010)). Alternatively, binding of TNF to its receptor under conditions promoting the deubiquitination of RIP 1 (by proteins such as A20 and CYLD or inhibition of the cIAPs) results in receptor internalization and the formation of complex II or DISC (death-inducing signaling complex) (Cell Death Dis., 2, e230 (2011)). Formation of tiie DISC, which contains RIP1, TRADD, FADD and caspase 8, results in the activation of caspase 8 and the onset of programmed apoptotic cell death also in a RIP1 kinase independent fashion (FEBS J, 278, 877-887 (2012)). Apoptosis is largely a quiescent form of cell death, and is involved in routine processes such as development and cellular homeostasis.

Under conditions where the DISC forms and RIP3 is expressed, but apoptosis is inhibited (such as FADD/caspase 8 deletion, caspase inhibition, or viral infection), a third RIP1 kinase-dependent possibility exists. RIP3 can now enter this complex, become phosphory lated by RIP 1 and initiate a caspase-independent programmed necrotic cell death through the activation of MLKL and PGAM5 (Cell, 148, 213-227 (2012)); (Cell, 148, 228- 243 (2012)); (Proc. Natl. Acad. Sci. USA, 109, 5322-5327 (2012)). As opposed to apoptosis, programmed necrosis (not to be confused with passive necrosis which is not programmed) results in the release of danger associated molecular patterns (DAMPs) from the cell. These DAMPs are capable of providing a“danger signal” to surrounding cells and tissues, eliciting proinflammatory responses including inflammasome activation, cytokine production and cellular recruitment (Nat. Rev. Immunol., 8, 279-289 (2008)).

Dysregulation of RIP1 kinase-mediated programmed cell death has been linked to various inflammatory diseases, as demonstrated by use of the RIP3 knockout mouse (where RIPl-mediated programmed necrosis is completely blocked) and by Necrostatin-1 (a tool inhibitor of RIP1 kinase activity with poor oral bioavailability). The RIP3 knockout mouse has been shown to be protective in inflammatory bowel disease (including ulcerative colitis and Crohn’s disease) (Nature, 477, 330-334 (2011)), psoriasis (Immunity, 35, 572-582 (2011)), retinal-detachment-induced photoreceptor necrosis (PNAS, 107, 21695-21700, (2010)), retinitis pigmentosa (Proc. Natl. Acad. Sci., 109:36, 14598-14603 (2012)), cerulein- induced acute pancreatits (Cell, 137, 1100-1111 (2009)), and sepsis/systemic inflammatory' response syndrome (SIRS) (Immunity, 35, 908-918 (2011)). Necrostatin-1 has been shown to be effective in alleviating ischemic brain injury (Nat. Chem Biol., 1, 112-119 (2005)), retinal ischemia/reperfusion injury (J. Neurosci. Res., 88, 1569-1576 (2010)), Huntington’s disease (Cell Death Dis., 2 ell5 (2011)), renal ischemia reperfusion injury (Kidney Int, 81, 751-761 (2012)), cisplatin induced kidney injury (Ren. Fail., 34, 373-377 (2012)), and traumatic brain injury (Neurochem. Res., 37, 1849-1858 (2012)). Other diseases or disorders regulated at least in part by RIP 1 -dependent apoptosis, necrosis or cytokine production include hematological and solid organ malignancies (Genes Dev., 27, 1640-1649 (2013)), bacterial infections and viral infections (Cell Host & Microbe, 15, 23-35 (2014)) (including, but not limited to, tuberculosis and influenza (Cell, 153, 1-14 (2013)) and Lysosomal storage diseases (particularly, Gaucher Disease, Nature Medicine Advance Online Publication, 19 January 2014, doi: 10.1038/nm.3449).

A potent, selective, small molecule inhibitor of RIP 1 kinase activity would block RIP 1 -dependent cellular necrosis and thereby provide a therapeutic benefit in diseases or events associated with DAMPs, cell death, and/or inflammation.

SUMMARY OF THE INVENTION

The present invention relates to compounds according to Formula (I) or

pharmaceutically acceptable salts thereof:

wherein:

R² is phenyl or 5-6 membered heteroaryl,

wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C₁-C₄)alkyl, halo(Ci- C₄)alkyl,

(C₁-C₄)alkoxy, and -CN; and

each R³, R⁴, R⁵, and R⁶ are independently selected from hydrogen, deuterium, and (C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen.

The present invention relates to compounds according to Formula (II) or

pharmaceutically acceptable salts thereof:

wherein:

R² is phenyl or 5-6 membered heteroaryl,

(C₁-C₄)alkoxy, and -CN; and

The compounds according to Formulas (I) and (II), or pharmaceutically acceptable salts thereof, inhibit the activity and/or function of R1P1 kinase. Accordingly, these compounds may be particularly useful for the treatment of RIP 1 kinase-mediated diseases or disorders. Such RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP 1 kinase, and as such, are diseases or disorders where inhibition of RIP 1 kinase would provide benefit.

Another aspect of this invention relates to a pharmaceutical composition comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Another aspect of this invention relates to a pharmaceutical composition comprising a compound of Formula (II) or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Another aspect of this invention relates to a method of treating a RIP 1 -mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Another aspect of this invention relates to a method of treating a RIP 1 -mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (II) or pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising of a compound of Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Another aspect of this invention relates to a method of treating RIP 1 -mediated disease or disorder in a human in need thereof, wherein the the RIP 1 -mediated disease is amyotrophic lateral sclerosis.

In another aspect, the invention provides a compound of Formula (I) or a

pharmaceutically acceptable salt thereof for use in therapy.

In another aspect, the invention provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in therapy.

In another aspect, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP 1 -mediated diseases or disorders.

In another aspect, there is provided a compound of Formula (II) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP 1 -mediated diseases or disorders.

In another aspect, there is provided a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP 1 -mediated diseases or disorders, wherein the RIP-1 mediated disease or disorder is amyotrophic lateral sclerosis.

In another aspect, there is provided a compound of Formula (P) or a pharmaceutically acceptable salt thereof for use in the treatment of RIP 1 -mediated disease or disorders, wherein the RIPl-mediated disease or disorder is amyotrophic lateral sclerosis.

In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases or disorders mediated by RIP1.

In another aspect, there is provided the use of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of diseases or disorders mediated by RIP1. In another aspect, there is provided the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of amyotrophic lateral sclerosis.

In another aspect, there is provided the use of a compound of Formula (II) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of amyotrophic lateral sclerosis.

In another aspect, there is provided methods of co-administering the presently invented compounds of Formula (I) or a pharmaceutically acceptable salt thererof with other active ingredients.

In another aspect, there is provided methods of co-administering the presently invented compounds of Formula (II) or a pharmaceutically acceptable salt thererof with other active ingredients.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 A shows the temperature loss over time in mice after oral pre-dosing with Compounds A, B, C, D, or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.

FIG. IB shows the temperature loss in mice 3 hours after oral pre-dosing with Compounds A, B, C, D, or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.

FIG. 2A shows the temperature loss over time in mice after oral pre-dosing with Compounds E, F, G, H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.

FIG. 2B shows the temperature loss in mice 3 hours after oral pre-dosing with Compounds E, F, G, H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.

FIG. 3A show's the temperature loss over time in mice after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.

FIG. 3B shows the temperature loss in mice 3 hours after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD. Figure 4A shows the temperature loss over time in mice after oral pre-dosing with Compound H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.

FIG. 4B shows the temperature loss in mice 2 hours after oral pre-dosing with Compound H or vehicle followed by simultaneous i.v. administration of mouse TNF and zVAD.

FIG. 5A shows the temperature loss over time in mice after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF.

FIG. 5B shows the temperature loss in mice 7.5 hours after oral pre-dosing with Compound A or vehicle followed by simultaneous i.v. administration of mouse TNF.

FIG 6A shows the scotopic B-wave electroretinography recordings at P39 and P46 in RdlO mice after startof daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.

FIG. 6B shows the photopic B-wave electroretinography recordings at P39 and P46 in RdlO mice after startof daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.

FIG. 6C shows the measurement of the thickness of the Outer Nuclear Cell (ONL) layers at various distances from the Optic Nerve Head (ONH) in hematoxylin and eosin stained retinal tissue sections collected at P46 in RdlO mice after start of daily in-diet dosing with Compound A or control diet at P28 followed by switch from dark rearing to 12-hour light/dark cycle at P30.

FIG. 7 shows the clinical scores over time in mice after daily in-diet dosing with Compound A or control diet followed by induction of experimental autoimmune

encephalomyelitis with MOGbs-ss, heat inactivated Mycobacterium tuberculosis, and pertussis toxin.

FIG. 8 A show's Compound A improves fed blood glucose over time without altering body weight in db/db mice.

(* p<0.05)

FIG. 8B shows Compound A improves fed blood glucose over time without altering body weight in db/db mice.

FIG. 9A shows Compound A improves fasted blood glucose without altering body weight in db/db mice at 8 weeks of dosing. (* p<0.05) FIG. 9B shows Compound A improves fasted blood glucose without altering body weight in db/db mice at 8 weeks of dosing.

FIG 10A shows effect of Compound A on food intake and body weight in obese, high fat diet-fed mice. (* p<0.05; ** p<0.001)

FIG 10B shows effect of Compound A on food intake and body weight in obese, high fat diet-fed mice. (**p<0.001)

FIG. 11 A shows subcutaneous pancreatic tumor model with Compound A alone or in combination with anti-PDl.

FIG. 1 IB shows subcutaneous bladder tumor model with Compound A alone or in combination with anti-PD 1.

FIG. 12A shows the percentage of mice without severe dermatitis over time. After weaning mice received daily in-diet dosing with Compound A or control diet as indicated and were monitored for development of dermatitis.

FIG. 12B shows the percentage of mice without severe dermatitis over time. Once mice developed clinical signs of dermatitis (about 6 weeks of age), mice received daily indiet dosing with Compound A or control diet as indicated and were monitored for development of severe dermatitis.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to compounds of Formulas (I) and (II) as defined above or pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of Formula (I) wherein R¹ is

-COCH₃.

In one embodiment, this invention relates to compounds of Formula (I) wherein R² is phenyl, wherein said phenyl is optionally substituted by two or three substituents independently selected from halogen, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, and -CN. In another embodiment, this invention relates to compounds of Formula (I) wherein R² is phenyl, wherein said phenyl is optionally substituted by two or three fluoros.

In one embodiment, this invention relates to compounds of Formula (I) wherein each R³, R⁴, R⁵, and R⁶is independently selected from hydrogen, deuterium, or methyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein each R³, R⁴, R⁵, and R⁶is independently selected from hydrogen or deuterium wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen or methyl wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen.

In one embodiment, this invention relates to compounds of Formula (I) wherein R¹ is -CO(C₁-C₄)alkyl; R²is phenyl, wherein said phenyl is optionally substituted by one, two, or three substituents independently selected from halogen, halo(Ci -Chalky 1, and -CN; and each R³, R⁴, R^$, and R⁶ is independently selected from hydrogen, deuterium, and (C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein R¹ is -CO(C₁-C₄)alkyl; R² is phenyl, wherein said phenyl is optionally substituted by two or three substituents independently selected from halogen, halo(C₁-C₄)alkyl, and -CN; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen, deuterium, and (C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein R¹ is -CO(C₁-C₄)alkyl; R² is phenyl, wherein said phenyl is optionally substituted by two or three substituents independently selected from halogen and halo(C₁-C₄)alkyl; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and deuterium, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein R¹ is -CO(C₁-C₄)alkyl; R² is phenyl, wherein said phenyl is optionally substituted by two or three substituents independently selected from halogen and halo(C₁-C₄)alkyl; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and (C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein R* is -CO(Ci- C₄)alkyl; R²is phenyl, wherein said phenyl is optionally substituted by two substituents independently selected from halogen and halo(C₁-C₄)alkyl; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and (C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein R¹ is -COCHs; R²is phenyl, wherein said phenyl is optionally substituted by two fluoros; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and methyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (I) wherein R¹ is -COCH3; R² is phenyl, wherein said phenyl is optionally substituted by two fluoros; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and deuterium, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In one embodiment, this invention relates to compounds of Formula (P) wherein R¹ is

-COCHs.

In one embodiment, this invention relates to compounds of Formula (II) wherein R²is phenyl, wherein said phenyl is optionally substituted by two or three substituents

independently selected from halogen, halo(C₁-C₄)alkyl, (Ci-C-Oalkoxy, and -CN. In another embodiment, this invention relates to compounds of Formula (II) wherein R²is phenyl, wherein said phenyl is optionally substituted by two or three fluoros.

In one embodiment, this invention relates to compounds of Formula (II) wherein each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen, deuterium, or methyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (II) wherein each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen or deuterium wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen.

In another embodiment, this invention relates to compounds of Formula (II) wherein each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen or methyl wherein at least one R³, R⁴,

R⁵, or R⁶ is not hydrogen.

In one embodiment, this invention relates to compounds of Formula (P) wherein R¹ is -CO(Ci -Chalky 1; R²is phenyl, wherein said phenyl is optionally substituted by one, two, or three substituents independently selected from halogen, halo(C₁-C₄)alkyl, and -CN; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen, deuterium, and

(C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (II) wherein R¹ is -CO(C₁-C₄)alkyl; R² is phenyl, wherein said phenyl is optionally substituted by two or three substituents

independently selected from halogen, halo(C₁-C₄)alkyl, and -CN; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen, deuterium, and (C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (II) wherein R¹ is -CO(C₁-C₄)alkyl; R² is phenyl, wherein said phenyl is optionally substituted by two or three substituents independently selected from halogen and halo(C₁-C₄)alkyl; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and deuterium, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another

embodiment, this invention relates to compounds of Formula (II) wherein R¹ is -CO(Ci- C₄)alkyl; R² is phenyl, wherein said phenyl is optionally substituted by two or three substituents independently selected from halogen and halo(C₁-C₄)alkyl; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and (C₁-C₄)alkyl, wherein at least one R³,

R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (II) wherein R¹ is -CO(C₁-C₄)alkyl; R²is phenyl, wherein said phenyl is optionally substituted by two substituents independently selected from halogen and halo(C₁-C₄)alkyl; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and (C₁-C₄)alkyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (P) wherein R¹ is -COCFb; R²is phenyl, wherein said phenyl is optionally substituted by two fluoros; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and methyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen. In another embodiment, this invention relates to compounds of Formula (II) wherein R¹ is - COCHs; R² is phenyl, wherein said phenyl is optionally substituted by two fluoros; and each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen and deuterium, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen.

Specific compounds of this invention include:

1 -(4-((4S,5S)-5-(3,5-difluoropheny l)-4-methyl-4,5-dihydro-lH-pyrazoIe- 1 - carbonyl)piperidin-l -yl)ethanone;

or pharmaceutically acceptable salts thereof.

It will be appreciated that die present invention encompasses compounds of Formula (I) and Formula (P) as the free base or free acid and as pharmaceutically acceptable salts thereof. In one embodiment, the invention relates to compounds of Formula (I) and Formula (P) in the form of a free base. In one embodiment, the invention relates to compounds of Formula (I) and Formula (P) in the form of a free acid. In another embodiment, the invention relates to compounds of Formulas (I) and (II) in the form of a pharmaceutically acceptable salt. It will be further appreciated that, in one embodiment, the invention relates to compounds of the Examples in the form of a free base. In another embodiment, the invention relates to compounds of the Examples in the form of a a pharmaceutically acceptable salt.

It is to be understood that the references herein to a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of Formula (I). In another embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of Formula (I). In a further embodiment, the invention is directed to a compound of Formula (I) or a pharmaceutically acceptable salt thereof. It is to be understood that the references herein to a compound of Formula (II) or a pharmaceutically acceptable salt thereof. Thus, in one embodiment, the invention is directed to a compound of Formula (II). In another embodiment, the invention is directed to a pharmaceutically acceptable salt of a compound of Formula (II). In a further embodiment, the invention is directed to a compound of Formula (P) or a pharmaceutically acceptable salt thereof.

Because of their potential use in medicine, it will be appreciated that a salt of a compound of Formula (I) or Formula (II) is ideally pharmaceutically acceptable.

Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm. Sri., 66, 1-19, (1977) or those listed in P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition

Stahl/Wermuth: Wiley- VCH/VHCA (2011) (see

http://www.wiley.com/WileyCDAAVileyTitle/productCd-3906390519.html).

Suitable pharmaceutically acceptable salts can include arid or base addition salts. Such base addition salts can be formed by reaction of a compound of Formula (I) or Formula (II) (which, for example, contains a carboxylic acid or other acidic functional group) with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

Such add addition salts can be formed by reaction of a compound of Formula (I) or Formula (II) (which, for example contains a basic amine or other basic functional group) with the appropriate add, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

Salts may be prepared in situ during the final isolation and purification of a compound of Formula (I) or Formula (P). If a basic compound of Formula (I) or Formula (P) is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound. Similarly, if a compound of Formula (I) or Formula (II) containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic add. This invention also provides for the conversion of one salt of a compound of this invention, e.g., a hydrochloride salt, into another salt of a compound of this invention, e.g., a sulfate salt.

It will be understood that if a compound of Formula (I) or Formula (II) contains two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.

Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a compound of Formula (I) or Formula (II) are included within the scope of the invention, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.

Representative pharmaceutically acceptable add addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate,

benzenes ulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, caldum edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, dtrate, cyclamate, digluconate, 2, 5-dihydroxy benzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1, 2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine -di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene- 1 ,5 -disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicy elate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), py roglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)- 1 , 3-propanediol (TRIS), arginine, benethamine (/V-benzylphenethylamine), benzathine ( N,N ’-dibenzylethylenediamine), bis-(2- hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -p chlorobenzyl- 2-pyrrolildine-l’-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethyl enediamine, L-histidine, iron, isoquinohne, lepidine, lithium, lysine, magnesium, meglumine (JV-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, f-butylamine, tromethamine

(im(hydroxymethyl)aminomethane), and zinc.

It will be understood that if a compound of Formula (I) or Formula (P) contained two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts w ould contain 1, 2 or more acid counterions, for example, a diacetate or a dihydrochloride salt.

Because the compounds of Formulas (I) and (P), or a pharmaceutically acceptable salt thereof, are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. The compounds of this invention may be particularly useful for the treatment of RIP 1 kinase-mediated diseases or disorders. Such RIP1 kinase-mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP 1 kinase, and as such, are diseases or disorders where inhibition of RIP 1 kinase would provide benefit.

In this invention, RIP1 kinase- mediated diseases or disorders are diseases or disorders that are mediated by activation of RIP 1 kinase, and as such, are diseases or disorders where inhibition of RIP 1 kinase would provide benefit. Such RIP1 kinase-mediated diseases or disorders are diseases/disorders which are likely to be regulated at least in part by programmed necrosis, apoptosis or the production of inflammatory cytokines, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age- related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, juvenile idiopathic arthritis (systemic onset juvenile idiopathic arthritis (SoJIA)), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver damage/diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepalotoxicity), non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney' damage/injury (nephritis, renal transplant, surgery, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury (AK1)) Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rejection of transplant organs, tissues and cells), ischemia reperfusion injury' of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury', neonatal hypoxic brain injury, ischemic brain injury, traumatic brain injury allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity, Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin-1 converting enzyme (ICE, also known as caspase-1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, peridontitis, NEMO- mutations (mutations ofNF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency (also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-l deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency' syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and

mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency', Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), Stevens- Johnson syndrome, toxic epidermal necrolysis, glaucoma, spinal cord injury, fibrosis, complement- mediated cytotoxicity, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, melanoma, metastasis, breast cancer, non-small cell lung carcinoma

(NSCLC), radiation induced necrosis, ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, acute liver failure and radiation protection/mitigation, auditory disorders such as noise-induced hearing loss and drugs associated with ototoxicity such as cisplatin, or for the treatment of cells ex vivo to preserve vitality and function.

The compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders: inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, age-related macular degeneration, pancreatitis, atopic dermatitis, arthritis (including rheumatoid arthritis, spondyloarthritis, gout, systemic onset juvenile idiopathic arthritis (SoJIA), psoriatic arthritis), lupus, systemic lupus erythematosus (SLE), Sjogren’s syndrome, systemic scleroderma, anti-phospholipid syndrome (APS), vasculitis, osteoarthritis, liver

damage/diseases (non-alcohol steatohepatitis (NASH), alcohol steatohepatitis (ASH), autoimmune hepatitis, autoimmune hepatobiliary' diseases, primary sclerosing cholangitis (PSC), acetaminophen toxicity, hepatotoxidty), non-al cholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), kidney damage/injmy (nephritis, renal transplant, surgeiy, administration of nephrotoxic drugs e.g. cisplatin, acute kidney injury (AKI)) Celiac disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), transplant rejection (rej ection of transplant organs, tissues and cells), ischemia reperfusion injury of solid organs, sepsis, systemic inflammatory response syndrome (SIRS), cerebrovascular accident (CVA, stroke), myocardial infarction (MI), atherosclerosis, Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), neonatal brain injury, neonatal hypoxic brain injury, traumatic brain injury, allergic diseases (including asthma and atopic dermatitis), peripheral nerve injury, bums, multiple sclerosis, type I diabetes, type II diabetes, obesity', Wegener’s granulomatosis, pulmonary sarcoidosis, Behcet’s disease, interleukin- 1 converting enzyme (ICE, also known as caspase- 1) associated fever syndrome, chronic obstructive pulmonary disease (COPD), cigarette smoke-induced damage, cystic fibrosis, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), a neoplastic tumor, melanoma, metastasis, breast cancer, non-small cell lung carcinoma (NSCLC), radiation induced necrosis, ischemic kidney damage,

ophthalmologic ischemia, intracerebral hemorrhage, subarachnoid hemorrhage, peridontitis, NEMO-mutations (mutations of NF-kappa-B essential modulator gene (also known as IKK gamma or IKKG)), particularly, NEMO-deficiency syndrome, HOIL-1 deficiency ((also known as RBCK1) heme-oxidized IRP2 ubiquitin ligase-l deficiency), linear ubiquitin chain assembly complex (LUBAC) deficiency syndrome, hematological and solid organ malignancies, bacterial infections and viral infections (such as influenza, staphylococcus, and mycobacterium (tuberculosis)), and Lysosomal storage diseases (particularly, Gaucher disease, and including GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency', cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidoses disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinoses, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs, and Wolman disease), spinal cord injury, Stevens- Johnson syndrome, fibrosis, complement-mediated cytotoxicity, toxic epidermal necrolysis, and/or for the treatment of cells ex vivo to preserve vitality and function.

The compounds of the invention, particularly the compounds of Formula (I) and Formula (11), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of the following RIP1 kinase-mediated diseases or disorders, that is,

diseases/disorders which are likely to be regulated at least in part by R1P1 kinase activity, particularly inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), asthma, cigarette smoke-induced damage, cystic fibrosis, psoriasis, retinal detachment, retinal degeneration, retinitis pigmentosa, macular degeneration, atopic dermatitis, bum injury, periodontitis, a bacterial or viral infection (an infection with a pathogen including but not limited to influenza, staphylococcus, and/or mycobacterium (tuberculosis), systemic scleroderma (particularly, topical treatment of hardened and/or tightened skin areas), and/or ischemia reperfusion injury of solid organs/transplant rejection (particularly, topical treatment of donor organ (particularly kidney, liver, and heart and/or lung transplants), infusion of organ recipient), and topical treatment of bowels.

The compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of glaucoma.

The compounds of the invention, particularly the compounds of Formulas (I) and (P), or a pharmaceutically acceptable salt thereof, may be particularly useful for treatment of pancreatic ductal adenocarcinoma, hepatocellular carcinoma, mesothelioma, or melanoma The compounds of the invention, particularly the compounds of Formulas (I) and (P), or a pharmaceutically acceptable salt thereof, may be particularly useful for the treatment of tiie following RIP1 kinase-mediated disease or disorder: rheumatoid arthritis, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), and psoriasis.

The treatment of the above-noted diseases/disorders may concern, more specifically, the amelioration of organ injury or damage sustained as a result of the noted

diseases/disorders. For example, the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following ischemic brain injury or traumatic brain injury, or for amelioration of heart tissue injury or damage following myocardial infarction, or for amelioration of brain tissue injury or damage associated with Huntington’s disease, Alzheimer’s disease or Parkinson’s disease, or for amelioration of liver tissue injury or damage associated with non-alcohol steatohepatitis, alcohol steatohepatitis, autoimmune hepatitis autoimmune hepatobiliary diseases, or primary sclerosing cholangitis, or overdose of acetaminophen.

The compounds of this invention may be particularly useful for the amelioration of organ injury or damage sustained as a result of radiation therapy, or amelioration of spinal tissue injury or damage following spinal cord injury or amelioration of liver tissue injury or damage associated acute liver failure. The compounds of this invention may be particularly useftd for amelioration of auditory disorders, such as noise-induced hearing loss or auditory disorders following the administration of ototoxic drugs or substances e.g. cisplatin.

The compounds of this invention may be particularly useful for amelioration of solid organ tissue (particularly kidney, liver, and heart and/or lung) injury or damage following transplant or the administration of nephrotoxic drugs or substances e.g. cisplatin. It will be understood that amelioration of such tissue damage may be achieved where possible, by pretreatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof; for example, by pre-treatment of a patient prior to administration of cisplatin or pre-treatment of an organ or the organ recipient prior to transplant surgery. Amelioration of such tissue damage may be achieved by treatment with a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, during transplant surgery.

Amelioration of such tissue damage may also be achieved by short-term treatment of a patient with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, after transplant surgery.

In one embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa.

In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of multiple sclerosis.

In one embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of traumatic brain injury.

In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useftd for the treatment of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease. In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy (PSP), and Alzheimer’s disease.

In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of age-related macular degeneration.

The treatment of retinal detachment, macular degeneration, retinitis pigmentosa, multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease may concern, more specifically, the amelioration of organ injury or damage sustained as a result of these diseases/disorders. For example, the compounds of this invention may be particularly useful for amelioration of brain tissue injury or damage following traumatic brain injury', or for amelioration of brain tissue injury or damage associated of Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of retinal detachment, macular degeneration, and retinitis pigmentosa, and the amelioration of brain tissue injury or damage as a result of multiple sclerosis, traumatic brain injury, Huntington's Disease, Alzheimer's Disease, amyotrophic lateral sclerosis, and Niemann-Pick disease.

In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of Crohn’s disease, ulcerative colitis, psoriasis, rheumatoid arthritis,

spondyloarthritis, systemic onset juvenile idiopathic arthritis (SoJIA), and osteoarthritis.

In yet another embodiment, the compounds of this invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of psoriasis, rheumatoid arthritis, and ulcerative and colitis.

In another embodiment, the compounds of this invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of lupus, inflammatory' bowel disease (IBD), Crohn’s disease, and ulcerative colitis.

In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of cerebrovascular accident (CVA, stroke), Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), traumatic brain injury, multiple sclerosis, Gaucher disease, Niemann-Pick disease, and spinal cord injury.

In another embodiment, the compounds of the invention, particularly the compounds of Formulas (I) and (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of amyotrophic lateral sclerosis (ALS).

In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for die treatment of pancreatic ductal adenocarcinoma (PD AC), metastasis, melanoma, breast cancer, non-small cell lung carcinoma (NSCLC), and radiation induced necrosis.

In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PD AC), metastasis, melanoma, breast cancer, and non-small cell lung carcinoma (NSCLC).

In another embodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of pancreatic ductal adenocarcinoma (PD AC).

In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of intracerebral hemorrhage and subarachnoid hemorrhage.

In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of type P diabetes and obesity.

In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of atherosclerosis.

In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of vasculitis. In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or a pharmaceutically acceptable salt thereof, may be useful for the treatment of bums.

In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or pharmaceutically acceptable salt thereof, may be useful for die treatment of ischemic kidney damage, ophthalmologic ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage.

In another emobodiment, the compounds of the invention, particularly the compounds of Formula (I) and Formula (P), or pharmaceutically acceptable salt thereof, may be useful for the treatment of non-alcholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), autoimmune hepatitis, and non-alcoholic fatty liver disease (NAFLD).

The compounds of the invention, particularly the compounds of Formulas (I) and (P), or a pharmaceutically acceptable salt thereof, max' be particularly useful for the treatment of the following R1P1 kinase-mediated diseases or disorders. In one aspect the human has a solid tumor. In one aspect the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma (NSCLC), prostate cancer, colorectal cancer, ovarian cancer, pancreatic cancer, and pancreatic ductal adenocarcinoma. In one aspect the human has one or more of the following: colorectal cancer (CRC), esophageal cancer, cervical, bladder, breast cancer, head and neck cancer, ovarian cancer, melanoma, renal cell carcinoma (RCC), EC squamous cell carcinoma, non-small cell lung carcinoma, mesothelioma, prostate cancer, and pancreatic ductal adenocarcinoma. In another aspect, the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lyphomblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia and chronic myelogenous leukemia.

The present disclosure also relates to a method for treating or lessening the severity of a cancer selected from: brain (gliomas), glioblastomas, astrocytomas, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, breast cancer, triple negative breast cancer, inflammatory breast cancer, Wilrris tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer (including squamous cell carcinoma of head and neck), kidney cancer, lung cancer (including lung squamous cell carcinoma, lung adenocarcinoma, lung small cell carcinoma, and non-small cell lung carcinoma), liver cancer (including hepatocellular carcinoma), melanoma, ovarian cancer, pancreatic cancer (including squamous pancreatic cancer), prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin^'s lymphoma, Non-Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulval cancer, cervical cancer, endometrial cancer, cancer of the uterus, renal cancer (including kidney clear cell cancer, kidney papillary cancer, renal cell carcinoma), mesothelioma, esophageal cancer, salivary- gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor) and testicular cancer.

Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia; lymphomas such as non- Hodgkin’s lymphoma, Hodgkin’s lymphoma; and the like.

The cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblastic) leukemia (undifferentiated or differentiated), acute promyeloid (or promy elocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocytic (or

megakaryoblastic) leukemia. These leukemias may be referred together as acute myeloid (or my elocytic or my elogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polcythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); as well as

myelofibrosis (MFS) with or without agnogenic myeloid metaplasia.

Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and/or extranodal sites. Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non-

Hodgkin’s lymphomas (B-NHLs). B-NHLs may be indolent (or low-grade), intermediate- grade (or aggressive) or high-grade (very aggressive). Indolent B cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranodal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated-lymphoid tissue

(MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) witii or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHLs include Burkitt’s lymphoma (BL), Burkitt-like lymphoma, small non-cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom’s macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman’s disease. NHL may also include T-cell non-Hodgkin’s lymphoma s(T- NHLs), which include, but are not limited to T-cell non-Hodgkin’s lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T- cell lymphoma, gamma/delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome. Hematopoietic cancers also include Hodgkin’s lymphoma (or disease) including classical Hodgkin’s lymphoma, nodular sclerosing Hodgkin’s lymphoma, mixed cellularity Hodgkin’s lymphoma, lymphocyte predominant (LP) Hodgkin’s lymphoma, nodular LP Hodgkin’s lymphoma, and lymphocyte depleted Hodgkin’s lymphoma. Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenstrom’s Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues which include hematopoietic cells referred herein to as "hematopoietic cell tissues" include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyefs patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings.

Treatment of RIP 1 -mediated disease conditions may be achieved using a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a

pharmaceutically acceptable salt thereof, of as a monotherapy, or in dual or multiple combination therapy, particularly for the treatment of refractory cases, such as in combination with other anti-inflammatory and/or anti-TNF agents, which may be administered in therapeutically effective amounts as is known in the art.

The compounds of the invention, particularly the compounds of Formula (I) and Formula (II), or a pharmaceutically acceptable salt thereof, may be employed alone or in combination with one or more other therapeutic agents, e.g., pharmaceutically active compounds or biologic products (e.g., monoclonal antibodies). Combination therapies according to the present invention thus comprise the administration of at least one compound of the invention, particularly a compound of Formula (I) or Formula (II), or a

pharmaceutically acceptable salt thereof, and at least one other theraputically active agent. Combination therapies according to the present invention comprise the administration of at least one compound of tire invention, particularly a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.

For example, amelioration of tissue damage may be achieved by treatment with a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent during transplant surgery . Amelioration of tissue damage may also be achieved by short-term treatment of a patient with a compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent after transplant surgery. Amelioration of tissue damage ex vivo, that is ex vivo preservation of tissues, organs and cells may also be achieved by short-term treatment of tissues, organs and cells with a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic ally active agent, prior to or during transplant surgery.

The compound(s) of the invention, particularly tire compounds of Formula (I) and Formula (II), or pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order.

The amounts of the compound(s) of the invention, particularly a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Thus, in a further aspect, there is provided a combination comprising a compound of the invention, particularly a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.

Thus, in one aspect of this invention, a compound of the invention, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of the invention, particularly a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, may be used in combination with or include one or more other therapeutic agents, for example an anti-inflammatoiy agent and/or an anti-TNF agent.

The pharmaceutical compositions of the invention typically contain one compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention contain more than one compound of the invention. In other embodiments, the pharmaceutical compositions of the invention may comprise one or more additional therapeutic agents, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.

A compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with other anti-inflammatory agents for any of the indications above, including oral or topical corticosteroids, anti-TNF agents, 5-aminosalicyclic acid and mesalamine preparations, hydroxycloroquine, thiopurines, methotrexate, cyclophosphamide, cyclosporine, calcineurin inhibitors, mycophenolic acid, mTOR inhibitors, JAK inhibitors, Syk inhibitors, anti-inflammatory biologic agents, including anti-IL6 biologies, anti-ILl agents, anti-IL17 biologies, anti-CD22, anti-integrin agents, anti-IFNa, anti-CD20 or CD4 biologies and other cytokine inhibitors or biologies to T-cell or B-cell receptors or interleukins.

In the treatment of CVA, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with antiplatelets (e.g., aspirin, clopidogrel (Plavix®), dipyridamole (Persantine®), ticolpidine (Ticlid®); aspirin and omeprazole (Ysprala®)), anticoagulants (e.g., warfarin (Coumadin®), heparin®, dabigitran (Pradaxa®), apixaban (Eliquis®), rivaroxaban®), antihypertensives - dimetics (e.g., Hygroton®, Diuril®, Lasix®, Esidrix®, Hydrodiuril®, Microzide®, Lozol®, Mykrox®, Zaroxolyn®, Midarmar®, Aldactone®, Dyrenium®, Bumex®, Moduretic®, Aldatazide®, Dyazide®, Maxzide®), other antihypertensives - beta blockers, ace inhibitors, angiotensin II receptor blockers, calcium channel blockers, alpha blockers, alpha2 receptor agonist, combined alpha and beta-blockers, central agonists, peripheral adrenergic inhibitors, blood vessel dilators, or tissue plasminogen activator (Alteplase®).

In the treatment of SIRS, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a broad-spectrum antibiotic (such as vacomycin) or other anti-MRSA therapy (cefeprime (Maxipime®), piperacillin/tazobactam(Zosyn®), carbapenem (imipenem, meropenem, doripenem), quinolones (ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, etc.), or low dose steroids such as hydrocortisones.

In tire treatment of inflammatory bowel disease (particularly, Crohn’s disease and/or ulcerative colitis), a compound that inhibits R1P1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with vedolizumab (Entyvio®), alicaforsen, remestemcel-L (Prodiymal®), etrolizumab, eldelumab, or bertilimumab.

In the treatment of psoriasis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with ixekizumab, tildrakizumab (MK-3222), secukinumab (AIN457), Alefacept (Amevive®), calcipotriene and betametiiasone dipropionate (Enstilar®), prednisone (Ray os®), tazorac topical gel, Methotrexate (Trexall®, Rheumatrex®, Folex PFS®, Otrexup®, Rasuvo®, Methotrexate LPF Sodium®), Cyclosporine®¹, fumaric acid, acitretin®, Tretinate®, UV A, UVB, Psoralen, coal tar, TNF inhibitors (Etanercept (Enbrel®), Infliximab (Remicade®), adalimumab (Humira®); certolizumab pegol (Cimzia®)), PDE-4 inhibitors (apremilast (Otezla®)), JAK inhibitors (Tofacitinib (Xeljanz® CP-690550), IL 12/23 (ustekinumab (Stelara®)), IL17 (secukinumab (Coxentyx®), ixekizumab (Taltz®), brodalumab with AMG-827), IL23 (tildrakizumab with MK-3222, guselkumab CNTO-1959, B1 655066, itolizumab (Alzumab®), biosimilars infliximab (Remsima (Inflectra®), Sandoz GP 11111), biosimilars rituximab (CT-P10 (Mabthera®), PF-05280586 (MabThera®)), biosimilars etanercept (CHS-2014), biosimilars adalimumab (GP-2017), M-518101 topical vitamin D; Maruho GK-664, or CT-327 (topical Tropomyosin-receptor kinase A), CF-101, or dimethyl fumarate LAS-41008.

In the treatment of periodonitis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an antimicrobial agent, (such as chlorhexidine

(Peridex®, PerioChip®, PerioGard®, etc.)) or an antibiotic (such as doxycycline (Vibrox®, Periostat®, Monodox®, Oracea®, Doryx®, etc.), or minocycline (Dynacin®, Minocin®, Arestin®, Dynacin®, etc.).

In the treatment of asthma, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an inhaled corticosteroid (ICS) such as fluticasone proprionate (Flovent®), fluticasone furcate (V eramyst®/Avamys®), beclomethasone dipropionate (QVAR®), budesonide (Pulmicort), trimcinolone acetonide (Azmacort®), flunisolide (Aerobid®), mometasone fuorate (Asmanex® Twisthaler®), or Ciclesonide (Alvesco®), a long acting beta agonist (LABA) such as formoterol fumarate (Foradil®), salmeterol xinafoate (Serevent®), indacaterol (Arcapta®Neohaler®); a combination of an ICS and LABA (such as fluticasone furoate and vilanterol (Breo Ellipta®/Relvar Ellipta®), formoterol/budesonide inhalation (Symbicort®), mometasone furcate/ formoterol fumarate dihydrate (Dulera®), beclomethasone dipropionate/formoterol (Inuvair®), fluticasone propionate/eformoterol fumarate dehydrate (Flutiform®), and fluticasone

propionate/salmeterol (Advair®), a short acting beta agonist ((SABA) such as salbutamol diy- powder inhalation, albuterol sulfate (ProAir®, Proventil UFA®, Ventolin HFA®, AccuNeb® Inhalation Solution), levalbuterol tartrate (Xopenex® HFA), an antimuscarinic agent such as ipratropium bromide (Atrovent® HFA); an antimuscarinic in combination with a beta-agonist such as ipratropium bromide/albuterol (Combivent® Respimat®); a long-acting muscarinic antagonist ((LAMA) such as umeclidinium bromide (Incruse®) or tiotropium bromide (Spiriva®HandiHaler; a combination of a LAMA and a LAB A, such as umeclidinium bromide and vilanterol (Anoro®) a leukotriene modifier (sudi as montelukast sodium

(Singulair®), zafirlukast (Accolate®),or zileuton (Zyflo®), and anti-IgE (such as omalizumab (Xolair®)), a methylxanthine bronchodilator (such as theophylline (Accurbron®, Aerolate®, Aquaphyllin®, Asbron®, Bronkodyl®, Duraphyl®, Elixicon®, Elixomin®, Elixophyllin®, Labid®, Lanophyllin®, Quibron-T®, Slo-Bid®, Slo-Phyllin®, Somophyllin®, Sustaire®¹, Synophylate®, T-Phyll®, Theo-24®, Theo-Dur®, Theobid®, Theochron®, Theoclear®, Theolair®, Theolixir®, Theophyl®, Theovent®, Uni-dur®, Uniphyl®), a mast cell inhibitor (such as cromulyn sodium (Nasalcrom®) and nedocromil sodium (Tilade®)).

Other agents that may be suitable for use in combination therapy in the treatment of asthma include a protein tyrosine kinase inhibitor (masitinib), CRTH2/D-prostanoid receptor antangonist (AMG 853), an epinephrine inhalation aerosol (E004), reslizumab, Vectura^'s VR506, lebrikizumab (RG3637), a combination phosphodiesterase (PDE)-3 and (PDE)-4 inhibitor (RPL554).

In tiie treatment of COPD, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a LABA (such as salmeterol xinafoate (Serevent), aformoterol tartrate (Brovana®), formoterol fumarate inhalation powder (Foradil®), indacterol maleate (Arcapta® Neohaler®), a long-acting inhaled anticholinergic (or muscarinic antagonist, such as umeclidinium (Incruse Ellipta®), tiotropium bromide

(Spiriva®), and aclidinium bromide (Tudorza® Pressair®), a phosphodiesterase (PDE-r) inhibitor (such as roflumilast, Daliresp®), a combination ICS/LABA (such as fluticasone furcate and vilanterol (Breo Ellipta®/Relvar Ellipta®), fluticasone propionate/salmeterol (Advair®), budesonide/formoterol (Symbicort®), mometasone/formoterol (Dulera®), or fluticasone propionate/eformoterol fumarate dehydrate (Flutiform®); an antimuscarinic such as such as ipratropium bromide (Atrovent®); an antimuscarinic in combination with a beta- agonist such as ipratropium bromide/albuterol (Combivent® Respimat®); a long-acting antimuscarinic such as umeclidinium bromide (Incruse®) or tiotropium bromide (Spiriva®); umeclidinium/vilanterol (Anoro Ellipta®); a combination of a LAMA and a LABA, such as umeclidinium bromide and vilanterol (Anoro®) .

Other agents that may be suitable for use in combination therapy in the treatment of COPD include SCH527123 (a CXCR2 antagonist), glycoprronium bromide ((NVA237) Seebri® Breezhaler®), glycopyrronium bromide and indacaterol maleate ((QVA149) Ultibro® Breezhaler®), gly copyrrolate and formoterol fumarate (PT003), indacaterol maleate

(QVA149), olodaterol (Striverdi® Respimat®), tiotropium (Spiriva®)/olodaterol (Striverdi® Respimat®), and aclidinium/formoterol inhalation.

In the treatment of a mycobacterium infection (tuberculosis), a compound that inhibits R1P1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an antimycobacterial agent (such as isoniazid (INH), ehambutol (Myambutol®), rifampin (Rifadin®), and pyrazinamide (PZA)) a bactericidal antibiotic (such as rifabutin (Mycobutin®) or rifapentine (Priftin®)), an aminoglycoside (Capreomycin®), a fluorquinolone (levofloxacin, moxifloxicin, ofloxacin), thioamide (ehionamide), cyclosporine (Sandimmune®), para-aminosalicyclic acid

(Paser®), cycloserine (Seromycin®), kanamycin (Kantrex®), streptomycin, viomycin, capreomycin (Capastat®)), bedaquiline fumarate (Sirturo®), oxazolidinone (Sutezolid®), or delamanid (OPC-67683).

In the treatment of systemic scleroderma, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an oral corticosteroid (such as prednisolone (Delalsone®, Orapred, Millipred, Omnipred, Econopred, Flo-Pred), an immunosuppressive agent (such as methotrexate (Rhuematrex®, Trexall®), cyclosporine (Sandimmune®), antithymocyte globulin (Atgam®), mycophenolate mofetil (CellCept®), cyclophosphamide (Cytoxan®), FK506 (tacrolimus), thalidomide (Thalomid®), chlorambucil (Leukeran®), azathioprine (Imuran®, Azasan®)), a calcium channel blocker (such as nifedipine

(Procardia®, Adalat®) or nicardipine (Cardene®), a topical emollient (nitroglycerin ointment), an ACE inhibitor (such as lisinopril (Zestril®, Prinivil®), diltaizem (Cardizem®, Cardizem SR®, Cardizem CD®, Cardia®, Dilacor®, Tiazac®)), a serotonin reuptake inhibitor (such as fluoxetine (Prozac®)), an endothelin-1 receptor inhibitor (such as bosentan (Tracleer®) or epoprostenol (Flolan®, Veletri®, Prostacyclin®)) an anti-fibrotic agent (such as colchicines (Colcrys®), para-aminobenzoic acid (PABA), dimethyl sulfoxide (KMSO), and D-penicillamine (Cuprimine®, Depen®), interferon alpha and interferon gamma (INF-g)), a proton-pump Inhibitor (such as omeprazole (Prilosec®), metoclopramide (Reglan®), lansoprazole (Prevacid®), esomeprazole (Nexium®), pantoprazole (Protonix®), rabeprazole (Aciphex®)) or imatinib (Gleevec®) ARG201 (arGentis Pharmaceutical), belimumab (Benlysta®), tocilizumab (Actema®).

In tiie treatment of cystic fibrosis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator (ivacftor (Kalydeco®)) a mucolytic agent (such as domase alpha

(Pulmozyme®)), pancreatic enzymes (such as Pancrelipase (Creon®, Pancreaze®, Ultresa®, Zenpep®)), a bronchodilator (such as albuterol (AccuNeb®, ProAir®, Proventil HFA®, VoSpire ER®, Ventolin HFA®)), an antibiotic (including inhaled, oral or parenteral, such as tobramycin solution for inhalation (TOBI®, Bethkis®, TOBI Podhaler®), aztreonam inhalation (Azactam®, Cayston®), colistimethate sodium (Coly-Mycin®), cephalosporins (cefadroxil monohydrate (Duricef®), cefazolin (Kefzol®), cephalexin (Keflex®), cefazolin (Ancef®, etc.), fluoroquinolones (moxifloxacin, levofloxacin, gemifloxacin, etc.), azithromycin (Zithromax®), gentamicin (Garamycin®), piperacillin/tazobacam (Zosyn®), cephalexin (Keflex), ceftazidime (Fortaz, Tazicef), ciprofloxin (Cipro XR, Proquin XR), trimethoprim/sulfamethoxazolyl (Bactrim DS, Septra DS), chloramphenicol)), or ivacftor (Kalydeco®)/lumacaftor (VX-809), ataluren (Translama®), or with tiopropium bromide (Spiriva® Handihaler®) as add on to standard therapy.

In the treatment of retinitis pigmentosa, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a ciliary neurtotrophic growth factor (NT- 501-CNTF) or gene transfer agent, UshStat®.

In the treatment of macular degeneration, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with opthalmalic intravitreal injections

(afibercept (Eylea®)) or with an anti-vascular endothelial growth factor (VEGF) inhibitor (such as ranibizumab (Lucentis®) or pegaptanib sodium (Macugen®)), a ciliary neurotrophic growth factor agent (NT501), iSONEP®, or bevacizumab (Avastin®).

In the treatment of influenza, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a trivalent (IIV3) inactivated influenza vaccine (such as Afluria®, Fluarix®, Flucelvax®, FluLaval®, Fluvirin®, Fluzone®), a quadrivalent (IIV4) inactivated influenza vaccine (such as Fluarix® Quadrivalent, Flulaval® Quadrivalent, Fluzone® Quadrivalent), a trivalent recombinant influenza vaccine (such as FluBlok®), a quadrivalent live attenuated influenza vaccine (such as FluMist® Quadrivalent), an antiviral agent (such as oseltamivir (Tamiflu®), zanamivir (Relenza®), rimantadine (Flumadine®), or amantadine (Symmetrel®)), or Fluad®, Fludase, FluNhance®¹, Preflucel, or VaxiGrip®.

In the treatment of a staphylococcus infection, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with an antibiotic (such as a b-Lactam cephalosporin (Duricef®, Kefzol®, Ancef®, Biocef®, etc.), nafcillin (Unipen®), a sulfonamide (sulfamethoxazolyl and trimethoprim (Bacrim®, Septra®,) sulfasalazine (Azulfidine®), acetyl sulfisoxazolyl (Gantrisin®, etc.), or vancomycin (Vancocin®)).

In the treatment of transplant rejection, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a high-dose corticosteroid (such as prednisone (Deltasone®), methylprednisolone (SoluMedrol®) etc.) a calcineurin inhibitor (such as cyclosporine (Sandimmune®, Neoral®, Gengraf®), tacrolimus (Prograf®, Astragraf XL®)), an mTor inhibitor (such as sirolimus (Rapamune®) or everolimus (Afinitor®)), an anti-proliferative agent (such as azathioprine (Imuran®, Azasan®), mycophenolate mofetil (CellCept®), or mycophenolate sodium (Myfortic®)), a monoclonal antibo<ty (such as muromonab-CD3 (Orthoclone OKT3®)),an interleukine-2 receptor antagonist

((Basiliximab®, Simulect®), daclizumab (Zenapax®), or rituximab (Rituxan®)), a polyclonal anti-T-cell antibody (such as anti-thymocyte gamma globulin-equine (Atgam®), or antithymocyte globulin-rabbit (Thymoglobulin®)) an anti-CD40 antagonist (ASKP-1240), a JAK inhibitor (ASP015K), or an anti-TCR murine mAb (TOL101 ).

In tiie treatment of atopic dermatitis, a compound that inhibits RIP1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a topical immunomodulator or calcineurin inhibitor (such as pimecrolimus (Elidel®) or tacrolimus ointment (Protopic®)), a topical corticosteroid (such as hydrocortizone (Synacort®, Westcort®), betamethasone (Diprolene®), flurandrenolide (Cordan®), fluticasone (Cutivate®), triamcinolone (Kenalog®), fluocinonide (Lidex®), and clobetasol (Temovate®)), an oral corticosteroid (such as hydrocortisone (Cortef®), methylprednisolone (Medrol®), or prednisolone (Pediapred®, Prelone®), an immunosuppressant (such as cyclosporine (Neoral®) or interferon gamma (Alferon N®, Infergen®, Intron A, Roferon-A®)), an antihistamine (for itching such as Atarax®, Vistaril®, Benadryl®), an antibiotic (such as penicillin derivatives flucloxacillin (Floxapen®) or dicloxacillin (Dynapen®), erythromycin (Eryc®, T-Stat®, Erythra-Derm®, etc.)), anon- steroidal immunosuppressive agent (such as azathioprine (Imuran®, Azasan®), methotrexate (Rhuematrex®, Trexall®), cyclosporin (Sandimmime®), or mycophenolate mofetil

(CellCept®)).

In the treatment of spondyloarthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, may be administered in combination with NS AIDs, DMARDs such as Sulfasalazine®¹,

Methotrexate®, and corticosteroids; prednisolone delayed-release tablets (Rayos®), TNF inhibitors (Enbrel®, Remicade®, Humira® and Simponi®), or IL-17A (Cosentyx®).

In the treatment of systemic onset juvenile idiopathic arthritis (sJIA), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a

pharmaceutically acceptable salt thereof, may be administered in combination with NSAIDs such as Celebrex®, diclofenac (Voltaran®), ibuprofen (Advil®, Motrin®), naproxen (Aleve, Naprosyn®), corticosteroids (prednisone, glucocorticoids), Methotrexate®¹, or biologies (ankinra (Kineret®), tocilizumab (Actemra®), canakinumab (ILARIS®)).

In tiie treatment of osteoarthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with analgesics and NSAIDs (acetaminophen, opioid narcotics (e.g., tramadol®, Vicodin®, Darvon®, Percocet®); ibuprofen and famotidine (Duexis®); Etadolac®; naproxen sodium (Naprelan®), diclofenac sodium topical solution (Pennsaid®); sodium hyaluronate (Supartz®); meloxicam (Vivlodex®, Mobic®);

acetaminophen, ibuprofen, aspirin, Celecoxib®, COX-2 (Celebrex®), valdecoxib (Bextra®)), corticosteroid injections, hyaluronic acid injection (Gelsyn-3®); hylan GF 20 (Synvisc, ® Synvisc-One®), or duloxetine hydrochloride (Cymbalta®).

In the treatment of or medication management of Huntington’s disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with tetrabenazine (Xenazine®), antipsychotic drugs (haloperidol (Haldol®), chlorpromazine HCL (Thorazine®), risperidone (Risperdal®) and quetiapine (Seroquel®)), drugs to suppress chorea (amantadine, devetiracetam (Keppra®), clonazepam (Klonopin®)), antidepressants (dtalopram (Celexa®, Lexapro®), fluoxetine (Prozac®, Sarafem®), sertraline (Zoloft®)), antipsychotics (quetiapine (Seroquel®), risperidone (Risperdal®), olanzapine (Zyprexa®)), or mood-stabilizing drugs (vaproate (Depacon®), carbamazepine (Carbatrol®, Epitol®, Equetro®), lamotrigine (Lamictal®)).

In the treatment of Alzheimer’s, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with Donepzil hydrocholoride (Aricept®), Rivas tigmine tartrate (Exelon®), caprylidene (Axona®), butoconazole nitrate 2% (Femstat 3®),

Galantamine hydrobromide (Razadyne®, Reminyl®), Memantine HCL (Namenda®), memantine hy drocholoride ext aided release + donepezil hy drochloride (Namzaric®),

Solanezumab, beta-secretase with Merck (MK-8931), beta-secretase with Cerespir (CSP- 1103), or drugs that targets tau protein (AADvacl).

In the treatment of amyotrophic lateral sclerosis (ALS), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a glutamate blocker (Riluzole, Rilutek®).

In the treatment of amyotrophic lateral sclerosis (ALS), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with a edaravone (Radicava®, Radicut®).

In the treatment of symptoms with ALS, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with quinidine (Nuedexta®), anticholinergics (amitriptyline®, Artane®, scopolamine patch (Transderm Scop®)), sympathomimetics (pseudoephedrine), mucolytics (guaifenesin), or analgesics (tramadol (Ultram®); ketorolac (Toradol®); morphine; fentanyl patch (Duragesic®)).

In the treatment of multiple sclerosis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with corticosteroids (prednisone,

methylprednisolone), Interferon Beta 1 -A (Avonex®, Extavia®, Rebif®, Betaseron®), peginterferon beta-IA (Plegridy®), Glatiramer acetate (Copaxone®); glatiramer acetate (Glatopa® - generic equivaleit of Copaxone); Dimethyl fumarate (Tecfidera®); Fingolimod (Gilenya®); teriflunomide (Aubagio®); dalfampridine (Ampyra®); daclizumab (Zinbryta); alemtuzumab (Lemtrada®); natalizumab (Tysabri®); or mitoxantrone hydrochloride (Novantrone®).

In the treatment of gaucher disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with enzyme replacement therapy (imiglucerase (Cerezyme®), velaglucerase alfa (VPRIV®), taliglucerase alfa (Elelyso®)) or substrate reduction therapy (miglustat (Zavesca®), eliglustat (Cerdelga®)).

In the treatment of Niemann-Pick Disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with bone marrow transplant, enzyme replacement therapy, gene therapy, miglustat (Zavesca®), Arimoclomol (BRX-345), NCT02612129, Hydroxypropyl-beta-cyclodexin (HPbCD), NCT01747135, or

Hydroxypropyl-P-cyclodextrin (VTS-2702) (NCT02534844).

In tiie treatment of rheumatoid arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with Tocilizumab (Actemra®), Arava, sulfasalazine delayed release tablets (Azulfidine EN-tabs®, Bextra, certolizumab pegol (Cimzia®), ibuprofen and famotidine (Duexis®), naproxen sodium (Etodolac®), adalimumab (Humira®), Kineret; etodolac (Lodine®), naproxen sodium (Naprelan), abatacept (Orencia), prednisone (Rayos®), inflimimab (Remicade®), golimuma (Simponi®), rofecoxib (Vioxx®), tofadtinib (Xeljanz®), methotrexate (Trexall®, Rheumatrex®, Folex PFS®, Otrexup®, Rasuvo®, Methotrexate LPF Sodium®, selective JAK1 & JAK2 inhbitor (baracitinib), antiseise oligonucleotide (alicafosen), biosimilars for infliximab (Remsima (Inflectra®)), GS-071 infliximab (Aprogen), SB2 infliximab, PF-06438179 infliximab, GP 11111, biosimilars for rituximab (CT-P10 rituximab Celltrion), BI-695500, GP-2013, PF-05280586, biosimilars for etanercept (etanercept SB4 (Brenzys™), Benepali®; CHS-0214 etanercept, GP-2015, biosimilars for adalimumab (ABP-501 adalimumab, BI-695501,

Samsung SB5, GP-2017. PF-06410293, Momenta M923, or biosimilar for abatacept (M834).

In the treatment of ulcerative colitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with alicafosen, Mesalamine (Asacol®), balsalazide disodium (Colazal®), vedolizumab (Entyvio®), golimumab (Simponi®), budesonide (Uceris®), adalimumab (Humira®), RG-7413 (alpha4beta7 integrin), CNTO- 1275 (ustekinumab), biosimiar infliximab (Remsima (Inflectra®)), BMS eldelumab (CXCL 10), or Immune Pharma bertilimumab (CCR3).

In the treatment of Crohn’s disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered in combination with Remestemcel-L (Prochymal®), vedolizumab (Entyvio®), ustekinumab (Stelara®), certolizumab pegol (Cimzia®), natalizumab (Tysabri®), budesonide (Entocort EC®), .anti-inflammatories (mesalamine (Lialda®, Apriso®, Canasa®, Asacol®, Rowasa®), sulfasalazine (Azulfidine®¹)), steroids (hydrocortisone, prednisone), immunosuppressants (methotrexate (Trexall®, Rasuvo®, Rheumatrex®), infliximab (Remicade®), azathioprine (Azasan®, Imuran®), adalimumab (Humira®), mercaptopurine (Purinethol®, Purixan®); cyclosporine (Gengraf®, Neoral®, Sandimuune®); tacrolimus (Astagraf XL®, Hecoria®)), or antibiotics (metronidazole

(Flagyl®, Metrogel®, Noritate®, MetroCream®, Rosadan®, MetroLotion®); ciprofloxacin (Cipro®)).

In one embodiment of this invention, the at least one other therapeutically active agent is selected from a thrombolytic agent, a tissue plasminogen activator, an anticoagulant, and a platelet aggregation inhibitor. In another embodiment, the at least one other therapeutically active agent is selected from heparin, coumadin, clopidrogel, dipyridamole, ticlopidine HCL, eptifibatide, and aspirin. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is a cerebrovascular accident.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from broad-spectrum antibiotic, anti-MRSA therapy and a low dose steroid. In another embodiment, the at least one other therapeutically active agent is selected from vacomycin, cefeprime, a combination of piperacillin and tazobactam, imipenem, meropenem, doripenem, ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin, and hydrocortisone. In one embodiment, the R1P1 kinase-mediated disease or disorder treated with these agents is systemic inflammatory' response syndrome.

In one embodiment of this invention, the at least one other therapeutically active agent is alicaforse or remestemcel-L. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is Crohn’s disease or ulcerative colitis. In one embodiment of this invention, the at least one other therapeutically active agent is ixekizumab, or tildrakizumab. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is psoriasis.

In one embodiment of this invention, the at least one other therapeutically active agent is an antimicrobial agent or an antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from chlorhexidine, doxy cy dine and minocycline. In one embodiment, the R1P1 kinase-mediated disease or disorder treated with these agents is periodonitis.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from an inhaled corticosteroid, a long acting beta agonist, a combination of an inhaled corticosteroid and a long acting beta agonist, a short acting beta agonist, a leukotriene modifier, an anti-IgE, a methylxanthine bronchodilator, a mast cell inhibitor, and a long-acting muscarinic antagonist. In another embodiment, the at least one other therapeutically active agent is selected from fluticasone proprionate, beclomethasone dipropionate, budesonide, trimcinolone acetonide, flunisolide, mometasone fuorate, or ciclesonide, formoterol fumarate, salmeterol xinafoate, a combination of fluticasone furoate and vilanterol, a combination of formoterol and budesonide inhalation, a combination of beclomethasone dipropionate and formoterol, a combination of fluticasone propionate and salmeterol, albuterol sulfate, levalbuterol tartrate, a combination of ipratropium bromide and albuterol, ipratropium bromide, montelukast sodium, zafirlukast, zileuton, omalizumab theophylline, cromulyn sodium, nedocromil sodium, and a combination of mometasone furoate and formoterol fumarate dihydrate. In another embodiment, the at least one other therapeutically active agent is selected from protein tyrosine kinase inhibitor, a CRTH2/D-prostanoid receptor antangonist, an epinephrine inhalation aerosol, and a combination of a phosphodiesterase-3 inhibitor and a phosphodiesterase-4 inhibitor. In another embodiment, the at least one other therapeutically active agent is selected from masitinib, AMG 853, indacaterol, E004, a combination of fluticasone furoate and fluticasone proprionate, a combination of vinanterol fluticasone furoate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, reslizumab, salbutamol, tiotropium bromide, a combination of formoterol and budesonide, fluticasone furoate, VR506, lebrikizumab, and RPL554. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is asthma.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from a long acting beta agonist, a long-acting inhaled anticholinergic or muscarinic antagonist, a phosphodiesterase inhibitor, a combination an inhaled corticosteroid long acting beta agonist, a short acting beta agonist, and an inhaled corticosteroid. In another

embodiment, the at least one other therapeutically active agent is selected from salmeterol xinafoate, a combination of umeclidinium and vilanterol, umeclidinium, aformoterol tartrate, formoterol fumarate, indacterol maleate, a combination of fluticasone propionate and eformoterol fumarate dehydrate, tiotropium bromide, aclidinium bromide, roflumilast, a combination of fluticasone furoate and vilanterol, a combination of fluticasone propionate and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of ipratropium bromide and albuterol sulfate, a combination of albuterol and ipratropium, ipratropium bromide, albuterol sulfate, budesonide, fluticasone propionate, and beclometasone dipropionate. In another embodiment, the at least one other therapeutically active agent is selected from SCH527123, glycoprronium bromide, a combination of glycopyrronium bromide and indacaterol maleate, a combination of glycopyrrolate and formoterol fumarate, indacaterol maleate, olodaterol, tiotropium, olodaterol, and a combination of aclidinium and formoterol. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is COPD.

In one embodiment of this invention, tbe at least one other therapeutically active agent is an antimycobacterial agent or a bactericidal antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from isoniazid, ehambutol, rifampin, pyrazinamide, rifabutin, rifapentine, capreomycin, levofloxacin, moxifloxicin, ofloxacin, ehionamide, cycloserine, kanamycin, streptomycin, viomydn, bedaquiline fumarate, PNU- 100480, and delamanid. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is a mycobacterium infection.

In one embodiment of this invention, tbe at least one other therapeutically active agent is selected from an oral corticosteroid, anti-thymocyte globulin, thalidomide, chlorambucil, a calcium channel blocker, a topical emollient, an ACE inhibitor, a serotonin reuptake inhibitor, an endothelin-1 receptor inhibitor, an anti-fibrotic agent, a proton-pump inhibitor or imatinib, ARG201, and tocilizumab. In another embodiment, the at least one other therapeutically active agent is selected from prednisolone, anti-thymocyte globulin, FK506 (tacrolimus), thalidomide, chlorambucil, nifedipine, nicardipine, nitroglycerin ointment, lisinopril, diltaizem, fluoxetine, bosentan, epoprostenol, colchicines, para-aminobenzoic acid, dimethyl sulfoxide, D-penidllamine, interferon alpha, interferon gamma (INF-g)), omeprazole, metoclopramide, lansoprazole, esomeprazole, pantoprazole, rabeprazole, imatinib, ARG201, and tocilizumab. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is systemic scleroderma.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from a cystic fibrosis transmembrane conductance regulator potentiator, a mucolytic agent, pancreatic enzymes, a bronchodilator, an antibiotic, or ivacftor/lumacaftor, ataluren, and tiopropium bromide. In another embodiment, the at least one other

therapeutically active agent is selected from ivacftor, domase alpha, pancrelipase, albuterol, tobramycin, aztreonam, colistimethate sodium, cefadroxil monohydrate, cefazolin, cephalexin, cefazolin, moxifloxacin, levofloxadn, gemifloxacin, azithromycin, gentamicin,

piperacillin/tazobacam, ceftazidime, ciprofloxin, trimethoprim/sulfamethoxazolyl, chloramphenicol, or ivacftor/lumacaftor, ataluren, and tiopropium bromide. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is cy stic fibrosis.

In one embodiment of this invention, the at least one other therapeutically active agent is a ciliary neurtotrophic growth factor or a gene transfer agent. In another embodiment, the at least one other therapeutically active agent is NT-501-CNTF or a gene transfer agent encoding myosin VILA (MY07A). In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is retinitis pigmentosa.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from opthalmalic intravitreal injections, an anti-vascular endothelial growth factor inhibitor, and a ciliary neurotrophic growth factor agent. In another embodiment, the at least one other therapeutically active agent is selected from afibercept, ranibizumab, pegaptanib sodium, NT501, humanized sphingomab, and bevacizumab. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is macular degeneration.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from a trivalent (ILV3) inactivated influenza vaccine, a quadrivalent (IIV4) inactivated influenza vaccine, a trivalent recombinant influenza vaccine, a quadrivalent live attenuated influenza vaccine, an antiviral agent, or inactivated influenza vaccine. In another embodiment, the at least one other therapeutically active agent is selected from oseltamivir, zanamivir, rimantadine, or amantadine. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is influenza.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from a b-Lactam, nafcillin, sulfamethoxazolylm, trimethoprim, sulfasalazine, acetyl sulfisoxazolyl, and vancomycin. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is a staphylococcus infection.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from a monoclonal antibody, a polyclonal anti-T-cell antibody, an anti-thymocyte gamma globulin-equine antibody, an antithymocyte globulin-rabbit antibody, an anti-CD40 antagonist, a JAK inhibitor, and an anti-TCR murine mAb. In another embodiment, the at least one other therapeutically active agent is selected from muromonab-CD3, ASKP-1240, ASP015K, and TOL101. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is transplant rejection.

In one embodiment of this invention, the at least one other therapeutically active agent is selected from a topical immunomodulator or calcineurin inhibitor, a topical corticosteroid, an oral corticosteroid, an interferon gamma, an antihistamine, or an antibiotic. In another embodiment, the at least one other therapeutically active agent is selected from pimecrolimus, tacrolimus, hydrocortizone, betamethasone, flurandrenolide, fluticasone, triamcinolone, fluocinonide, clobetasol, hydrocortisone, methylprednisolone, prednisolone, an interferon alpha protein, a recombinant synthetic ty pe I interferon, interferon alpha-2a, interferon alpha- 2b, hydroxyzine, diphenhydramine, flucloxacillin, dicloxacillin, and erythromycin. In one embodiment, the RIP1 kinase-mediated disease or disorder treated with these agents is atopic dermatitis.

In another embodiment, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a patient in need thereof, in combination with at least one other therapy and/or with at least one other active therapeutic agent that is considered standard of care (U.S. Department of Health and Human Services, Agency for Healthcare Research and Quality, National Guideline Clearinghouse, https://www.guideline.gov/ and World Health Organization, http://www.who.int/management/quality/standards/en/) for any of the diseases and/or disorders recited herein.

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a patient in need thereof, in combination with at least one other active therapeutic agent, wherein the at least one other active therapeutic agent is: a corticosteroid [administered orally, topically, by injection, or as a suppository; prednisone, methylprednisolone, prednisolone, budesonide, betamethasone, dexamethasone, hydrocortisone, triamcinolone, fluticasone (fluticasone furcate, fluticasone propionate), fludroxycortide (flurandrenolide, flurandrenolone), fluocinonide, clobetasol (clobetasol propionate)], an anti-TNF biologic agent (etanecerpt, adalimumab, infliximab, certolizumab, golimumab), an other biologic agent (vedolizumab, etrolizumab, eldelumab, or bertilimumab), biosimilars to any of the above biologic agents, a PDE-4 inhibitor (apremilast), 5-aminosalicyclic acid (mesalazine/mesalamine; sulfasalazine, balsalazide), a DMARD (a disease-modifying anti-rheumatic drug: methotrexate, hydroxychloroquine, sulfasalazine, leflunomide), a thiopurine (azathioprine,

mercaptopurine), a JAK inhibitor (tofadtinib, Baracitinib), an NS AID (aspirin,

acetaminophen, ibuprofen, naproxen (naproxen sodium), etodolac, celecoxib, diclofenac, meloxicam), an anti-IL6 biologic agent (tocilizumab), an anti-ILl biologic agent (anakinra, canakinumab, rilonacept), an anti-IL12 or IL23 biologic agent (ustekinumab, risankizumab, guselkumab, lildrakizumab), an anti-CD6 biologic agent (itolizumab), an anti-integrin agent (natalizumab (Tysabri®), etrolizumab), an anti-ILl 7 biologic agent (secukinumab, ixekizumab, brodalumab), an anti-CD22 biologic agent (epratuzumab), an anti-CD20 biologic agent (rituximab, ofatumumab), an anti-CD20 or CD4 biologic agent and other cytokine inhibitor or biologic to T-cell or B-cell receptors or interleukins, T cell inhibitors (abatacept) a calcineurin inhibitor (cyclosporine, pimecrolimus,

tacrolimus), acitretin, fumaric acid, dimethyl fumarate, cyclophosphamide, cyclosporine (or ciclosporin), methotrexate, mycophenolic acid (or mycophenolate mofetil), topical vitamin D (calcipotriol or calcipotriene), an mTOR inhibitor (temsirolimus, everolimus), a Syk inhibitor (fostamatinib), an anti-IFNa biologic agent (sifalimumab), a retinoid

(tazarotene), coal tar preparations, aryl hydrocarbon receptor agonist or modulating agent (tapinarof), hydroxyurea, 6-tioguanineor light therapy with or without psoralen.

Examples of other active therapeutic agents that may be used in combination with a compound of this invention for the treatment of ulcerative colitis and/or Crohn’s disease include vedolizumab, etrolizumab, eldelumab, or bertilimumab.

Examples of other suitable biologic agents include abatacept, belimumab, and alicafosen. Examples of other active therapeutic agent that may be used in combination with a compound of this invention include baracitinib and Remestemcel-L.

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a pediatric or an adult patient in need thereof, in combination with at least one other therapy, for example, in combination with UVA and/or UVB phototherapy as indicated for the treatment of psoriasis.

In the treatment of pediatric and/or adult psoriasis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms including body surface area, pruritis, nail disease, and scalp involvement, and to improve quality of life, in pediatric and/or adult patients with moderate to severe psoriasis.

In the treatment of pediatric and/or adult psoriasis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, max' be administered as initial treatment or after treatment with another agent in pediatric and/or adult patients with moderate to severe psoriasis.

In the treatment of pediatric and/or adult psoriasis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to maintain reductions in signs and symptoms and improvements in quality of life after treatment with another agent in pediatric and/or adult patients with moderate to severe psoriasis.

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered for the treatment of moderately to severely active rheumatoid arthritis.

In the treatment of rheumatoid arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms, to induce a major clinical response, to inhibit the progression of structural damage, or to improve physical function in a patient, particularly an adult patient with moderately to severely active rheumatoid arthritis.

In the treatment of rheumatoid arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate or other nonbiologic disease-modifying anti-rheumatic drugs (DMARDs). In a specific embodiment, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate, or corticosteroids in the treatment of rheumatoid arthritis.

In the treatment of juvenile idiopathic arthritis (JIA), a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

In the treatment of juvenile idiopathic arthritis, particularly polyarticular juvenile idiopathic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (H), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate.

In the treatment of psoriatic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms, inhibiting the progression of structural damage, of active arthritis, and/or to improve physical function in adult patients with psoriatic arthritis.

In the treatment of psoriatic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate, corticosteroids, or other non-biologic disease-modifying anti-rheumatic drags (DMARDs).

In a specific embodiment, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, maybe administered alone or in combination with methotrexate for the treatment of psoriatic arthritis.

In the treatment of psoriatic arthritis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to a patient, particularly an adult patient with moderate to severe chronic plaque psoriasis, who is a candidate for systemic therapy or phototherapy.

In the treatment of axial Spondyloarthritis and ankylosing spondylitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of active ankylosing spondylitis in a patient, either an adult or a pediatric patient, in need thereof

In the treatment of axial Spondyloarthritis and ankylosing spondylitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered alone or in combination with methotrexate, corticosteroids, or other non-biologic disease-modifying anti-rheumatic drugs

(DMARDs).

In the treatment of Crohn’s Disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of Crohn’s disease. A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (H), or a pharmaceutically acceptable salt thereof, may be administered to induce or maintain a clinical response (clinical remission) in a patient, particularly an adult patient with moderately to severely active Crohn’s disease.

In tiie treatment of Crohn’s Disease, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of Crohn’s disease. A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (H), or a pharmaceutically acceptable salt thereof, may be administered to induce or maintain a clinical response (clinical remission) in a patient, particularly a pediatric patient 6 years of age and older with moderately to severely active Crohn’s disease.

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to reduce the signs and symptoms of Crohn’s disease, particularly, moderately to severely active Crohn’s disease, in a patient who has had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, may be administered to treat a patient, particularly an adult patient or a pediatric patient 6 years and older, with moderately to severely active ulcerative colitis.

In the treatment of ulcerative colitis, a compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to induce and/or sustain clinical remission in a patient, particularly an adult patient or a pediatric patient 6 years and older, with moderately to severely active ulcerative colitis.

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered to induce and/or sustain a clinical response (clinical remission) in a patient, particularly a patient with moderately to severely active ulcerative colitis, who has had an inadequate response to immunosuppressants such as aminosalicylates, corticosteroids, azathioprine or 6- mercaptopurine (6-MP).

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, may be administered for the treatment of moderate to severe hidradenitis suppurativa.

A compound that inhibits RIP 1 kinase, particularly a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, may be administered for the treatment of uveitis, particularly non-infectious intermediate, posterior and panuveitis, in a patient, particularly an adult patient, in need thereof.

Accordingly, one embodiment of this invention is directed to a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of the invention. Another embodiment of this invention is a method of inhibiting RIP1 kinase comprising contacting a cell with a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof. A particular embodiment of this invention is to a method of inhibiting RIP 1 kinase comprising contacting a cell with a compound of Formula (P) or Formula (II) or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention is directed to a method of treating a RIP 1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention is directed to a method of treating a RIP1 kinase-mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof. In a particular embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention is directed to a method of treating a RIP1- mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of the compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating a RIP 1 -mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of the compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating a RIP 1 -mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of the compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (1) or Formula (P), or pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating a RIPl-mediated disease or disorder disclosed hererin in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof.

In another embodiment, the invention is directed to a method of treating a RIP1- mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (1) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating a RIP 1 -mediated disease or disorder (for example, a disease or disorder recited herein) in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating a RIP 1 -mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating a RIP1- mediated disease or disorder disclosed herein in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) or Formula (P), or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent. In another embodiment, the invention is directed to a method of treating amyotrophic lateral sclerosis in a human in need thereof comprising administering to tiie human a therapeutically effective amount of a compound disclosed herein, or

pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound disclosed herein, or pharmaceutically acceptable salt thereof, which further comprises at least one other therapeutically active agent.

This invention also provides a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, for use in therapy. This invention provides a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder (for example, a disease or disorder recited herein). This invention provides a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase- mediated disease or disorder disclosed herein.

In another embodiment, this invention provides a compound of tiie invention for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein. This invention provides a compound described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein.

This invention specifically provides for the use of a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance. More specifically, this invention provides for the use of the compounds described herein for the treatment of a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein. Accordingly, the invention provides for the use of a compound of Formula (I) or Formula (II) as an active therapeutic substance in the treatment of a human in need thereof with a RIP1 kinase-mediated disease or disorder, specifically, a disease or disorder recited herein.

This invention further provides for the use of a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof. In another embodiment, this invention provides for the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

The invention further provides for the use of a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. Specifically, the invention also provides for the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder, for example the diseases and disorders recited herein. In one embodiment, this invention further provides for the use of a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder disclosed herein. Specifically, the invention also provides for the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a RIP1 kinase- mediated disease or disorder disclosed herein.

The compounds of the invention max' be administered by any suitable route of administration, including both systemic administration and topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion. Inhalation refers to administration into the patient's lungs whether inhaled through the mouth or through the nasal passages. Topical administration includes application to the skin.

The compounds of the invention may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half-life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the disease or disorder being treated, the severity of the disease or disorder being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens max' require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change. Total daily dosages range from 1 mg to 2000 mg. For use in therapy, the compounds of the invention wall be normally, but not necessarily, formulated into a pharmaceutical composition prior to administration to a patient. Accordingly, the invention also is directed to pharmaceutical compositions comprising a compound of the invention and one or more pharmaceutically acceptable excipients. The invention is directed to a pharmaceutical composition comprising a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

The invention is further directed to a pharmaceutical composition comprising a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and at least one other therapeutically active agent, specifically one or two other therapeutically active agents, more specifically one other therapeutically active agent.

The pharmaceutical compositions of the invention may be prepared and packaged in bulk form wherein an effective amount of a compound of the invention can be extracted and then given to the patient such as with powders, syrups, and solutions for injection.

Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form A dose of the pharmaceutical composition contains at least a therapeutically effective amount of a compound of this invention (i.e., a compound of Formula (I) or Formula (P), or a pharmaceutically acceptable salt, thereof). When prepared in unit dosage form, the pharmaceutical compositions may contain from 1 mg to 1000 mg of a compound of this invention.

As provided herein, unit dosage forms (pharmaceutical compositions) containing from 1 mg to 1000 mg of a compound of the invention may be administered one, two, three, or four times per day, preferably one, two, or three times per day, and more preferably, one or two times per day, to effect treatment of a RIP1 kinase-mediated disease or disorder.

The compounds of the invention and the pharmaceutically acceptable excipient or excipients will typically be formulated into a dosage form adapted for administration to the patient by the desired route of administration. Conventional dosage forms suitable for use with the compounds of this invention include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration such as sterile solutions, suspensions, and powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6) topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients may be chosen for a particular function that they may serve in the composition. For example, certain pharmaceutically acceptable excipients max' be chosen for their ability to facilitate the production of uniform dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be chosen for their ability to facilitate the carrying or transporting the compound or compounds of the invention once administered to the patient from one organ, or portion of the body, to another organ, or portion of the body. Certain pharmaceutically acceptable excipients may- be chosen for their ability to enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents. The skilled artisan will appreciate that certain pharmaceutically acceptable excipients may serve more than one function and may serve alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enable them to select suitable pharmaceutically acceptable excipients in appropriate amounts for use in the invention. In addition, there are a number of resources that are available to the skilled artisan which describe pharmaceutically acceptable excipients and may be useful in selecting suitable pharmaceutically acceptable excipients. Examples include Remington's

Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (the American Pharmaceutical Association and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared using techniques and methods known to those skilled in the art. Some of the methods commonly used in the art are described in Remington’s Pharmaceutical Sciences (Mack Publishing Company). Accordingly, another embodiment of this invention is a method of preparing a

pharmaceutical composition comprising the step of admixing a compound of Formula (I) or Formula (II), or a pharmaceutically acceptable salt, thereof, with one or more

pharmaceutically acceptable excipients.

In one aspect, the invention is directed to a topical dosage form such as a cream, ointment, lotion, paste, or gel comprising an effective amount of a compound of the invention and one or more pharmaceutically acceptable excipients. Lipophilic formulations, such as anhydrous creams and ointments, generally will have a base derived from fatty alcohols, and polyethylene glycols. Additional additives include alcohols, non-ionic surfactants, and antioxidants. For ointments, the base normally will be an oil or mixture of oil and wax, e.g., petrolatum. Also, an antioxidant normally will be included in minor amounts. Because the compositions are applied topically and the effective dosage can be controlled by the total composition applied, the percentage of active ingredient in the composition can vary widely. Convenient concentrations range from 0.5% to 20%.

Topically applied gels can also be a foamable suspension gel comprising a compound of the invention, as an active agent, one or more thickening agents, and optionally, a dispersing/wetting agent, a pH-adjusting agent, a surfactant, a propellent, an antioxidant, an additional foaming agent, a chelating/sequestering agent, a solvent, a fragrance, a coloring agent, a preservative, wherein the gel is aqueous and forms a homogenous foam.

In one aspect, the invention is directed to a topical dosage form that can be administered by inhalation, that is, by intranasal and oral inhalation administration.

Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques. Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants. Solutions for inhalation by nebulization may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials.

Formulations for administration by inhalation or foamable gel often require the use of a suitable propellant. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated using a suitable powder base such as lactose or starch.

In another aspect, the invention is directed to a solid oral dosage form such as a tablet or capsule comprising an effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g. com starch, potato starch, and pre-gelatinized starch), cellulose and its derivatives (e.g. microcrystalline cellulose), calcium sulfate, and dibasic calcium phosphate. The oral solid dosage form may further comprise a binder. Suitable binders include starch (e.g. com starch, potato starch, and pre-gelatinized starch), gelatin, acacia, sodium alginate, alginic acid, tragacanth, guar gum, povidone, and cellulose and its derivatives (e.g. microcrystalline cellulose). The oral solid dosage form may further comprise a disintegrant. Suitable disintegrants include crospovidone, sodium starch glycolate, croscarmelose, alginic acid, and sodium carboxymethyl cellulose. The oral solid dosage form may further comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate, and talc.

DEFINITIONS

As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon group having the specified number of carbon atoms. The term "(Ca-Cejalkyl" refers to an alkyl moiety containing from 2 to 6 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, «-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and /-butyl.

When a substituent term such as "alkyl" is used in combination with another substituent term, for example as in“(C₄-Ce)cycloalkyl-alkyl-”, the linking substituent term (e.g., alkyl) is intended to encompass a multi-valent moiety, wherein the point of attachment is through that linking substituent. Generally, the linking substituent is di-valent. An example of a“(C3-C?)cycloalkyl-alkyl-” group includes, but is not limited to, cyclopentyl-methyl-.

The term '¾alo(C i-C₄)alkyl” represents a group having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms. Examples of "halo(C₁-C₄)alkyl" groups include, but are not limited to, -CFs (trifluoromethyl), -CCb (trichloromethyl), 1,1-difluoroethyl, 2,2,2- trifluoroethyl, and hexafluoroisopropyl.

"Alkenyl" refers to straight or branched hydrocarbon group having at least 1 and up to 3 carbon-carbon double bonds. Examples include ethenyl and propenyl.

"Alkoxy" refers to an "alkyl-oxy-" group, containing an alkyl moiety attached through an oxygen linking atom For example, the term "(C₁-C₄)alkoxy" represents a saturated, straight or branched hydrocarbon moiety having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(C₁-C₄)alkoxy" groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, and /- butoxy.

The term ^c¾alo(C₁-C₄)alkoxy” refers to a "haloalkyl-oxy-" group, containing a “halo(C₁-C₄)alkyl” moiety' attached through an oxygen linking atom, which

halo(C₁-C₄)alkyl” refers to a moiety having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety containing from 1 to 4 carbon atoms. Exemplary“halo(C₁-C₄)alkoxy” groups include, but are not limited to, - OCHFa (difluoromethoxy), -OCFs (trifluoromethoxy), -OCH2CF3 (trifluoroethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy).

“Cycloalkyl” refers to a non-aromatic, saturated, cyclic hydrocarbon group containing the specified number of carbon atoms. For example, the term“(C3-C6)cycloalkyl” refers to a non-aromatic cyclic hydrocarbon ring having from three to six ring carbon atoms. Exemplary“(C3-C6)cycloalkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

"Aryl" refers to a group or moiety comprising an aromatic, monocyclic or bicyclic hydrocarbon radical containing from 6 to 10 carbon ring atoms and having at least one aromatic ring. Examples of "aryl" groups are phenyl, naphthyl, indenyl, and dihydroindenyl (indanyl). Generally, aryl is phenyl.

A heterocyclic group is a cyclic group having, as ring members, atoms of at least two different elements, which cyclic group may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).

"Heterocycloalkyl" refers to a non-aromatic, monocyclic or bicyclic group containing 3-10 ring atoms, being saturated and containing one or more (generally one or two) ring heteroatoms independently selected from oxygen, sulfur, and nitrogen. Examples of “heterocycloalkyl” groups include, but are not limited to, aziridinyl, thiiranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-dioxanyl, 1,4-oxathiolanyl, 1,4- oxatiiianyl, 1,4-dithianyl, morpholinyl, and thiomorpholinyl, and dihydroimidazole.

The term "5-6-membered heterocycloalkyl" represents a nonaromatic, monocyclic group, which is fully saturated, containing 5 or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. Illustrative examples of 5 to 6-membered heterocycloalkyl groups include, but are not limited to pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, and dihydroimidazole.

"Heteroaryl" represents a group or moiety comprising an aromatic monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic- aryl groups containing either an aryl ring moiety fused to a heterocycloalkyl ring moiety or a heteroaryl ring moiety fused to a cycloalkyl ring moiety.

Illustrative examples of heteroaryls include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl (pyridyl), oxo-pyridyl (pyridyl-N-oxide), pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3- dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzothiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7- naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl.

As used herein, "5-6-membered heteroaryl" represents an aromatic monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Examples of 5- membered heteroaryl groups include furyl (furanyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl and oxo-oxadiazolyl. Selected 6-membered heteroaryl groups include pyridinyl, oxo-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

As used herein, "9-10-membered heteroaiyl" represents an aromatic cyclic group containing 9 or 10 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Selected 9-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 10-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Examples of 9-membered heteroaiyl groups include 7H-purinyl, 9H-purinyl, pyrazolo[l,5-a]pyrimidinyl, imidazo[l,2-b]pyridazinyl, lH-pyrazolo[3,4- d]pyrimidinyl, and imidazo[l,2-b]pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl. Selected 10-membered heteroaiyl groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1 ,6-naphthy ridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl.

Bicyclic heteroaiyl groups include 6,5-fused heteroai>^rl (9-membered heteroaryl) and 6,6-fused heteroaiyl (10-membered heteroaryl) groups. Examples of 6,5-fused heteroaiyl (9-membered heteroaiyl) groups include benzothienyl, benzofuranyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, indolizinyl, isobenzofuiyl, 2,3-dihydrobenzofuiyl, benzo- 1,3-dioxyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzoxadiazolyl,

benzothiadiazolyl, benzotriazolyl, purinyl and imidazopyridinyl.

Unless otherwise specified, all bicyclic ring systems may be attached at any suitable position on either ring.

The terms "halogen" and "halo" represent chloro, fluoro, bromo, or iodo substituents. “Oxo” represents a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C = O). "Hydroxy" or hydroxyl” is intended to mean the radical -OH. As used herein, the term“cyano” refers to the group -CN.

As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur, and includes both event(s) that occur and event(s) that do not occur. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

The term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

The term "pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term "treatment" or“treating” refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.

As used herein, the term "cancer," refers to cells that have undergone a malignant transformation that makes them pathological to the host organism. Primary cancer cells can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of a cancer cell, as used herein, includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that normally manifests as a solid tumor, a

"clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X- ray, ultrasound or palpation on physical examination, and/or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient. Tumors may be a hematopoietic (or hematologic or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as

“liquid tumors.”

A therapeutically "effective amount" is intended to mean that amount of a compound that, when administered to a patient in need of such treatment, is sufficient to effect treatment, as defined herein. Thus, e.g., a therapeutically effective amount of a compound of Formula (1) or Formula (P), or a pharmaceutically acceptable salt thereof, is a quantity of an inventive agent that, when administered to a human in need thereof, is sufficient to modulate and/or inhibit the activity of RIP 1 kinase such that a disease condition which is mediated by that activity is reduced, alleviated or prevented. The amount of a given compound that will correspond to such an amount will vary depending upon factors such as the particular compound (e.g., the potency (plCso), efficacy (ECso), and the biological half-life of the particular compound), disease condition and its severity', the identity (e.g., age, size and weight) of the patient in need of treatment, but can nevertheless be routinely determined by one skilled in the art. Likewise, the duration of treatment and the time period of

administration (time period between dosages and the timing of the dosages, e.g.,

before/with/after meals) of the compound will vary according to the identity of the mammal in need of treatment (e.g., weight), the particular compound and its properties (e.g., pharmacokinetic properties), disease or disorder and its severity and the specific composition and method being used, but can nevertheless be determined by one of skill in the art. As used herein, "pharmaceutically acceptable excipient" means a material, composition or vehicle involved in giving form or consistency to the composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when commingled such that interactions which would substantially reduce the efficacy of the compound of the invention when administered to a patient and interactions which would result in pharmaceutical compositions that are not pharmaceutically acceptable are avoided. In addition, each excipient must of course be of sufficiently high purity to render it pharmaceutically acceptable.

Compound Preparation

Generic synthesis schemes

The compounds of this invention may be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are set out below and then specific compounds of the invention are prepared in the working examples.

The skilled artisan will appreciate that if a substituent described herein is not compatible with tiie synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. In all of the schemes described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T.W. Green and P.G.M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention. Starting materials are commercially available or are made from commercially available starting materials using methods known to those skilled in the art.

As will be understood by the skilled chemist, references to preparations carried out in a similar manner to, or by the general method of, other preparations, may encompass variations in routine parameters such as time, temperature, workup conditions, minor changes in reagent amounts, etc.

The syntheses of intermediates herein are applicable for producing intermediates of the invention having a variety of R groups employing appropriate precursors, which are protected if needed, to achieve compatibility with the reactions described.

Compounds of Formula (I) can be prepared according to Scheme 1, Scheme 2,

Scheme 3, Scheme 4, Scheme 5, or analogous methods. For Scheme 1, reaction of a compound of Formula A with hydrazine provides a dihydropyrazole of Formula B. An amide bond formation between an acid chloride of Formula C with a 4,5-dihydropyrazole of Formula B affords a compound of Formula (I).

Alternatively, compounds of Formula (I) can be prepared according to Scheme 2. The reaction of a compound of Formula D with hydrazine provides a dihydropyrazole of Formula E. An amide bond formation between an acid chloride of Formula C with a 4,5- dihydropyrazole of Formula E affords a compound of Formula (I).

Alternatively, compounds of Formula (I) can be prepared according to Scheme 3. For Scheme 3, a Wittig reaction of an aldehyde or ketone of Formula F with

(triphenylphosphoranylidene)-acetaldehyde or a base mediated condensation of an aldehyde or ketone of Formula F with acetaldehyde affords an unsaturated aldehyde of Formula G. Reaction of an aldehyde of Formula G with hydrazine provides a dihydropyrazole of Formula H. An amide bond formation between an acid chloride of Formula C with a 4,5- dihydropyrazole of Formula H affords a compound of Formula (I).

Compounds of Formula (II) can be prepared according to Scheme 4. Compounds of Formula (I) can be subjected to chiral separation methods to afford compounds of Formula

(P).

Alternatively, compounds of Formula (II) can be prepared according to Scheme 5. In Scheme 5, chiral compounds of Formula J, prepared according to methods described herein, can be reacted with a compound of Formula C under amide bond forming conditions to afford a compound of Formula (II). Scheme 1 : Synthesis of Compounds of Formula (I).

Scheme 3: Alternate Synthesis of Compounds of Formula (I).

10

Scheme 4: Synthesis of Compounds of Formula (II).

Scheme 5: Alternate Synthesis of Compounds of Formula (11).

EXPERIMENTAL

The following examples illustrate the invention. These examples are not intended to limit tiie scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention.

While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention.

The reactions described herein are applicable for producing compounds of Formulas (I) and (II) having a variety of different substituent groups (e.g., R¹, R², etc.), as defined herein. The skilled artisan will appreciate that if a particular substituent is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY, 1999.

Names for the intermediate and final compounds described herein were generated using the naming program in ChemDraw, Struct=Name Pro 12.0, as part of ChemBioDraw Ultra, available from CambridgeSoft. 100 CambridgePark Drive, Cambridge, MA 02140 USA (www.cambridgesoft.com).

It will be appreciated by those skilled in the art that in certain instances these programs may name a structurally depicted compound as a tautomer of that compound. It is to be understood that any reference to a named compound or a structurally depicted compound is intended to encompass all tautomers of such compounds and any mixtures of tautomers thereof.

'H NMR spectra were recorded in either CDCl o₃r DMSO-t/6 on either a BRUKER AVANCE PI 400MHz or BRUKER FOURIER 300MHz. The internal standard used was either tetramethylsilane or the residual protonated solvent at 7.26 ppm for CDC olr₃2.50 ppm for DMSO-i/s. Chemical shifts are reported in parts per million (ppm). Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, m = multiple!, br s = broad singlet, dd = doublet of doublets, dt = doublet of triplets, tt = triplet of triplets, ddd = doublet of doublet of doublets, sextuple! of d = sextuplet of doublets / indicates the ¾ NMR coupling constant measured in Hertz.

Mass spectrum was recorded on a Waters ZQ mass spectrometer using alternative-scan positive and negative mode electrospray ionisation. Cone voltage: 30V.

acetonitrile cesium carbonate

dichloromethane diisopropyl ethylamine

N,N-dimethylformamide

dimethylsulfoxide

ethyl

A tri ethylamine

diethyl ether

ethanol

ethyl acetate

hour(s)

hydrochloric acid

N’,N’-diisopropylethylamine

diisopropyl ether

potassium hydroxide

potassium /erf-butoxide

liquid chromatography -mass spectroscopy lithium hydroxide

methyl

acetonitrile methanol minute(s)

mass spectrum

sodium carbonate

sodium hydride

sodium bicarbonate

sodium hydroxide

sodium sulfate

ammonium chloride

ammonium hydroxide

N-methyl-2-pyrrolidone

phenyl

triphenyl phospine

phosphoiyl chloride

propyl

room temperature

thionyl chloride

tert-butanol

triethylamine

tert-butyl(methoxy)dimethylsilyl trifluoroacetic acid

tetrahydrofuran

ultra performance liquid chromatography ultraviolet

Examples

10

Step 1

To a suspension of 3,5-difluorobenzaldehyde (286 g, 2.01 mmol) and acetaldehyde in (380 g, 3.02 mmol) in H2O (2.5 mL) was added IN sodium hydroxide solution (2.1 L) at 0 °C under nitrogen. The resulting mixture was stirred at rt for 16 hours. The mixture was diluted with water (1 L), extracted with ethyl acetate (3 x 2 L). The combined organic phase was washed with brine (2 L), dried over anhydrous sodium sulfate, concentrated to give a residue. The resulting residue was purified by normal phase column chromatography (ethyl

acetate/petroleum ether = 1/10) to give 3-(3,5-difluorophenyl)aciylaldehyde as pale yellow solid (230.0 g, 1.368 mol, 68% yield). ¾ NMR (300 MHz,CDCl₃) d 9.74 (d, J = 7.5 Hz, 1H), 7.40 (d, J = 15.9 Hz, 1H), 7.13-7.06 (m, 2H), 6.91 (t, J = 17.1 Hz, 1H), 6.73 (dd, J = 7.2 Hz, 16.2 Hz, 1H).

Step 2

To a solution of 3-(3,5-difluorophenyl)acrylaldehyde (5.0 g, 29.76 mmol) in THF (150 mL) and HiO (15 mL) was added NaBD4 (1.87 g, 44.64 mmol) slowly at 0 °C under air atmosphere. The mixture was stirred at rt for 1 hour. The mixture was quenched with acetone (5 mL), and the solvent was removed under reduced pressure. The resulting residue was purified by normal phase column chromatography (petroleum ether/EtOAc = 2/1) to afford (E)-3-(3,5-difluorophenyl)prop-2-en- 1 , 1 -d₂- 1 -ol (4.4 g, 25.58 mmol, 86% yield) as a pale yellow oil. ΉNMK ^OO MHZ, CDCl₃) d 6.90-6.88 (m, 2H), 6.73-6.67 (m, 1H), 6.59-6.54 (m, 1H), 6.41-6.34 (m, 1H), 6.34 (s, 1H).

Step 3

To a solution of (E)-3-(3,5-difluoropheny l)prop-2-en- 1 , 1 -d₂- 1 -ol (4.4 g, 25.58 mmol) in DCM (250 mL) was added MnOz (17.78 g, 204.65 mmol). The mixture was stirred at rt for 72 hours. The mixture was filtered, washed with EtOAc (500 mL), and concentrated under reduced pressure to afford a residue. The resulting residue was purified by normal phase column chromatography (petroleum ether/EtOAc = 10/1) to afford (E)-3-(3,5- difluorophenyl)acrylaldehyde-l-d (3.3 g, 19.53 mmol, 75% yield) as white solid.‘H NMR (300 MHz, CDCl₃) d 7.40 (d, J=16.2 Hz, 1H), 7.11-7.09 (m, 2H), 6.95-6.88 (m, 1H), 6.69 (d, J=15.9 Hz, 1H).

Step 4

To a solution of (E)-3-(3,5-difluorophenyl)acrylaldehyde-l -d (2.5 g, 14.80 mmol) and hydrazine hydrate (2.27 g, 44.4 mmol) in ethanol (140 mL) was added acetic acid (1.2 mL). The resulting mixture was stirred at 90 °C under N₂ atmosphere for 16 hours. The solvent was removed under reduced pressure to afford a residue. The resulting residue was diluted with EtOAc (200 mL) and washed with water (3 x 200 mL), dried over anhydrous sodium sulfate, and concentrated to give crude 5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-3-d (2.5 g) as a yellow oil, which was used for the next step without further purification. ¾ NMR (300 MHz, CDCh) d 6.95-6.88 (m, 2H), 6.76-6.69 (m, 1H), 4.72 (t, J=10.2 Hz, 1H), 3.21- 3.10 (m, 1H), 2.70-2.61 (m, 1H); MS (m/z) 184.2 (M+H)⁺, retention time: 1.21 min,

UPLC/MS Method 4 using 20% ACN.

Step 5

To a solution of 5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-3-d (800 mg, 4.37 mmol) and EtoN (883 mg, 8.74 mmol) in DCM (10 mL) was added 1 -acetyl-pi peridine-4-carbonyl chloride (1.66 g, 8.74 mmol) in DCM (10 mL) at 0 °C under Nz atmosphere. The mixture was stirred at rt for 5 h. The solvent was concentrated and the result mixture was purified by preparative medium pressure liquid chromatography (Cl 8 column; 20%-95% acetonitrile in water) to give l-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-caibonyl-3- d)piperidin- 1 -y l)ethan- 1 -one (1.0 g, 2.98 mmol, 68% yield) as white solid. MS (m/z) 337.3

(M+H)⁺, retention time: 1.13 min, UPLC/MS Method 4 using 20% ACN.

The racemate (700 mg in 10 mL MeOH) was separated via chiral HPLC separation method 11 (using 30% EtOH at 20 mL/min) to provide (S)-l-(4-(5-(3,5-difluorophenyl)-4,5-dihydro- IH-py razole-1 -carbonyl-3-d)piperidin-l -yl)ethan- 1 -one and (R)-l-(4-(5-(3,5- difluoropheny l)-4,5 -dihydro- 1 H-py razole- 1 -carbonyl-3 -d)piperidin- 1 -yl)ethan- 1 -one.

Example 1

An enantiomer was afforded as a solid. LCMS (m/z) 337 (M+H)⁺, retention time: 2.492 min, LCMS Method 1. Chiral HPLC Anal. Method 3, retention time: 3.765 min, % ee = 99.9%. ¾ NMR (400 MHz, CDCh) ppm 6.72-6.65 (m, 3H), 5.34-5.30 (m 1H), 4.60-4.55 (m, 1H), 3.87- 3.84 (m, 1H), 3.48-3.42 (m, 1H), 3.40-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.81-2.69 (m, 2H), 2.09 (s, 3H), 1.99-1.62 (m, 4H).

Example 2

An enantiomer was afforded as a solid. LCMS (m/z) 337 (M+H)^f, retention time: 2.462 min, LCMS Method 1. Chiral HPLC Anal. Method 3, retention time: 4.569 min, % ee = 99.1%. ^!H NMR (400 MHz, CDCh) ppm 6.72-6.65 (m, 3H), 5.34-5.29 (m, 1H), 4.60-4.55 (m, 1H), 3.87-3.84 (m, 1H), 3.48-3.42 (m, 1H), 3.40-3.29 (m, 1H), 3.20-3.11 (m, 1H), 2.81-2.70 (m, 2H), 2.09 (s, 3H), 1.99-1.62 (m, 4H).

Step 1

To a mixture of 3,5-difluorobenzaldehyde (lO.Og, 70 mmol) and acetic acid-d* (5.4 g, 84 mmol) in DCM (100 mL) was added titanium tetrachloride (147 mL, 1M in DCM) over 0.5 hour at 20 °C under nitrogen. EtsN was added (17.5 g, 175 mmol) over 30 min. The resulting reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was diluted with water (100 mL). Combined organic layers were washed with brine, dried over NazSCb, and concentrated to give a residue. The resulting residue was purified by normal phase column chromatography (3% dichloromethane in methanol) to give (E)-3-(3,5- difluorophenyl)acrylic-2-d acid (2.9 g, 15.6 mol, 22 % yield) as a pale yellow solid. *H NMR (300 MHz, CDCl₃) d 12.6 (br s, 1H), 7.55-7.50 (m, 3H), 7.32-7.28 (m, 1H).

Step 2

To a solution of (E)-3-(3,5-difluorophenyl)acrylic-2-d acid (3.2 g, 17.3 mmol) in

dichloromethane (30 mL) was added HOBT (3.5 g, 26.0 mmol), EDCI (4.98 g, 26.0 mmol), and DIEA (6.7 g, 51.9 mmol). To this mixture was added N,O-dimethylhydroxylamine hydrochloride (2.5 g, 26.0 mmol). The resulting mixture was stirred at rt overnight. The reaction was diluted with water (50 mL). Combined organic phases were washed with brine, dried over NaaSCU, and concentrated to give a residue. The resulting residue was purified by normal phase column chromatography (1% dichloridemethane in methanol) to give (E)-3- (3,5-difluorophenyl)-N-methoxy-N-methylacrylamide-2-d (3.7 g, 94 % yield) as a pale yellow solid. MS (m/z) 246.1 [M+H]⁺, retention time: 1.40 min, UPLC/MS Method 4 using 20% ACN.

Step 3

To (E)-3-(3,5-difluorophenyl)-N-methoxy-N-methylacr>lamide-2-d (3.7 g, 15.1 mol) in dry tetrahydrofuran (50 mL) was added diisobutyalumium (19.4 mL, 19.4 mmol, 1M in tetrahydrofuran) at -78°C. The resulting mixture was stirred at -78°C for 2 hours. The reaction was quenched with saturated sodium sulfate. The mixture was extracted with ethyl acetate (3 x 20 mL). Combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a residue. The resulting residue was purified by normal phase column chromatography (20% ethyl acetate in petroleum) to give (E)-3-(3,5- difluorophenyl)acrylaldehyde-2-d (1.8 g, 10.6 mol, 66% yield) as a white solid. ¾ NMR (300 MHz, CDCl₃) d 9.74 (s, 1H), 7.39 (m, 1H), 7.11-7.08 (m, 2H), 6.94-6.88 (m, 1H). Step 4

To a mixture of (E)-3-(3,5-difluorophenyl)aciylaldehyde-2-d (500 mg, 2.95 mmol) in EtOH (5 mL) was added hydrazine hydrate (750 mg, 14.8 mmol) and acetic acid (277 mg, 6 mmol). The reaction mixture was stirred at 80 °C for 16 hours. The solvent was removed under reduced pressure. The resulting mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give 5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-4-d (530 mg, crude), which was used for the next step without further purification. MS (m/z) 184.2 |M+H]⁺, retention time: 1.15 min, UPLC/MS Method 4 using 20% ACN.

Step 5

To a mixture of 5-(3,5-difluoropheny l)-4,5-dihy dro- 1 H-pyrazole-4-d (530 mg, crude) and DIEA (1.1 g, 8.7 mmol) in dichloromethane (5 mL) was slowly added a solution of 1- acetylpiperidine-4-carbonyl chloride (656 mg, 3.74 mmol) in dichloromethane (10 mL) at 0 °C under nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure to afford a residue. The resulting residue was purified by silica gel column (1-5% methanol in dichloromethane) to give l-(4-(5-(3,5- difluorophenyl)-4, 5-dihydro- 1 H-py razole- 1 -carbony l-4-d)piperidin- 1 -yl)ethan- 1 -one (430 mg, 1.28 mmol, 36% yield). MS (m/z) 337.1 |M+H|⁺, retention time: 1.27 min, UPLC/MS Method 4 using 5% ACN.

The racemate (430 mg in 20 ml MeOH) was separated via Chiral HPLC Separation Method 1 (using 20% DCM in MeOH at 20 mL/min) to provide l-(4-((5S)-5-(3,5-difluorophenyl)-4,5- dihydro- lH-pyrazole-1 -carbonyl-4-d)piperidin-l -yl)ethan- 1-one and l-(4-((5R)-5-(3,5- difluorophenyl)-4, 5-dihydro- lH-pyrazole-1 -carbonyl-4-d)piperidin- 1 -yl)ethan- 1 -one.

Example 3

An enantiomer was afforded as a white solid (133 mg, 11% yield). LCMS (m/z) 337

(M+H)+, retention time: 2.321 min, LCMS Method 2. Chiral HPLC Anal. Method 1, retention time: 3.002 min, % ee = 99.8%. ¾ NMR (400 MHz, CDC)l₃ ppm 6.97 (s, 1H), 6.72-6.64 (m, 3H), 7.19-7.16 (m, 1H), 7.01 (s, 1H), 6.84-6.81 (m, 2H), 5.41-5.37 (dd,

J=12.0Hz, 1H), 4.35 (br, 1H), 3.45-3.33 (m, 2H), 3.17-3.08 (m, 3H), 2.08 (m, 2H), 1.76-1.72 (m, 2H). Example 4

An enantiomer was afforded as a solid (146 mg, 12% yield). LCMS (m/z) 337 (M+H)+, retention time: 3.247 min, LCMS Method 3. Chiral HPLC Anal. Method 1, retention time: 4.073 min, % ee = 99.9%.‘H NMR (400 MHz,CDCl₃) ppm 6.97 (s, 1H), 6.72-6.64 (m, 3H), 7.19-7.16 (m, 1H), 7.01 (s, 1H), 6.84-6.81 (m, 2H), 5.41-5.37 (dd, J=12.0Hz, 1H), 4.35 (hr,

1H), 3.45-3.33 (m, 2H), 3.17-3.08 (m, 3H), 2.08 (m, 2H), 1.76-1.72 (m, 2H).

Step 1

To a solution of 3,5-difluorobenzaldehyde (8.0 g, 56.3 mmol) in THF (180 mL) and H2O (18 mL) was added NaBD* (3.54 g, 84.5 mmol) slowly at 0 °C. The mixture was stirred at rt for 2 hours. The mixture was quenched with acetone (5 mL), and the solvent was removed under reduced pressure to afford a residue. The resulting residue was purified by normal phase column chromatography (petroleum ether/EtOAc = 5/1) to afford (3,5- difluorophenyl)methan-d2-ol (8.0 g, 54.79 mmol, 97% yield) as a colorless oil. ¾ NMR (300 MHz,CDCl₃ ) d 6.90-6.88 (m, 2H), 6.75-6.69 (m, 1H), 4.67 (s, 1H). Step 2

To a solution of (3,5-difluorophenyl)methan-d2-ol (8.0 g, 54.79 mmol) in DCM (540 mL) was added MnCh (23.8 g, 273.97 mmol). The mixture was stirred at rt for 72 hours. The mixture was filtered and washed with EtOAc (500 mL). The solvent was removed under reduced pressure to give crude 3,5-difluorobenzaldehyde-di (6.3 g, purify~80%) as yellow solid, which was used to next step without further purification. *H NMR (300 MHz, CD)C dl₃ 7.44-7.42 (m, 2H), 7.14-7.08 (m, 1H).

Step 3

To a suspension of 3,5-difluorobenzaldehyde-di (6.3 g, 44.06 mmol) and acetaldehyde in H2O (2.5 mL, 66.08 mmol) was added IN sodium hydroxide solution (46.3 mL) at 0 °C under N2. The resulting mixture was stirred at rt for 16 hours. TLC showed SM was consumed. The mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL x 3). The combine organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, concentrated to give crude product, purified by silica gel column ethyl

acetate/petroleum ether = 1/20 to give 3-(3,5-difluorophenyl)acrylaldehyde-3-d as yellow solid (3.5 g, 20.71 mmol, 47% yield). Ή NMR (300 MHz, CDC)l₃ d 9.74 (d, J=7.5 Hz, 1H), 7.11-7.09 (m, 2H), 6.91 (t, J=8.4 Hz, 1H), 6.70-6.67 (m, 1H).

Step 4

To a solution of 3-(3,5-difluorophenyl)aciyIaldehyde-3-d (2.0 g, 11.83 mmol) and hydrazine hydrate (1.8 g, 35.50 mmol) in ethanol (110 mL) was added acetic acid (1.0 mL). The resulting mixture was stirred at 90 °C under N2 atmosphere for 16 hours. The solvent was removed under reduced pressure. The resulting residue was diluted with EtOAc (200 mL), washed with water (3 x 200 mL), dried over anhydrous sodium sulfate, and concentrated to give crude 5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-5-d (2.0 g, 80% purify) as a yellow oil, which was used for the next step without further purification. ¾i NMR (300 MHz, CDCk) d 6.93-6.85 (m, 2H), 6.82-6.81 (m, 1H), 6.76-6.69 (m, 1H), 3.16 (d, J=17.1 Hz, 1H), 2.66 (m, d, J=16.8 Hz, 1H); MS (m/z) 184.3 (M+H)+, retention time: 1.16 min, UPLC/MS

Method 4 using 20% ACN.

Step 5

To a solution of 5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-5-d (600 mg, 3.28 mmol) and EtoN (662 mg, 6.56 mmol) in DCM (10 mL) was added 1 -acetyl-pi peridine-4-carbonyl chloride (1.24 g, 6.56 mmol) in DCM (5 mL) at 0 °C under Nz atmosphere. Tlie mixture was stirred at rt for 3 h. The mixture was concentrated to afford a residue. The resulting residue was purified by preparative medium pressure liquid chromatography (Cl 8 column; 20-95% acetonitrile in water) to give 1 -(4-(5-(3,5-difluorophenyl)-4,5-dihy dro- lH-pyrazole- 1 - carbonyl-5 -d)piperidin- 1 -y l)ethan- 1 -one (243 mg, 0.72 mmol, 22% yield) as pale yellow solid. MS (m/z) 337.5 (M+H)⁺, retention time: 1.20 min, UPLC/MS Method 4 using 20% ACN.

The racemate (243 mg in 5 mL MeOH) was separated via Chiral HPLC Separation Method 2 (using 15% ACN, 85% MeOH with 0.05% DEA at 20 mL/min) to provide

(S)-l-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-caibonyl-5-d)piperidin-l- yl)ethan-l-one and (R)-l-(4-(5-(3,5-difluorophenyl)-4, 5-dihydro- lH-pyrazole-l-carbonyl-5- d)piperidin- 1 -yl)ethan- 1 -one.

Example 5

An enantiomer was afforded as a solid. LCMS (m/z.) 337 (M+H)+, retention time: 2.274 min, LCMS Method 2. Chiral HPLC Anal. Method 1, retention time: 2.476 min, % ee = 98.5%. Ή NMR (400 MHz, CDCl₃) ppm 6.95 (s, 1H), 6.72-6.65 (m, 3H), 4.60-4.55 (m, 1H), 3.87-3.84 (m, 1H), 3.46-3.40 (m, 1H), 3.35-3.31 (m, 1H), 3.19-3.12 (m, 1H), 2.80-2.70 (m, 2H), 2.09

(s, 3H), 1.99-1.82 (m, 2H), 1.76-1.60 (m, 2H). Example 6

An enantiomer was afforded as a solid. LCMS (m/z) 337 (M+H)+, retention time: 2.251 min, LCMS Method 2. Chiral HPLC Anal. Method 1, retention time: 2.821 min, % ee = 96.2%. ¾ NMR (400 MHz, CDCl₃) ppm 6.98 (s, 1H), 6.72-6.65 (m, 3H), 4.60-4.55 (m, 1H), 3.87-3.84 (m, 1H), 3.46-3.40 (m, 1H), 3.35-3.29 (m, 1H), 3.20-3.12 (m, 1H), 2.80-2.69 (m, 2H), 2.09

(s, 3H), 1.99-1.82 (m, 2H), 1.80-1.60 (m, 2H).

Step 1

To a suspended solution of 3,5-difluorobenzaldehyde (11 g, 77 mmol) in water (100 mL) was added propionaldehyde (5.35 g, 92 mmol) at 0°C. Then a solution of sodium hydroxide (3.08 g, 77 mmol, 2 M) was added dropwise over 20 minutes. The resulting mixture was stirred at room temperature for 16 hours. The mixture was extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine (2 L), dried over anhydrous sodium sulfate, and concentrated to give a residue. The resulting residue purified by normal phase column chromatography (3% ethyl acetate in petroleum) to give 3-(3,5-difluorophenyl)-2- methylacrylaldehyde (8.6 g, 47.2 mol, 61% yield) as a pale yellow oil. ¾ NMR (300 MHz,CDCl₃ ) d 9.60 (s, 1H), 7.18 (s, 1H), 7.05-7.03 (d, J=8.4Hz, 2H), 6.89-6.84 (t, J= 11.2 Hz, 1H), 2.07 (s, 3H). Step 2

To a solution of hydrazine hydrate (25.0 g, 500.0 mmol) in ethanol (150 mL) was added 3- (3,5-difluorophenyl)-2-methylacrylaldehyde (18.2 g, 100.0 mmol). The resulting mixture was stirred at 20 °C under nitrogen for 20 hours. The reaction mixture was concentrated under reduced pressure to afford a residue. The residue was diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the crude 5-(3,5-difluorophenyl)-4-methyl-4,5-dihydro-lH-pyrazole (17.4 g, crude) as yellow oil, which can used directly in next step without further purification. MS (m/z) 197.1 (M+H)⁺, retention time: 1.48 min, UPLC/MS Method 4 using 5% ACN.

Step 3

To a solution of 5 -(3 ,5-di fl uorophenyl)-4-methy 1-4,5 -dihy dro- 1 H-pyrazol e (4.5 g, crude) and

DIPEA (5.9 g, 45.8 mmol) in DCM (5 mL) was added 1 -acety l-piperidine-4-carbony 1 chloride (6.4 g, 34.3 mmol) in DCM (5 mL) at 0 °C under N2 atmosphere. The mixture was stirred at rt for 3 h. The solvent was concentrated to afford a residue. The resulting residue was purified by normal phase column chromatography (DCM : MeOH=100/l to 20/1) to give l-(4-(5-(3,5-difluorophenyl)-4-methyl-4,5-dihydro-lH-pyrazole-l-carbonyl)piperidin-l- yl)ethanone (850 mg, 2.42 mmol, 11% yield) as white solid. MS (m/z) 350.2 (M+H)⁺, retention time: 1.35 min, UPLC/MS Method 4 using 20% ACN.

Racemic 1 -(4-(5-(3,5-difluorophenyl)-4-methyl-4, 5-dihydro- IH-pyrazole- 1 - carbonyl)piperidin- 1 -y l)ethanone (850 mg in 10 mL MeOH) was separated via Chiral HPLC

Separation Method 3 (using 50% hexane in EtOH + 0.1% DEA at 20 mL/min) to afford examples 7-10:

Example 7

An enantiomer was afforded as a solid (126 mg, 15% yield). LCMS (m/z) 350 (M+H)⁺, retention time: 3.049 min, LCMS Method 1. Chiral HPLC Anal. Method 2, retention time: 5.061 min, % de = 96.2%. ¾ NMR (400 MHz, CDC)l₃ ppm 6.88 (s, 1H), 6.71-6.62 (m, 3H), 4.81 (s, 1H), 4.60-4.56 (m,lH), 3.87-3.84 (d, ./= 14.0Hz, 1H), 3.34-3.31 (m, 1H), 3.20-3.12 (m, 1H), 3.01-2.97 (m, 1H), 2.75-2.71 (m, 1H), 2.08 (s, 3H), 1.99-1.69 (m, 4H), 1.31-1.29 (d, J= 6.8Hz, 3H).

Examples 8 and 9

A mix of stereoisomers were afforded as a solid, Chiral HPLC Anal. Method 2, retention time: 7.627 min, which was further separated via Chiral HPLC Method 4 (using 70% hexane in EtOH + 0.1 % DEA at 20 mL/min) to afford two isomers (Examples 8 and 9).

Example 8

An enantiomer was afforded as a solid (132 mg, 16% yield). LCMS (m/z) 350 (M+H)⁺, retention time: 3.064 min, LCMS Method 1. Chiral HPLC Anal. Method 4, retention time: 5.401 min, % de = 100%. ¾ NMR (400 MHz, CDC)l₃ ppm 6.88 (s, 1H), 6.87-6.62 (m, 3H), 4.81-4.80 (m, 1H), 4.60-4.56 (m,lH), 3.87-3.84 (d, J= 14.0Hz, 1H), 3.34-3.31 (m, 1H), 3.20- 3.12 (m, 1H), 3.01-2.97 (m, 1H), 2.75-2.71 (m, 1H), 2.08 (s, 3H), 1.99-1.69 (m, 4H), 1.31- 1.29 (d, J= 6.8Hz, 3H).

Example 9

An enantiomer was afforded as a solid (105 mg, 12% yield). LCMS (m/z) 350 (M+H)⁺, retention time: 3.009 min, LCMS Method 1. Chiral HPLC Anal. Method 4, retention time: 7.015 min, % de = 100%. ¹H NMR (400 MHz, CDC)l₃ ppm 6.80 (s, 1H), 6.80-6.68 (m, 1H), 6.67-6.54 (m, 2H), 5.36-5.33 (d, J= 11.6 Hz, 1H), 4.58-4.56 (m,lH), 3.87-3.85 (m, 1H), 3.34-3.31 (m, 1H), 3.20-3.14 (m, 1H), 2.775-2.73 (m, 1H), 2.08 (s, 3H), 1.99-1.63 (m, 4H), 0.82-0.80 (d, J= 7.6Hz, 3H). Example 10

An enantiomer was afforded as a solid (98 mg, 11% yield). LCMS (m/z) 350 (M+H)⁺, retention time: 3.008 min, LCMS Method 1. Chiral HPLC Anal. Method 2, retention time: 12.372 min, % de = 100%. ¾ NMR (400 MHz, CDC)l₃ ppm 6.80 (s, 1H), 6.80-6.68 (m, 1H), 6.67-6.54 (m, 2H), 5.36-5.33 (d, J= 11.6 Hz, 1H), 4.58-4.56 (m, 1H), 3.87-3.85 (m, 1H), 3.34-3.31 (m, 1H), 3.20-3.14 (m, 1H), 2.775-2.73 (m, 1H), 2.08 (s, 3H), 1.99-1.63 (m, 4H),

0.82-0.80 (d, J= 7.6Hz, 3H).

Biological Assays

Biological ADP-Glo Kinase Assay

The potency of RIP1 inhibitors can be tested in ADP-Glo kinase assay. As determined using the method described in J. Med. Chem. 60, 1247-1261 (2017), the compounds of Examples 1-10 exhibited apICso between approximately 6.0 and 9.0.

As determined using the above method, the compounds of Examples 2-4 and 7-10 exhibited a pICso between approximately 6.0 and 8.0.

For instance, the compounds of Examples 2, 3, 4, 7, 8, 9, and 10 inhibited RIP1 kinase in the above method with a pICso of approximately 6, 7.7, 6, 6, 6, 6, and 6.6 respectively.

Biological in vitro cell assay

The efficacy of RIP1 inhibitors can be tested in mice in vitro using a human monocytic leukemia U937 fibrosarcoma cells in a necroptosis assay. As determined using the method described in S. He et al.. Cell, 137(6): 1100-1111 (2009) and International Patent Appln.No. PCT/IB2014/059004, now, International Patent Appln. Pub. No.

WO2014/125444, the compounds of Examples 1-10 exhibited apICso between

approximately 5.0 and 8.0.

For instance, the compounds of Examples 1, 3, and 5 inhibited necrosis in U937 cells in the above method with a pICso between approximately 6.0 and 8.0.

For instance, the compounds of Examples 1, 3, 5, and 10 inhibited necrosis in U937 cells in the above method with a mean pICso of approximately 7.1, 7.1, 7.3, and 5.8 respectively.

Viability was measured by quantitating cellular levels of ATP using the Cell Titer- Glo kit. All data are means ± standard deviation of the mean.

Biological in vivo assay

For biological in vivo assays and models, Compounds A, B, C, D, E, F, G, and H were used. Compounds A, B, C, D, E, F, G, and H, or pharmaceutically acceptable salts thereof, and the methods of making are disclosed in PCT/IB2017/057225.

The efficacy ofRIPl inhibitors can be tested in mice in vivo using a TNF-driven systemic inflammatory response syndrome model (L. Duprez et al. Immunity 35(6):908-918, (2011)) using TNF plus the caspase inhibitor zVAD or TNF alone. The TNF/zVAD model is terminated at ~3hrs and the TNF alone model is terminated at ~8hrs (vmder IACUC guidelines for temperature loss). TNF (or TNF/zVAD) induced manifestations include temperature loss, the production of numerous cytokines (including IL-6, IL-lb, MIRIb and MIP2) in the periphery, liver and intestinal inflammation and an increase of markers of cellular (LDH and CK) and liver damage (AST and ALT) in the serum. Inhibition of these TNF alone or TNF/zVAD induced manifestations can be shown by PO pre-dosing with selected compounds. For example, mice (8 mice per group) were pre-dosed PO with vehicle or compound 15 minutes before i.v. administration of mouse TNF (30 pg/mouse) alone or in combination with zVAD (0.4 mg/mouse) simultaneously. Temperature loss in the mice was measured by rectal probe. The study was terminated when the control group lost 7 degrees, per our IACUC protocol. All data are shown as means ± standard error of the mean.

Representative data for Compounds A, B, C, D, E, F, G, and H were expressed over time and at the 2.0, 3.0, and 7.5 hour time points, respectively, are provided in FIGS. 1 A-5B. Data for Compounds A, B, C, D, E, F, G, and H were tested in this model are provided in Table A.

RdlO mouse model of human retinitis pigmentosa

Inhibition of RIP 1 has been implicated in protection against the RdlO mouse model of human retinitis pigmentosa (RP) (Y. Murakami et al., PNAS 109(36): 14598-14603 (2012)). RdlO mice have a mutation, the rod-specific gene that encodes rod cGMP phosphodiesterase b-subunit. Mice were dark reared to P30, at which point they were moved to a 12-hour light/dark cycle to induce retinal degeneration. Mice were pre-dosed with RIP1 inhibitors in food-based dosing on day P28, two days prior to the switch to normal cyclic light, such that mice (15 mice per group) received on average 100 mg/kg/day RIP1 inhibitor in diet or control diet. Electroretinography (ERG) recordings were made at P39 and P46 as a measure of retinal cell function. Retinal cell loss was assessed by measurement of the thickness of the Outer Nuclear Cell (ONL) layers at various distances from the Optic Nerve Head (ONH) in hematoxylin and eosin stained retinal tissue sections collected at P46.

Representative data for Compound A are provided in FIGS. 6A and 6B.

EAE mouse model of human MS

Inhibition of RIP 1 has been implicated in protection against the experimental autoimmune encephalomyelitis (EAE) mouse model of human Multiple Sclerosis (MS) (D. Ofengeim et al. Cell Reports 10(11):1836-1849, (2015)). Mice were pre-dosed with RIP1 inhibitors in food-based dosing one day prior to EAE induction, such that mice (15 mice per group) received on average 96 mg/kg/day or 9.6 mg/kg/day of RIP1 inhibitor in diet or control diet. Mice were inoculated with 100 ul of inoculum containing 100 ug of myelin oligodendrocyte protein amino add 35-55 (MOG35-55) and 200ug heat inactivated

Mycobacterium tuberculosis in mineral oil. Inoculation was done by giving each mouse two 100 ul injections subcutaneously to the lower and higher aspect of the back, respectively. Intraperitoneal injections of pertussis toxin (4 ug/ml) 100 ul each were given at 2 hours and

24 hours after inoculation. Mice were monitored daily until day 35 post-induction and clinical signs were scored as follows: 0.5 for partial tail weakness, 1.0 for complete tail paralysis (all of tail dragging along), 1.5 for flactid tail and abnormal gait, 2.0 for flaccid tail and clear weakness of hind legs, 2.5 for partial paralysis in one hindlimb (no movement preserved in affected limb), 3.0 for complete paralysis in both hindlimbs, 4.0 for complete paralysis in hindlimbs and partial weakness in forelimbs, and 5.0 for complete paralysis in both forelimbs and hindlimbs (tetraplegia) or moribund. Representative data for Compound A are provided in FIG. 7. Glucose homeostasis

Blocking the actions of TNF at the TNF receptor has been shown to improve glucose homeostasis in animals and humans (Stagakis et al., Arthritis Research & Therapy (2012)). We therefore investigated the ability of our small molecule RIPK1 inhibitor to improve glucose homeostasis in a diabetic animal model. Mice genetically deficient for the leptin receptor (db/db mice; Jackson Labs, BKS.Cg-Dock7m +/+ Leprdb/J) are a widely used animal model of insulin resistance and diabetes. In our study, 4-week old male db/db mice were acclimated for a period of one week. At this point, when the mice were 5 weeks of age, the study was started. Mice were then divided into two group (n = 10/group) and baseline measurements of non-fas ted blood glucoses (using a glucometer) and body weight were taken. After baseline measurements, one group of mice was fed chow containing RIPK1 inhibitor (100 mg/kg/day, n = 10) and the other remained on normal chow (n = 10). Animals remained on these diets for 6 weeks. Additional measurements of non-fasted blood glucose and body weight were taken 2 and 4 weeks after study start. At week 8, mice were fasted overnight (16 hours) and fasted blood glucose and body weight were measured on the following day. Reduced non-fasted blood glucose at weeks 2 and 4 was observed (FIGS. 8A and 8B). Additionally, fasted blood glucose at week 8 was also significantly lower in db/db mice receiving the RIPK1 inhibitor versus normal chow controls (FIGS. 9A and 9B). These data demonstrate a significant improvement in glucose homeostasis, in db/db mice receiving R1PK1 inhibitor in their diet versus the control diet cohort. Measurements of both non-fasted and fasted body weight showed no difference between groups, suggesting that the improved glycemic control observed in mice receiving RIPK1 inhibitor were not secondary to a loss in body weight. These data therefore demonstrate a direct, beneficial effect of blocking RIPK1 kinase activity to improve glucose homeostasis. Representative data for Compound A are provided in FIGS. 8A, 8B, 9A, and 9B.

Obesity

Inflammation is known to be a contributing factor in the pathogenesis of diabetes and obesity (Chen. et. al., International Journal of Endocrinology (2015)). We therefore explored tiie effect of blocking RIPK1 kinase activity on body weight in mice made obese by chronic feeding of a high fat diet (HFD). Diet-induced obese, male mice C57B1/6J (Jackson Labs Stock#380050) arrived at 22 weeks of age, with average body weight of 40 g and acclimated for one week and maintained on HFD. Mice were then acclimated to oral gavage with water for 7 days before study start. Thereafter mice received RIPK 1 inhibitor (50 mg/kg, bid, n = 9) or vehicle (bid, n = 9) for 19 days. Food intake was measured twice weekly and body weight was measured daily throughout the study. Although high fat diet-fed mice dosed with the R1PK1 inhibitor initially reduced their food intake (day 2 and day 5 (FIG. 10A)), after the first week food intake in the two groups was equivalent. However while control animals continued to gain weight on the HFD, the HFD-fed mice PO dosed with the RIPK1 inhibitor did not gain weight and in fact showed a modest decrease in body weight from precompound exposure levels (FIG. 10B). By the end of the first week, control animals were significantly heavier than mice given treated with RIPK1 inhibitor and this was maintained for at least 21 days. We demonstrated, therefore, that RIPK1 inhibition has therapeutic potential as a treatment for obesity'. Representative data for Compound A are provided in FIGS. 10A and 10B.

Subcutaneous tumor efficacy

The efficacy of RIP 1 inhibition was tested in 12 different murine (6-8 week old) syngeneic subcutaenous tumor models. RIP1 inhibition was tested as a single agent in all models, with anti-PDl combination arms added to the five of the final models.

Note:

• N: animal number

• Dosing volume: adjust dosing volume based on body weight (10 mΐ/g).

• Treatment regimen may be changed per BW (body weight) loss.

• The interval of BID dosing is 8 hours. Study endpoints: The major endpoints of the study include the following:

1) Tumor growth inhibition (TGI): TGI% is an indication of antitumor effectiveness, and expressed as: TGI (%)=100 x (1-T/C). T and C are the mean tumor volume of the treated and control groups, respectively, on a given day.

2) Tumor and plasma collection at study aid for further investigation.

Experimental Methods

Cell Culture

The 12 syngenic cell lines were maintained in vitro with different medium (indiciated in Table C) at 37 °C in an atmosphere of 5% CCh in air. The tumor cells were routinely subcultured twice weekly. The cells in an exponential growth phase were harvested and counted for tumor inoculation.

Tumor Inoculation

Each mouse was inoculated subcutaneously with tumor cells in 0.1 mL of PBS for tumor development. The treatments were started when the mean tumor size reached approximately 80-120mm³(around 100mm³). The test article (Compound A or anti-PDl (anti-mouse PD-1 antibody (clone RPM1-14), BioXcell) administration and the animal numbers in each study group are shown in the experimental design Table B. The date of tumor cell inoculation is denoted as day 0.

Sharpin-deficient mouse model of TNF-dependent dermatitis

Sharpin-deficient mice (cpdm) develop a spontaneous and severe TNF- and RIPK1- dependent dermatitis and multi-organ immunopathology around 6-8 weeks of age (S.B. Berger et al., Journal of Immunology, 192(12):5476-5480, (2014)). Mice were dosed with RIP1 inhibitors at the time of weaning (3-4 weeks of age) prior to the development of dermatitis lesions or therapeutically after the development of dermatitis lesions (about 6 weeks of age) using a food-based dosing regimen, such that mice (4-7 mice per group) received on average 100 mg/kg/day or 10 mg/kg/day of RIP 1 inhibitor in diet or control diet. Mice were observed for signs of proliferative dermatitis by using a dermatitis scoring system based on lesion character and regions affected. The character of the lesion was categorized according the following, in order of increasing severity, 0 = none, 1 = excoriation only or one small punctuated crust (< 2 mm), 2 = multiple, small punctuate crusts or coalescing crust (> 2 mm), 3 = erosion or ulceration. The regions were identified as: Region 1 : the head cranial to the medial pinna attachment and/or lesions affecting the mandible cranial to the sternum, Region 2: inner and outer pinna, dorsal cervical region caudal to the medial pinna attachment, dorsal and ventral thorax, and thoracic limbs, Region 3: any region caudal to the ribcage. A score for the regions affected was categorized per the following: 0 = none; 1 = Region 2 or 3; 2 = Region 2 and 3; 3 = Region 1+/- other affected regions. To calculate the dermatitis severity score, the lesion score and regions affected score were summed, divided by 6, and then multiplied by 100. A severity score of 66 was considered severe dermatitis. Pre-dosing with R1P1 inhibitors in food-based dosing resulted in a complete protection from the development of severe dermatitis. Additionally, therapeutic dosing with RIP1 inhibitors in food-based dosing rescued established dermatitis. Representative data for Compound A are provided in FIGS. 12A and 12B.

Claims

1. A compound according to Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

R² is phenyl or 5-6 membered heteroaryl,

(C₁-C₄)alkoxy, and -CN; and

2. A compound according to Formula (P) or a pharmaceutically acceptable salt thereof:

wherein:

R² is phenyl or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl is optionally substituted by one, two, or three substituents independently selected from halogen, (C₁-C₄)alkyl, halo(Ci- C₄)alkyl,

(C₁-C₄)alkoxy, and -CN; and

3. The compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 and 2, wherein R¹ is -COCH3.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, wherein R²is phenyl, wherein said phenyl is optionally substituted by two or three substituents independently selected from halogen, halo(C₁-C₄)alkyl, (C₁-C₄)alkoxy, and

-CN.

5. The compound or pharmaceutically acceptable salt thereof according to claim 4, wherein R² is phenyl, wherein said phenyl is optionally substituted by two or three fluoros.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 -5, wherein each R³, R⁴, R⁵, and R⁶ is independently selected from hydrogen, deuterium, or methyl, wherein at least one R³, R⁴, R⁵, or R⁶ is not hydrogen.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 and 2, wherein:

R² is phenyl, wherein said phenyl is optionally substituted by one, two, or three substituents independently selected from halogen, halo(C₁-C₄)alkyl, and -CN; and

8. The compound according to claim 1 which is: (S)-l-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl-3-d)piperidin- l-yl)ethan-l-one;

(R)-l-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl-3-d)piperidin- l-yl)ethan-l-one;

l-(4-((5S)-5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-caibonyl-4-d)piperidin- l-yl)ethan-l-one;

l-(4-((5R)-5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl-4-d)piperidin- l-yl)ethan-l-one;

(S)-l-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl-5-d)piperidin- l-yl)ethan-l-one;

(R)-l-(4-(5-(3,5-difluorophenyl)-4,5-dihydro-lH-pyrazole-l-carbonyl-5-d)piperidin- l-yl)ethan-l-one;

l-(4-((4R,5S)-5-(3,5-difluorophenyl)-4-methyl-4,5-dihydro-lH-pyrazole-l- carbonyl)piperidin-l -yl)ethanone;

l-(4-((4S,5R)-5-(3,5-difluorophenyl)-4-methyl-4,5-dihydro-lH-pyrazole-l- carbonyl)piperidin-l -yl)ethanone;

l-(4-((4R,5R)-5-(3,5-difluorophenyl)-4-methyl-4,5-dihydro-lH-pyrazole-l- caibonyl)piperidin-l-yl)ethanone; and

l-(4-((4S,5S)-5-(3,5-difluorophenyl)-4-methyl-4,5-dihydro-lH-pyrazole-l- carbonyl)piperidin-l -yl)ethanone

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8 and a pharmaceutically acceptable excipient.

10. A pharmaceutical composition according to claim 9, which further comprises at least one other therapeutically active agent.

1 1. A method of treating a RIP 1 -mediated disease or disorder in a human in need thereof comprising administering to the human a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8 or the pharmaceutical composition according to claim 9 or 10.

12. The method according to claim 11, wherein the disease or disorder is amyotrophic lateral sclerosis.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8 for use in therapy.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8 for the use in the treatment of amyotrophic lateral sclerosis.

15. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8.

16. Use of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8 in the manufacture of a medicament for use in the treatment of a RIP1 kinase-mediated disease or disorder.

17. The use according to claim 16, wherein the disease or disorder is amyotrophic lateral sclerosis.