Methods, compositions, and kits for treatment of inflammatory diseases by targeting RIPK2

Abstract

Provided herein are methods, compositions, and kits for treating inflammatory disease, fibrostenotic disease, and / or fibrotic disease by targeting receptor-interacting serine / threonine-protein kinase 2 (RIPK2). Also provided herein are methods of treating inflammatory, fibrotic, or fibrostenotic diseases in a subject with an inhibitor of RIPK2 activity or expression, and methods of selecting a subject with an inflammatory, fibrotic, or fibrostenotic disease for treatment with an inhibitor of RIPK2 activity or expression.

Description

Attorney Docket No.: 223335-203003 / PCT METHODS, COMPOSITIONS, AND KITS FOR TREATMENT OF INFLAMMATORY DISEASES BY TARGETING RIPK2 CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 667,437, filed July 3, 2024, which is hereby incorporated by reference in its entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically and is hereby incorporated by reference in its entirety. Said copy, created on July 2, 2025, is named 223335-203003_PCT_SL.xml and is 1,560,889 bytes in size. 1. FIELD

[0003] Provided herein are methods, compositions, and kits for treating inflammatory disease, fibrostenotic disease, and / or fibrotic disease by targeting receptor-interacting serine / threonine-protein kinase 2 (RIPK2). 2. BACKGROUND

[0004] Inflammatory disease, fibrostenotic disease, and fibrotic disease pose a significant health burden worldwide due to the vast number of individuals affected and heterogeneous disease pathogenesis and varied clinical manifestations. One such disease is inflammatory bowel disease (IBD), which has two common forms, Crohn’s disease (CD) and ulcerative colitis (UC). IBD is the chronic, relapsing inflammatory disorders of the gastrointestinal tract. Incidences of IBD are prevalent, affecting nearly three million individuals in the United States alone.

[0005] Limited treatment options are available to patients that suffer from inflammatory disease, fibrostenotic disease, and fibrotic disease. Existing anti-inflammatory therapy such as steroids, tumor necrosis factor (TNF) inhibitors, and inhibitors of interleukin-23, among others, are typically used as treatment for treating IBD. Unfortunately, a significant number of patients experience a lack of response or a loss of response to existing anti-inflammatory therapies. While the patient is treated with an anti-inflammatory therapy that is ineffective, the disease worsens. Surgery, in the form of structureplasty (reshaping of the intestine) or resection (removal of the intestine), is the common treatment option for patients with a worsening disease that does not respond to first line therapies. Surgical treatments for IBD 1 ACTIVE 712622340v1are invasive, causing post-operative risks for an estimated one-third of patients undergoing surgery, such as anastomotic leak, infection, and bleeding.

[0006] As such, there is an unmet need for methods, compositions, and kits for treating inflammatory disease, fibrostenotic disease, and / or fibrotic disease, which is provided herein. 3. SUMMARY

[0007] The genotypes described herein are associated (individually or together) with (i) an increase in a level of RIPK2 protein expression in a sample obtained from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease, as compared to a reference level of RIPK2 protein expression (e.g., derived from a healthy subject), (ii) an increase in a level of RIPK2 signaling in a sample obtained from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease, as compared to a reference level of RIPK2 signaling (e.g., derived from a healthy subject), (iii) an increase in the probability of a subject having an inflammatory, a fibrotic, or a fibrostenotic disease to have a therapeutic response to the treatment with an inhibitor of RIPK2 expression or activity (also referred to as “RIPK2 inhibitor”), (iv) an increase in the level of the subject’s therapeutic response to the treatment with an inhibitor of RIPK2 expression or activity, wherein the subject has an inflammatory, a fibrotic, or a fibrostenotic disease, (v) an increase in a level of RIPK2 mRNA in a sample obtained from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease, as compared to a reference level of RIPK2 mRNA (e.g., RIPK2 mRNA level derived from a normal tissue of the subject or from a healthy subject); (vi) an increase in the risk of the subject having an inflammatory, a fibrotic, or a fibrostenotic disease such as IBD; or (vii) any one or more combinations of (i) to (vi). Accordingly and as an example, the genotypes described herein are associated (individually or together) with an increase in a level of RIPK2 protein or mRNA expression in a sample obtained from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease, as compared to a reference level of RIPK2 protein or mRNA expression (e.g., derived from a normal tissue of the subject or a healthy subject). Additionally, the genotypes described herein are associated (individually or together) with an increase of RIPK2-mediated activities (e.g. RIPK2 mediated signaling pathways) that are related to the pathogenesis of inflammatory disease, fibrostenotic disease, and / or fibrotic disease (such as inflammatory bowel disease (IBD)). Additionally, the genotypes described herein are associated (individually or together) with an increase of a positive therapeutic response in inflammatory disease, fibrostenotic disease, and / or fibrotic disease patients (e.g. 2 ACTIVE 712622340v1IBD patients) to a treatment with the inhibitor of RIPK2 activity or expression, as compared to the reference level of response in patients not selected by the genotypes. The genotypes disclosed herein can be located at gene or genetic loci that are involved either directly or indirectly with RIPK2-mediated inflammatory pathways. In addition, some of the genotypes provided herein can also be significantly associated with inflammatory bowel disease (IBD), such as Crohn’s disease (CD) and ulcerative colitis (UC). The genotypes are useful for selecting a patient or a subject for treatment with a RIPK2 inhibitor. The patient may be diagnosed with UC, CD, or both. The subject may be suspected of having UC, CD, or both. As is clear from the description of this paragraph, in some embodiments, the subject is a patient having an inflammatory disease, a fibrostenotic disease, and / or a fibrotic disease and the healthy subject is a healthy human subject. Certain embodiments of (i) to (vi) of this paragraph are further described and exemplified in Examples 1 and 7 and Tables 4 and 9.

[0008] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), wherein the subject is determined to have a presence of a combination of genotypes selected from the polymorphisms of Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0009] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject comprises a combination of genotypes.

[0010] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject comprises a combination of genotypes, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80. 3 ACTIVE 712622340v1

[0011] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject tested positive for a presence of a combination of genotypes in a biological sample obtained from the subject.

[0012] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject tested positive for a presence of a combination of genotypes in a biological sample obtained from the subject, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0013] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject is identified based on a presence of a combination of genotypes identified in a biological sample obtained from the subject, wherein the combination of genotypes is predictive of an increased expression level or increased signaling level of RIPK2, wherein the increased expression level or increased signaling level of RIPK2 is relative to a baseline expression or signaling level of RIPK2 in subjects not suffering from the inflammatory, fibrotic, or fibrostenotic disease or condition, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0014] In one aspect, provided herein is a method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a therapeutically effective amount of a RIPK2 inhibitor, the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of genotypes; (b) selecting a subject determined to have the presence of the combination of genotypes in (a), wherein the 4 ACTIVE 712622340v1presence of the combination of genotypes comprises one or more polymorphisms selected from the polymorphisms of Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80..

[0015] In one aspect, provided herein is a method of determining presence of a combination of genotypes in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) contacting genetic materials in a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition with one or more nucleic acid primer pairs having forward and reverse primers suitable for hydridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of a combination of genotypes; (b) amplifying the target nucleic acid sequences by polymerase chain reactions with the nucleic acid primer pairs of (a); and (c) analysing the results of (b) to determine the presence in the target nucleic acid sequences of the combination of genotypes of step (a), wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0016] In some embodiments, the increased expression level or increased signaling level of RIPK2 comprises: (i) increased level of RIPK2 mRNA; (ii) increased level of RIPK2 protein; (iii) increased level of signaling molecules that stimulate the RIPK2 signaling pathway (such as NOD2 and CARD9). In some embodiments, the increased expression level or increased signaling level of RIPK2 comprises: (i) increased level of RIPK2 mRNA; (ii) increased level of RIPK2 protein; (iii) increased level of NOD2 protein; (iv) increased level of NOD2 mRNA; (v) increased level of CARD9 protein; (vi) increased level of CARD9 mRNA; or (vii) any combination of 1, 2, 3, 4, 5, or 6 features selected from (i) to (vi). In some embodiments, the increased level of RIPK2 mRNA is increased level of RIPK2 mRNA in the diseased tissue as compared to level of RIPK2 mRNA in a healthy tissue of the subject or as compared to level of RIPK2 mRNA in a healthy subject. In some embodiments, the increased level of signaling molecules that stimulate the RIPK2 signaling pathway (such as NOD2 and CARD9) is increased level of such signaling molecules in the diseased tissue as 5 ACTIVE 712622340v1compared to level of such signaling molecules in a healthy tissue of the subject or as compared to level of such signaling molecules in a healthy subject. In some embodiments, the increased level of RIPK2 protein is increased level of RIPK2 protein in the diseased tissue of the subject as compared to level of RIPK2 protein in a healthy tissue of the subject or as compared to level of RIPK2 protein in a healthy subject. In some embodiments, the increased level of NOD2 mRNA is increased level of NOD2 mRNA in the diseased tissue as compared to level of NOD2 mRNA in a healthy tissue of the subject or as compared to level of NOD2 mRNA in a healthy subject. In certain embodiments, the increased level of NOD2 protein is increased level of NOD2 protein in the diseased tissue of the subject as compared to level of NOD2 protein in a healthy tissue of the subject or as compared to level of NOD2 protein in a healthy subject. In some embodiments, the increased level of CARD9 mRNA is increased level of CARD9 mRNA in the diseased tissue as compared to level of CARD9 mRNA in a healthy tissue of the subject or as compared to level of CARD9 mRNA in a healthy subject. In certain embodiments, the increased level of CARD9 protein is increased level of CARD9 protein in the diseased tissue of the subject as compared to level of CARD9 protein in a healthy tissue of the subject or as compared to level of CARD9 protein in a healthy subject.

[0017] In some embodiments, the method further comprises preparing DNA from the sample.

[0018] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with a RIPK2 inhibitor by: (i) obtaining or having obtained a sample from the subject; (ii) subjecting the sample to an assay adapted to detect a combination of genotypes, wherein the subject is determined to be suitable for treatment with the RIPK2 inhibitor if the combination of genotypes are detected; and (b) treating the subject by administering a therapeutically effective amount of the RIPK2 inhibitor to the subject, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80. 6 ACTIVE 712622340v1

[0019] In one aspect, provided herein is a method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a therapeutically effective amount of a RIPK2 inhibitor, the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of genotypes; (b) selecting a subject determined to have the presence of the combination of genotypes in (a), wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80; and (c) administering a therapeutically effective amount of the RIPK2 inhibitor to the subject selected in (b).

[0020] In one aspect, provided herein is a method of determining a combination of genotypes for a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; and (c) determining the combination of genotypes for the subject; wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0021] In one aspect, provided herein is a method of determining presence of a combination of genotypes in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) contacting genetic materials in a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition with one or more nucleic acid primer pairs having forward and reverse primers suitable for hydridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of a combination of genotypes; (b) amplifying the target nucleic acid sequences by polymerase chain reactions with the nucleic acid primer pairs of (a); and (c) analysing the results of (b) to determine the presence in the target nucleic acid sequences of the combination of genotypes of step (a), wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a 7 ACTIVE 712622340v1separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0022] In one aspect, provided herein is a method of selecting a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a RIPK2 inhibitor, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; (c) selecting the subject for treatment with the RIPK2 inhibitor if the combination of genotypes are detected, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0023] In some embodiments, the linkage disequilibrium is linkage disequilibrium with an r2value of about 0.8, about 0.85, about 0.9, about 0.95, about 1, at least 0.80, at least 0.85, at least 0.90, or at least 0.95.

[0024] In some embodiments of the methods provided herein, the Table 1 referred to in the method is Table 1 Part I. In some embodiments of the methods provided herein, the Table 1 referred to in the method is Table 1 Part II. In some embodiments of the methods provided herein, the Table 1 referred to in the method is Table 1 Part III. In some embodiments of the methods provided herein, the Table 1 referred to in the method is Table 1 Part IV. In some embodiments of the methods provided herein, the Table 1 referred to in the method is Table 1 Part V. In some embodiments of the methods provided herein, the Table 1 referred to in the method is Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, and Table 1 Part V.

[0025] In some embodiments, the increased expression level or increased signaling level of RIPK2 comprises: (i) increased level of RIPK2 mRNA; (ii) increased level of RIPK2 protein; (iii) increased level of signaling molecules that stimulate the RIPK2 signaling pathway (such as NOD2 and CARD9); or (iv) any combination of 1, 2, or 3 features selected from (i) to (iii). In some embodiments, the increased expression level or increased signaling level of RIPK2 comprises: (i) increased level of RIPK2 mRNA; (ii) increased level of RIPK2 protein; (iii) increased level of NOD2 protein; (iv) increased level of NOD2 mRNA; (v) increased level of CARD9 protein; (vi) increased level of CARD9 mRNA; or (vii) any 8 ACTIVE 712622340v1combination of 1, 2, 3, 4, 5, or 6 features selected from (i) to (vi). In some embodiments, (i) the increased level of RIPK2 mRNA is increased level of RIPK2 mRNA in the diseased tissue as compared to level of RIPK2 mRNA in a healthy tissue of the subject or as compared to level of RIPK2 mRNA in a healthy subject; (ii) the increased level of RIPK2 protein is increased level of RIPK2 protein in the diseased tissue of the subject as compared to level of RIPK2 protein in a healthy tissue of the subject or as compared to level of RIPK2 protein in a healthy subject; (iii) the increased level of NOD2 mRNA is increased level of NOD2 mRNA in the diseased tissue as compared to level of NOD2 mRNA in a healthy tissue of the subject or as compared to level of NOD2 mRNA in a healthy subject; (iv) the increased level of NOD2 protein is increased level of NOD2 protein in the diseased tissue of the subject as compared to level of NOD2 protein in a healthy tissue of the subject or as compared to level of NOD2 protein in a healthy subject; (v) the increased level of CARD9 mRNA is increased level of CARD9 mRNA in the diseased tissue as compared to level of CARD9 mRNA in a healthy tissue of the subject or as compared to level of CARD9 mRNA in a healthy subject; (vi) the increased level of CARD9 protein is increased level of CARD9 protein in the diseased tissue of the subject as compared to level of CARD9 protein in a healthy tissue of the subject or as compared to level of CARD9 protein in a healthy subject; or (vii) any combination of 1, 2, 3, 4, 5, or 6 features selected from (i) to (vi).

[0026] In some embodiments, the combination of genotypes or the combination of polymorphisms comprise at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, or at least sixteen polymorphisms. In some embodiments, the combination of genotypes or the combination of polymorphisms is detected in the sample by subjecting the sample to an assay configured to detect a presence of a nulceotide corresponding to nuleotide position 101 within the sequence of the polymorphisms listed in Table 2.

[0027] In some embodiments, the inflammatory, fibrotic, or fibrostenotic disease or condition is inflammatory bowel disease.

[0028] In some embodiments, the inflammatory, fibrotic, or fibrostenotic disease or condition is ulcerative colitis. In some embodiments, the inflammatory, fibrotic, or fibrostenotic disease or condition is Crohn’s disease. In some embodiments, the subject has been treated with an advanced IBD therapy prior to the treatment with the RIPK2 inhibitor. In some embodiments, the subject has not been treated with an advanced IBD therapy prior to 9 ACTIVE 712622340v1the treatment with the RIPK2 inhibitor. In some embodiments, the advanced IBD therapy comprises one or more selected from the group consisting of a biologic therapeutic agent for IBD, an S1P1 modulator, or a JAK inhibitor. In some embodiments, the biologic therapeutic agent for IBD comprises an anti-TNFα antibody, an anti-IL23 antibody, or an anti-integrin α4β7 antibody.

[0029] In some embodiments of the combination of administering or using the RIPK2 inhibitor and the TL1A inhibitor, the RIPK2 inhibitor is a compound that has the structure of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein: one or two of X, Y, and Z1is independently N and the other of X, Y, and Z1is C; each is a single bond or a double bond; R5is hydrogen, -NH2, or halogen; Ring A is phenyl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, or 4; each R1is independently: (i) C1-C6 alkoxy optionally substituted with hydroxyl or phenyl; (ii) C1-C6 deuteroalkoxy; (iii) C1-C6 alkoxyalkyl; (iv) 5-6 membered heteroaryl; (v) –N(R6)-S(O2)R7; (vi) –(C=O)NR6R7, -NR6(C=O)OR7, or –(C=O)OR7; (vii) halogen; (viii) cyano; (ix) hydroxyl; (x) –NR6R8; 10 ACTIVE 712622340v1(xi) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl and 4-8 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl; (xii) C1-C6 haloalkyl; (xiii) C1-C6 haloalkoxy; (xiv) C3-C6 cycloalkyl; (xv) 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl; (xvi) –S(O2)C1-C6 alkyl; (xvii) 4-10 membered heterocyclyloxy optionally substituted with acyl; (xviii) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, and C1-C6 haloalkyl; each R6is independently hydrogen or C1-C6 alkyl; each R7is independently: (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from: (a) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (b) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, C1-C6 alkoxy,C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and cyano; (c) -NR6R7; (d) hydroxyl; (e) halogen; (f) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3- C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1- C6 alkyl; (g) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen, cyano,C1-C6 alkyl, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with –(C=O)OC1-C6 alkyl; (ii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl; (iii) C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl; (iv) ethylenyl; 11 ACTIVE 712622340v1(v) C1-C6 haloalkyl; (vi) 4-10 membered heterocyclyl optionally substituted with –(C=O)OC1-C6 alkyl; or (vii) phenyl optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, and –(C=O)NR6R7; or R6and R7with the atom to which they are attached together form a 5-12 membered heterocyclyl or 9-10 membered heteroaryl each optionally substituted with phenyl; R8is (i) hydrogen; (ii) –S(O2)C1-C6 alkyl; (iii) C3-C6 cycloalkyl optionally substituted with hydroxyl or C1-C6 alkoxy; (iv) –(C=O)C1-C6 alkyl; (v) –(C=O)OC1-C6 alkyl; (vi) 4-8 membered heterocyclyl optionally substituted with hydroxyl; or (vii) C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, hydroxyl, -NR9R10, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, and 4-8 membered heterocyclyl optionally substituted with –C(=O)C1-C6 alkyl or C1-C6 alkyl; (viii) –(C=O)5- or 6- membered heteroaryl optionally substituted with C1-C6 alkyl; R2is (i) hydrogen; (ii) halogen; (iii) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from (a) hydroxyl; (b) halogen; (c) phosphate; (d) -NR11R12; (e) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl; (f) 5-6 membered heteroaryl optionally substituted with C1-C6 alky; (g) C3-C6 cycloalkyl optionally substituted with hydroxyl or hydroxyalkyl; 12 ACTIVE 712622340v1(h) CO2H,; (i) C(O)R11; (j) C1-C6 alkoxy; or (k) oxo; (iv) C1-C6 haloalkoxy; (v) 4-10 membered heterocyclyloxy; (vi) –(C=O)NR11R12; (vii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR11R12; (viii) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or C1-C6 alkoxy; or (ix) –NR11R12; each R11and R12are independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, or C1-C6 hydroxyalkyl; R3is (i) C1-C6 thioalkyl;(iv) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; (v) C1-C6 alkyl optionally substituted with NR16R17or hydroxyl; (vi) -CO2H; (vii) -C(=O)NR16R17; (viii) C1-C6 alkoxy optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkoxy; (ix) hydrogen; (x) C1-C6 haloalkyl; (xi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xii) C1-C6 alkoxyalkyl, or (xiii) C1-C6 hydroxyalkyl; 13 ACTIVE 712622340v1Z is O or NR4; R13is (i) C1-C6 haloalkyl, (ii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, (iii) C1-C6 alkyl optionally substituted with (a) C3-C6 cycloalkyl, (b) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, (c) hydroxyl, (d) C1-C6 alkoxy, or (e) 4-6 membered heterocyclyl optionally substituted with 4-6 membered heterocyclyl or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, (iv) C1-C6 alkoxyalkyl, (v) C1-C6 hydroxyalkyl, (vi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, or (vii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1- C6 alkoxy, (viii) -N(C1-C6 alkyl)2; R14and R15are each independently C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, or R14and R15with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; R4is hydrogen or C1-C6 alkyl; and each R9and R10are each independently hydrogen, -(C=O)C1-C6 alkyl, or C1-C6 alkyl optionally substituted with oxo; each R16and R17are each independently hydrogen or C1-C6 alkyl, or R16and R17with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with hydroxyl.

[0030] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound that has the structure of Formula (I-n): 14 ACTIVE 712622340v1Formula (I-n), or a pharmaceutically acceptable salt thereof, wherein: each R18, R19, and R20are independently: C1-C6 alkoxyalkyl, -N(R6)-S(O2)R7, or halogen; each R6is independently hydrogen or C1-C6 alkyl; and each R7is independently C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; or each R7is independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl; or each R7is independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl.

[0031] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound selected from the group consisting of15 ACTIVE 712622340v1, or a pharmaceutically acceptable salt or solvate thereof.

[0032] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound that has the structure of Formula (Formula (II), or a pharmaceutically acceptable salt thereof, wherein: R22is selected fromR6is hydrogen or C1-C6 alkyl; R7is selected from: (i) C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from: (a) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (b) phenyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and cyano; (c) hydroxyl; (d) halogen; (e) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl; and (f) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen, cyano,C1-C6 alkyl, and C1-C6 alkoxy; 16 ACTIVE 712622340v1(ii) C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, phenyl optionally substituted with 1-2 independently selected halogen and 5-10 membered heteroaryl; (iii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl; (iv) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, and C1-C6 haloalkyl; (v) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl; (vi) C1-C6 alkoxy; or (vii) C3-C6 cycloalkoxy; or R6and R7with the atom to which they are attached together form a 5-12 membered heterocyclyl or 9-10 membered heteroaryl each optionally substituted with phenyl; and R23is C1-C3 alkyl or C3-C4 cycloalkyl.

[0033] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound selected from the group consisting of17 ACTIVE 712622340v1or a pharmaceutically acceptable salt or solvate thereof.

[0034] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound that has the structure of Formula (III):or a pharmaceutically acceptable salt thereof, wherein:YA1, YA2, and YA3are each independently N, CH, or CRA4; ZAis N or CRA5; RA1is C3-C6 alkyl, C3-C6 cycloalkyl, C5-C12 bridged bicyclic carbocyclyl, or 4-10 membered heterocyclyl, wherein the C3-C6 alkyl, C3-C6 cycloalkyl, C5- C12 bridged bicyclic carbocyclyl, or 4-10 membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, NRA10S(O)RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1- C6 alkyl, C1-C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1- C3 alkylcarbonylamino(C1-C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6-C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; 18 ACTIVE 712622340v1RA9is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, NRA10S(O)RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1- C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1- C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1- C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6- C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; RA2is H or C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2)RA10, NRA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1- C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1- C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1- C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6- C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; WAis selected from a bond, -O-, -NRA10-, -O(C1-C2 alkylene)-, NH(C1- C2 alkylene), C1-C2 alkylene, and C3-C6 cycloalkylene; RA3is selected from S(=O)2RA6, halogen, 4-10 membered heterocyclyl, 5-12 membered heteroaryl, C(=O)N(RA10)2, NH(C=O)RA6, cyano, N(RA10)2, and P(=O)(RA10)2;each RA4is independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, N RA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1- C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-3alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1- C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6- C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; 19 ACTIVE 712622340v1nAis 0, 1, 2, or 3; each RA5is each independently selected from H, C1-C6 alkyl, halogen, and cyano, wherein the C1-C6 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, N RA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1-C6 deuteroalkyl, C3- C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1-C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6-C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; and RA6is selected from C1-C6 alkyl, -N(RA10)2, C3-C6 cycloalkyl, and 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, and 4-10 membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2)RA10, N RA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1-C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1-C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6-C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; and each RA10is independently C1-C6 alkyl or C3-C6 cycloalkyl optionally substituted 1 to 3 substituents independently selected from with hydroxyl, halogen, or C1-C6 alkoxy, or two RA10are taken together with the atom they are attached to form a cyclic structure.

[0035] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound selected from the group consisting of 20 ACTIVE 712622340v1, or a pharmaceutically acceptable salt or solvate thereof.

[0036] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound that has the structure of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt thereof, wherein: X2is N and X3is CH or X2is CH and X3is N; R2is: (i) hydrogen; (ii) halogen; (iii) C1-C6 alkoxy; (iv) C1-C6 haloalkoxy; 21 ACTIVE 712622340v1(v) –(C=O)NR11R12; or (vi) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR11R12; each R11and R12are independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, or C1-C6 hydroxyalkyl; R3is: (i) C1-C6 thioalkyl;(iii) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; (vi) -C(=O)NR16R17; (v) hydrogen; (vi) C1-C6 haloalkyl; (vii) C1-C6 alkoxyalkyl; or (viii) C1-C6 hydroxyalkyl; Z is O; R13is (i) C1-C6 haloalkyl; (ii) C3-C6 cycloalkyl; (iii) C1-C6 alkyl, (iv) C1-C6 alkoxyalkyl; (v) C1-C6 hydroxyalkyl; or (vi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1- C6 alkoxy; each R16and R17are each independently hydrogen or C1-C6 alkyl, or R16and R17with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with hydroxyl; R24is C1-3alkyl or Cl; and R25is hydrogen or F. 22 ACTIVE 712622340v1

[0037] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound selected from the group consisting of:or a pharmaceutically acceptable salt or solvate thereof.

[0038] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound that has the structure of Formula (V):Formula (V), or a pharmaceutically acceptable salt thereof, wherein: RAis halogen, -CN, -O-(C1-C6 alkyl), C2-C6 alkynyl, C1-C6 alkyl, C3-C6 cycloalkyl, - C(=O)C1-C6 alkyl, -C(=O)C1-C6cycloalkyl, -C(=O)RM, -C(=O)NRaRb, or -RL, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected 23 ACTIVE 712622340v1from deuterium, halogen, -O-(C1-C6 alkyl), C3-C6 cycloalkyl, phenyl, -RL, -RM, and -OH, wherein C2-C6alkynyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, and -CH2-O-(C1-C6 alkyl); Rais hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium and C1-C6 alkyl; Rbis hydrogen, C1-C6 alkyl, or -O-(C1-C6 alkyl), wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium, C1-C5 alkyl, and C3-C5 cycloalkyl; RLand RNare each independently a 5 to 6-membered heteroaryl having from 1 to 3 heteroatoms selected from O, N and S, wherein each of RLor RNis optionally substituted with 1-3 C1-C6 alkyl, wherein C1-C6 alkyl being optionally substituted with one or more substituents selected from -D, halogen, -O-(C1-C6 alkyl), and -OH; RBis hydrogen or halogen; RC, RCC, RD, RDD, RG, and RHare each independently hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more -O-(C1-C6 alkyl); wherein when at least one of RCor RCCis C1-C6 alkyl, then RDand RDDare each hydrogen; wherein when at least one of RDor RDDis C1-C6 alkyl, then RCand RCCare each hydrogen; REis -OH, -NRcRc, -NHC(=O)Rc, -NC(=O)RcRc, -NC(=O)ORc, -NHS(O2)Rc, halogen, - O-(C1-C6 alkyl), -O-(C3-C5 cycloalkyl), -O-RM, C1-C6 alkyl, and -CN, wherein C1- C6 alkyl is optionally substituted with one or more substituents selected from deuterium, -OH, C1-C6 alkyl, C3-C5 cycloalkyl, -O-(C1-C6 alkyl) and RM; Rcis hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium and C1-C6 alkyl; RMis 4-6 membered saturated heterocycle having from 1 to 3 heteroatoms selected from O and N, wherein each RMis optionally substituted with 1-3 C1-C6 alkyl, wherein C1-C6 alkyl being optionally substituted with one or more substituents selected from -D, halogen, -O-(C1-C6 alkyl), and -OH; RFis hydrogen, halogen, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-RP, and RN, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium and -O-(C1-C6 alkyl); 24 ACTIVE 712622340v1RPis 4-10 membered saturated heterocycle having from 1 to 3 heteroatoms selected from O and N, wherein each RPis optionally substituted with 1-3 C1-C6 alkyl, wherein C1-C6 alkyl being optionally substituted with one or more substituents selected from -D, halogen, -O-(C1-C6 alkyl), and -OH; RJis hydrogen, C1-C6 alkyl, -C(=O)C1-C6 alkyl, or -C(=O)-O-(C1-C6 alkyl); and RKis hydrogen or halogen.

[0039] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound selected from the group consisting ofor a pharmaceutically acceptable salt or solvate thereof.

[0040] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound that has the structure of Formula (VI):Formula (VI) 25 ACTIVE 712622340v1or a pharmaceutically acceptable salt or solvate thereof, wherein: nBis 0, 1, 2 or 3; LBis a bond, —O—, —N(RB6)—,wherein # denotes a connection to RB3; ring ABis C6-C10 aryl or 5-10 membered heteroaryl; each RB1is independently hydrogen, -D, halogen, hydroxyl, amino, cyano, C1- C6 alkyl, C3-C6 cycloalkyl, —OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1- C6 alkyl)2, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C3- C6 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with 1 to 3 groups independently selected from RBa; RB2is hydrogen, -D, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups independently selected from RBb; RB3is hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, —OC1- C6 alkyl, 3-6 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted with 1 to 3 groups independently selected from RBc; RB4is C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted with 1 to 3 groups independently selected from RBd; RB5is C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted with 1 to 3 groups independently selected from RBe; or RB4and RB5together with the phosphorus atom attached thereto form 5-6 membered heterocycloalkyl or 5-8 membered heterocycloalkenyl, wherein the 5-6 membered heterocycloalkyl or 5-8 membered heterocycloalkenyl are optionally substituted with 1 to 3 groups independently selected from RBd; RB6is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3- C6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from RBf; RB7is hydrogen, -D, F, Cl, Br, hydroxyl, amino, cyano, C1-C6 alkyl, C3- C6 cycloalkyl, —OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, C2- C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2- 26 ACTIVE 712622340v1C6 alkenyl or C2-C6 alkynyl is optionally substituted with 1 to 3 groups independently selected from RBg; each RBa, RBb, RBd, RBe, RBf, and RBgare each independently F, Cl, Br, I, hydroxyl, amino, methyl or methoxy; each RBcis independently deuterium, F, Cl, Br, I, hydroxyl, amino, methyl, methoxywherein each heterocycloalkyl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl comprises 1 to 3 heteroatoms or heteroatom groups independently selected from N, NH, O, S and P(═O).

[0041] In some embodiments of the combination of administering or using the RIPK2 inhibitor and TL1A inhibitor, the RIPK2 inhibitor is a compound selected from the group consisting of: ,, ,27 ACTIVE 712622340v1acceptable salt or solvate thereof.

[0042] In some embodiments, the RIPK2 inhibitor is administered in a therapeutically effective amount. In some embodiments, the RIPK2 inhibitor is administered in a therapeutically effective amount, and the therapeutically effective amount of the RIPK2 inhibitor comprises about 5 mg to 100 mg, about 5 mg to 200 mg, or 5 mg to 300 mg and is administered to the patient once or twice daily. In some embodiments, the RIPK2 inhibitor is systemically administered to the patient. In some embodiments, the RIPK2 inhibitor is orally administered to the patient. In some embodiments, the RIPK2 inhibitor is administered to the patient as a pharmaceutical composition comprising the RIPK2 inhibitor and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is an oral solution, oral suspension, powder, pill, tablet or capsule. In some embodiments, the RIPK2 inhibitor is non-systemically administered to the patient. In some embodiments, the RIPK2 inhibitor is administered to the patient daily. In some embodiments, the RIPK2 inhibitor is administered to the patient once daily. In some embodiments, the RIPK2 inhibitor is administered to the patient twice daily. In some embodiments, the RIPK2 inhibitor is administered to the patient on a continuous daily dosing schedule. 28 ACTIVE 712622340v1

[0043] In some embodiments of the RIPK2 inhibitor for the methods provided herein, the RIPK2 inhibitor is a compound of Formula (I). In some embodiments, such compound of Formula (I) is selected from compounds further described in Section 5.4.1 under Formula (I) . In some embodiments of the RIPK2 inhibitor for the methods provided herein, the RIPK2 inhibitor is a compound of Formula (I-b). In some embodiments, such compound of Formula (I-b) is selected from compounds further described in Section 5.4.1. In some embodiments of the RIPK2 inhibitor for the methods provided herein, the RIPK2 inhibitor is a compound of Formula (I-m). In some embodiments, such compound of Formula (I-m) is selected from compounds further described in Section 5.4.1. In some embodiments of the RIPK2 inhibitor for the methods provided herein, the RIPK2 inhibitor is a compound of Formula (I-n). In some embodiments, such compound of Formula (I-n) is selected from compounds further described in Section 5.4.1. In some embodiments of the RIPK2 inhibitor for the methods provided herein, the RIPK2 inhibitor is a compound of Formula (I-o). In some embodiments, such compound of Formula (I-o) is selected from compounds further described in Section 5.4.1. In some embodiments of the RIPK2 inhibitor for the methods provided herein, the RIPK2 inhibitor is a compound of Formula (I-p). In some embodiments, such compound of Formula (I-p) is selected from compounds further described in Section 5.4.1.

[0044] In some embodiments, the RIPK2 inhibitor is a compound of Formula (II). In some embodiments, such RIPK2 inhibitor of Formula (II) is selected from compounds further described in Section 5.4.1 under Formula (II). In some embodiments, the RIPK2 inhibitor is a compound of Formula (IV). In some embodiments, such RIPK2 inhibitor of Formula (IV) is selected from compounds further described in Section 5.4.1 under Formula (IV). In some embodiments, the RIPK2 inhibitor is a compound of Formula (V). In some embodiments, such RIPK2 inhibitor of Formula (V) is selected from compounds further described in Section 5.4.1 under Formula (V). In some embodiments, the RIPK2 inhibitor is a compound of Formula (Va). In some embodiments, such RIPK2 inhibitor of Formula (Va) is selected from compounds further described in Section 5.4.1 under Formula (Va). In some embodiments, the RIPK2 inhibitor is a compound of Formula (III). In some embodiments, such RIPK2 inhibitor of Formula (III) is selected from compounds further described in Section 5.4.1 under Formula (III). In some embodiments, the RIPK2 inhibitor is a compound of Formula (IIIa). In some embodiments, such RIPK2 inhibitor of Formula (IIIa) is selected from compounds further described in Section 5.4.1 under Formula (IIIa). In some embodiments, the RIPK2 inhibitor is a compound of Formula (IIIb). In some embodiments, 29 ACTIVE 712622340v1such RIPK2 inhibitor of Formula (IIIb) is selected from compounds further described in Section 5.4.1 under Formula (IIIb). In some embodiments, the RIPK2 inhibitor is a compound of Formula (VI). In some embodiments, such RIPK2 inhibitor of Formula (VI) is selected from compounds further described in Section 5.4.1 under Formula (VI). In some embodiments, the RIPK2 inhibitor is a compound of Formula (VIa). In some embodiments, such RIPK2 inhibitor of Formula (VIa) is selected from compounds further described in Section 5.4.1 under Formula (VIa). In some embodiments, the RIPK2 inhibitor is a compound of Formula (VIb). In some embodiments, such RIPK2 inhibitor of Formula (VIb) is selected from compounds further described in Section 5.4.1 under Formula (VIb). In some embodiments, the RIPK2 inhibitor is a compound of Formula (VIc). In some embodiments, such RIPK2 inhibitor of Formula (VIc) is selected from compounds further described in Section 5.4.1 under Formula (VIc).

[0045] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. 4. INCORPORATION BY REFERENCE

[0046] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. 5. DETAILED DESCRIPTION

[0047] Provided herein are methods, compositions, and kits for treating a subject who may be suitable for treatment with an inhibitor of RIPK2 activity or expression (RIPK2 inhibitor), provided the subject is a carrier of a combination of genotypes. The subject may be a patient, who may be diagnosed with an inflammatory disease, a fibrostenotic disease, or a fibrotic disease, such as inflammatory bowel disease (IBD) or Crohn’s disease (CD). The 30 ACTIVE 712622340v1genotype can be useful for selecting patients of the inflammatory fibrostenotic, or fibrotic disease or condition, that is mediated by RIPK2. The subject, in some embodiments, is treated by administering the RIPK2 inhibitor (e.g., RIPK2 small molecule inhibitor) to the subject, provided the combination of genotypes is detected. In some cases, identifying the subject as being suitable for treatment with the RIPK2 inhibitor is required in order to administer the RIPK2 inhibitor to the subject.

[0048] The genotypes described herein are detected using suitable genotyping devices (e.g., array, sequencing). In some instances, a sample is obtained from the subject or patient indirectly or directly. In some instances, the sample may be self-obtained by the subject. In other instances, the sample may be obtained by a healthcare professional, such as a nurse or physician. The sample can be derived from virtually any biological fluid or tissue containing genetic information, such as blood.

[0049] The subject disclosed herein can be a mammal, such as for example a mouse, rat, guinea pig, rabbit, non-human primate, or farm animal. In some instances, the subject is human. In some embodiments, the subject is a human patient having an inflammatory, a fibrotic, or a fibrostenotic disease. In some embodiments, the subject is a human patient having IBD. In some embodiments, the subject is a human patient having UC. In some embodiments, the subject is a human patient having CD. In some instances, the subject is suffering from a symptom related to a disease or condition disclosed herein (e.g., abdominal pain, cramping, diarrhea, rectal bleeding, fever, weight loss, fatigue, loss of appetite, dehydration, and malnutrition, anemia, or ulcers).

[0050] In some embodiments, the subject is susceptible to, or is inflicted with, thiopurine toxicity, or a disease caused by thiopurine toxicity (such as pancreatitis or leukopenia). The subject may experience, or is suspected of experiencing, non-response or loss-of-response to a standard anti-inflammatory treatment (e.g., anti-TNF alpha antibody therapy (adalimumab), anti-integrin α4β7 antibody therapy (vedolizumab), anti-IL12p40 antibody therapy (ustekinumab), anti-IL23p19 antibody, an S1P1 modulator, or a JAK inhibitor).

[0051] The disease or condition disclosed herein may be an inflammatory disease, a fibrostenotic disease, or a fibrotic disease. In some embodiments, the disease or condition treated by the methods provided herein is IBD (such as UC or CD). In some embodiments, the disease or condition treated by the methods provided herein is UC. In some embodiments, the disease or condition treated by the methods provided herein is CD. In some instances, the disease or the condition is an inflammatory disease, a fibrostenotic disease, or a fibrotic 31 ACTIVE 712622340v1disease that is mediated by RIPK2. In other embodiments, the inflammatory disease, fibrostenotic disease, or fibrotic disease is IBD (e.g. UC or CD) mediated by RIPK2. In some embodiments, the disease or condition treated by the methods provided herein is UC mediated by RIPK2. In other embodiments, the disease or condition treated by the methods provided herein is CD mediated by RIPK2. The term, (i) “RIPK2-mediated” or (ii) “mediated by RIPK2” when used in reference to a disease or condition, refers to such disease or a condition of which the pathology or pathogenesis is driven, at least in part, by increased level of RIPK2 expression, signaling, or other RIPK2 function.

[0052] As already described, in some embodiments the inflammatory disease, fibrostenotic disease, or fibrotic disease is an inflammatory disease or disorder that is mediated, at least in part, by RIPK2 signaling. Non-limiting examples of such inflammatory disease, fibrostenotic disease, or fibrotic diseases include, inflammatory bowel disease (IBD) such as Crohn’s disease and ulcerative colitis.

[0053] In some embodiments, the inflammatory disease, fibrostenotic disease, or fibrotic disease is an inflammatory bowel disease, such as Crohn’s disease (CD) or ulcerative colitis (UC). In some cases, the CD is severe CD. The severe CD may result from inflammation that has led to the formation of scar tissue in the intestinal wall (fibrostenosis) and / or swelling. In some cases, the severe CD is characterized by the presence of fibrotic and / or inflammatory strictures. The strictures may be determined by computed tomography enterography (CTE), and magnetic resonance imaging enterography (MRE). The disease or condition may be characterized as refractory, which in some cases, means the disease is resistant to a standard treatment (e.g., anti-TNFα therapy). Non-limiting examples of standard treatment include glucocorticosteriods, anti-TNFα antibody therapy (adalimumab), anti-α4β7 antibody therapy (vedolizumab), anti-IL12p40 antibody therapy (ustekinumab), anti-IL23p19 antibody therapy, an S1P1 modulator, or a JAK inhibitor. 5.1 Genotypes

[0054] Disclosed herein are genotypes that may be detected in a sample obtained from a subject by analyzing the genetic material in the sample. In some instances, the subject can be human. In some embodiments, the genetic material is obtained from a subject having an inflammatory, fibrostenotic, or fibrotic disease or condition disclosed herein. In some cases, the genetic material is obtained from blood, plasma, hair, buccal swab, saliva, and other techniques known by one of skill in the art. In some cases, the genetic material is obtained from a biopsy, e.g., from the intestinal track of the subject. 32 ACTIVE 712622340v1

[0055] The genotypes of the present disclosure are determined in genetic materials that are or comprise deoxyribonucleic acid (DNA). In some instances, the genetic materials for determining the genotypes comprises a denatured DNA molecule or fragment thereof. In some instances, the genetic materials for determining the genotypes comprises DNA selected from: genomic DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, or exosomal DNA. In some instances, the DNA is single- stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, PCR amplified DNA, and combinations thereof. The circular DNA may be cleaved or fragmented. In other embodiments, the genotypes of the present disclosure are determined in genetic materials that are or comprise ribonucleic acid (RNA), which RNA can be messenger RNA (mRNA). In certain additional embodiments, the genotypes of the present disclosure are determined in genetic materials that comprise both DNA and RNA, each as further exemplified herein.

[0056] The genotypes disclosed herein can comprise one or more polymorphisms at one or more genes or genetic loci described herein. In some instances, the gene or genetic locus is selected from the group consisting of ATG16L1, CARD9, IRGM, NOD2, and RIPK2. In some instances, the gene or genetic locus comprises a gene or genetic locus provided in Table 1 (e.g. those listed in column 1 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). The genotypes disclosed herein are, in some cases, a haplotype. In some instances, the genotype comprises a particular polymorphism, a polymorphism in linkage disequilibrium (LD) therewith, or a combination thereof. In some cases, LD is defined by an r2of at least or about 0.70, 0.75, 0.80, 0.85, 0.90, or 1.0. The genotypes disclosed herein can comprise at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more single nucleotide polymorphisms. The genotypes disclosed herein can comprise at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or more polymorphisms selected from Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 3 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 4 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 33 ACTIVE 712622340v1Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 5 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 6 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 7 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 8 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 9 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 10 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 11 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 12 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 13 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 14 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 15 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 34 ACTIVE 712622340v1Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 16 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 17 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 18 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 19 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 20 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V). In some embodiments, the genotypes disclosed herein comprise a combination of 21 polymorphisms, selected from those provided in Table 1 (e.g. those listed in column 2 of Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V).

[0057] The polymorphisms described herein can be a single nucleotide polymorphism, or an indel (insertion / deletion). In some instances, the polymorphism is an insertion or a deletion of at least one nucleotide (e.g., an indel). In some instances, the genotype may comprise a copy number variation (CNV), which is a variation in the number of copies of a nucleic acid sequence between individuals in a given population. In some instances, the CNV comprises at least or about two, three, four, five, six, seven, eight, nine, ten, twenty, thirty, forty or fifty nucleic acid molecules. In some instances, the genotype is heterozygous. In some instances, the genotype is homozygous.

[0058] Disclosed herein, in the following embodiments, are genotypes provided for the methods, kits, or compositions described herein: 1. A genotype comprising at least one polymorphism at at least one gene or genetic locus. 2. The genotype of embodiment 1 comprising a polymorphism provided in Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part 35 ACTIVE 712622340v1V. 3. The genotype of embodiments 1-2 that is heterozygous. 4. The genotype of embodiments 1-2 that is homozygous. 5. A combination of genotypes comprising two or at least two polymorphisms at at least one gene or genetic locus. 6. The combination of genotypes of embodiment 5, comprising three or at least three polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 7. The combination of genotypes of embodiments 5-6, comprising four or at least four polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 8. The combination of genotypes of embodiments 5-7, comprising five or at least five polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 9. The combination of genotypes of embodiments 5-8, comprising six or at least six polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 10. The combination of genotypes of embodiments 5-9, comprising seven or at least seven polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 11. The combination of genotypes of embodiments 5-10, comprising eight or at least eight polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 12. The combination of genotypes of embodiments 5-11, comprising nine or at least nine polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 13. The combination of genotypes of embodiments 5-10, comprising ten or at least ten polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 14. The combination of genotypes of embodiments 5-10, comprising eleven or at least eleven polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 15. The combination of genotypes of embodiments 5-10, comprising twelve or at least 36 ACTIVE 712622340v1twelve polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 16. The combination of genotypes of embodiments 5-10, comprising (i) 13 or at least 13 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V, (ii) 14 or at least 14 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V, (iii) 15 or at least 15 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V, (iv) 16 or at least 16 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V, (v) 17 or at least 17 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V, (vi) 18 or at least 18 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V, (vii) 19 or at least 19 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V, or (viii) 20 or at least 20 polymorphisms selected from Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V. 17. The genotype of embodiments 1-4 or combination of genotypes of embodiments 5-16, wherein one polymorphism in the genotype or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 polymorphisms in the combination of genotypes are substituted by an equal number of polymorphisms in linkage disequilibrium (LD) with the polymorphisms to be substituted. 18. The genotype of embodiment 17, wherein LD is defined by (i) a D’ value of at least about 0.70, (ii) an r2value of at least about 0.70, or (iii) both (i) and (ii). 19. The genotype of embodiment 17, wherein LD is defined by (i) a D’ value of at least about 0.80, (ii) an r2value of at least about 0.80, or (iii) both (i) and (ii). 20. The genotype of embodiment 17, wherein LD is defined by (i) a D’ value of at least about 0.90, (ii) an r2value of at least about 0.90, or (iii) both (i) and (ii). 21. The genotype of embodiment 17, wherein LD is defined by (i) a D’ value of at least about 0.95, (ii) an r2value of at least about 0.95, or (iii) both (i) and (ii). 22. The genotype of embodiments 1-21, wherein the gene or genetic locus is selected from the group consisting of those provided in Table 1, Table 1 Part I, Table 1 Part 37 ACTIVE 712622340v1II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V (e.g. those listed in column 1 of Table 1). 23. The genotype of embodiments 5-6, wherein the genotype comprises at least two polymorphisms selected from the group consisting of those provided in Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V (e.g. those listed in column 2 of each Part of Table 1). 24. The genotype of embodiments 1-23, wherein the genotype comprises an alternative allele provided in Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V for at least one polymorphism. 25. The genotype of embodiments 1-23, wherein the genotype comprises a reference allele provided in Table 1, Table 1 Part I, Table 1 Part II, Table 1 Part III, Table 1 Part IV, or Table 1 Part V for at least one polymorphism.

[0059] Aspects disclosed herein provide genotypes that are associated with, and therefore indicative of, a subject having or being susceptible to developing a particular disease or condition, or a subclinical phenotype thereof. In addition, the genotypes disclosed herein are associated with an increase RIPK2 expression or activity. Thus, the genotypes are indicative that the subject will have a positive therapeutic response to a RIPK2 inhibitor. Table 1 provides exemplary polymorphisms associated with, and therefore predictive of, a positive therapeutic response to an inhibitor of RIPK2 expression or activity. 38 ACTIVE 712622340v1msihp e e ;r htv )itat nie to ; ab s he ehreehthtdme nr(aEsinulat setvi d ing en wtirylleoletelzi niniFv-Psiltanu” itc nehPeh lta a setc ez-neh” retlan em lfulni .2di eic htef itwoen nernif sotntNsIFlaimerocera elloieeceni tsi_se o,ne eht ef reehtsebatff ycl”AT bir _l pol ; pyTcu atoer hew seenhe EF EcBseavs dneztoniNeneh b tu“d p“ o y ne dlnt dir sqNga _ fnit s”is le na a h e;cstsielrf P“oL fose nap divSnaibiirr1 ec>od””Sele fg T grll onid Qeni gderseasaoerpna s itcAdv ag a“a ewsi es edtar efnf E_tc iedhreehhtnoid raesueb”ife ssr dEAeffaeeh dtn eh se taehstecacsR e“d“o fIf eoTE e hut Beheh h bti”qhiiti rccs ossnnaeuD dso h g“ttwerwesae qr”P nogt ni Ntni r id fosts hti nftln d”L mIesld o0aeS ah gi nl”w manul“mu LT aTQ M utb c ae> id olhat edaEFm ocfo locQee ehci castree hhht bteh ethNulo ehgtni eh “r ht h eht ii e_ c;ldt eh wsCh hthFe) a; dci nih”“ftifDiwtnhA t“ht NIeh sis nuh,) cihIow gnelmuif;wosnF( eh ytla ”ewni"Iwtnnaimir duelllaon gn aehsi hnptaoleM" r(ofa aleo k c“hc siemihul dapeornuniiwLT s“ ufssite,csnoVer t;ochE FnQfe e o e aNoht ht; eht )1 eeh hsnimule gn httirDIghtni idlisi<oht;th in ycohc tifdaseehQdwuibelta)tarS ini nFeueoehbirnin ESen eelhmlsA w dEn -n qhet; noiechse aileheuhlmo ae d( on mu on rfhsital thd”edts9tocnevit eaislonielenn up tiL netsi3hi ega ht c ell iowTmlt h n nr rA eza Fp nQr”:wt; ametl otsa ht i;st tcni ehet mu “ o)On)IBuh ae0<a E na ce efffe leuln ri oe ”RNmulC83 ht te niisb yf acdAe e v- yc e nDuO“Ioc Ne( gh nihtneec,oinn tti rsehe htetht uasPEst tsienheht; ”e (o QEtuq sisusitaS“1a,s hfw i qen i sil l”sterf ylsitr sfelmrele(eelelrfeu ”NI sil )a “1nfd odgbaof lla leT nI e lllaelel laEF F_” >ao Log oenidnIygvi a ktsila v-NP_ FN AIF ita Tnih tae.ol a evi r tmo nrteceeA T“f _PrsQe dae se hesi nean htff hets E o“f ddehthebirhth htlp cr e aretsie tsB i“gni ooefto htcshtioo d laelehtls” fodgani ht)ed hti dw mi naehllatsiSAgnyiehda roetw”snemlBr ect nse ecl ”E_ da eh eth0c>er npy ulooPfer bi neS P“ ehhethtatreom tculo ocy rr ea t efl nercsrefAEfehiwhtb nuonceehhtp err ed er_oti e (e F ght nwhte eh P“;emCelo / xa d ”tlhtA“ nidim wul nfi ulat; re cnEnonaA“ dnfo aenocmul ele v- no dn atirIiIta,nfoagnhemue oclla pl itaiu” ehdNoit geleildah tlo ht; ehtc anico Inn ei Mia ht so nid laehhti ce sn t;eff m ss r naiIy pe aeksietb hwht a;ephsie oen a oLRled 1r d sa he r-thnm)Eor nnihtse TOa et “ nev04sb, ht noti ulFuEF sibirQ ceffom32P oe1hm htni ewoncN(s hsinihcise ogot 262eelsobaswhtesmht nan ezihwd”ezi nidgn 17aboatmnormi uulello;n ep niec F st( eai or-n cefelLstaeideT r EV Qcef hocITTaDhcoc llaht sAuEonfe llae“fe ehtcaC AW E_ ASA41.5 42 1.2 45 1.5 41.5G B T E0 0 04 0 2FES3.63.1 3.53.9A_ A 022 050501- -1-1 2-l 4 1 2 4- Pa veu.3E126.2E26.1E 26.4E36ff t 6 0 3Ec e 2.011 7 2.031 1 2.031 4 2.031 4tl erq4.64.6 4.64.9AF 066 06 06 096tlAg g t afeRa a c grn23_823_ 2_ 2_ 3 A3A833C8 33G8n hoit2 _oiCa23g2 _03g2 _43g 2 _13gtc _22 h_ _20 h_ _240 h__27 h_aotl rh7c47Grh2c46Grhc17 T rh7c57A on0n83 1 1aD87319101v0tI14802 2 43nsar29 9i 27 7 7 22rsr 6sr 3sr 3sr62a1oiyL L L L7Ve,i tnea 6 6 6 6En c a 1goltufiG1 1G1 1G1 1G1VITmsn TATATATA C A4.- 3E6903.- 3E5901.- 3E290 3.2 - E 9041.4 40 4 1.5 43 5 10 2 1.02 1.043.10531 36 31.022.023 2.02- - - -22.2E9364.1E3263.4E3261.4E4902.041 8 2.021 5 2.011 5 1.0724.994.7 4.6 3.10 6 066 066 075a c g ag t a g23_823 _23_82_ 3 G3 T 8 3A33G82_3g_ 3 _3 _3_327 g24 g24 g2r5h3hc7_ _239h_ _26 h_ _24 h_7Arhc25Crh7c17Grh1c06A 430 94129 0 2 v64 3 0 018 4838203 2 337 8 5 2sr 6sr 3sr 3s2r62L16L L L7161616EG1G1G1 1G1VITT T T TA A A A C A5 4 1 041.8 41.4 41 6-004-0020 3 03.04.09.093.936 3 539 06 01 .01 .01. 6 . 68.-2-2 0- -0 0-07 3E8263.9E5263.3E1362.4E7228.2E1012.011 8 2.011 2 2.041 5 1.0327 3.02614.7 0643 49 5 3 6.076.093 6.032 7.071a t t c gg c c a a23_ 3 G823_ 2 3 C8 3_ 3 3 C8 6_ 7 3 A80_ A82_3 _3_3_35_3_27 gr5 h 2_3gh2_1gh1_4 gh _60 ghh8 _2r91_ 2r26_ 9r41 _1 79 _c46Ahc05 Thc67 Thc96Crhc22G 990 4384676 1v9091105547 0427 22 08 1 367 310sr 16sr 31sr 10sr 22s2r62L16L L916 6D2 7EG1 1G1 1G1R D VITT TA OTA A A C N C A9.- 1E9209.- 6E610 7.0700.2 040590.600220.0095 70.4 010225.1 048-80.4 00 8-0.8 00 8-0.4 809-0.5 70 9-0.8 60 9-0.3 906-0.2 1 109-0.031.74792 6 3 004 2.013 7.011.022.091.051.0395.04-0 9 0 2 97.3E1608.- 8E4020.- 9E3320.- 1E8600.- 7E4601.- 3E1830.- 1E8609.- 1E132- 0.028 6 - 1.0126 1.062 - 0.048 2 - 0.0778 - 1.0977 - 0.0979 - 1.083 51.456.533.7 1.9 2.3.8 2.7 7.8 07 0 4 017 068 0 099 090 020t a g t t t g gc g a a g c t a28 T60_836_808 T08 T60_ 18 G6_ 9_8 5G3A9 _8 9 _8C8_80A88C3 __3 _3 A3 G35_3 9T35_3_8_r9g 63h1h_1r5g4h 1__89gh 8__7g8___1g 628 gh8__g_600ghc55hc85A9rh3 _c77G8rh8h_8r 0h_1r 2c36hc57hc1 _9T8r7h0h_1r 1 _c92hc06G 8839 3 863106084349458833126v096890977890041496477 4311sr 11sr 11sr 18sr 21sr 785sr 23sr 22s2r629127K2D2K2 2 2 2 EP D I O RPK D K D VIR N AIPIOPIOTC R R N R N C A-90.9-00.8-90.8-53.4-63.4-0.707 08 00 0 2 0 4 031.253.4 0.8 0.8 0.72.9 09 010 060 061 01 07.- - - - - -12 1E6603.1E5 7 4 5 6 522.1E701.5E070.7E270.7E102- 0.018 4 1.062 3.0266 - 1.023 7 - 1.003 7 1.02291.73.822.21.71.83.8 09 07 071 01 071 065cg a g a a t gg g c g g c a70_ 5 G8308 A__g 98_36_ G833C870_887 A1 _3 5G_77 T_46_8__39G839C833A_3617r6 h_ __g _93gh 683gh 8__g8__g1_1 ghh8C8r07h 9r 4 _ 1 9 _8r3 h 8r81h 9r41 _c9_2Ghc99hc96Grhc 42Ah3 _c77hc5_1hc40G 2327 888800013917 125159v090 8 499 378 79938101313 0 4s7 062450 22r 2sr 1srsr 3sr 3sr 1sr62122 9D K D2 2K2 9 7K DEV OPR DP PRINIR A OI IATC N R R C C A-90.4 405-1.5 50 7-3.5 902-0.081.12.6 0.818 08 0206 .08-8 1 16.3E7702.- 5E0734.- 1E3600.- 2E960- 0.048 9 - 1.0266 - 1.0627 -0.01.8 4.6 1 1 12 088 017.071.047t a a g g t tc c g a a c c36_ 3 7_ 7_ 8 5 _ 3 3 C8 8 T1__3 9A8_C8035G80A87 G_ _3_g 5__3g 98 A8633C8 8_1_3 98 C8394r4 g0h__8_g 61r77h 1 60h_ 61887h_ _8_6gh_982 g8h__8_5g3hh 2Th 0_ rh 8Arh 6Grh1 _ rh 8T rh 2_c 7 c 7 c 1 c 5 c07 c 0 c 5517 555916 6 01v7479205057590 0009325 95453843403r 133r 119 1 5r 31 1 2 2s s s sr 1sr 1sr 6s2r629122 9 2 7D K2 2K DER APD D K V I O OPRP ITC R N NIR AIC R C A.0493.0493.0326.0674.041 1.0393.085 53.- 636- 637- 522- 4312- 102751E0.9E0.1E0. E0. E0.051-01.2-90.1-63.5-51.3-901-0010 0 5 0 4 0 4.04.091.0871.50802.0710.4061 0.5 033 2.7015.-76.-63.-76.-20.-62-03 2- 4 1E5 0 4E20 6E20 2E78 2E1 0.3E92.1E60148 6 - 0.088 3 - 0.008 6 - 1.013 9 3.0606 - 0.018 3 1.0723 4.03281.091.1 001 8.7 072 1.6051 6.7 053 9.7011 7.2 015c c c g c g at a t c t a g389C8_28 C7C7_ 3 3 _ 6_ _T8 9 _879 _0T8 5C_83 89C_863A_83 05G_838_3g8_A_3g8__3g_61 gr4h8h_8r43h_8r15h 1r76h 8__T8_3g1_6 gr31h 9r47h __612 gr18h_c45hc15hc7_2hc50Ghc8_0hc47Ghc57A 08715015001 84801181 6 v012779303227217995 4314sr 32sr 275 2sr 18sr 286ssr3sr r22629127K2K2 2 2D2 EPIPK D K R D VIRIPRIOPR NIO R ATC N C A00 00 00 0 8 01 01-90.305-90.907-90.6 006 0.60 4-3.404-3.081.2 09161123 09 6 8.067.029.091.060.08- - - - -1-15.1E0608.2E0704.1E6605.1E9529.7E7709.8E970- 0.097 - 0.068 8 - 0.018 1 1.093 2 - 1.003 7 - 1.09282.3 0910.0981.90436 17 13 9.072.071.071a g t t c t gg c c c t c a36_ 3 G828 G48 T_08 T_36 _857 T_67 G1__9339 _C839C839C833 T_39C839 _A83r5g9h 8__8_g8__g8_ _g1_0r95h 8r25h 8r64h 9r5g0h 8__8_g8__gr45h 8 5 hh 1Ah_23_7_8Cc7_ r 9 _c 7 c6 hc 0hc 9hc 7h8hc42946 0 555 8118 5 9 6 9 4 v80 5 0 5 1 2 0740935 225 2812 8864 3122 1 2 2sr 64sr 33 8 3 3 2s2r 1sr 3sr 1sr 1sr62917D2 2 2 9 2 2 ER K APK IPK D IPIR K APK IPV IITC R R R C R R C ATT TC A GT TA C C A G G C C C G 707070707070707 75_6 3 8 9 8 7 5 01 0261 5_6 5_9 5_2 5_5 5_5 5_1 5_5_1r361 861 361 6606060619619h11rh22rh11r 22 1r 11 1r 11 1r 21 1r 01 1r 01C C ChChChChChChC 45998455445454445451v8402398 28698 798 68698 2980406 4174r 507 6r 104 7 47 6 4 6 416 3r 20r10r10r20 0 2s s s s s s sr 1sr 1s2r621,9,5, L ,8 3 2 4 47262126 20 ,28 ,22,20 ,23 ,23ED4 ED+D9D9G D3 S83U7 P 3 P 3NV OUHPO8S 8O4S UEOYLR A OULYD LOPS LD G OG RRD T OG RRD TOGLIGTNELNVINIH N G N G N A N A N R A N A C AC C CT T TCG A A A G A GAA C A A C C C C C G C G G G C G G A C A 70850363 3 3 3 3 3 3_856 6 6 6 6 6 61 631 131 231 231 031 631 831 535661r8_34_10_34_63_ 83_99_ 8743 154h92 5r 84 9r 27 9r 17 9r 07 9r 07 9r 07 9r 7 _69r 1 _79r 17ChChChChChChChChChC 747 8197323832031232081v656662121 219821 3325 17421 403 80400202 5177 8796 1323 8 6 4119331 2 941 8 6 8 1 31936 2s2rsrs s s s s s s7s 62,, ,5,r,rS,r5,r r r r r9,8,3,1, 172 P,C MT-09T D3929998959790S 9 P,ED OB-S01NI 20GC1U 3 UELR2ARRD E R7AYRD LER2ANRLED T R2ANRLED T R1ANRLED T R3O D G ARRPR1D GY C RB-SV 4NIITN3RI13ELCESAR A C G C G C G C G C A C A C C AUFC ED OFOCUC SF EFMLEDTPTNIN UUS OTNA ILN FWHEOOCM,M3NSI0IBR 1C(US05C C G C C C A 36231 5 332_29r4 22h0 _72r747ChC 000 158 v033810453 4 372sr 22s2r62, L 01C7G9DP, G6 03AET1 TRBS 9 1,LVI9 -1A C1NI18GT 1R ATAHTC ATable 1 PART III Additional Exemplary Polymorphism as described in Example 7. In Table 1 PART III, the column with the heading of “Variant (chr_pos_ref_alt hg38)” describes genotype annotation with chromosome number, base position, the reference allele and the alternative allele, in hg38 human genome build; the column with the heading of “rsID” lists dbSNP rsID for the genotype as used in Single Nucleotide Polymorphism Database hosted by the National Center for Biotechnology Information (NCBI); the column with the heading of “Disease Trait” describes the disease(s) with which the genotype is(are) associated with in GWAS; the column with the heading of “Disease Beta” describes beta coefficient (one measurement of effect size) of the genotype in the GWAS; the column with the heading of “Disease Odds Ratio” describes odds ratio (another measurement of effect size) of the genotype in the GWAS, wherein the alternative allele is the risk allele if the beta>0 or the odds ratio>1; and wherein the alternative allele is the non-risk allele and the reference allele is the risk allele if the beta<0 or the odds ratio<1; the column with the heading of “Disease P-value” lists the P-value of the genotype in the GWAS; the column with the heading of “Disease Source” describes the source data for such GWAS; the column with the heading of “AF” describes the alternative allele frequency in all populations; the column with the heading of “EAS_AF” lists the effect allele frequency in East Asian (EAS) population; the column with the heading of “NFE_AF” lists the effect allele frequency in non-Finnish Europeans (NFE); the column with the heading of “QTL (Gene;Tissue;Type;P-value;Beta)” describes the QTL attributes of the genotype, including the target gene, the type of tissue where the QTL was determined, the type of QTL (eQTL or pQTL), the p-value of the QTL analyses, and the regression beta coefficient (reflecting the effect size of QTL association), wherein the alternative allele is the effect allele if the beta>0 or the odds ratio>1; the column with the heading of “RIPK2_path_genes_at_locus” describes the gene(s) of the RIPK2- related pathway that the genotype (the variant locus) maps to. The actual sequences of the genotypes are provided in Table 2.51 ACTIVE 712622340v152 ACTIVE 712622340v153 ACTIVE 712622340v154 ACTIVE 712622340v1Table 1 PART IV Additional Exemplary Polymorphism as described in Example 7. In Table 1 PART IV, the column headings have the same meaning as described above for Table 1, PART III. The actual sequences of the genotypes are provided in Table 2.55 ACTIVE 712622340v156 ACTIVE 712622340v157 ACTIVE 712622340v158 ACTIVE 712622340v159 ACTIVE 712622340v160 ACTIVE 712622340v161 ACTIVE 712622340v162 ACTIVE 712622340v163 ACTIVE 712622340v164 ACTIVE 712622340v165 ACTIVE 712622340v166 ACTIVE 712622340v167 ACTIVE 712622340v168 ACTIVE 712622340v169 ACTIVE 712622340v170 ACTIVE 712622340v171 ACTIVE 712622340v172 ACTIVE 712622340v173 ACTIVE 712622340v174 ACTIVE 712622340v175 ACTIVE 712622340v176 ACTIVE 712622340v177 ACTIVE 712622340v178 ACTIVE 712622340v179 ACTIVE 712622340v180 ACTIVE 712622340v181 ACTIVE 712622340v1Table 1 PART V Additional Exemplary Polymorphism as described in Example 7. In Table 1 PART V, the column headings have the same meaning as described above for Table 1, PART III. The actual sequences of the genotypes are provided in Table 2.82 ACTIVE 712622340v183 ACTIVE 712622340v184 ACTIVE 712622340v185 ACTIVE 712622340v186 ACTIVE 712622340v187 ACTIVE 712622340v188 ACTIVE 712622340v189 ACTIVE 712622340v190 ACTIVE 712622340v191 ACTIVE 712622340v192 ACTIVE 712622340v193 ACTIVE 712622340v194 ACTIVE 712622340v195 ACTIVE 712622340v196 ACTIVE 712622340v197 ACTIVE 712622340v198 ACTIVE 712622340v199 ACTIVE 712622340v1100 ACTIVE 712622340v1101 ACTIVE 712622340v1102 ACTIVE 712622340v1103 ACTIVE 712622340v1104 ACTIVE 712622340v1105 ACTIVE 712622340v1106 ACTIVE 712622340v1107 ACTIVE 712622340v1108 ACTIVE 712622340v1109 ACTIVE 712622340v1110 ACTIVE 712622340v1111 ACTIVE 712622340v1112 ACTIVE 712622340v1113 ACTIVE 712622340v1114 ACTIVE 712622340v1115 ACTIVE 712622340v1116 ACTIVE 712622340v1117 ACTIVE 712622340v1118 ACTIVE 712622340v1119 ACTIVE 712622340v1120 ACTIVE 712622340v1121 ACTIVE 712622340v1122 ACTIVE 712622340v1123 ACTIVE 712622340v1124 ACTIVE 712622340v1125 ACTIVE 712622340v1126 ACTIVE 712622340v1127 ACTIVE 712622340v1128 ACTIVE 712622340v1129 ACTIVE 712622340v1130 ACTIVE 712622340v1131 ACTIVE 712622340v1132 ACTIVE 712622340v1133 ACTIVE 712622340v1134 ACTIVE 712622340v1135 ACTIVE 712622340v1136 ACTIVE 712622340v1137 ACTIVE 712622340v1138 ACTIVE 712622340v1139 ACTIVE 712622340v1140 ACTIVE 712622340v1141 ACTIVE 712622340v1142 ACTIVE 712622340v1143 ACTIVE 712622340v1144 ACTIVE 712622340v1145 ACTIVE 712622340v1146 ACTIVE 712622340v1147 ACTIVE 712622340v1148 ACTIVE 712622340v1149 ACTIVE 712622340v1150 ACTIVE 712622340v1151 ACTIVE 712622340v1152 ACTIVE 712622340v1153 ACTIVE 712622340v1154 ACTIVE 712622340v1155 ACTIVE 712622340v1156 ACTIVE 712622340v1157 ACTIVE 712622340v1158 ACTIVE 712622340v1Table 2. Sequences of the SNPs in Table 1: the sequences listed include the 50 nucleotide sequences before the nucleoposition of the polymorphisms (the sequence before the “” , the nucleoposition of the polymorphisms indicated as “[ ]”, followed by nucleotide sequences after the nucleoposition of the polymorphisms (the sequence following “]”)159 ACTIVE 712622340v1160 ACTIVE 712622340v1161 ACTIVE 712622340v1162 ACTIVE 712622340v1163 ACTIVE 712622340v1164 ACTIVE 712622340v1165 ACTIVE 712622340v1166 ACTIVE 712622340v1167 ACTIVE 712622340v1168 ACTIVE 712622340v1169 ACTIVE 712622340v1170 ACTIVE 712622340v1171 ACTIVE 712622340v1172 ACTIVE 712622340v1173 ACTIVE 712622340v1174 ACTIVE 712622340v1175 ACTIVE 712622340v1176 ACTIVE 712622340v1177 ACTIVE 712622340v1178 ACTIVE 712622340v1179 ACTIVE 712622340v1180 ACTIVE 712622340v1181 ACTIVE 712622340v1182 ACTIVE 712622340v1183 ACTIVE 712622340v1184 ACTIVE 712622340v1185 ACTIVE 712622340v1186 ACTIVE 712622340v1187 ACTIVE 712622340v1188 ACTIVE 712622340v1189 ACTIVE 712622340v1190 ACTIVE 712622340v1191 ACTIVE 712622340v1192 ACTIVE 712622340v1193 ACTIVE 712622340v1194 ACTIVE 712622340v1195 ACTIVE 712622340v1196 ACTIVE 712622340v1197 ACTIVE 712622340v1198 ACTIVE 712622340v1199 ACTIVE 712622340v1200 ACTIVE 712622340v1

[0060] The genotypes, e.g. the single nucleotide polymorphisms, provided herein in Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) have already been validated as the genotypes that correlate with increased RIPK2 expression in inflammatory cells, with increased RIPK2 activity in inflammatory cells, with increased inflammation, with phenotypes of IBD, with increased risk of developing IBD, with one of the features listed in Table 4 or Table 9, and / or with an increase of a positive therapeutic response in IBD patients to a treatment with the RIPK2 inhibitor, as further described in Section 7 (EXAMPLES). As such, the disclosure provides that the genotypes, e.g. the polymorphisms such as the SNPs, or the combinations of genotypes, e.g. the combinations of polymorphisms such as the combination of SNPs, provided herein can be used as criteria for identifying subjects or patients for the various methods provided herein including in Sections 3, 5.2, and 7 (EXAMPLES). Similarly, the disclosure provides that the 201 ACTIVE 712622340v1genotypes or the combinations of genotypes (e.g. the polymorphisms such as SNPs or the combinations of polymorphisms such as the combinations of SNPs) provided herein can be used as criteria for identifying subjects or patients for the various kits and compositions provided herein including in Sections 3, 1.1.1, 5.5, and 7 (EXAMPLES). Additionally, the disclosure provides that the genotypes or the combinations of genotypes (e.g. the polymorphisms such as SNPs or the combinations of polymorphisms such as the combinations of SNPs) provided herein can be used as criteria for the various methods of selecting patients provided herein including in Sections 3, 5.2, and 7.

[0061] The disclosure further provides simple methods to validate the suitability of the genotypes or the combinations of genotypes (e.g. the polymorphisms such as SNPs or the combinations of polymorphisms such as the combinations of SNPs) for the various methods of treatment, methods of selecting patients, and / or the kits and compositions provided herein including in Sections Sections 3, 5.2, 1.1.1, 5.5, and 7.

[0062] The genotypes identified in the analysis provided in the Examples above and below can be used to predict a positive therapeutic response in a subject or a patient to a RIPK2 inhibitor (e.g., small molecule RIPK2 inhibitors), either alone, or in combinations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). The genotypes identified in the analysis provided in the Examples above and below can also be used to predict an increased expression level or increased signaling level of RIPK2 in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease, either alone, or in combinations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more). The genotypes, e.g. the polymorphisms such as SNPs, described herein can be used in a diagnostic or prognostic test to identify a subject suitable for treatment with a RIPK2 inhibitor to treat a disease or condition described herein in the subject. In some cases, the diagnostic is a companion diagnostic test, such as for example, an RIPK2 companion diagnostic test (“RIPK2 CDx”).

[0063] In some embodiments of the methods provided herein, the genotype comprises polymorphism. In certain embodiments of the methods provided herein, the polymorphism comprises SNP. In some embodiments of the methods provided herein, the combination of genotype comprises a combination of polymorphisms. In certain embodiments of the methods provided herein, the combination of polymorphisms comprises a combination of SNPs.

[0064] Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) provides exemplary polymorphisms such as SNPs 202 ACTIVE 712622340v1predictive of therapeutic response (including clinical response or clinical remission) in patients treated with RIPK2 inhibitor therapy. The disclosure provides that the various combinations of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprise combinations of genotypes predictive of elevated RIPK2 expression, combinations of genotypes predictive of elevated RIPK2 activity (e.g. features listed in Table 4 or Table 9), or combinations of both genotypes predictive of elevated RIPK2 expression and genotypes predictive of elevated RIPK2 activity (e.g. features listed in Table 4 or Table 9). The disclosure also provides that the various combinations of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprise combinations of genotypes predictive of clinical response or remission in patients treated with RIPK2 inhibitor therapy, as determined in a clinical trial.

[0065] Accordingly, in one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 2 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 3 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 4 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 5 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 6 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 7 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 8 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to 203 ACTIVE 712622340v1the inhibitor of the RIPK2 activity or expression comprises a combination of 9 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 10 polymorphisms (such as SNPs) predictive of elevated RIPK2 expression. In one embodiment, the genotype predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises 1 polymorphism (such as SNP) predictive of elevated RIPK2 expression. In some embodiments, the genotype or the combinations of genotypes predictive of elevated RIPK2 expression provided herein for the various methods (including in this paragraph) are selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment). In some embodiments, the elevated RIPK2 expression is determined as compared to such RIPK2 expression in a healthy subject.

[0066] Alternatively, in one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 2 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 3 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 4 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 5 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 6 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 7 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 8 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of 204 ACTIVE 712622340v1genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 9 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the combination of genotypes predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises a combination of 10 polymorphisms (such as SNPs) predictive of elevated RIPK2 activity. In one embodiment, the genotype predictive of a positive therapeutic response to the inhibitor of the RIPK2 activity or expression comprises 1 genotypes predictive of elevated RIPK2 activity. In some embodiments, the genotype or the combinations of genotypes predictive of elevated RIPK2 activity provided herein for the various methods (including in this paragraph) are selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment). 5.2 Methods of Treatment

[0067] Disclosed herein are methods of treating a disease or condition, or a symptom of the disease or condition, in a subject, comprising administrating of therapeutic effective amount of one or more therapeutic agents to the subject. In some embodiments, the one or more therapeutic agents is administered to the subject alone (e.g., standalone therapy). In some embodiments, the one or more therapeutic agents is administered in combination with an additional agent. In some embodiments, the therapeutic agent is a first-line therapy for the disease or condition. In some embodiments, the therapeutic agent is a second-line, third-line, or fourth-line therapy, for the disease or condition. In some embodiments, the therapeutic agent comprises a RIPK2 inhibitor.

[0068] Various embodiments provide for methods of treating an inflammatory, fibrostenotic, or fibrotic disease or condition in a subject having such disease or condition, comprising administering a RIPK2 inhibitor described herein to the subject in need thereof. In some embodiments, the subject comprises one or more risk genotypes. In some embodiments, the inflammatory, fibrostenotic, or fibrotic disease is IBD. In certain embodiments, the IBD is a severe form of IBD.

[0069] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject is determined to have a presence of a combination of genotypes selected from the polymorphisms of Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage 205 ACTIVE 712622340v1disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80. In some embodiments of the method of this paragraph, the presence of a combination of genotypes is determined with a biological sample obtained from the subject.

[0070] In one aspect, provided hereis is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject comprises a combination of genotypes. In some embodiments of the method of this paragraph, the presence of a combination of genotypes is determined with a biological sample obtained from the subject.

[0071] In another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject comprises a combination of genotypes, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0072] In a further aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject tested positive for a presence of a combination of genotypes in a biological sample obtained from the subject.

[0073] In yet another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject tested positive for a presence of a combination of genotypes in a biological sample obtained from the subject, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80. 206 ACTIVE 712622340v1

[0074] In yet another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject is identified based on a presence of a combination of genotypes identified in a biological sample obtained from the subject, wherein the combination of genotypes is predictive of an increased expression level or increased signaling level of RIPK2, wherein the increased expression level or increased signaling level of RIPK2 is relative to a baseline expression or signaling level of RIPK2 in subjects not suffering from the inflammatory, fibrotic, or fibrostenotic disease or condition, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0075] In one aspect, provided herein is a method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a therapeutically effective amount of a RIPK2 inhibitor, the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of genotypes; (b) selecting a subject determined to have the presence of the combination of genotypes in (a), wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80; and (c) administering a therapeutically effective amount of the RIPK2 inhibitor to the subject selected in (b).

[0076] In another aspect, provided herein is a method of determining presence of a combination of genotypes in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) contacting genetic materials in a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition with one or more nucleic acid primer pairs having forward and reverse primers suitable for hydridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of a combination of genotypes; (b) amplifying the target nucleic acid sequences by polymerase chain reactions 207 ACTIVE 712622340v1with the nucleic acid primer pairs of (a); and (c) analysing the results of (b) to determine the presence in the target nucleic acid sequences of the combination of genotypes of step (a), wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0077] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject is determined to have a presence of a presence of a combination of polymorphisms such as SNPs identified in a biological sample obtained from the subject, wherein the combination of polymorphisms such as SNPs comprises one or more polymorphisms selected from the polymorphisms of Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0078] In one aspect, provided hereis is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject comprises a combination of polymorphisms such as SNPs. In some embodiments of the method of this paragraph, the presence of a combination of polymorphisms is determined with a biological sample obtained from the subject.

[0079] In another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject comprises a combination of polymorphisms such as SNPs, wherein the combination of polymorphisms comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80. 208 ACTIVE 712622340v1

[0080] In a further aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject tested positive for a presence of a combination of polymorphisms such as SNPs in a biological sample obtained from the subject.

[0081] In yet another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject tested positive for a presence of a combination of polymorphisms such as SNPs in a biological sample obtained from the subject, wherein the combination of polymorphisms comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0082] In yet another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject is identified based on a presence of a combination of polymorphisms such as SNPs identified in a biological sample obtained from the subject, wherein the combination of polymorphisms such as SNPs is predictive of an increased expression level or increased signaling level of RIPK2, wherein the increased expression level or increased signaling level of RIPK2 is relative to a baseline expression or signaling level of RIPK2 in subjects not suffering from the inflammatory, fibrotic, or fibrostenotic disease or condition, wherein the combination of polymorphisms comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0083] In one aspect, provided herein is a method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a therapeutically effective amount of a RIPK2 inhibitor, the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of polymorphisms such as SNPs; 209 ACTIVE 712622340v1(b) selecting a subject determined to have the presence of the combination of polymorphisms such as SNPs in (a), wherein the combination of polymorphisms such as SNPs comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80; and (c) administering a therapeutically effective amount of the RIPK2 inhibitor to the subject selected in (b).

[0084] In another aspect, provided herein is a method of determining presence of a combination of polymorphisms such as SNPs in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) contacting genetic materials in a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition with one or more nucleic acid primer pairs having forward and reverse primers suitable for hydridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of a combination of polymorphisms such as SNPs; (b) amplifying the target nucleic acid sequences by polymerase chain reactions with the nucleic acid primer pairs of (a); and (c) analysing the results of (b) to determine the presence in the target nucleic acid sequences of the combination of polymorphisms such as SNPs of step (a), wherein the combination of polymorphisms such as SNPs comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0085] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject comprises a combination of genotypes, wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0086] In yet another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: 210 ACTIVE 712622340v1administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject tested positive for a presence of a combination of genotypes in a biological sample obtained from the subject, wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0087] In yet another aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of a RIPK2 inhibitor, wherein the subject is identified based on a presence of a combination of genotypes identified in a biological sample obtained from the subject, wherein the combination of genotypes is predictive of an increased expression level or increased signaling level of RIPK2, wherein the increased expression level or increased signaling level of RIPK2 is relative to a baseline expression or signaling level of RIPK2 in subjects not suffering from the inflammatory, fibrotic, or fibrostenotic disease or condition, wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0088] In one aspect, provided herein is a method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a therapeutically effective amount of a RIPK2 inhibitor, the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of genotypes; (b) selecting a subject determined to have the presence of the combination of genotypes in (a); and (c) administering a therapeutically effective amount of the RIPK2 inhibitor to the subject selected in (b), wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80. 211 ACTIVE 712622340v1

[0089] In another aspect, provided herein is a method of determining presence of a combination of genotypes in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) contacting genetic materials in a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition with one or more nucleic acid primer pairs having forward and reverse primers suitable for hydridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of a combination of genotypes; (b) amplifying the target nucleic acid sequences by polymerase chain reactions with the nucleic acid primer pairs of (a); and (c) analysing the results of (b) to determine the presence in the target nucleic acid sequences of the combination of genotypes of step (a), wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0090] In some embodiment of the various methods provided herein, including in this Sections 3, 5.2 (such as the preceding paragraphs of Section 5.2), and 7, the method further comprises preparing DNA from the sample.

[0091] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with a RIPK2 inhibitor by: (i) obtaining or having obtained a sample from the subject; (ii) subjecting the sample to an assay adapted to detect a combination of genotypes, wherein the subject is determined to be suitable for treatment with a RIPK2 inhibitor if the combination of genotypes are detected; and (b) treating the subject by administering a therapeutically effective amount of the RIPK2 inhibitor to the subject. In some embodiments of the method of this paragraph, the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0092] In another aspect, provided herein is a method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a 212 ACTIVE 712622340v1therapeutically effective amount of a RIPK2 inhibitor, the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of genotypes; (b) selecting a subject determined to have the presence of the combination of genotypes in (a); and (c) administering a therapeutically effective amount of the RIPK2 inhibitor to the subject selected in (b). In some embodiments of the method of this paragraph, the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0093] In another aspect, provided herein is a method of determining a combination of genotypes for a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; and (c) determining the combination of genotypes for the subject; wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0094] In a further aspect, provided herein is a method of selecting a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a RIPK2 inhibitor, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; (c) selecting the subject for treatment with the RIPK2 inhibitor if the combination of genotypes are detected. In some embodiments of the methods of this paragraph, the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0095] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with a RIPK2 inhibitor by: (i) obtaining or having obtained a sample 213 ACTIVE 712622340v1from the subject; (ii) subjecting the sample to an assay adapted to detect a combination of genotypes, wherein the subject is determined to be suitable for treatment with a RIPK2 inhibitor if the combination of genotypes are detected, and wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80; and (b) treating the subject by administering a therapeutically effective amount of the RIPK2 inhibitor to the subject.

[0096] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with a RIPK2 inhibitor by: (i) obtaining or having obtained a sample from the subject; (ii) subjecting the sample to an assay adapted to detect a combination of genotypes, wherein the subject is determined to be suitable for treatment with a RIPK2 inhibitor if the combination of genotypes are detected; and (b) treating the subject by administering a therapeutically effective amount of the RIPK2 inhibitor to the subject, wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0097] In another aspect, provided herein is a method of selecting a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; and (c) determining the combination of genotypes for the subject; wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0098] In a further aspect, provided herein is a method of selecting a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a RIPK2 214 ACTIVE 712622340v1inhibitor, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; (c) selecting the subject for treatment with the RIPK2 inhibitor if the combination of genotypes are detected, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0099] In one aspect, provided herein is a method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with a RIPK2 inhibitor by: (i) obtaining or having obtained a sample from the subject; (ii) subjecting the sample to an assay adapted to detect a combination of polymorphisms such as SNPs, wherein the subject is determined to be suitable for treatment with the RIPK2 inhibitor if the combination of polymorphisms such as SNPs comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80; and (b) treating the subject by administering a therapeutically effective amount of the RIPK2 inhibitor to the subject.

[0100] In another aspect, provided herein is a method of determining a combination of polymorphisms such as SNPs for a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of polymorphisms such as SNPs; and (c) determining the combination of polymorphisms such as SNPs for the subject; wherein the combination of polymorphisms comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0101] In a further aspect, provided herein is a method of selecting a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a RIPK2 inhibitor, the method comprising: (a) obtaining or having obtained a sample from the subject; 215 ACTIVE 712622340v1(b) subjecting the sample to an assay adapted to detect a combination of polymorphisms such as SNPs, wherein the combination of polymorphisms such as SNPs comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80; (c) selecting the subject for treatment with the RIPK2 inhibitor if the combination of polymorphisms such as SNPs are detected.

[0102] In another aspect, provided herein is a method of determining a combination of genotypes for a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; and (c) determining the combination of genotypes for the subject; wherein the combination of genotypes comprises one or more genotypes selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy genotype in linkage disequilibrium with any of the genotypes of Table 1 (or the corresponding Part of Table 1) as determined with an r2of at least 0.80.

[0103] In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the method further comprises preparing DNA from the sample. Such step of preparing DNA is further provided in Section 5.6.

[0104] In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of genotypes comprises a combination of polymorphisms. In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of genotypes consists of a combination of polymorphisms. In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises a combination of SNPs. In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms consists of a combination of SNPs.

[0105] In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises or consists of 2 polymorphisms. In some embodiments, the combination of polymorphisms comprises or consists of 3 polymorphisms. In certain embodiments, the combination of polymorphisms comprises or consists of 4 polymorphisms. In some other embodiments, the 216 ACTIVE 712622340v1combination of polymorphisms comprises or consists of 5 polymorphisms. In some additional embodiments, the combination of polymorphisms comprises or consists of 6 polymorphisms. In some embodiments, the combination of polymorphisms comprises or consists of 7 polymorphisms. In certain embodiments, the combination of polymorphisms comprises or consists of 8 polymorphisms. In some other embodiments, the combination of polymorphisms comprises or consists of 9 polymorphisms. In some additional embodiments, the combination of polymorphisms comprises or consists of 10 polymorphisms. In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises or consists of at least 2 polymorphisms. In some embodiments, the combination of polymorphisms comprises or consists of at least 3 polymorphisms. In certain embodiments, the combination of polymorphisms comprises or consists of at least 4 polymorphisms. In some other embodiments, the combination of polymorphisms comprises or consists of at least 5 polymorphisms. In some additional embodiments, the combination of polymorphisms comprises or consists of at least 6 polymorphisms. In some embodiments, the combination of polymorphisms comprises or consists of at least 7 polymorphisms. In certain embodiments, the combination of polymorphisms comprises or consists of at least 8 polymorphisms. In some other embodiments, the combination of polymorphisms comprises or consists of at least 9 polymorphisms. In some additional embodiments, the combination of polymorphisms comprises or consists of at least 10 polymorphisms. As is already clear from the descriptions herein, in some embodiments, the polymorphisms in this paragraph are SNPs. Accordingly, additional embodiments are provided herein with each embodiment of paragraph wherein the term “polymorphisms” is substituted with the term “SNPs”.

[0106] In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the method further comprises preparing DNA from the sample obtained from the subject.

[0107] In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the method further comprises contacting the sample with one or more probes adapted to detect the presence of the combination of genotype or the combination of polymorphisms (e.g. SNPs). In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the method further comprises contacting the sample with an assay adapted to detect the presence of the combination of genotype or the combination of polymorphisms (e.g. SNPs). 217 ACTIVE 712622340v1

[0108] In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the method further comprises processing the sample to enrich the genetic materials. In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the method further comprises processing the sample to enrich the genetic materials targeted by the assay or the one or more probes.

[0109] The terms “increased signaling level of RIPK2” or “increased RIPK2 signaling” refer to cellular, biochemical, enzymatic, or molecular activity (i) that is increased in a diseased tissue of patients over non-diseased control tissues and (ii) the increase of which is associated with RIPK2-mediated inflammatory, a fibrotic, or a fibrostenotic disease or condition, such as IBD, UC, and CD and therefore the increase of which are predictive of enhanced probability of responding to treatment with a RIPK2 inhibitor. Such increased signaling level of RIPK2 is increased in IBD related tissues, the increased signaling level of RIPK2 is associated with RIPK2 disease pathology, and the increased signaling level of RIPK2 can be identified by analyzing the up- or down-regulation of various cellular pathways in IBD diseased tissues as described in Section 7. In some examples, the increased signaling level of RIPK2 include (i) increased level of RIPK2; (ii) increased level of NOD2; (iii) increased level of CARD9; (iv) decreased level of ATG16L1; or (v) decreased level of IRGM. As is clear from the description herein, the activity of RIPK2 (or RIPK2 activity) can comprise RIPK2 signaling and RIPK2 signaling is a form of RIPK2 activity.

[0110] In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the increased expression level of RIPK2 comprises an increase of RIPK2 mRNA expression level. In certain embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the increased expression level of RIPK2 comprises an increase of RIPK2 protein expression level. In certain embodiment of the methods provided herein such as in this paragraph, the increase is determined by a comparison between the level in a disease afflicted tissue and the level in a tissue not affected by the disease. In certain embodiment of the methods provided herein such as in this paragraph, the tissue not affected by the disease can be a tissue from a healthy subject or a tissue of a healthy organ in the disease-affected patient.

[0111] In certain embodiment of the methods provided herein such as in this paragraph, the increase is determined by a comparison between the level in a disease afflicted tissue and the level in a tissue not affected by the disease. In certain embodiment of the 218 ACTIVE 712622340v1methods provided herein such as in this paragraph, the tissue not affected by the disease can be a tissue from a healthy subject or a tissue of a healthy organ in the disease-affected patient.

[0112] In certain embodiment of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the increase of expression level of RIPK2 or signaling level of RIPK2 signaling is determined by a comparison between the level in a disease afflicted tissue and the level in a tissue not affected by the disease. In certain embodiment of the methods provided herein such as in this paragraph, the tissue not affected by the disease can be a tissue from a healthy subject or a tissue of a healthy organ in the disease-affected patient. In various embodiments of the methods provided herein including in this paragraph, the disease is an inflammatory, a fibrotic, or a fibrostenotic disease or condition. In various embodiments of the methods provided herein including in this paragraph, the inflammatory, fibrotic, or fibrostenotic disease or condition is IBD. In various embodiments of the methods provided herein including in this paragraph, IBD is Crohn’s Disease (CD) or ulcerative colitis (UC). In some embodiments, the IBD is a severe form of IBD. In some embodiments, the IBD is a moderate to severe form of IBD. In some embodiments, the IBD is a moderate form of IBD.

[0113] As used herein, the term “positive therapeutic response” is intended to mean improvement of one or more aspects of the symptoms of the inflammatory, fibrotic, or fibrostenotic disease or condition in a subject after treatment with the RIPK2 inhibitor provided herein, as determined by clinical parameters for such disease or condition. As is clear from the description herein, the inflammatory, fibrotic, or fibrostenotic disease or condition can be inflammatory bowel disease such as Crohn’s disease or ulcerative colitis. In the context of ulcerative colitis, such improvement of the disease symptoms can be measured by Mayo Score (based on stool frequency, rectal bleeding, the endoscopic appearance of the mucosa (endoscopic score), and a Physician’s Global Assessment (PGA), each of which were scored on a scale from 0 to 3, giving a Mayo Score of 0-12) or Modified Mayo Score (based on stool frequency, rectal bleeding, and the endoscopic appearance of the mucosa (endoscopic score), each of which were scored on a scale from 0 to 3, giving a Modified Mayo Score of 0-9), as known and practiced in the field. For example, in one embodiment, the positive therapeutic response in UC can be an improvement of the 3-component Modified Mayo Score, as determined by a reduction from baseline by ≥ 2 points and ≥ 30% in the 3- component Modified Mayo Score, accompanied by a reduction ≥ 1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤ 1. In the context of Crohn’s disease, such 219 ACTIVE 712622340v1improvement of the disease symptoms can be measured by Crohn’s disease activity index (CDAI), simple endoscopy score for Crohn’s disease (SES-CD, e.g. as further described in Gastrointest Endosc 2004; 60:505-512), or both CDAI and SES-CD, as known and practiced in the field. For example, in one embodiment, the positive therapeutic response can be an improvement of the CDAI, as determined by a reduction from baseline by ≥ 100 in CDAI. In another example, the positive therapeutic response can be a clinical remission, as defined below. In another example, the positive therapeutic response can be an endoscopic improvement, as defined below.

[0114] As used herein, the term “clinical remission” is intended to mean (i) the symptoms of the inflammatory, fibrotic, or fibrostenotic disease or condition in a subject have improved to the extent that the symptoms are absent, close to be absent, or moving close towards disappearance, or (ii) the inflammatory, fibrotic, or fibrostenotic disease or condition in the subject becomes a mild or less than a mild disease, after treatment with the RIPK2 inhibitor provided herein, as determined by clinical parameters for such disease or condition. As is clear from the description herein, the inflammatory, fibrotic, or fibrostenotic disease or condition can be inflammatory bowel disease such as Crohn’s disease or ulcerative colitis. In the context of ulcerative colitis, the clinical remission can be measured by Mayo Score or Modified Mayo Score, each as described above in the definition of “positive therapeutic response”. For example, in one embodiment, the clinical remission in UC can be determined based on the 3-component Modified Mayo Score as an endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than baseline. In the context of Crohn’s disease, such improvement of the disease symptoms can be measured by CDAI, SES-CD, or both CDAI and SES-CD, as known and practiced in the field. For example, in one embodiment, the clinical remission in CD can be determined based on the CDAI, as CDAI<150.

[0115] As used herein, the term “endoscopic improvement” is intended to mean (i) the inflammation in the mucosa of the digestive tract of the subject is absent, close to be absent, or moving close towards disappearance, or (ii) substantial reduction (≥50% reduction) of the inflammation in the mucosa of the digestive tract in a subject, after treatment with the RIPK2 inhibitor provided herein, as determined by a colonoscopy, a sigmoidoscopy, or other applicable endoscopy. As is clear from the description herein, the subject can be a subject affected by inflammatory, fibrotic, or fibrostenotic disease or condition, for example, inflammatory bowel disease such as Crohn’s disease or ulcerative colitis. In the context of 220 ACTIVE 712622340v1ulcerative colitis, the endoscopic improvement can be measured by the endoscopy subscore that is used as a component of the Mayo Score or Modified Mayo Score. For example, in one embodiment, the endoscopic improvement in UC can be determined based on endoscopy subscore ≤ 1 with no friability. In the context of Crohn’s disease, such endoscopic improvement can be measured by SES-CD, as known and practiced in the field. For example, in one embodiment, the endoscopic improvement in CD can be determined based on decrease in simple endoscopy score for Crohn’s disease (SES-CD)50% from baseline.

[0116] In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is clinical remission. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is endoscopic improvement. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is histologic remission (determined by Geboes score ≤3.1, as known and practiced in the field of IBD). In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is histologic-endoscopic mucosal improvement (determined by Geboes score ≤ 3.1 and endoscopy subscore1 with no friability). In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is histologic improvement (determined by Geboes score ≤3.1). In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is mucosal healing (determined by Geboes score2B.1 and endoscopy subscore of ≤ 1). In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is inflammatory bowel disease qestionnaire (IBDQ) response, as determined by16-point increase from baseline.

[0117] In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is determined at the end of a dosing regimen. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the positive therapeutic response is determined at week 12. 221 ACTIVE 712622340v1

[0118] In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In certain embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises one polymorphism selected from Table 1, or proxy polymorphisms in linkage disequilibrium therewith as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises two polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises three polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises four polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises five polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments 222 ACTIVE 712622340v1of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises six polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises seven polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises eight polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises nine polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises ten polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In certain embodiments of the methods provided in this paragraph, any polymorphism from Table 1 used in the combination of polymorphisms of the methods can be replaced with a proxy polymorphism in linkage disequilibrium therewith as determined with an R2of at least 0.85. Similarly, any 1 to 10 polymorphisms (each an original polymorphism) from Table 1 used in the combination of polymorphisms of the methods can 223 ACTIVE 712622340v1be replaced with corresponding proxy polymorphisms, wherein each proxy polymorphism is in linkage disequilibrium with the original polymorphism as determined with an R2of at least 0.85. Accordingly and specifically, in some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) one or more polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein one or more (up to all) such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In certain embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises one polymorphism selected from Table 1, or a proxy polymorphism in linkage disequilibrium therewith as determined with an R2of at least 0.85, or a combination thereof. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) two polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein one or two such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) three polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein one, two or all three such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) four polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein 1, 2, 3, or all 4 such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) five polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein 1, 2, 3, 4, or all 5 such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with 224 ACTIVE 712622340v1the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) six polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein 1, 2, 3, 4, 5, or all 6 such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) seven polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein 1, 2, 3, 4, 5, 6, or all 7 such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) eight polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein 1, 2, 3, 4, 5, 6, 7, or all 8 such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) nine polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein 1, 2, 3, 4, 5, 6, 7, 8, or all 9 such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85. In some embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of polymorphisms comprises (i) ten polymorphisms selected from Table 1, or (ii) the selected polymorphisms of (i) wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, or all 10 such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85.

[0119] For various embodiments of the methods provided herein, including in Sections 3, 5.2 (including in this paragraph), and 7, the method comprises various elements or combinations of elements provided herein, for example, as described in the following: further embodiments of the therapeutic agent including RIPK2 inhibitors (including small molecule 225 ACTIVE 712622340v1RIPK2 inhibitors) are provided in Sections 3, 5.4, and 7; assays for detecting the genotypes or polymorphisms are provided in Sections 3, 5.3, 1.1, 5.6.5, and 7; assays for validating the genotypes or genetic polymorphisms for the methods are provided in in Sections 3, 5.3, 1.1, and 7; methods of preparing the samples for detecting the genotypes or polymorphisms are provided in Section 5.6 (including Sections 5.6.1 to 5.6.4); genotypes, genetic polymorphisms, or other criteria used for selecting patients or subjects for the methods are provided in Section 3, 5.1, 5.2 (including in this paragraph), and 7; methods for selecting the patients for the treatment is provided in Section 3, 5.1, 5.2 (including in this paragraph), and 7; pharmaceutical compositions for the RIPK2 inhibitors (including small molecule RIPK2 inhibitors) are described and provided in Sections 3, 5.4, 1.1.1, and 7; and / or further specific and validated embodiments for the RIPK2 inhibitors and the methods of using the same are provided in Sections 3, 5.4 (e.g. Section 5.4.1), and 7. As such, the disclosure provides the various combinations of the RIPK2 inhibitors, the pharmaceutical compositions of such RIPK2 inhibitors, the methods of generating the RIPK2 inhibitors, the methods of assaying the genotypes and polymorphisms, the methods of preparing the sample, the combination of genotypes, the polymorphism, or the combination of polymorphisms, and / or the methods of using the RIPK2 inhibitors for treatment.

[0120] As is clear from the above description, the patients or subjects are selected with the methods of selecting patients or subjects as provided herein including in Sections 3, 5.2 (including in the preceding paragraphs), and 7, and then subject to the various methods of treatment as provided herein including in Sections 3, 5.2 (including in the preceding paragraphs), and 7.

[0121] For various embodiments of the methods provided herein, including in Sections 3, 5.2 (including in the preceding paragraphs), and 7, the inflammatory disease comprises or is inflammatory bowel disease.

[0122] For various embodiments of the methods provided herein, including in Sections 3, 5.2 (including in the preceding paragraphs), and 7, the inflammatory disease comprises or is Crohn’s disease. In some embodiments, the IBD comprises or is Crohn’s disease.

[0123] For various embodiments of the methods provided herein, including in Sections 3, 5.2 (including in the preceding paragraphs), and 7, the Crohn’s disease comprises or consists of ileal, ileocolonic, or colonic Crohn’s disease. 226 ACTIVE 712622340v1

[0124] For various embodiments of the methods provided herein, including in Sections 3, 5.2 (including in the preceding paragraphs), and 7, the inflammatory disease comprises or is ulcerative colitis (UC). In some embodiments, the IBD comprises or is UC.

[0125] For various embodiments of the methods provided herein, including in Sections 3, 5.2 (including in the preceding paragraphs), and 7, the UC is medically refractory UC.

[0126] For various embodiments of the methods provided herein, including in Sections 3, 5.2 (including in the preceding paragraphs), and 7, the sample is a biological sample.

[0127] For various embodiments of the methods, kit, processes, or compositions provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the corresponding alternative methods, kit, processes, or compositions are also provided herein in which “comprising” is replaced by “consisting of.” In various embodiments of the methods, kit, processes, or compositions provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the corresponding alternative methods, kit, processes, or compositions are also provided herein in which “comprise(s)” is replaced by “consist(s) of.”

[0128] Additionally, the disclosure provides various assays for determining or detecting the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms. As such, in various embodiments of the methods provided herein including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, determining or detecting the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms comprises or consists of assaying for the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms via any assays as described in Sections 3, 5.3, 5.6.5, and 7. In some embodiments of the methods provided herein including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, determining or detecting the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms comprises or consists of determining or detecting the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms via any assays as described in Sections 3, 5.3, 5.6.5, and 7. In some embodiments of the methods provided herein including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, determining or detecting the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms comprises or consists of determining or detecting the 227 ACTIVE 712622340v1genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms via any or any combination of method steps as described in Sections 3, 5.3, 5.6.5, and 7. Alternatively, in various embodiments of the methods provided herein including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises assaying for the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms via any assays as described in Sections 3, 5.3, 5.6.5, and 7. In certain embodiments of the methods provided herein including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises assaying for the genotypes, combinations of genotypes, polymorphisms, or combinations of polymorphisms via any or any combination of method steps as described in Sections 3, 5.3, 5.6.5, and 7.

[0129] Specifically, for various embodiments of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the RIPK2 inhibitor used in the methods is any one selected from the RIPK2 inhibitors described in Section 5.4. Additionally, for various embodiments of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the RIPK2 inhibitor is a compound of Formula (I), Formula (I-b), Formula (I-m), Formula (I-n), Formula (I-o), or Formula (I-p), each of which is further described in Section 5.4.1. In one specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the RIPK2 inhibitor used in the method is a compound of Formula (II), Formula (IV), Formula (V), Formula (Va), Formula (III), Formula (IIIa), Formula (IIIb), Formula (VI), Formula (VIa), Formula (VIb), or Formula (VIc), each of which is further described in Section 5.4.1. In another specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the RIPK2 inhibitor used in the method is selected from those described in Section 5.4.1. In one specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a genotype selected from the genotypes described in Section 5.1. In another specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a combination of genotypes selected from the combinations of genotypes described in Section 5.1. In yet another specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a combination of polymorphisms selected from the combination of polymorphisms described in Section 5.1. In one specific 228 ACTIVE 712622340v1embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a genotype selected from the genotypes described in Section 5.1 and the RIPK2 inhibitor used in the methods is any one selected from the RIPK2 inhibitor compounds described in Section 5.4.1. In another specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a combination of genotypes selected from the combinations of genotypes described in Section 5.1 and the RIPK2 inhibitor used in the methods is any one selected from RIPK2 inhibitor compounds described in Section 5.4.1. In yet another specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a combination of polymorphisms selected from the combination of polymorphisms described in Section 5.1 and the RIPK2 inhibitor used in the methods is any one selected from the RIPK2 inhibitor compounds described in Section 5.4.1.

[0130] In one specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a genotype selected from the genotypes described in Section 5.1. In another specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a combination of genotypes selected from the combinations of genotypes described in Section 5.1. In yet another specific embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subject in the method has a combination of polymorphisms selected from the combination of polymorphisms described in Section 5.1.

[0131] In one embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises determining a combination of polymorphisms provided herein, e.g. a combination of polymorphisms provided in Sections 3, 5.1, and 7. In one embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises determining a combination of genotypes provided herein, e.g. a combination of genotypes provided in Sections 3, 5.1, and 7. In some embodiments of the methods provided herein (e.g. in this paragraph), the step of determining the combination of genotypes or polymorphisms is performed as described in Sections 5.3, 5.6.5, and 7. In one embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises preparing a sample from the 229 ACTIVE 712622340v1patient. In some embodiments of the methods provided herein (e.g. in this paragraph), the step of preparing a sample from the patient is performed as described in Section 5.6. In some embodiments of the methods provided herein (e.g. in this paragraph), the step of determining a combination of genotypes or polymorphisms comprises determining combination of genotypes or polymorphisms in the sample prepared as described in Sections 5.3, 5.6.5, and 7.

[0132] In one embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises preparing a sample from the patient and determining a combination of polymorphisms in the sample, e.g. a combination of polymorphisms provided in Sections 3, 5.1, and 7. In one embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises preparing a sample from the patient and determining a combination of genotypes in the sample, e.g. a combination of genotypes provided in Sections 3, 5.1, and 7. In some embodiments of the methods provided herein (e.g. in this paragraph), the step of preparing a sample from the patient is performed as described in Section 5.6. In some embodiments of the methods provided herein (e.g. in this paragraph), the step of determining the combination of genotypes or polymorphisms is performed as described in Sections 5.3, 5.6.5, and 7.

[0133] In one embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises preparing a sample from the patient, determining a combination of polymorphisms in the sample, e.g. a combination of polymorphisms provided in Sections 3, 5.1, and 7, and determining the combination of genotypes or the combination of polymorphisms, wherein the combination of polymorphisms is indicative (i) an increase in a level of RIPK2 protein expression in a sample obtained from a subject or patient, as compared to a reference level of RIPK2 protein expression in a tissue not affected by IBD, (ii) an increase of RIPK2 signaling level in an IBD-affected tissue as compared to a reference level in a tissue not affected by IBD, and / or (iii) an increase of a positive therapeutic response in IBD patients to a treatment with the RIPK2 inhibitor as compared to the reference level of response in patients not selected by the genotypes. In one embodiment of the methods provided herein, including in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the method further comprises preparing a sample from the patient, determining a combination of genotypes in the sample, e.g. a combination of genotypes provided in Sections 3, 5.1, and 7, wherein the combination of 230 ACTIVE 712622340v1genotypes is indicative (i) an increase in a level of RIPK2 protein expression in a sample obtained from a subject or patient, as compared to a reference level of RIPK2 protein expression in a tissue not affected by IBD, (ii) an increase of RIPK2 signaling level in an IBD-affected tissue as compared to a reference level in a tissue not affected by IBD, and / or (iii) an increase of a positive therapeutic response in IBD patients to a treatment with the RIPK2 inhibitor as compared to the reference level of response in patients not selected by the genotypes. In some embodiments of the methods provided herein (e.g. in this paragraph), the step of preparing a sample from the patient is performed as described in Section 5.6. In some embodiments of the methods provided herein (e.g. in this paragraph), the step of determining the combination of genotypes or polymorphisms is performed as described in Sections 5.3, 5.6.5, and 7.

[0134] In some embodiments of the methods provided herein (e.g. in this paragraph), the step of determining the combination of genotypes or the combination of polymorphisms is performed as described in Sections 3, 5.2, and 7. In some embodiments of the methods provided herein (e.g. in this paragraph), the combination of polymorphisms comprises at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 polymorphisms. In some embodiments of the methods provided herein (e.g. in this paragraph), the combination of polymorphisms comprises at least 2 polymorphisms. In some embodiments of the methods provided herein (e.g. in this paragraph), the combination of genotypes comprises at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 genotypes. In some embodiments of the methods provided herein (e.g. in this paragraph), the combination of genotypes comprises at least 2 genotypes.

[0135] In various embodiments, provided herein is a method of treating inflammatory bowel disease (IBD) in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of RIPK2 inhibitor. In some embodiments of the methods provided herein, such as those provided in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subjects can be selected by various selection criteria described in Sections 3, 5 (including in the paragraphs of Sections 5.1 and 5.2), and 7. In some embodiments of the methods provided herein, such as those provided in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the subjects can be selected by various selection criteria described in Sections 3, 5 (including in the paragraphs of Sections 5.1 and 5.2), and 7, and the RIPK2 inhibitor can be any one described in Section 3, 5.4 and 7. In some embodiments of the methods provided herein, such as those provided in Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, the RIPK2 inhibitor can be any one 231 ACTIVE 712622340v1described in Section 3, 5.4 and 7. In some embodiments, the RIPK2 inhibitor is a small molecule RIPK2 inhibitor, wherein the RIPK2 inhibitor is a compound of Formula (I), Formula (I-b), Formula (I-m), Formula (I-n), Formula (I-o), or Formula (I-p), each of which is further described in Section 5.4.1. In some embodiments, the RIPK2 inhibitor is small molecule RIPK2 inhibitor, wherein the RIPK2 inhibitor is a compound of Formula (II) ), Formula (IV), Formula (V), Formula (Va), Formula (III), Formula (IIIa), Formula (IIIb), Formula (VI), Formula (VIa), Formula (VIb), or Formula (VIc), each of which is further described in Section 5.4.1. In some embodiments, the RIPK2 inhibitor is small molecule RIPK2 inhibitor, wherein the RIPK2 inhibitor is a compound of selected from those of Formula (I), Formula (I-b), Formula (I-m), Formula (I-n), Formula (I-o), Formula (I-p), Formula (II), Formula (IV), Formula (V), Formula (Va), Formula (III), Formula (IIIa), Formula (IIIb), Formula (VI), Formula (VIa), Formula (VIb), or Formula (VIc), as described in Section 5.4.1.

[0136] In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of genotypes or the combinationof polymorphisms comprises one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment) and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 (or the corresponding Part of Table 1) as determined with an R2of at least 0.85, or a combination thereof. In various embodiments of the methods provided herein including in Sections 3, 5.2 (e.g. the preceding paragraphs), and 7, the combination of genotypes or the combinationof polymorphisms comprises (i) one or more polymorphisms selected from Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment), or (ii) the selected polymorphisms of (i) wherein one or more (up to all) such selected polymorphisms are substituted with a corresponding number of proxy polymorphisms, each in linkage disequilibrium with the polymorphism to be substituted as determined with an R2of at least 0.85.

[0137] As is already clear from the descriptions herein, in some embodiments, the genotypes are polymorphisms. Accordingly, additional embodiments are provided herein for each embodiment reciting genotypes wherein the term “genotypes” is substituted with the term “polymorphisms.” Similarly, in some embodiments, the polymorphisms are SNPs. Accordingly, additional embodiments are provided herein for each embodiment reciting polymorphisms wherein the term “polymorphisms” is substituted with the term “SNPs.” 232 ACTIVE 712622340v1

[0138] In some embodiments, the genotypes in the methods provided herein (including in Section 5.2) are the genotypes of risk alleles as listed in Table 1. In some embodiments, the genotypes in the methods provided herein (including in Section 5.2) are the genotypes of minor alleles as listed in Table 1. In some embodiments, the genotypes in the methods provided herein (including in Section 5.2) are the genotypes of alternative alleles as listed in Table 1. In some embodiments, the genotypes in the methods provided herein (including in Section 5.2) are the genotypes of effect alleles as listed in Table 1. In some embodiments, the polymorphisms in the methods provided herein (including in Section 5.2) are the polymorphisms of risk alleles as listed in Table 1. In some embodiments, the polymorphisms in the methods provided herein (including in Section 5.2) are the polymorphisms of minor alleles as listed in Table 1. In some embodiments, the polymorphisms in the methods provided herein (including in Section 5.2) are the polymorphisms of alternative alleles as listed in Table 1. In some embodiments, the polymorphisms in the methods provided herein (including in Section 5.2) are the polymorphisms of effect alleles as listed in Table 1.

[0139] In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with IBD, wherein the IBD is an IBD in the ileal. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with IBD, wherein the IBD is an ileocolonic IBD. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with IBD, wherein the IBD is a colonic IBD. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with CD, wherein the CD is an CD in the ileal. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with CD, wherein the CD is an ileocolonic CD. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with CD, wherein the CD is a colonic CD. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with UC, wherein the UC is an UC in the ileal. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with UC, wherein the UC is an ileocolonic UC. In some embodiments, the subject in the methods provided herein (including in Section 5.2) is a human patient with UC, wherein the UC is a colonic UC.

[0140] Methods disclosed herein provide methods of treating an inflammatory bowel disease (IBD) in a subject by administering RIPK2 inhibitor described herein to the subject. 233 ACTIVE 712622340v1In various embodiments, IBD is Crohn’s Disease (CD) or ulcerative colitis (UC). In some embodiments, the IBD is a severe form of IBD. In some embodiments, the IBD is a moderate to severe form of IBD. In some embodiments, the IBD is a moderate form of IBD. In various other embodiments, the subject is determined to have an increased RIPK2 expression. In some embodiments, the administration of a therapeutically effective amount of an RIPK2 inhibitor causes a decrease in RIPK2 activity in the subject treated. 5.3 Methods Of Detection

[0141] Methods disclosed herein for detecting a genotype in a sample from a subject comprise analyzing the genetic material in the sample to detect at least one of a presence and an absence of a nucleic acid sequence encompassing the genotype of interest and administering a RIPK2 inhibitor as disclosed herein. In some embodiments, the sample is assayed to determine a presence or an absence of at least three polymorphisms. In some embodiments, the sample is assayed to determine a presence or an absence of at least four polymorphisms. In some embodiments, the sample is assayed to determine a presence or an absence of at least five polymorphisms. In some embodiments, the sample is assayed to determine a presence or an absence of at least six polymorphisms. In some embodiments, the sample is assayed to determine a presence or an absence of at least seven polymorphisms. In some embodiments, the sample is assayed to determine a presence or an absence of at least eight polymorphisms. In some embodiments, at least three genotypes are detected, using the methods described herein. In some embodiments, at least eight genotypes are detected, using the methods described herein.

[0142] In some cases, the nucleic acid sequence comprises DNAsequence. In some instances, the nucleic acid sequence comprises sequence of a denatured DNA molecule or fragment thereof. In some instances, the nucleic acid sequence comprises sequence of DNA selected from: genomic DNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-free DNA, and exosomal DNA. In some instances, the DNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturing double-stranded DNA, or combinations thereof. The circular DNA may be cleaved or fragmented. In some instances, the nucleic acid sequence comprises RNA sequence. In some instances, the nucleic acid sequence comprises sequence of fragmented RNA. In some instances, the nucleic acid sequence comprises sequence of partially degraded RNA. In some instances, the nucleic acid sequence comprises sequence of a microRNA or portion thereof. In some instances, the 234 ACTIVE 712622340v1nucleic acid sequence comprises sequence of an RNA molecule or a fragmented RNA molecule (RNA fragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri- miRNA, a mRNA, a pre-mRNA, circular RNA (circRNA), a long non-coding RNA (lncRNA), a small nuclear RNA (snRNA), a circulating RNA, a cell-free RNA, an exosomal RNA, an RNA transcript, and combinations thereof.

[0143] Nucleic acid-based detection techniques that may be useful for the methods herein include quantitative polymerase chain reaction (qPCR), gel electrophoresis, immunochemistry, in situ hybridization such as fluorescent in situ hybridization (FISH), and next generation sequencing. In some embodiments, the methods involve TaqMan™ qPCR, which involves a nucleic acid amplification reaction with a specific primer pair, and hybridization of the amplified nucleic acids with a hydrolysable probe specific to a target nucleic acid.

[0144] In some instances, the methods involve hybridization and / or amplification assays that include, but are not limited to, Southern or Northern analyses, polymerase chain reaction analyses, and probe arrays. Non-limiting amplification reactions include, but are not limited to, qPCR, self-sustained sequence replication, transcriptional amplification system, Q-Beta Replicase amplification, rolling circle replication, or any other nucleic acid amplification known in the art. As discussed, reference to qPCR herein includes use of TaqMan™ methods. An additional exemplary hybridization assay includes the use of nucleic acid probes conjugated or otherwise immobilized on a bead, multi-well plate, or other substrate, wherein the nucleic acid probes are configured to hybridize with a target nucleic acid sequence of a genotype provided herein. A non-limiting method is one employed in Anal Chem.2013 Feb 5; 85(3):1932-9.

[0145] In one embodiment, determining the genotype of a gene is performed at the nucleic acid level by performing RNA-seq, a reverse transcriptase polymerase chain reaction (RT-PCR) or a hybridization assay with oligonucleotides that are substantially complementary to portions of cDNA molecules of the at least one biomarker gene under conditions suitable for RNA-seq, RT-PCR or hybridization and obtaining expression levels of the at least one biomarker gene.

[0146] In another embodiment, determining the genotype of a gene is performed at the nucleic acid level by performing DNA sequencing as described herein, a polymerase chain reaction (PCR, e.g., real time PCR or quantitative PCR) and / or a hybridization assay with oligonucleotides that are substantially complementary to portions of amplified DNA 235 ACTIVE 712622340v1molecules of the gene under conditions suitable for hybridization, thereby obtaining the genotype of the biomarker genes.

[0147] In some embodiments, detecting the presence or absence of a genotype comprises sequencing genetic material from the subject. In some embodiments, detecting the presence or absence of a genotype comprises sequencing DNA molecules amplified from the genetic material from the subject. Sequencing can be performed with any appropriate sequencing technology, including but not limited to single-molecule real-time (SMRT) sequencing, Polony sequencing, sequencing by ligation, reversible terminator sequencing, proton detection sequencing, ion semiconductor sequencing, nanopore sequencing, electronic sequencing, pyrosequencing, Maxam-Gilbert sequencing, chain termination (e.g., Sanger) sequencing, +S sequencing, or sequencing by synthesis. Sequencing methods also include next-generation sequencing, e.g., modern sequencing technologies such as Illumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrent sequencing, and SOLiD sequencing. In some cases, next-generation sequencing involves high-throughput sequencing methods. Additional sequencing methods available to one of skill in the art may also be employed.

[0148] In some instances, a number of nucleotides that are sequenced are at least 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400, 500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than 100000 nucleotides. In some instances, the number of nucleotides sequenced is in a range of about 1 to about 100000 nucleotides, about 1 to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1 to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 to about 200 nucleotides, about 1 to about 100 nucleotides, about 5 to about 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 to about 1000 nucleotides, about 5 to about 500 nucleotides, about 5 to about 300 nucleotides, about 5 to about 200 nucleotides, about 5 to about 100 nucleotides, about 10 to about 100000 nucleotides, about 10 to about 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 to about 500 nucleotides, about 10 to about 300 nucleotides, about 10 to about 200 nucleotides, about 10 to about 100 nucleotides, about 20 to about 100000 nucleotides, about 20 to about 10000 nucleotides, about 20 to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20 to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 to about 100 nucleotides, about 30 to about 100000 nucleotides, about 30 to about 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 to about 500 nucleotides, about 30 to about 300 nucleotides, about 30 to about 200 nucleotides, about 30 to about 100 236 ACTIVE 712622340v1nucleotides, about 50 to about 100000 nucleotides, about 50 to about 10000 nucleotides, about 50 to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50 to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50 to about 100 nucleotides.

[0149] Exemplary probes comprise a nucleic acid sequence of at least 10 contiguous nucleotides provided in (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1- 68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105-512, including the nucleotide indicated at the nucleoposition of the nucleotide variation (e.g. the position of the polymorphism), or a reverse complement thereof. In some instances, the probes may be used to detect the polymorphisms provided in Table 1 (including Table 1 in its entirety or each Part (Part I, II, III, IV, or V) of Table 1 as a separate embodiment), wherein the probe comprises a nucleic acid sequence of at least 10 contiguous nucleotides provided in a corresponding SEQ ID NO or reverse complement thereof, the 10 contiguous nucleotides comprising the “risk allele” also provided in Table 1 at a nucleoposition indicated therein, or reverse complement thereof. In some embodiments, the probe comprises at least 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1-68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105-512, or its reverse complement. In some instances, forward and reverse primers are used to amplify the target nucleic acid sequence. In some instances, forward and reverse primers are used to amplify the target nucleic acid sequence and the amplified target nucleic acid are contacted with probes to detect the presence or absence of the genotype or combination of genotypes. In some embodiment, the amplification of the target nucleic acid was completed before the amplified target nucleic acid is contacted with probes to detect the presence or absence of the genotype or combination of genotypes. In other embodiments, the amplification of the target nucleic acid is performed concurrently (e.g. in real time) as the amplified target nucleic acid is contacted with probes to detect the presence or absence of the genotype or combination of genotypes. Forward and reverse primers may comprise a nucleic acid sequence flanking the risk allele provided in Table 1 corresponding to the nucleic acid sequence provided in (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1-68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105-512, or a reverse complement thereof. 237 ACTIVE 712622340v1

[0150] Examples of molecules that are utilized as probes include, but are not limited to, RNA and DNA. In some embodiments, the term “probe” with regards to nucleic acids, refers to any molecule that is capable of selectively binding to a specifically intended target nucleic acid sequence. In some instances, probes are specifically designed to be labeled, for example, with a radioactive label, a fluorescent label, an enzyme, a chemiluminescent tag, a colorimetric tag, or other labels or tags that are known in the art. In some instances, the fluorescent label comprises a fluorophore. In some instances, the fluorophore is an aromatic or heteroaromatic compound. In some instances, the fluorophore is a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole, indole, benzindole, oxazole, thiazole, benzothiazole, canine, carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin. Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes. Fluorescein and rhodamine dyes include, but are not limited to 6-carboxyfluorescein (FAM), 2′7′-dimethoxy- 4′5′-dichloro-6-carboxyfluorescein (JOE), tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N; N′-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX). Suitable fluorescent probes also include the naphthylamine dyes that have an amino group in the alpha or beta position. For example, naphthylamino compounds include 1- dimethylaminonaphthyl-5-sulfonate, 1-anilino-8-naphthalene sulfonate and 2-p-toluidinyl-6- naphthalene sulfonate, 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS). Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin; acridines, such as 9- isothiocyanatoacridine and acridine orange; N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g., indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5), indodicarbocyanine 5.5 (Cy5.5), 3-(-carboxy-pentyl)-3′-ethyl-5,5′-dimethyloxacarbocyanine (CyA); 1H, 5H, 11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i′j′]diquinolizin-18-ium, 9-[2 (or 4)-[[[6- [2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4 (or 2)-sulfophenyl]-2,3, 6,7, 12,13, 16,17-octahydro-inner salt (TR or Texas Red); or BODIPYTM dyes. In some cases, the probe comprises FAM as the dye label.

[0151] In some instances, primers and / or probes described herein for detecting a target nucleic acid are used in an amplification reaction. For example, the amplification of the target nucleic acid can be performed concurrently (e.g. in real time) as the amplified target nucleic acid is contacted with probes to detect the presence or absence of the genotype or combination of genotypes. In some instances, the amplification reaction is qPCR. An exemplary qPCR is a method employing a TaqMan™ assay. PCT primers and probes can be designed with tools known and used in the art. For example, forward and reverse primers for 238 ACTIVE 712622340v1regions containing SNPs can be designed by uploading the flanking sequences into the Thermofisher OligoPerfect Primer Designer tool. The primer set with longest amplicon can be selected for the forward and reverse primers. Flanking sequences of SNPs can be obtained from the NCBI dbSNP database. Probes can be designed with the Thermofisher SNP genotype tool. The resulting probe design from the SNP genotype tool can be then truncated to 10~20 nucleotide flanks for the final design. Non-limiting examples of primer pairs useful for detecting one or more polymorphisms described herein are provided in Table 3, below. Alternatively, the forward and reverse primers as well as wt and mutant probes for genotyping certain SNPs are available commercially, e.g. from THERMO FISHER SCIENTIFIC INC. catalog using TaqMan™ assays with the TaqMan™ assay ID listed in Table 3. The nucleotide sequences for the forward and reverse primers as well as wt and mutant probes can be identified from the commercial kit available under the TaqMan™ assay ID, and are incorporated herein in their entireties by reference herein and specifically to Table 3. The probes provided in Table 3 are some embodiments of the probes or the binding agents referenced herein. The primers in Table 3 can be used to amplify the target sequences comprising the polymorphisms and binding of the probes in Table 3 with such amplified target sequences can increase the signals from bound probes. Table 3. Exemplary Primer Sequences239 ACTIVE 712622340v1240 ACTIVE 712622340v1“Wt_Probe_Hex” and “Mut_Probe_FAM” mean “Wild type_probes_tagged with HEX reporter dye” and“Mut_probe_tagged with FAM reporter dye”, respectively. The nucleotides in square brackets are the nulceopositions for the SNP, which could be bases as indicated in the brackets or the corresponding LNA bases (Locked nucleotides), which are analogues that are modified at 2'-O, 4'-C and form a bridge. This bridge results in restricted base pairing giving room to adjust the Tm as needed for the probes. 241 ACTIVE 712622340v1

[0152] In some instances, qPCR comprises using an intercalating dye. Examples of intercalating dyes include SYBR green I, SYBR green II, SYBR gold, ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, Blue View or phycoerythrin. In some instances, the intercalating dye is SYBR.

[0153] In some instances, a number of amplification cycles for detecting a target nucleic acid in an amplification assay is about 5 to about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at least about 5 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is at most about 30 cycles. In some instances, the number of amplification cycles for detecting a target nucleic acid is about 5 to about 10, about 5 to about 15, about 5 to about 20, about 5 to about 25, about 5 to about 30, about 10 to about 15, about 10 to about 20, about 10 to about 25, about 10 to about 30, about 15 to about 20, about 15 to about 25, about 15 to about 30, about 20 to about 25, about 20 to about 30, or about 25 to about 30 cycles.

[0154] In one aspect, the methods provided herein for determining the presence, absence, and / or quantity of a nucleic acid sequence from a particular genotype comprise an amplification reaction such as qPCR. In an exemplary method, genetic material is obtained from a sample of a subject, e.g., a sample of blood, tissue biopsy, buccal swab, or saliva. In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol, or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, one non-limiting example would be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification.

[0155] In the exemplary qPCR assay, the nucleic acid sample is combined with primers and probes specific for a target nucleic acid that may be present in the sample, and a DNA polymerase. An amplification reaction is performed with a thermal cycler that heats and cools the sample for nucleic acid amplification, and illuminates the sample at a specific wavelength 242 ACTIVE 712622340v1to excite a fluorophore on the probe and detect the emitted fluorescence. For TaqMan™ methods, the probe may be a hydrolysable probe comprising a fluorophore and quencher that is hydrolyzed by DNA polymerase when hybridized to a target nucleic acid. In some cases, the presence of a target nucleic acid is determined when the number of amplification cycles to reach a threshold value is less than 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.

[0156] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1-68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105-512, comprising an alternative allele at nucleoposition 51 within that SEQ ID NO. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1-68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105-512, comprising a reference allele at nucleoposition 51 within that SEQ ID NO. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a reference allele at nucleoposition 51 within (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1-68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105-512 is sufficient to detect the polymorphism corresponding to the SEQ ID NO. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1-68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105-512 comprising an alternative allele at nucleoposition 51 within that SEQ ID NO. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an alternative allele at nucleoposition 51 within any one of (i) any one of SEQ ID NOS: 1-1334, (ii) any one of SEQ ID NOS: 1-68, (iii) any one of SEQ ID NOS: 37-68, (iv) any one of SEQ ID NOS: 37-108, or (v) any one of SEQ ID NOS: 37-68 and 105- 512 is sufficient to detect the polymorphism corresponding to the SEQ ID NO.

[0157] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 1 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 1. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 1 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 1. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 1 is sufficient to detect the polymorphism at rs2241880. 243 ACTIVE 712622340v1

[0158] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 2 comprising alternative allele at nucleoposition 51 within SEQ ID NO: 2. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 2 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 2. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 2 is sufficient to detect the polymorphism at rs6708373.

[0159] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 3 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 3. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 3 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 3. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 3 is sufficient to detect the polymorphism at rs3792111.

[0160] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 4 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 4. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 4 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 4. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 4 is sufficient to detect the polymorphism at rs3792109.

[0161] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 5 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 5. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 5 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 5. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 5 is sufficient to detect the polymorphism at rs3816234.

[0162] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 6 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 6. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 6 comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 6. In some embodiments, detecting the at least 10 contiguous nucleotides 244 ACTIVE 712622340v1comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 6 is sufficient to detect the polymorphism at rs6738490.

[0163] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 7 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 7. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 7 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 7. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 7 is sufficient to detect the polymorphism at rs3828309.

[0164] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 8 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 8. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 8 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 8. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 8 is sufficient to detect the polymorphism at rs35300242.

[0165] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 9 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 9. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 9 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 9. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 9 is sufficient to detect the polymorphism at rs12994997.

[0166] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 10 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 10. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 10 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 10. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 10 is sufficient to detect the polymorphism at rs10210302.

[0167] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 11 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 11. In some embodiments, the target nucleic acid is at least 10 contiguous 245 ACTIVE 712622340v1nucleotides of SEQ ID NO: 11 comprising an “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 11. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 11 is sufficient to detect the polymorphism at rs36001488.

[0168] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 12 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 12. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 12 comprising an “A” or a “C” allele at nucleoposition 51 within SEQ ID NO: 12. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “C” allele at nucleoposition 51 within SEQ ID NO: 12 is sufficient to detect the polymorphism at rs11145763.

[0169] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 13 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 13. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 13 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 13. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 13 is sufficient to detect the polymorphism at rs2076756.

[0170] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 14 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 14. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 14 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 14. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 14 is sufficient to detect the polymorphism at rs16900888.

[0171] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 15 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 15. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 15 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 15. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 15 is sufficient to detect the polymorphism at rs1109863. 246 ACTIVE 712622340v1

[0172] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 16 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 16. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 16 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 16. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 16 is sufficient to detect the polymorphism at rs11793497.

[0173] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 17 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 17. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 17 comprising an “A” or a “T” allele at nucleoposition 51 within SEQ ID NO: 17. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “T” allele at nucleoposition 51 within SEQ ID NO: 17 is sufficient to detect the polymorphism at rs11989430.

[0174] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 18 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 18. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 18 comprising a “G” or a “T” allele at nucleoposition 51 within SEQ ID NO: 18. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or a “T” allele at nucleoposition 51 within SEQ ID NO: 18 is sufficient to detect the polymorphism at rs28405481.

[0175] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 19 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 19. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 19 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 19. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 19 is sufficient to detect the polymorphism at rs7194886.

[0176] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 20 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 20. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 20 comprising a “T” or a “G” (a deletion) allele at nucleoposition 51 within SEQ ID NO: 20. In some embodiments, detecting the at least 10 contiguous 247 ACTIVE 712622340v1nucleotides comprising a “T” or a “G” (a deletion) allele at nucleoposition 51 within SEQ ID NO: 20 is sufficient to detect the polymorphism at rs28461337.

[0177] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 21 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 21. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 21 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 21. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 21 is sufficient to detect the polymorphism at rs2357623.

[0178] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 22 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 22. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 22 comprising a “G” or a “GC” allele at nucleoposition 51 within SEQ ID NO: 22. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or a “GC” allele at nucleoposition 51 within SEQ ID NO: 22 is sufficient to detect the polymorphism at rs199883290.

[0179] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 23 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 23. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 23 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 23. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 23 is sufficient to detect the polymorphism at rs2338882.

[0180] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 24 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 24. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 24 comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 24. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 24 is sufficient to detect the polymorphism at rs10870077.

[0181] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 25 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 25. In some embodiments, the target nucleic acid is at least 10 contiguous 248 ACTIVE 712622340v1nucleotides of SEQ ID NO: 25 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 25. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 25 is sufficient to detect the polymorphism at rs749910.

[0182] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 26 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 26. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 26 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 26. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 26 is sufficient to detect the polymorphism at rs36032938.

[0183] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 27 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 27. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 27 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 27. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 27 is sufficient to detect the polymorphism at rs34211510.

[0184] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 28 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 28. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 28 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 28. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 28 is sufficient to detect the polymorphism at rs1051957.

[0185] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 29 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 29. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 29 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 29. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 29 is sufficient to detect the polymorphism at rs4077515. 249 ACTIVE 712622340v1

[0186] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 30 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 30. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 30 comprising a “C” or an “A” allele at nucleoposition 51 within SEQ ID NO: 30. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or an “A” allele at nucleoposition 51 within SEQ ID NO: 30 is sufficient to detect the polymorphism at rs10094579.

[0187] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 31 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 31. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 31 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 31. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 31 is sufficient to detect the polymorphism at rs13332952.

[0188] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 32 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 32. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 32 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 32. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 32 is sufficient to detect the polymorphism at rs3135501.

[0189] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 33 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 33. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 33 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 33. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 33 is sufficient to detect the polymorphism at rs11995065.

[0190] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 34 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 34. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 34 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 34. In some embodiments, detecting the at least 10 contiguous nucleotides 250 ACTIVE 712622340v1comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 34 is sufficient to detect the polymorphism at rs11145765.

[0191] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 35 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 35. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 35 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 35. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 35 is sufficient to detect the polymorphism at rs62530908.

[0192] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 36 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 36. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 36 comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 36. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 36 is sufficient to detect the polymorphism at rs12155807.

[0193] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 37 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 37. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 37 comprising an “A” or a “C” allele at nucleoposition 51 within SEQ ID NO: 37. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “C” allele at nucleoposition 51 within SEQ ID NO: 37 is sufficient to detect the polymorphism at rs34970073.

[0194] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 38 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 38. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 38 comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 38. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 38 is sufficient to detect the polymorphism at rs2230801.

[0195] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 39 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 39. In some embodiments, the target nucleic acid is at least 10 contiguous 251 ACTIVE 712622340v1nucleotides of SEQ ID NO: 39 comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 39. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 39 is sufficient to detect the polymorphism at rs17221417.

[0196] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 40 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 40. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 40 comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 40. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 40 is sufficient to detect the polymorphism at rs28528187.

[0197] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 41 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 41. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 41 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 41. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 41 is sufficient to detect the polymorphism at rs3829110.

[0198] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 42 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 42. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 42 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 42. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 42 is sufficient to detect the polymorphism at rs6596.

[0199] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 43 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 43. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 43 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 43. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 43 is sufficient to detect the polymorphism at rs10781499. 252 ACTIVE 712622340v1

[0200] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 44 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 44. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 44 comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 44. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 44 is sufficient to detect the polymorphism at rs62530862.

[0201] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 45 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 45. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 45 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 45. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 45 is sufficient to detect the polymorphism at rs34525502.

[0202] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 46 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 46. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 46 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 46. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 46 is sufficient to detect the polymorphism at rs13280951.

[0203] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 47 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 47. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 47 comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 47. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “T” or a “C” allele at nucleoposition 51 within SEQ ID NO: 47 is sufficient to detect the polymorphism at rs3812565.

[0204] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 48 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 48. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 48 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 48. In some embodiments, detecting the at least 10 contiguous nucleotides 253 ACTIVE 712622340v1comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 48 is sufficient to detect the polymorphism at rs13281958.

[0205] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 49 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 49. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 49 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 49. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 49 is sufficient to detect the polymorphism at rs13262484.

[0206] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 50 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 50. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 50 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 50. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 50 is sufficient to detect the polymorphism at rs104895460.

[0207] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 51 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 51. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 51 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 51. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 51 is sufficient to detect the polymorphism at rs5743289.

[0208] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 52 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 52. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 52 comprising an “A” or a “T” allele at nucleoposition 51 within SEQ ID NO: 52. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “T” allele at nucleoposition 51 within SEQ ID NO: 52 is sufficient to detect the polymorphism at rs104895472.

[0209] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 53 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 53. In some embodiments, the target nucleic acid is at least 10 contiguous 254 ACTIVE 712622340v1nucleotides of SEQ ID NO: 53 comprising a “G” or a “C” allele at nucleoposition 51 within SEQ ID NO: 53. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or a “C” allele at nucleoposition 51 within SEQ ID NO: 53 is sufficient to detect the polymorphism at rs2066845.

[0210] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 54 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 54. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 54 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 54. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 54 is sufficient to detect the polymorphism at rs104895477.

[0211] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 55 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 55. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 55 comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 55. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 55 is sufficient to detect the polymorphism at rs104895476.

[0212] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 56 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 56. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 56 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 56. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 56 is sufficient to detect the polymorphism at rs2066844.

[0213] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 57 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 57. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 57 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 57. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 57 is sufficient to detect the polymorphism at rs104895462. 255 ACTIVE 712622340v1

[0214] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 58 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 58. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 58 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 58. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 58 is sufficient to detect the polymorphism at rs104895461.

[0215] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 59 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 59. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 59 comprising a “CCC” or a “CCCC” allele at nucleoposition 51 within SEQ ID NO: 59. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “CCC” or a “CCCC” allele at nucleoposition 51 within SEQ ID NO: 59 is sufficient to detect the polymorphism at rs2066847.

[0216] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 60 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 60. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 60 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 60. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 60 is sufficient to detect the polymorphism at rs10065172.

[0217] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 61 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 61. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 61 comprising a “G” or an “T” allele at nucleoposition 51 within SEQ ID NO: 61. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “T” allele at nucleoposition 51 within SEQ ID NO: 61 is sufficient to detect the polymorphism at rs775267971.

[0218] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 62 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 62. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 62 comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 62. In some embodiments, detecting the at least 10 contiguous nucleotides 256 ACTIVE 712622340v1comprising a “C” or a “T” allele at nucleoposition 51 within SEQ ID NO: 62 is sufficient to detect the polymorphism at rs398122362.

[0219] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 63 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 63. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 63 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 63. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 63 is sufficient to detect the polymorphism at rs121918338.

[0220] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 64 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 64. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 64 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 64. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 64 is sufficient to detect the polymorphism at rs398122363.

[0221] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 65 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 65. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 65 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 65. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 65 is sufficient to detect the polymorphism at rs1342330215.

[0222] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 66 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 66. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 66 comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 66. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “C” or a “G” allele at nucleoposition 51 within SEQ ID NO: 66 is sufficient to detect the polymorphism at rs149712114.

[0223] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 67 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 67. In some embodiments, the target nucleic acid is at least 10 contiguous 257 ACTIVE 712622340v1nucleotides of SEQ ID NO: 67 comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 67. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “G” or an “A” allele at nucleoposition 51 within SEQ ID NO: 67 is sufficient to detect the polymorphism at rs398122364.

[0224] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 68 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 68. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 68 comprising an “AGCA” or an “AGCAAGCA” allele at nucleoposition 51 within SEQ ID NO: 68. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “AGCA” or an “AGCAAGCA” allele at nucleoposition 51 within SEQ ID NO: 68 is sufficient to detect the polymorphism at rs768308018.

[0225] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 69 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 69. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 69 comprising a “CC” or a “CCC” allele at nucleoposition 51 within SEQ ID NO: 69. In some embodiments, detecting the at least 10 contiguous nucleotides comprising a “CC” or a “CCC” allele at nucleoposition 51 within SEQ ID NO: 69 is sufficient to detect the polymorphism at rs753050033.

[0226] In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 70 comprising an alternative allele at nucleoposition 51 within SEQ ID NO: 70. In some embodiments, the target nucleic acid is at least 10 contiguous nucleotides of SEQ ID NO: 70 comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 70. In some embodiments, detecting the at least 10 contiguous nucleotides comprising an “A” or a “G” allele at nucleoposition 51 within SEQ ID NO: 70 is sufficient to detect the polymorphism at rs2241880.

[0227] In some embodiments, one target nucleic acid (e.g., a polymorphism) is detected with the methods disclosed herein. In some embodiments, at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 target nucleic acids are detected. In some embodiments, the at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 target nucleic acids are detected in a single multiplexed assay. Each polymorphism detected may be heterozygous or homozygous.

[0228] To practice the methods provided herein, genetic material may be extracted from a sample obtained from a subject, e.g., a sample of blood, saliva, tissue biopsy, or buccal swab. 258 ACTIVE 712622340v1In certain embodiments where nucleic acids are extracted, the nucleic acids are extracted using any technique that does not interfere with subsequent analysis. In certain embodiments, this technique uses alcohol precipitation using ethanol, methanol or isopropyl alcohol. In certain embodiments, this technique uses phenol, chloroform, or any combination thereof. In certain embodiments, this technique uses cesium chloride. In certain embodiments, this technique uses sodium, potassium or ammonium acetate or any other salt commonly used to precipitate DNA. In certain embodiments, this technique utilizes a column or resin based nucleic acid purification scheme such as those commonly sold commercially, of which one non-limiting example can be the GenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. In certain embodiments, after extraction the nucleic acid is stored in water, Tris buffer, or Tris-EDTA buffer before subsequent analysis. In an exemplary embodiment, the nucleic acid material is extracted in water. In some cases, extraction does not comprise nucleic acid purification. In certain embodiments, RNA may be extracted from cells using RNA extraction techniques including, for example, using acid phenol / guanidine isothiocyanate extraction (RNAzol B; Biogenesis), RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix, Switzerland).

[0229] In some embodiments, methods of detecting a presence, absence, or level of a target protein (e.g., biomarker) in the sample obtained from the subject involve detecting protein activity or expression. In some embodiments, the target protein is RIPK2, or a binding partner of RIPK2 such as XIAP, NOD2 or CARD9. A target protein may be detected by use of an antibody-based assay, where an antibody specific to the target protein is utilized. In some embodiments, antibody-based detection methods utilize an antibody that binds to any region of target protein. An exemplary method of analysis comprises performing an enzyme- linked immunosorbent assay (ELISA). The ELISA assay may be a sandwich ELISA or a direct ELISA. Another exemplary method of analysis comprises a single molecule array, e.g., Simoa. Other exemplary methods of detection include immunohistochemistry and lateral flow assay. Additional exemplary methods for detecting target protein include, but are not limited to, gel electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), hyperdiffusion chromatography, and the like, or various immunological methods such as fluid or gel precipitation reactions, immunodiffusion (single or double), immunoelectrophoresis, radioimmunoassay (RIA), immunofluorescent assays, and Western blotting. In some embodiments, antibodies, or antibody fragments, are used in methods such as Western blots or immunofluorescence 259 ACTIVE 712622340v1techniques to detect the expressed proteins. The antibody or protein can be immobilized on a solid support for Western blots and immunofluorescence techniques. Suitable solid phase supports or carriers include any support capable of binding an antigen or an antibody. Exemplary supports or carriers include glass, polystyrene, polypropylene, polyethylene, dextran, nylon, natural and modified celluloses, polyacrylamides, and magnetite.

[0230] In some cases, a target protein may be detected by detecting binding between the target protein and a binding partner of the target protein. Non-limiting examples of binding partners to RIPK2 include XIAP, NOD2, or CARD9. Exemplary methods of analysis of protein-protein binding comprise performing an assay in vivo or in vitro, or ex vivo. In some instances, the method of analysis comprises an assay such as a co-immunoprecipitation (co- IP), pull-down, crosslinking protein interaction analysis, labeled transfer protein interaction analysis, or Far-western blot analysis, FRET based assay, including, for example FRET- FLIM, a yeast two-hybrid assay, BiFC, or split luciferase assay.

[0231] Disclosed herein are methods of detecting a presence or a level of one or more serological markers in a sample obtained from a subject. In some embodiments, the one or more serological markers comprises anti-Saccharomyces cerevisiae antibody (ASCA), an anti-neutrophil cytoplasmic antibody (ANCA), antibody against E.coli outer membrane porin protein C (anti-OmpC), anti-chitin antibody, pANCA antibody, anti-I2 antibody, and anti- Cbir1 flagellin antibody. In some embodiments, the antibodies comprises immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin E (IgE), or immunoglobulin M (IgM), immunoglobulin D (IgD), or a combination thereof. Any suitable method for detecting a target protein or biomarker disclosed herein may be used to detect a presence, absence, or level of a serological marker. In some embodiments, the presence or the level of the one or more serological markers is detected using an enzyme-linked immunosorbent assay (ELISA), a single molecule array (Simoa), immunohistochemistry, internal transcribed spacer (ITS) sequencing, or any combination thereof. In some embodiments, ELISA units (EU) are used to measure positivity of a presence or level of a serological marker (e.g., seropositivity), which reflects a percentage of a standard or reference value. In some embodiments, the standard comprises pooled sera obtained from well-characterized patient population (e.g., diagnosed with the same disease or condition the subject has, or is suspected of having) reported as being seropositive for the serological marker of interest. In some instances, a quartile sum scores are calculated using, for example, the methods reported in Landers C J, Cohavy O, 260 ACTIVE 712622340v1Misra R. et al., Selected loss of tolerance evidenced by Crohn’s disease‐associated immune responses to auto‐ and microbial antigens. Gastroenterology (2002)123:689–699. 5.4 Therapeutic agents 5.4.1 Small Molecule RIPK2 Inhibitors

[0232] Receptor interacting protein kinase 2 (RIPK2) is a serine-threonine protein kinase, and is a signaling molecule downstream of nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs). The RIPK2 protein includes a kinase domain (KD), an intermediate domain (INTD), and a caspase activation and recruitment domain (CARD). The CARD domain of RIPK2 mediates interaction with NOD1 and NOD2. RIPK2 is expressed in the cytoplasm of antigen-presenting cells including dendritic cells and macrophages, and is also expressed in T cells and epithelial cells.

[0233] NOD receptors function in the innate immune system, detecting bacterial pathogens by binding to diaminopimelic acid or muramyl dipeptide residues present in bacterial peptidoglycans. Interactions between RIPK2 and NOD1, NOD2 and TLRs trigger the release of pro-inflammatory cytokines including TNF-α, IL-6, and IL-12 / 23p40, and RIPK2-mediated induction of NF-kappa-B-dependent inflammatory responses. Activation of RIPK2 and dysregulation of the RIPK2-NOD signaling pathways may also have a role in the pathogenesis of various inflammatory diseases. RIPK2 has been reported to be a prognostic indicator and candidate therapeutic target for various cancers.

[0234] In some embodiments, the RIPK2 inhibitor is a compound that has the structure of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein: one or two of X, Y, and Z1is independently N and the other of X, Y, and Z1is C; each is a single bond or a double bond; R5is hydrogen, -NH2, or halogen; Ring A is phenyl or 5-10 membered heteroaryl; 261 ACTIVE 712622340v1m is 0, 1, 2, 3, or 4; each R1is independently: (i) C1-C6 alkoxy optionally substituted with hydroxyl or phenyl; (ii) C1-C6 deuteroalkoxy; (iii) C1-C6 alkoxyalkyl; (iv) 5-6 membered heteroaryl; (v) –N(R6)-S(O2)R7; (vi) –(C=O)NR6R7, -NR6(C=O)OR7, or –(C=O)OR7; (vii) halogen; (viii) cyano; (ix) hydroxyl; (x) –NR6R8; (xi) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl and 4-8 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl; (xii) C1-C6 haloalkyl; (xiii) C1-C6 haloalkoxy; (xiv) C3-C6 cycloalkyl; (xv) 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl; (xvi) –S(O2)C1-C6 alkyl; (xvii) 4-10 membered heterocyclyloxy optionally substituted with acyl; (xviii) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, and C1-C6 haloalkyl; each R6is independently hydrogen or C1-C6 alkyl; each R7is independently (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from: (a) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (b) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, C1-C6 alkoxy,C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and cyano; (c) -NR6R7; (d) hydroxyl; (e) halogen; 262 ACTIVE 712622340v1(f) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3- C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1- C6 alkyl; (g) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen, cyano,C1-C6 alkyl, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with –(C=O)OC1-C6 alkyl; (ii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl; (iii) C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl; (iv) ethylenyl; (v) C1-C6 haloalkyl; (vi) 4-10 membered heterocyclyl optionally substituted with –(C=O)OC1-C6 alkyl; or (vii) phenyl optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, and –(C=O)NR6R7; or R6and R7with the atom to which they are attached together form a 5-12 membered heterocyclyl or 9-10 membered heteroaryl each optionally substituted with phenyl; R8is (i) hydrogen; (ii) –S(O2)C1-C6 alkyl; (iii) C3-C6 cycloalkyl optionally substituted with hydroxyl or C1-C6 alkoxy; (iv) –(C=O)C1-C6 alkyl; (v) –(C=O)OC1-C6 alkyl; (vi) 4-8 membered heterocyclyl optionally substituted with hydroxyl; or (vii) C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, hydroxyl, -NR9R10, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, and 4-8 membered heterocyclyl optionally substituted with –C(=O)C1-C6 alkyl or C1-C6 alkyl; (viii) –(C=O)5- or 6- membered heteroaryl optionally substituted with C1-C6 alkyl; R2is (i) hydrogen; 263 ACTIVE 712622340v1(ii) halogen; (iii) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from (a) hydroxyl; (b) halogen; (c) phosphate; (d) -NR11R12; (e) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl; (f) 5-6 membered heteroaryl optionally substituted with C1-C6 alky; (g) C3-C6 cycloalkyl optionally substituted with hydroxyl or hydroxyalkyl; (h) CO2H,; (i) C(O)R11; (j) C1-C6 alkoxy; or (k) oxo; (iv) C1-C6 haloalkoxy; (v) 4-10 membered heterocyclyloxy; (vi) –(C=O)NR11R12; (vii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR11R12; (viii) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or C1-C6 alkoxy; or (ix) –NR11R12; each R11and R12are independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, or C1-C6 hydroxyalkyl; R3is (i) C1-C6 thioalkyl;(iii)264 ACTIVE 712622340v1(iv) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; (v) C1-C6 alkyl optionally substituted with NR16R17or hydroxyl; (vi) -CO2H; (vii) -C(=O)NR16R17; (viii) C1-C6 alkoxy optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkoxy; (ix) hydrogen; (x) C1-C6 haloalkyl; (xi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xii) C1-C6 alkoxyalkyl, or (xiii) C1-C6 hydroxyalkyl; Z is O or NR4; R13is (i) C1-C6 haloalkyl, (ii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, (iii) C1-C6 alkyl optionally substituted with (a) C3-C6 cycloalkyl, (b) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, (c) hydroxyl, (d) C1-C6 alkoxy, or (e) 4-6 membered heterocyclyl optionally substituted with 4-6 membered heterocyclyl or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, (iv) C1-C6 alkoxyalkyl, (v) C1-C6 hydroxyalkyl, (vi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, or (vii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1- C6 alkoxy, (viii) -N(C1-C6 alkyl)2; R14and R15are each independently C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, or 265 ACTIVE 712622340v1R14and R15with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; R4is hydrogen or C1-C6 alkyl; and each R9and R10are each independently hydrogen, -(C=O)C1-C6 alkyl, or C1-C6 alkyl optionally substituted with oxo; each R16and R17are each independently hydrogen or C1-C6 alkyl, or R16and R17with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with hydroxyl.

[0235] In some embodiments, X and Y are each N and Z1is C.

[0236] In some embodiments, the RIPK2 inhibitor is a compound that has the structure of Formula (I-b):Formula (I-b) or a pharmaceutically acceptable salt thereof, wherein: R5is hydrogen; Ring A is phenyl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, or 4; each R1is independently: (i) C1-C6 alkoxy; (iii) C1-C6 alkoxyalkyl; (v) –N(R6)-S(O2)R7; (vi) –(C=O)NR6R7, -NR6(C=O)OR7, or –(C=O)OR7; (vii) halogen; (viii) cyano; (ix) hydroxyl; (xi) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl and 4-8 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl; (xii) C1-C6 haloalkyl; 266 ACTIVE 712622340v1(xiii) C1-C6 haloalkoxy; (xvi) –S(O2)C1-C6 alkyl; each R6is independently hydrogen or C1-C6 alkyl; each R7is independently: (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from: (a) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (b) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, C1-C6 alkoxy,C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and cyano; (c) -NR6R7; (d) hydroxyl; (e) halogen; (f) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3- C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1- C6 alkyl; (g) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen, cyano,C1-C6 alkyl, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with –(C=O)OC1-C6 alkyl; (ii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl; or R6and R7with the atom to which they are attached together form a 5-12 membered heterocyclyl or 9-10 membered heteroaryl each optionally substituted with phenyl; R2is (i) hydrogen; (ii) halogen; or (iii) C1-C6 alkoxy; R3is267 ACTIVE 712622340v1(ii) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; or (iii) C1-C6 haloalkyl; wherein Z is O; R13is (i) C1-C6 haloalkyl; (ii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl; or (iii) C1-C6 alkyl.

[0237] In some embodiments, Ring A is 5-6 membered heteroaryl. In some embodiments, Ring A is selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and pyridonyl. In some embodiments, Ring A is phenyl.

[0238] In some embodiments,selected from the group consisting of:268 ACTIVE 712622340v1

[0239] In some embodiments, the compound of Formula (I) has the structure of Formula (I-m):pharmaceutically acceptable salt thereof, wherein ring C is morpholine, N-methylmorpholine, pyrrolidinone, imidazole, or pyrrole. In some embodiments, ring C is morpholine. In some embodiments, ring C is N-methylmorpholine. In some embodiments, ring C is pyrrolidinone. In some embodiments, ring C is imidazole. In some embodiments, ring C is pyrrole.

[0240] In some embodiments, the compound of Formula (I) has the structure of Formula (In):or a pharmaceutically acceptable salt thereof, wherein: each R18, R19, and R20are independently: (i) C1-C6 alkoxyalkyl; (ii) –N(R6)-S(O2)R7; or (vii) halogen, wherein each R6is independently hydrogen or C1-C6 alkyl; and 269 ACTIVE 712622340v1each R7is independently (i) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (ii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3- C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1- C6 alkyl; or (ii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl.

[0241] In some embodiments, the compound of Formula (I) has the structure of Formula (I-o):Formula (I-o), or a pharmaceutically acceptable salt thereof, wherein: each R18, R19, and R20are independently C1-C6 alkoxyalkyl, –N(R6)-S(O2)R7, or halogen; each R6is independently hydrogen or C1-C6 alkyl; and each R7is independently C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; or each R7is independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl; or each R7is independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl.

[0242] In some embodiments, compound of Formula (I) has the structure of Formula (I-p): 270 ACTIVE 712622340v1Formula (I-p), or a pharmaceutically acceptable salt thereof, wherein: each R18, R19, and R20are independently: (i) C1-C6 alkoxyalkyl; (ii) –N(R6)-S(O2)R7; or (vii) halogen, wherein each R6is independently hydrogen or C1-C6 alkyl; and each R7is independently (i) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (ii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3- C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1- C6 alkyl; or (ii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl. Q is -NH(SO2)- or -NH(C1-C6 alkyl)-; and R26, R27, and R28are each independently hydrogen, C1-C6 alkyl, or C1-C6 hydroxyalkyl, wherein at least one of R26, R27, and R28is hydrogen.

[0243] In some embodiments of Formula (I-p), R20is fluoro or methoxy and R20is fluoro or methoxy. In some embodiments of Formula (I-p), R19is methoxy and R20is fluoro or methoxy. In some embodiments of Formula (I-p), R19is methoxy and R20is fluoro.

[0244] In some embodiments of Formula (I-p), R26is hydrogen or methyl and R27and R28are each hydrogen. In some embodiments of Formula (I-p), R26is methyl.

[0245] In some embodiments of Formula (I-p), Q is -NH(SO2)-, wherein the nitrogen atom is connected to the phenyl ring of Formula (I-p) and the sulfur atom is attached to the pyrazole ring of Formula (I-p). 271 ACTIVE 712622340v1

[0246] In some embodiments of Formula (I-p), Q is -NH(C1-C6 alkyl)-, wherein the nitrogen atom is connected to the phenyl ring of Formula (I-p) and a carbon atom is attached to the pyrazole ring of Formula (I-p).

[0247] Specific embodiments of RIPK2 inhibitors for the various methods, kits, and compositions described herein, including Sections 3, 5 (including in the paragraphs of Section 5.2), and 7, are provided in Table 5, which are further described, including the methods of synthesis for each and the methods of use, in International Application No. PCT / US2024 / 033121, which is incorporated herein in its entirety. Table 5. Exemplary small molecule RIPK2 inhibitors of Formula (I) 272 ACTIVE 712622340v1273 ACTIVE 712622340v1274 ACTIVE 712622340v1275 ACTIVE 712622340v1276 ACTIVE 712622340v1277 ACTIVE 712622340v1Ex.No.Structure Name2-((6-(tert- butylsulfonyl)- 3-(6-fluoro- 1H- 52 pyrrolo[2,3- b]pyridin-5- yl)imidazo[1,2 -a]pyridin-7- yl)oxy)ethan- 1-ol 2-((6-(tert- butylsulfonyl)- 3-(1H- pyrrolo[2,3- 53 b]pyridin-5- yl)imidazo[1,2 -a]pyridin-7- yl)oxy)ethan- 1-ol 3-((3-(6- amino-2,5- difluoropyridin -3-yl)-6-(tert- 54 butylsulfonyl)i midazo[1,2- a]pyridin-7- yl)oxy)-2,2- difluoropropan -1-ol 3-((3-(6- amino-2,5- difluoropyridin -3-yl)-6-(tert- 55 butylsulfonyl)i midazo[1,2- a]pyridin-7- yl)oxy)propan e-1,2-diol (1-(((3-(6- amino-2,5- difluoropyridin -3-yl)-6-(tert- 56 butylsulfonyl)i midazo[1,2- a]pyridin-7- yl)oxy)methyl) cyclopropyl)m ethanol278 ACTIVE 712622340v1279 ACTIVE 712622340v1280 ACTIVE 712622340v1281 ACTIVE 712622340v1282 ACTIVE 712622340v1283 ACTIVE 712622340v1284 ACTIVE 712622340v1285 ACTIVE 712622340v1286 ACTIVE 712622340v1287 ACTIVE 712622340v1288 ACTIVE 712622340v1289 ACTIVE 712622340v1290 ACTIVE 712622340v1291 ACTIVE 712622340v1292 ACTIVE 712622340v1293 ACTIVE 712622340v1294 ACTIVE 712622340v1295 ACTIVE 712622340v1296 ACTIVE 712622340v1297 ACTIVE 712622340v1298 ACTIVE 712622340v1299 ACTIVE 712622340v1300 ACTIVE 712622340v1301 ACTIVE 712622340v1302 ACTIVE 712622340v1303 ACTIVE 712622340v1304 ACTIVE 712622340v1

[0248] In some emdodiments, the RIPK2 inhibitor has the structure of Formula (II):Formula (II), or a pharmaceutically acceptable salt thereof, wherein: R22is selected fromR6is hydrogen or C1-C6 alkyl; R7is selected from: (i) C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from: (a) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (b) phenyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and cyano; (c) hydroxyl; (d) halogen; (e) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl; and (f) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen, cyano,C1-C6 alkyl, and C1-C6 alkoxy; (ii) C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, phenyl optionally substituted with 1-2 independently selected halogen and 5-10 membered heteroaryl; (iii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl; (iv) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, and C1-C6 haloalkyl; (v) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl;305 ACTIVE 712622340v1(vi) C1-C6 alkoxy; or (vii) C3-C6 cycloalkoxy; or R6and R7with the atom to which they are attached together form a 5-12 membered heterocyclyl or 9-10 membered heteroaryl each optionally substituted with phenyl; and R23is C1-C3 alkyl or C3-C4 cycloalkyl.

[0249] In some embodiments, the RIPK2 inhibitor has the structure of Formula (IV):Formula (IV) or a pharmaceutically acceptable salt thereof, wherein: X2is N and X3is CH or X2is CH and X3is N; R2is: (i) hydrogen; (ii) halogen; (iii) C1-C6 alkoxy; (iv) C1-C6 haloalkoxy; (v) –(C=O)NR11R12; or (vi) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR11R12; each R11and R12are independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, or C1-C6 hydroxyalkyl; R3is: (i) C1-C6 thioalkyl;(iii) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; (vi) -C(=O)NR16R17; (v) hydrogen; 306 ACTIVE 712622340v1(vi) C1-C6 haloalkyl; (vii) C1-C6 alkoxyalkyl; or (viii) C1-C6 hydroxyalkyl; Z is O; R13is (i) C1-C6 haloalkyl; (ii) C3-C6 cycloalkyl; (iii) C1-C6 alkyl, (iv) C1-C6 alkoxyalkyl; (v) C1-C6 hydroxyalkyl; or (vi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1- C6 alkoxy; each R16and R17are each independently hydrogen or C1-C6 alkyl, or R16and R17with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with hydroxyl; R24is C1-3alkyl or Cl; and R25is hydrogen or F.

[0250] In some embodiments, the RIPK2 inhibitor a compound that is described in Example 1 to Example 304 of WO2024254539A1, which is herein incorporated by reference for such compound.

[0251] In some embodiments, the compound is: N-(3-fluoro-5-(6-(4-hydroxytetrahydro-2H-pyran-4-yl)-7-methoxyimidazo[1,2- a]pyridin-3-yl)-2-methoxyphenyl)propane-1-sulfonamide; N-(3-chloro-5-(6-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)-7-methoxyimidazo[1,2- a]pyridin-3-yl)-2-methoxyphenyl)ethanesulfonamide; N-(3-chloro-5-(6-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)-7-methoxyimidazo[1,2- a]pyridin-3-yl)-2-methoxyphenyl)propane-1-sulfonamide; N-(5-(5-(tert-butylsulfonyl)-6-(2-hydroxyethoxy)pyrazolo[1,5-a]pyridin-3-yl)-3- fluoro-2-methoxyphenyl)ethanesulfonamide; N-(5-(5-(4,4-dimethyl-2-oxooxazolidin-3-yl)-6-methoxypyrazolo[1,5-a]pyrimidin-3- yl)-3-fluoro-2-methoxyphenyl)ethanesulfonamide; 307 ACTIVE 712622340v1N-(3-fluoro-5-(5-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)-6-methoxypyrazolo[1,5- a]pyridin-3-yl)-2-methoxyphenyl)propane-1-sulfonamide;; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- (methoxy-d3)phenyl)-1-(oxetan-3-yl)methanesulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-1-methyl-1H-pyrazole-3-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide; N-(3-fluoro-2-methoxy-5-(7-methoxy-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3- yl)phenyl)-1-methyl-1H-pyrazole-4-sulfonamide; N-(3-fluoro-2-methoxy-5-(7-methoxy-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3- yl)phenyl)-1H-pyrazole-4-sulfonamide; N-(5-(7-ethoxy-6-(isopropylsulfonyl)imidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-1-methyl-1H-pyrazole-4-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-1,3,5-trimethyl-1H-pyrazole-4-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-1H-pyrazole-4-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)pyridine-3-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)oxetane-3-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-2,2,2-trifluoroethane-1-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-2,3- dimethoxyphenyl)ethenesulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)cyclobutanesulfonamide; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3- yl)phenyl)cyclopropanesulfonamide; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)phenyl)tetrahydro- 2H-pyran-4-sulfonamide; 308 ACTIVE 712622340v1N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3- yl)phenyl)tetrahydrofuran-3-sulfonamide; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)phenyl)-1- methylcyclopropane-1-sulfonamide; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)phenyl)oxetane-3- sulfonamide; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)phenyl)-1- cyclopropylmethanesulfonamide; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3- yl)phenyl)cyclobutanesulfonamide; tert-butyl 3-(N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3- yl)phenyl)sulfamoyl)pyrrolidine-1-carboxylate; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3- yl)phenyl)pyrrolidine-3-sulfonamide; tert-butyl 3-(N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3- yl)phenyl)sulfamoyl)azetidine-1-carboxylate; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)phenyl)azetidine- 3-sulfonamide; tert-butyl 4-(N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3- yl)phenyl)sulfamoyl)piperidine-1-carboxylate; N-(3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)phenyl)piperidine- 4-sulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-1-cyclopropylmethanesulfonamide; N-(5-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-3-fluoro-2- methoxyphenyl)-1-(oxetan-3-yl)methanesulfonamide; or a pharmaceutically acceptable salt thereof.

[0252] In some embodiments, the compound is described in Example 1 to Example 193 of WO2024254533A1, which is incorporated by reference for such compounds.

[0253] In some embodiments, the compound is: (S)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-(1- (1-methyl-1H-pyrazol-3-yl)ethyl)-1H-pyrazole-5-carboxamide; 309 ACTIVE 712622340v1(R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-(1- (pyridin-2-yl)propyl)-1H-pyrazole-5-carboxamide; (S)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N- (2,2,2-trifluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(6,7-dihydro- 5H-cyclopenta[b]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide; (S)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(6,7-dihydro- 5H-cyclopenta[b]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((3- methylpyridin-2-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N- (pyrimidin-2-ylmethyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-(pyrazin- 2-ylmethyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N- (pyrimidin-4-ylmethyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N- (pyridazin-3-ylmethyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((1- methyl-1H-pyrazol-5-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-((3-chloropyridin- 2-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-((3- methoxypyridin-2-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(2- methoxybenzyl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(2- (hydroxymethyl)benzyl)-1-methyl-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)-N-(1- (2-methoxyphenyl)ethyl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((1- methyl-1H-imidazol-2-yl)methyl)-1H-pyrazole-5-carboxamide; 310 ACTIVE 712622340v13-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((5- methyl-1,2,4-oxadiazol-3-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((3- methyl-1,2,4-oxadiazol-5-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((4- methylpyrimidin-2-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-ethyl-N-(pyrimidin- 2-ylmethyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((1- methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-((3-cyanopyridin- 2-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(2-cyanobenzyl)-1- methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-(thiazol- 2-ylmethyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-(thiazol- 4-ylmethyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(isothiazol-3- ylmethyl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((5- methylisothiazol-3-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((4- methylthiazol-2-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((5- methylthiazol-2-yl)methyl)-1H-pyrazole-5-carboxamide; N-((1,2,4-thiadiazol-3-yl)methyl)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2- a]pyridin-3-yl)-1-methyl-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-((5- methyl-1,2,4-thiadiazol-3-yl)methyl)-1H-pyrazole-5-carboxamide; 3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-((4,5- dimethylthiazol-2-yl)methyl)-1-methyl-1H-pyrazole-5-carboxamide; 311 ACTIVE 712622340v1(R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-(1- (thiazol-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)-1- methyl-N-(1-(thiazol-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-ethyl-N-(1- (pyridin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-ethyl-N-(1- (pyrimidin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-ethyl-N-(1-(3- fluoropyridin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-ethyl-N-(1- (thiazol-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-cyclopropyl-N- (1-(pyridin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-cyclopropyl-N- (1-(pyrimidin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-isopropyl-N-(1- (pyridin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-isopropyl-N-(1- (pyrimidin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-methyl-N-(1- (pyrimidin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-N-(1-(5- fluoropyrimidin-2-yl)ethyl)-1-methyl-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-(2- methoxyethyl)-N-(1-(pyridin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-(2,2-difluoro-3- hydroxypropyl)-N-(1-(pyridin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-methoxyimidazo[1,2-a]pyridin-3-yl)-1-(2,2-difluoro-3- hydroxypropyl)-N-(1-(pyrimidin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; (R)-3-(6-(tert-butylsulfonyl)-7-(2-hydroxyethoxy)imidazo[1,2-a]pyridin-3-yl)-1- methyl-N-(1-(pyrimidin-2-yl)ethyl)-1H-pyrazole-5-carboxamide; or a pharmaceutically acceptable salt thereof. 312 ACTIVE 712622340v1

[0254] In some embodiments, the RIPK2 inhibitor has one of the following structures: , ,pharmaceutically acceptable salt thereof.

[0255] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0256] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof. 313 ACTIVE 712622340v1

[0257] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0258] In some embodiments, the RIPK2 inhibitor has the following structure:

[0259] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0262] In some embodiments, the RIPK2 inhibitor has one of the following structures: 314 ACTIVE 712622340v1pharmaceutically acceptable salt thereof.

[0263] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0264] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0265] In some embodiments, the RIPK2 inhibitor has the following structure: 315 ACTIVE 712622340v1

[0267] In some embodiments, the RIPK2 inhibitor has the following structure:

[0269] In some embodiments, the RIPK2 inhibitor is a compound disclosed in TABLE 1 of U.S. Patent No.10,138,241, which is herein incorporated by reference for such compounds.

[0270] In some embodiments, the RIPK2 inhibitor is: 3-{4-[5-(cyclopropylcarbamoyl)-4-fluoro-2- methylphenyl]-1H-pyrazol-1-yl}-7- methoxy- N,N-dimethylimidazo[1,2-a]pyridine-6- carboxamide; 316 ACTIVE 712622340v1methyl 3-{4-[5-(cyclopropylcarbamoyl)-4- fluoro-2-methylphenyl]-1H-pyrazol-1- yl}imidazo[1,2-a]pyridine-6-carboxylate; 3-{4-[5-(cyclopropylcarbamoyl)-2- methylphenyl]-1H-imidazol-1-yl}-N- methylimidazo[1,2-a]pyridine-6- carboxamide; 4-chloro-N-cyclopropyl-2-fluoro-5-(1- {imidazo[1,2-a]pyridin-3-yl}-1H-pyrazol- 4- yl)benzamide; 4-chloro-N-cyclopropyl-2-fluoro-5-(1- {imidazo[1,2-a]pyrazin-3-yl}-1H-pyrazol- 4- yl)benzamide; 4-chloro-N-cyclopropyl-2-fluoro-5-(1-{6- methoxyimidazo[1,2-a]pyrazin-3-yl}-1H- pyrazol-4-yl)benzamide; 4-chloro-N-cyclopropyl-2-fluoro-5-{1-[6- (2-methylpropane-2-sulfonyl)imidazo[1,2- a]pyridin-3-yl]-1H-pyrazol-4-yl}benzamide; N-cyclopropyl-3-(1-{imidazo[1,2-a]pyridin- 3-yl}-1H-pyrazol-4-yl)-4- methylbenzamide; N-cyclopropyl-4-methyl-3-{1-[6-(2- methylpropane-2-sulfonyl)imidazo[1,2- a]pyridin-3-yl]-1H-pyrazol-4-yl}benzamide; 4-chloro-N-cyclopropyl-2-fluoro-5-(1-{6- methanesulfonylimidazo[1,2-a]pyridin-3- yl}-1H-pyrazol-4-yl)benzamide; N-cyclopropyl-3-{1-[6-(ethanesulfonyl)-7- methoxyimidazo[1,2-a]pyridin-2-yl]-1H- pyrazol-4-yl}-4-methylbenzamide; N-cyclopropyl-3-{1-[7-methoxy-6-(2- methylpropane-2-sulfonyl)imidazo[1,2- a]pyridin-3-yl]-1H-pyrazol-4-yl}-4- methylbenzamide; N-cyclopropyl-2-fluoro-4-methyl-5-{1-[6- (morpholine-4-sulfonyl)imidazo[1,2- a]pyridin-3-yl]-1H-pyrazol-4-yl} benzamide; N-cyclopropyl-4-methyl-3-{1-[6- (morpholine-4-sulfonyl)imidazo [1,2-a]pyridin-3- yl]-1H- pyrazol-4-yl}benzamide; N-cyclopropyl-4-methyl-3-(1-{6-[(4- methylpiperazin-1-yl)sulfonyl]imidazo [1,2- a]pyridin-3-yl}-1H-pyrazol-4-yl) benzamide; N-cyclopropyl-4-methyl-3-{1-[6- (oxetane-3-sulfonyl)imidazo[1,2-a] pyridin-3-yl]- 1H-pyrazol-4-yl} benzamide; N-cyclopropyl-3-{1-[7-hydroxy-6-(2- methylpropane-2-sulfonyl)imidazo [1,2- a]pyridin-2-yl]-1H-pyrazol-4- yl}-4-methylbenzamide; 317 ACTIVE 712622340v13-{1-[6-(azetidine-3-sulfonyl)imidazo [1,2-a]pyridin-3-yl]-1H-pyrazol-4-yl}- N- cyclopropyl-4-methylbenzamide; N-cyclopropyl-4-methyl-3-{1-[6- (piperidine-4-sulfonyl)imidazo[1,2-a] pyridin-3-yl]- 1H-pyrazol-4-yl}benzamide; N-cyclopropyl-2-fluoro-5-[1-(6-{4- fluoro-1-methylpiperidin-4-yl}-7- methoxyimidazo[1,2-a]pyridin-3-yl)- 1H-pyrazol-4-yl]-4-methylbenzamide; N-Cyclopropyl-5-{1-[7-ethoxy-6-(4- fluoro-1-methyl-piperidin-4-yl)- imidazo[1,2- a]pyridin-3-yl]-1H-pyrazol- 4-yl}-2-fluoro-4-methyl-benzamide; N-Cyclopropyl-2-fluoro-4-methyl-5-{1- [6-(1-methyl-azetidin-3-yl)-imidazo [1,2- a]pyridin-3-yl]-1H-pyrazol-4-yl}- benzamide N-Cyclopropyl-2-fluoro-5-{1-[6-(4- fluoro-1-methyl-piperidin-4-yl)-7- methoxy- imidazo[1,2-a]pyridin-3-yl]- 1H-imidazol-4-yl}-4-methyl-benzamide; or N-Cyclopropyl-5-{1-[6-(1-ethyl-4- fluoro-piperidin-4-yl)-7-methoxy- imidazo[1,2- a]pyridin-3-yl]-1H- pyrazol-4-yl}-2-fluoro-4-methyl- benzamide; or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the RIPK2 inhibitor has one of the following structures:,, 318 ACTIVE 712622340v1

[0272] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable saltthereof.

[0274] In some embodiments, the RIPK2 inhibitor has the following structure:thereof.

[0275] In some embodiments, the RIPK2 inhibitor has the following structure: 319 ACTIVE 712622340v1thereof.

[0276] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the RIPK2 inhibitor has the following structure:pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the RIPK2 inhibitor is described in International Patent Application No. PCT / EP2021 / 052255, which is incorporated herein by reference for such RIPK2 inhibitor.

[0279] In some embodiments, the RIPK2 inhibitor is a compound of any one of Examples 1-146 from International Patent Application No. PCT / EP2021 / 052255, which is incorporated herein by reference for such compounds. In some embodiments, the RIPK2 inhibitor is the compound of Example 1 from International Patent Application No. PCT / EP2021 / 052255, which is incorporated herein by reference for such compound. In some embodiments, the RIPK2 inhibitor is the compound of Example 3 from International Patent Application No. PCT / EP2021 / 052255, which is incorporated herein by reference for such compound. In some embodiments, the RIPK2 inhibitor is the compound of Example 54 from International Patent Application No. PCT / EP2021 / 052255, which is incorporated herein by reference for such compound. In some embodiments, the RIPK2 inhibitor is the compound of Example 55 from International Patent Application No. PCT / EP2021 / 052255, which is 320 ACTIVE 712622340v1incorporated herein by reference for such compound. In some embodiments, the RIPK2 inhibitor is the compound of Example 67 from International Patent Application No. PCT / EP2021 / 052255, which is incorporated herein by reference for such compound. In some embodiments, the RIPK2 inhibitor is the compound of Example 79 from International Patent Application No. PCT / EP2021 / 052255, which is incorporated herein by reference for such compound.

[0280] In some embodiments, the RIPK2 inhibitor is: (12R,14S)-4-fluoro-12,18-dimethoxy-16-oxa-7,10,20,21 ,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1 (23),2(25),3,5,17(24),18,21- heptaen- 11-one; (12R,14S)-12,18- dimethoxy-4- (trifluoromethyl)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one (12R,14S)-4-fluoro-12- methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4-chloro-12-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4,12- dimeth oxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4,12- dimeth oxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-12-ethoxy-4- methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-4-ethoxy-12- methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; 321 ACTIVE 712622340v1(12R,14S)-12-methoxy-4- (propan-2-yloxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1 (23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-4-fluoro-12- (propan-2-yloxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-12- cyclobutoxy-4-fluoro-16- oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-12- (cyclopropylmethoxy)-4- fluoro-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-12-methoxy11-oxo-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaene-4- carbonitrile; (12R,14S)-4- (difluoromethoxy)-12- methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-4-(benzyloxy)- 12-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-3,4-difluoro-12-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-4-methoxy-12- (propan-2-yloxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-12-ethoxy-4- fluoro-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-12-ethoxy-4- fluoro-18-methyl-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; 322 ACTIVE 712622340v1(12R,14S)-4,12- dimethoxy-18-methyl-16- oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4-chloro-12- ethoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-12- (cyclopropylmethoxy)-4- methoxy-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-12-ethoxy-11- oxo-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaene-4- carbonitrile; (12R,14S)-4-chloro-12- methoxy-18-methyl-16- oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12S,14S)-4-fluoro-12- methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4,12-dilluoro16-oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-5-fluoro-4,12- dimeth oxy-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-4,12-diethoxy16-oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4,5-difluoro-12- methoxy-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentaco sa-1(23),2(25),3,5,17(24), 18,21- heptaen-11-one; (12R,14S)-4-fluoro-12- methoxy-18-methyl-16- oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; 323 ACTIVE 712622340v1E1-(12R,14S)-4-fluoro-12- (methoxymethyl)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; E2-(12S,14S)-4-fluoro-12- (methoxymethyl)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4-fluoro-12- methoxy-18- (methoxymethyl)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4,18-difluoro12-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4-fluoro-12-(2- methoxyethoxy)-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-4-fluoro-12- (2H3)methoxy-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-12- (2H3)methoxy-4-methoxy16-oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-4-chloro-12- (propan-2-yloxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (2Z,2E,5S,5R)-5- ethoxy-1'-methoxy-2'- methyl-3-oxa-8-aza2(3,5)-pyrazolo[1,5- a]pyrimidine-5(2,1)- pyrrolidina-1(1,3)- benzenacyclooctaphan5'-one; (12R,14S)-12-ethoxy-4- methoxy-18-methyl-16- oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R,14S)-12-methoxy-4- (1H-pyrazol-1-yl)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; 324 ACTIVE 712622340v1(12R,14S)-12-methoxy18-methyl-4-(1 H-pyrazol1-yl)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18, 21- heptaen-11-one; (12R,14S)-4-(4-iodo-5- methyl-1H-pyrazol-1-yl)- 12-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pen tacosa1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; E1-(12R,14S)-4-fluoro-12- methoxy-14-methyl-16- oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18,21- heptaen-11-one; E2-(12R,14R)-4-fluoro-12- methoxy-14-methyl-16- oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18,21- heptaen-11-one; (12R,14R)-12-ethoxy-4- methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-4-(1-[2-[(tertbutyldiphenylsilyl)oxy]ethyl )-1H-pyrazol-4-yl)-12- methoxy-16- oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]penta cosa1(23),2,4,6(25),17(24),18,21-heptaen-11-one; E1-(12R,14S,15R*)-4- fluoro-12-methoxy-15- methyl-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-4-cyclopropyl12-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-4- (difluo ro methoxy)-12-(2- methoxyethoxy)-16-oxa7,10,20,21,24- penta aza pentacyclo [15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11- one (12R,14S)-12-(2- methoxyethoxy)-11-oxo16-oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaene-4-carbonitrile; (12R,14S)-4-chloro-12-(2- methoxyethoxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; 325 ACTIVE 712622340v1(12R,14S)-4,18- dimethoxy-12-(2- methoxyethoxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-4-ethynyl-12-(2- methoxyethoxy)-16-oxa7,10,20,21,24- penta aza pentacyclo [15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18,21-heptaen-11-one; (12S,14S)-12-ethoxy-4-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-4-fluoro-18- methoxy-12-(2- methoxyethoxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-18-methoxy-12- (2-methoxyethoxy)-11-oxo16-oxa-7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaene-4-carbonitrile; (12R,14S)-4-ethyl-12- methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18, 21- heptaen-11-one; (12R, 14S)-12-methoxy-4-(pyridin-3-ylmethoxy)-16-oxa-7, 10,20,21 ,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1 (23),2(25),3,5,17(24),18,21- heptaen- 11-one; (12R,14S)-4- (cyclopropylmethoxy)-12- methoxy-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-12-methoxy-4- [(1-methyl-1H-pyrazol-4- yl)methoxy]-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-4-methoxy-12- (2-meth oxyethoxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2(25),3,5,17(24),18,21- heptaen-11-one; (12R,14S)-4- (cyclopropylmethoxy)-12- methoxy-18-methyl-16-oxa7, 10,20,21, 24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; 326 ACTIVE 712622340v1(12R,14S)-12-methoxy-18- methyl-4-(pyridin-3- ylmethoxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-12-methoxy-18- methyl-4-(oxolan-3-ylmethoxy)-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-12-methoxy-18- methyl-4-[(1-methyl-1Hpyrazol-4-yl)methoxy]-16- oxa- 7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa- 1(23),2,4,6(25),17(24),18,21-heptaen-11-one; (12R,14S)-4-(2H3)methoxy12-methoxy-16-oxa7,10,20,21,24- pentaazapentacyclo[15.5.2.12,6.01°,14.02°,23]pentacosa-1(23),2,4,6(25),17(24),18,21- heptaen-11-one; (12R,14S)-4,12-...

Claims

CLAIMS WHAT IS CLAIMED:

1. A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), wherein the subject is determined to have a presence of a combination of genotypes selected from the polymorphisms of Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

2. A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), wherein the subject comprises a combination of genotypes.

3. A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), wherein the subject comprises a combination of genotypes, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

4. A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), wherein the subject tested positive for a presence of a combination of genotypes in a biological sample obtained from the subject.

5. A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), wherein the subject tested positive for a presence of a combination of genotypes in a biological sample obtained from the subject, 410 ACTIVE 712622340v1wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an R2of at least 0.

80.

6. A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: administering to the subject a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), wherein the subject is identified based on a presence of a combination of genotypes identified in a biological sample obtained from the subject, wherein the combination of genotypes is predictive of an increased expression level or increased signaling level of RIPK2, wherein the increased expression level or increased signaling level of RIPK2 is relative to a baseline expression or signaling level of RIPK2 in subjects not suffering from the inflammatory, fibrotic, or fibrostenotic disease or condition, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

7. A method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of genotypes; (b) selecting a subject determined to have the presence of the combination of genotypes in (a), wherein the presence of the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.80; and (c) administering a therapeutically effective amount of the RIPK2 inhibitor to the subject selected in (b).

8. A method of determining presence of a combination of genotypes in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: 411 ACTIVE 712622340v1(a) contacting genetic materials in a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition with one or more nucleic acid primer pairs having forward and reverse primers suitable for hydridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of a combination of genotypes; (b) amplifying the target nucleic acid sequences by polymerase chain reactions with the nucleic acid primer pairs of (a); (c) analysing the results of (b) to determine the presence in the target nucleic acid sequences of the combination of genotypes of step (a), wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

9. The method of any one of claims 6 to 8, wherein the increased expression level or increased signaling level of RIPK2 comprises: (i) increased level of RIPK2 mRNA; (ii) increased level of RIPK2 protein; (iii) increased level of NOD2 protein; (iv) increased level of NOD2 mRNA; (v) increased level of CARD9 protein; (vi) increased level of CARD9 mRNA; or (vii) any combination of 1, 2, 3, 4, 5, or 6 features selected from (i) to (vi).

10. The method of claim 9, wherein the increased level of RIPK2 mRNA is increased level of RIPK2 mRNA in the diseased tissue as compared to level of RIPK2 mRNA in a healthy tissue of the subject or as compared to level of RIPK2 mRNA in a healthy subject.

11. The method of claim 9 or 10, wherein the increased level of NOD2 mRNA is increased level of NOD2 mRNA in the diseased tissue as compared to level of NOD2 mRNA in a healthy tissue of the subject or as compared to level of NOD2 mRNA in a healthy subject. 412 ACTIVE 712622340v112. The method of any one of claims 9 to 11, wherein the increased level of RIPK2 protein is increased level of RIPK2 protein in the diseased tissue of the subject as compared to level of RIPK2 protein in a healthy tissue of the subject or as compared to level of RIPK2 protein in a healthy subject.

13. The method of any one of claims 9 to 12, wherein the increased level of NOD2 protein is increased level of NOD2 protein in the diseased tissue of the subject as compared to level of NOD2 protein in a healthy tissue of the subject or as compared to level of NOD2 protein in a healthy subject.

14. The method of any one of claims 1 to 13, wherein the method further comprises preparing DNA from the sample.

15. A method of treating an inflammatory, a fibrotic, or a fibrostenotic disease or condition in a subject, the method comprising: (a) determining whether the subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition is suitable for treatment with an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor) by: (i) obtaining or having obtained a sample from the subject; (ii) subjecting the sample to an assay adapted to detect a combination of genotypes, wherein the subject is determined to be suitable for treatment with the RIPK2 inhibitor if the combination of genotypes are detected; and (b) treating the subject by administering a therapeutically effective amount of the RIPK2 inhibitor to the subject, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

16. A method of selecting a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with a therapeutically effective amount of an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), the method comprising: (a) providing a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition to determine presence of a combination of 413 ACTIVE 712622340v1genotypes; (b) selecting a subject determined to have the presence of the combination of genotypes in (a), wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.80; and (c) administering a therapeutically effective amount of the RIPK2 inhibitor to the subject selected in (b).

17. A method of determining a combination of genotypes for a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; and (c) determining the combination of genotypes for the subject; wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

18. A method of determining presence of a combination of genotypes in a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition, the method comprising: (a) contacting genetic materials in a biological sample from a subject having an inflammatory, a fibrotic, or a fibrostenotic disease or condition with one or more nucleic acid primer pairs having forward and reverse primers suitable for hydridizing to one or more target nucleic acid sequences, the one or more target nucleic acid sequences collectively comprising chromosome positions of a combination of genotypes; (b) amplifying the target nucleic acid sequences by polymerase chain reactions with the nucleic acid primer pairs of (a); and (c) analysing the results of (b) to determine the presence in the target nucleic acid sequences of the combination of genotypes of step (a), wherein the combination of genotypes comprises one or more polymorphisms 414 ACTIVE 712622340v1selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

19. A method of selecting a subject with an inflammatory, a fibrotic, or a fibrostenotic disease or condition for treatment with an inhibitor of RIPK2 activity or expression (a RIPK2 inhibitor), the method comprising: (a) obtaining or having obtained a sample from the subject; (b) subjecting the sample to an assay adapted to detect a combination of genotypes; (c) selecting the subject for treatment with the RIPK2 inhibitor if the combination of genotypes are detected, wherein the combination of genotypes comprises one or more polymorphisms selected from Table 1 and any proxy polymorphism in linkage disequilibrium with any of the polymorphisms of Table 1 as determined with an r2of at least 0.

80.

20. The method of any one of claims 1, 3, and 5 to 19, wherein the linkage disequilibrium is linkage disequilibrium with an r2value of about 0.8, about 0.85, about 0.9, about 0.95, about 1, at least 0.80, at least 0.85, at least 0.90, or at least 0.

95.

21. The method of any one of claims 1, 3, and 5 to 20, wherein the Table 1 is Table 1 Part I.

22. The method of any one of claims 1, 3, and 5 to 20, wherein the Table 1 is Table 1 Part II.

23. The method of any one of claims 1, 3, and 5 to 20, wherein the Table 1 is Table 1 Part III.

24. The method of any one of claims 1, 3, and 5 to 20, wherein the Table 1 is Table 1 Part IV.

25. The method of any one of claims 1, 3, and 5 to 20, wherein the Table 1 is Table 1 Part V. 415 ACTIVE 712622340v126. The method of any one of claims 1 to 25, wherein the expression level or signaling level of RIPK2 comprises: (i) increased level of RIPK2 mRNA; (ii) increased level of RIPK2 protein; (iii) increased level of NOD2 protein; (iv) increased level of NOD2 mRNA; (v) increased level of CARD9 protein; (vi) increased level of CARD9 mRNA; or (vii) any combination of 1, 2, 3, 4, 5, or 6 features selected from (i) to (vi).

27. The method of claim 26, wherein (i) the increased level of RIPK2 mRNA is increased level of RIPK2 mRNA in the diseased tissue as compared to level of RIPK2 mRNA in a healthy tissue of the subject or as compared to level of RIPK2 mRNA in a healthy subject; (ii) the increased level of RIPK2 protein is increased level of RIPK2 protein in the diseased tissue of the subject as compared to level of RIPK2 protein in a healthy tissue of the subject or as compared to level of RIPK2 protein in a healthy subject; (iii) the increased level of NOD2 mRNA is increased level of NOD2 mRNA in the diseased tissue as compared to level of NOD2 mRNA in a healthy tissue of the subject or as compared to level of NOD2 mRNA in a healthy subject; (iv) the increased level of NOD2 protein is increased level of NOD2 protein in the diseased tissue of the subject as compared to level of NOD2 protein in a healthy tissue of the subject or as compared to level of NOD2 protein in a healthy subject; (v) the increased level of CARD9 mRNA is increased level of CARD9 mRNA in the diseased tissue as compared to level of CARD9 mRNA in a healthy tissue of the subject or as compared to level of CARD9 mRNA in a healthy subject; (vi) the increased level of CARD9 protein is increased level of CARD9 protein in the diseased tissue of the subject as compared to level of CARD9 protein in a healthy tissue of the subject or as compared to level of CARD9 protein in a healthy subject; or (vii) any combination of 1, 2, 3, 4, 5, or 6 features selected from (i) to (vi).

28. The method of any one of claims 1 to 27, wherein the combination of genotypes comprise at least two, at least three, at least four, at least five, at least six, at least 416 ACTIVE 712622340v1seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, or at least sixteen polymorphisms.

29. The method of any one of claims 1 to 28, wherein the combination of genotypes is detected in the sample by subjecting the sample to an assay configured to detect a presence of a nulceotide corresponding to nuleotide position 51 within the sequence of the polymorphisms listed in Table 2.

30. The method of any one of claims 1 to 29, wherein the inflammatory, fibrotic, or fibrostenotic disease or condition is inflammatory bowel disease.

31. The method of claim 30, wherein the inflammatory, fibrotic, or fibrostenotic disease or condition is ulcerative colitis or Crohn’s disease.

32. The method of claim 31, wherein the subject has been treated with an advanced IBD therapy prior to the treatment with the RIPK2 inhibitor.

33. The method of claim 31, wherein the subject has not been treated with an advanced IBD therapy prior to the treatment with the RIPK2 inhibitor.

34. The method of claim 32 or 33, wherein the advanced IBD therapy comprises one or more selected from the group consisting of a biologic therapeutic agent for IBD, an S1P1 modulator, or a JAK inhibitor.

35. The method of claim 34, wherein the biologic therapeutic agent for IBD comprises an anti-TNFα antibody, an anti-IL23 antibody, or an anti-integrin α4β7 antibody.

36. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound that has the structure of Formula (I): 417 ACTIVE 712622340v1Formula (I) or a pharmaceutically acceptable salt thereof, wherein: one or two of X, Y, and Z1is independently N and the other of X, Y, and Z1is C; each is a single bond or a double bond; R5is hydrogen, -NH2, or halogen; Ring A is phenyl or 5-10 membered heteroaryl; m is 0, 1, 2, 3, or 4; each R1is independently: (i) C1-C6 alkoxy optionally substituted with hydroxyl or phenyl; (ii) C1-C6 deuteroalkoxy; (iii) C1-C6 alkoxyalkyl; (iv) 5-6 membered heteroaryl; (v) –N(R6)-S(O2)R7; (vi) –(C=O)NR6R7, -NR6(C=O)OR7, or –(C=O)OR7; (vii) halogen; (viii) cyano; (ix) hydroxyl; (x) –NR6R8; (xi) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxyl and 4-8 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl; (xii) C1-C6 haloalkyl; (xiii) C1-C6 haloalkoxy; (xiv) C3-C6 cycloalkyl; (xv) 4-8 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, and -(C=O)OC1-C6 alkyl; (xvi) –S(O2)C1-C6 alkyl; (xvii) 4-10 membered heterocyclyloxy optionally substituted with acyl; 418 ACTIVE 712622340v1(xviii) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, and C1-C6 haloalkyl; each R6is independently hydrogen or C1-C6 alkyl; each R7is independently: (i) C1-C6 alkyl optionally substituted with 1-3 substituents selected from: (a) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (b) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, C1-C6 alkoxy,C1-C6 haloalkyl, C1-C6 hydroxyalkyl, and cyano; (c) -NR6R7; (d) hydroxyl; (e) halogen; (f) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3- C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1- C6 alkyl; (g) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen, cyano,C1-C6 alkyl, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with –(C=O)OC1-C6 alkyl; (ii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl; (iii) C3-C6 cycloalkyl optionally substituted with 1-2 substituents independently selected from C1-C6 alkyl and C1-C6 hydroxyalkyl; (iv) ethylenyl; (v) C1-C6 haloalkyl; (vi) 4-10 membered heterocyclyl optionally substituted with –(C=O)OC1-C6 alkyl; or (vii) phenyl optionally substituted with 1-3 substituents selected from halogen, C1-C6 alkyl, and –(C=O)NR6R7; or R6and R7with the atom to which they are attached together form a 5-12 membered heterocyclyl or 9-10 membered heteroaryl each optionally substituted with phenyl; R8is (i) hydrogen; (ii) –S(O2)C1-C6 alkyl; (iii) C3-C6 cycloalkyl optionally substituted with hydroxyl or C1-C6 alkoxy; 419 ACTIVE 712622340v1(iv) –(C=O)C1-C6 alkyl; (v) –(C=O)OC1-C6 alkyl; (vi) 4-8 membered heterocyclyl optionally substituted with hydroxyl; or (vii) C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from: halogen, hydroxyl, -NR9R10, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, phenyl optionally substituted with C1-C6 alkoxy, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, and 4-8 membered heterocyclyl optionally substituted with –C(=O)C1-C6 alkyl or C1-C6 alkyl; (viii) –(C=O)5- or 6- membered heteroaryl optionally substituted with C1-C6 alkyl; R2is (i) hydrogen; (ii) halogen; (iii) C1-C6 alkoxy optionally substituted with 1-3 substituents independently selected from (a) hydroxyl; (b) halogen; (c) phosphate; (d) -NR11R12; (e) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 alkoxyalkyl; (f) 5-6 membered heteroaryl optionally substituted with C1-C6 alky; (g) C3-C6 cycloalkyl optionally substituted with hydroxyl or hydroxyalkyl; (h) CO2H,; (i) C(O)R11; (j) C1-C6 alkoxy; or (k) oxo; (iv) C1-C6 haloalkoxy; (v) 4-10 membered heterocyclyloxy; (vi) –(C=O)NR11R12; (vii) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR11R12; 420 ACTIVE 712622340v1(viii) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or C1-C6 alkoxy; or (ix) –NR11R12; each R11and R12are independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, or C1-C6 hydroxyalkyl; R3is (i) C1-C6 thioalkyl;(iii)(iv) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; (v) C1-C6 alkyl optionally substituted with NR16R17or hydroxyl; (vi) -CO2H; (vii) -C(=O)NR16R17; (viii) C1-C6 alkoxy optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkoxy; (ix) hydrogen; (x) C1-C6 haloalkyl; (xi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl; (xii) C1-C6 alkoxyalkyl, or (xiii) C1-C6 hydroxyalkyl; Z is O or NR4; R13is (i) C1-C6 haloalkyl, (ii) C3-C6 cycloalkyl optionally substituted with C1-C6 alkyl, (iii) C1-C6 alkyl optionally substituted with (a) C3-C6 cycloalkyl, (b) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, (c) hydroxyl, (d) C1-C6 alkoxy, or 421 ACTIVE 712622340v1(e) 4-6 membered heterocyclyl optionally substituted with 4-6 membered heterocyclyl or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, (iv) C1-C6 alkoxyalkyl, (v) C1-C6 hydroxyalkyl, (vi) 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl, or (vii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1- C6 alkoxy, (viii) -N(C1-C6 alkyl)2; R14and R15are each independently C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted with C3-C6 cycloalkyl, or R14and R15with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with C1-C6 alkyl; R4is hydrogen or C1-C6 alkyl; and each R9and R10are each independently hydrogen, -(C=O)C1-C6 alkyl, or C1-C6 alkyl optionally substituted with oxo; each R16and R17are each independently hydrogen or C1-C6 alkyl, or R16and R17with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with hydroxyl.

37. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound that has the structure of Formula (I-n):Formula (I-n), or a pharmaceutically acceptable salt thereof, wherein: each R18, R19, and R20are independently: C1-C6 alkoxyalkyl, -N(R6)-S(O2)R7, or halogen; each R6is independently hydrogen or C1-C6 alkyl; and 422 ACTIVE 712622340v1each R7is independently C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; or each R7is independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, benzyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, -(C=O)OC1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl; or each R7is independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6 alkyl, hydroxyl, and C1-C6 hydroxyalkyl.

38. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound selected from the group consisting ofthereof. 423 ACTIVE 712622340v139. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound that has the structure of Formula II:Formula (II), or a pharmaceutically acceptable salt thereof, wherein: R22is selected fromR6is hydrogen or C1-C6 alkyl; R7is selected from: (i) C1-C6 alkyl optionally substituted with 1-4 substituents independently selected from: (a) C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently from halogen or phenyl; (b) phenyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and cyano; (c) hydroxyl; (d) halogen; (e) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, and phenyl optionally substituted with C1-C6 alkyl; and (f) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen, cyano,C1-C6 alkyl, and C1-C6 alkoxy; (ii) C3-C10 cycloalkyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, phenyl optionally substituted with 1-2 independently selected halogen and 5-10 membered heteroaryl; (iii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from benzyl, C1-C6 alkyl, C3-C10 cycloalkyl, and phenyl optionally substituted with C1-C6 alkyl; (iv) phenyl optionally substituted with 1-3 substituents independently selected from halogen, nitro, and C1-C6 haloalkyl; 424 ACTIVE 712622340v1(v) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl; (vi) C1-C6 alkoxy; or (vii) C3-C6 cycloalkoxy; or R6and R7with the atom to which they are attached together form a 5-12 membered heterocyclyl or 9-10 membered heteroaryl each optionally substituted with phenyl; and R23is C1-C3 alkyl or C3-C4 cycloalkyl.

40. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound selected from the group consisting ofor a pharmaceutically acceptable salt or solvate thereof.

41. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound that has the structure of Formula III: 425 ACTIVE 712622340v1Formula (III) or a pharmaceutically acceptable salt thereof, wherein:YA1, YA2, and YA3are each independently N, CH, or CRA4; ZAis N or CRA5; RA1is C3-C6 alkyl, C3-C6 cycloalkyl, C5-C12 bridged bicyclic carbocyclyl, or 4-10 membered heterocyclyl, wherein the C3-C6 alkyl, C3-C6 cycloalkyl, C5- C12 bridged bicyclic carbocyclyl, or 4-10 membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, NRA10S(O)RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1- C6 alkyl, C1-C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1- C3 alkylcarbonylamino(C1-C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6-C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; RA9is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, NRA10S(O)RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1- C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1- C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1- C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6- C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; 426 ACTIVE 712622340v1RA2is H or C1-C3 alkyl, wherein the C1-C3 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2)RA10, NRA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1- C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1- C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1- C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6- C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; WAis selected from a bond, -O-, -NRA10-, -O(C1-C2 alkylene)-, NH(C1- C2 alkylene), C1-C2 alkylene, and C3-C6 cycloalkylene; RA3is selected from S(=O)2RA6, halogen, 4-10 membered heterocyclyl, 5-12 membered heteroaryl, C(=O)N(RA10)2, NH(C=O)RA6, cyano, N(RA10)2, and P(=O)(RA10)2; each RA4is independently selected from H, halogen, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, N RA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1- C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1- C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6- C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; nAis 0, 1, 2, or 3; each RA5is each independently selected from H, C1-C6 alkyl, halogen, and cyano, wherein the C1-C6 alkyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2) RA10, N RA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1-C6 deuteroalkyl, C3- C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1-C6)alkyl, C1-C3 alkoxy, C1-C3 427 ACTIVE 712622340v1haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6-C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; and RA6is selected from C1-C6 alkyl, -N(RA10)2, C3-C6 cycloalkyl, and 4-10 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, and 4-10 membered heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from deuterium, oxo, F, Cl, Br, cyano, ORA10, SRA10, N(RA10)2, S(O) RA10, S(O2)RA10, N RA10S(O) RA10, C(O)ORA10, C(O)N(RA10)2, NRA10C(O)RA10, C(S)N(RA10)2, C(O)RA10, C1-C6 alkyl, C1-C6 deuteroalkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C3 alkylsulfonylaminoalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, (C1-C6) alkylamino C1-C6 alkyl, C1-C6 cyanoalkyl, C1-C3 alkylcarbonylamino(C1-C6)alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C6 alkoxy(C1-C6)alkyl, C6-C12 aryl, 4-8 membered heterocyclyl, and 5-12 membered heteroaryl; and each RA10is independently C1-C6 alkyl or C3-C6 cycloalkyl optionally substituted 1 to 3 substituents independently selected from with hydroxyl, halogen, or C1-C6 alkoxy, or two RA10are taken together with the atom they are attached to form a cyclic structure.

42. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound selected from the group consisting of 428 ACTIVE 712622340v1, or a pharmaceutically acceptable salt or solvate thereof.

43. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound that has the structure of Formula IV:Formula (IV) or a pharmaceutically acceptable salt thereof, wherein: X2is N and X3is CH or X2is CH and X3is N; R2is: (i) hydrogen; (ii) halogen; (iii) C1-C6 alkoxy; (iv) C1-C6 haloalkoxy; 429 ACTIVE 712622340v1(v) –(C=O)NR11R12; or (vi) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, and -NR11R12; each R11and R12are independently hydrogen, C1-C6 alkyl optionally substituted with hydroxyl, or C1-C6 hydroxyalkyl; R3is: (i) C1-C6 thioalkyl;(iii) 4-8 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy; (vi) -C(=O)NR16R17; (v) hydrogen; (vi) C1-C6 haloalkyl; (vii) C1-C6 alkoxyalkyl; or (viii) C1-C6 hydroxyalkyl; Z is O; R13is (i) C1-C6 haloalkyl; (ii) C3-C6 cycloalkyl; (iii) C1-C6 alkyl, (iv) C1-C6 alkoxyalkyl; (v) C1-C6 hydroxyalkyl; or (vi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6 alkyl, -C(O)OC1-C6 alkyl, and C1- C6 alkoxy; each R16and R17are each independently hydrogen or C1-C6 alkyl, or R16and R17with the atom to which they are attached together form a 4-8 membered heterocyclyl optionally substituted with hydroxyl; R24is C1-3alkyl or Cl; and R25is hydrogen or F. 430 ACTIVE 712622340v144. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound selected from the group consisting of:or a pharmaceutically acceptable salt or solvate thereof.

45. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound that has the structure of Formula V:Formula (V), or a pharmaceutically acceptable salt thereof, wherein: RAis halogen, -CN, -O-(C1-C6 alkyl), C2-C6 alkynyl, C1-C6 alkyl, C3-C6 cycloalkyl, - C(=O)C1-C6 alkyl, -C(=O)C1-C6cycloalkyl, -C(=O)RM, -C(=O)NRaRb, or -RL, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, -O-(C1-C6 alkyl), C3-C6 cycloalkyl, phenyl, -RL, -RM, and 431 ACTIVE 712622340v1-OH, wherein C2-C6alkynyl is optionally substituted with one or more substituents selected from C1-C6 alkyl, and -CH2-O-(C1-C6 alkyl); Rais hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium and C1-C6 alkyl; Rbis hydrogen, C1-C6 alkyl, or -O-(C1-C6 alkyl), wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium, C1-C5 alkyl, and C3-C5 cycloalkyl; RLand RNare each independently a 5 to 6-membered heteroaryl having from 1 to 3 heteroatoms selected from O, N and S, wherein each of RLor RNis optionally substituted with 1-3 C1-C6 alkyl, wherein C1-C6 alkyl being optionally substituted with one or more substituents selected from -D, halogen, -O-(C1-C6 alkyl), and -OH; RBis hydrogen or halogen; RC, RCC, RD, RDD, RG, and RHare each independently hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more -O-(C1-C6 alkyl); wherein when at least one of RCor RCCis C1-C6 alkyl, then RDand RDDare each hydrogen; wherein when at least one of RDor RDDis C1-C6 alkyl, then RCand RCCare each hydrogen; REis -OH, -NRcRc, -NHC(=O)Rc, -NC(=O)RcRc, -NC(=O)ORc, -NHS(O2)Rc, halogen, - O-(C1-C6 alkyl), -O-(C3-C5 cycloalkyl), -O-RM, C1-C6 alkyl, and -CN, wherein C1- C6 alkyl is optionally substituted with one or more substituents selected from deuterium, -OH, C1-C6 alkyl, C3-C5 cycloalkyl, -O-(C1-C6 alkyl) and RM; Rcis hydrogen or C1-C6 alkyl, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium and C1-C6 alkyl; RMis 4-6 membered saturated heterocycle having from 1 to 3 heteroatoms selected from O and N, wherein each RMis optionally substituted with 1-3 C1-C6 alkyl, wherein C1-C6 alkyl being optionally substituted with one or more substituents selected from -D, halogen, -O-(C1-C6 alkyl), and -OH; RFis hydrogen, halogen, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-RP, and RN, wherein C1-C6 alkyl is optionally substituted with one or more substituents selected from deuterium and -O-(C1-C6 alkyl); 432 ACTIVE 712622340v1RPis 4-10 membered saturated heterocycle having from 1 to 3 heteroatoms selected from O and N, wherein each RPis optionally substituted with 1-3 C1-C6 alkyl, wherein C1-C6 alkyl being optionally substituted with one or more substituents selected from -D, halogen, -O-(C1-C6 alkyl), and -OH; RJis hydrogen, C1-C6 alkyl, -C(=O)C1-C6 alkyl, or -C(=O)-O-(C1-C6 alkyl); and RKis hydrogen or halogen.

46. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound selected from the group consisting ofor a pharmaceutically acceptable salt or solvate thereof.

47. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound that has the structure of Formula VI:433 ACTIVE 712622340v1or a pharmaceutically acceptable salt or solvate thereof, wherein: nBis 0, 1, 2 or 3; # O LBis a bond, —O—, —N(RB6)—, or RB6, wherein # denotes a connection to RB3; ring ABis C6-C10 aryl or 5-10 membered heteroaryl; each RB1is independently hydrogen, -D, halogen, hydroxyl, amino, cyano, C1- C6 alkyl, C3-C6 cycloalkyl, —OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1- C6 alkyl)2, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C3- C6 cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with 1 to 3 groups independently selected from RBa; RB2is hydrogen, -D, C1-C3 alkyl or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3-C6 cycloalkyl is optionally substituted with 1 to 3 groups independently selected from RBb; RB3is hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C3-C6 cycloalkyl, —OC1- C6 alkyl, 3-6 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl is optionally substituted with 1 to 3 groups independently selected from RBc; RB4is C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted with 1 to 3 groups independently selected from RBd; RB5is C1-C3 alkyl, wherein C1-C3 alkyl is optionally substituted with 1 to 3 groups independently selected from RBe; or RB4and RB5together with the phosphorus atom attached thereto form 5-6 membered heterocycloalkyl or 5-8 membered heterocycloalkenyl, wherein the 5-6 membered heterocycloalkyl or 5-8 membered heterocycloalkenyl are optionally substituted with 1 to 3 groups independently selected from RBd; RB6is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl, wherein the C1-C3 alkyl or C3- C6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from RBf; RB7is hydrogen, -D, F, Cl, Br, hydroxyl, amino, cyano, C1-C6 alkyl, C3- C6 cycloalkyl, —OC1-C6 alkyl, —NHC1-C6 alkyl, —N(C1-C6 alkyl)2, C2- C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, C2- 434 ACTIVE 712622340v1C6 alkenyl or C2-C6 alkynyl is optionally substituted with 1 to 3 groups independently selected from RBg; each RBa, RBb, RBd, RBe, RBf, and RBgare each independently F, Cl, Br, I, hydroxyl, amino, methyl or methoxy; each RBcis independently deuterium, F, Cl, Br, I, hydroxyl, amino, methyl, methoxywherein each heterocycloalkyl, heterocycloalkyl, heterocycloalkenyl, and heteroaryl comprises 1 to 3 heteroatoms or heteroatom groups independently selected from N, NH, O, S and P(═O).

48. The method of any one of claims 1 to 7, 9 to 16, and 19 to 35, wherein the RIPK2 inhibitor is a compound selected from the group consisting of: ,,,435 ACTIVE 712622340v1acceptable salt or solvate thereof. 436 ACTIVE 712622340v1

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