Derivatives of a jak inhibitor

Abstract

The application provides a derivative of a JAK inhibitor, which is a compound shown in formula (II) or formula (II'), a stereoisomer thereof or a pharmaceutically acceptable salt thereof. The compound provided by the application can be completely converted into the compound of formula (I) in the suprachoroidal space after injection, can play a therapeutic role on posterior uveitis, and can stay in the suprachoroidal space for more than 30 days after injection.

Description

Technical Field

[0001] This application relates to the field of drug synthesis technology, and in particular to a derivative of a JAK inhibitor. Background Technology

[0002] Janus kinases (JAKs) are intracellular kinases responsible for transmitting cellular signals, with a size of 120-140 kDa. JAK kinase inhibitors work by inhibiting JAK kinase activation, thereby blocking the intracellular JAK-STAT pathway and inhibiting the secretion of inflammatory and immune-related cytokines such as interferon, interleukin, and GM-CSF (granulocyte-macrophage colony-stimulating factor), thus achieving anti-inflammatory and anti-immune effects. Marketed JAK inhibitors such as tofacitinib, upadacitinib, and filgotinib block the corresponding signal transduction pathways, resulting in anti-inflammatory effects. The JAK family includes JAK1, JAK2, JAK3, and TyK2. Among existing therapies, JAK1 inhibitors are commonly used to treat various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, and ankylosing spondylitis; JAK2 inhibitors are commonly used to treat myelofibrosis; JAK3 inhibitors are commonly used to treat alopecia areata; and TyK2 inhibitors are commonly used to treat psoriasis.

[0003] The structure of the compound of formula (I) is as follows: It is a potent inhibitor of JAK1 and TYK2; its activity and uses are described in patent CN110483514A. Uveitis is a group of inflammatory diseases affecting intraocular tissues. Autoimmune and autoinflammatory reactions that trigger uveitis include Vogt-Koyanagi-Harada syndrome (VKH syndrome), spondyloarthritis, sarcoidosis, Behcet's disease, and tubulointerstitial nephritis. Uveitis can be classified according to its location as anterior uveitis, primarily affecting the cornea, ciliary muscle, and anterior chamber, and posterior uveitis, primarily affecting the choroid. Compared to traditional hormone therapy, treating uveitis with JAK inhibitor compounds of type (I) avoids adverse reactions such as increased intraocular pressure, cataracts, secondary infections, and ulcers. However, JAK inhibitors administered via eye drops are difficult to achieve sustained therapeutic concentrations in the posterior choroid. Posterior uveitis can be treated with suprachoroidal injection. Suprachoroidal injection is a novel drug delivery technique that uses a microneedle to inject a suspension of a compound into the space between the sclera and the choroid, allowing for slow drug release and penetration into the choroid. In rabbits, 24 hours after intrachoroidal injection of a suspension of compound (I), the residual concentration of compound (I) in the choroid decreased to less than 1% of the initial concentration. Therefore, compound (I) is not suitable for direct suprachoroidal drug delivery, and novel drugs need to be developed. Summary of the Invention

[0004] The purpose of this application is to provide a compound of formula (II) or formula (II'), its stereoisomer, or a pharmaceutically acceptable salt thereof, which, upon injection, is completely converted into the compound of formula (I) in the suprachoroidal space, and can exert a therapeutic effect on posterior uveitis; and can remain in the suprachoroidal space for more than 30 days after injection. The specific technical solution is as follows:

[0005] The first aspect of this application provides a compound of formula (II) or formula (II'), its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0006]

[0007] Wherein, R is selected from C1-C 20 Alkyl, -C(O)-R1, C1-C 20 Heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 12 Aryl or 5-12 heteroaryl groups;

[0008] R1 is selected from C1-C1 that is unsubstituted or substituted by one or more Ra. 20 Alkyl, unsubstituted or substituted with one or more Ra C1-C 20 heteroalkyl, unsubstituted or C substituted with one or more Ra 3- C8 cycloalkyl, unsubstituted or substituted by one or more Ra C6-C 12 aryl, unsubstituted or 5-12 heteroaryl groups substituted with one or more Ra, -OC 3- C8 cycloalkyl, -OC 2- C4 alkenyl, unsubstituted or substituted with one or more Ra groups 2- C4 alkenyl, C that is not substituted or is substituted by one or more Ra 1- C8 alkoxy, unsubstituted or substituted by one or more Ra-membered heterocyclic alkyl groups;

[0009] Ra is independently selected from C1-C each time it appears. 10 Alkyl, C 3- C8 cycloalkyl, unsubstituted or C6-C substituted with one or more Rb 12 Aryl, -OAc, methoxy, hydroxy, 3-8 membered heterocyclic alkyl, halogen, -NH- C6-C substituted with one or more methyl groups 12 Aryl group; Rb is selected from C1-C6 alkyl or methoxy groups;

[0010] Y is selected from -C(O)-LC(O)-, -C(O)-, -Ar-, Or -P(O)R3-;

[0011] L is selected from C1-C 20 Alkylene, C1-C 20 alkenyl, C1-C 20 Ethyne group, C1-C 20 Heteroalkyl, unsubstituted or substituted with one or more halogens, C6-C 12 5-12 membered heteroaryl, unsubstituted or substituted by one or more halogens;

[0012] Ar is selected from C6-C 12 arylene or 5-12 heteroarylene;

[0013] R3 is selected from C1-C 20 alkyl;

[0014] X1, X2, and X3 are each independently selected from CH or N each time they appear;

[0015] The heteroatom in the heteroaryl group, the heteroalkyl group, the heterocyclic alkyl group, the heteroalkylene group, and the heterocyclic aryl group is independently selected from O, N, or S.

[0016] In some embodiments of this application, the compound represented by formula (II) is selected from:

[0017]

[0018] R1 is selected from C1-C1 that is unsubstituted or substituted by one or more Ra. 20 Alkyl, unsubstituted or C substituted with one or more Ra 3- C8 cycloalkyl, unsubstituted or substituted by one or more Ra C6-C 12 aryl, unsubstituted or 5-12 heteroaryl groups substituted with one or more Ra, -OC 3- C8 cycloalkyl, -OC 2- C4 alkenyl, unsubstituted or substituted with one or more Ra groups 2- C4 alkenyl, C that is not substituted or is substituted by one or more Ra 1- C8 alkoxy, unsubstituted or substituted by one or more Ra-membered heterocyclic alkyl groups;

[0019] Ra is independently selected from C1-C each time it occurs. 10 Alkyl, C 3- C8 cycloalkyl, unsubstituted or C6-C substituted with one or more Rb 12 Aryl, -OAc, methoxy, hydroxy, 3-8 membered heterocyclic alkyl, halogen, -NH- C6-C substituted with two methyl groups 12Aryl; Rb is selected from C1-C6 alkyl or methoxy.

[0020] In some embodiments of this application, in the compound represented by formula (II), the -OC 2- The C4 alkenyl group is selected from -O-CH2-CH=CH2;

[0021] The unsubstituted or substituted C by one or more Ra 2- The C4 alkenyl group is selected from -CH=CH-CH3, -CH=C(CH3)2, or -CH=CH-C6-C. 12 Aryl.

[0022] In some embodiments of this application, the compound represented by formula (II') is selected from:

[0023]

[0024]

[0025] in,

[0026] The L is selected from C1-C 20 Alkylene, C1-C 20 alkenyl, C1-C 20 Ethyne group, C1-C 20 Heteroalkyl, unsubstituted or C6-C substituted with two Cl groups 12 aryl; the C1-C 20 The heteroatom in the heteroalkylene group is selected from O;

[0027] The Ar is selected from C6-C. 12 The heteroatom in the 5-12-membered heteroaryl group is selected from N.

[0028] In some embodiments of this application, the compound represented by formula (II') is selected from:

[0029]

[0030] in,

[0031] R3 is selected from C1-C3 alkyl groups.

[0032] In some embodiments of this application, the compound represented by formula (II') is selected from:

[0033]

[0034] Wherein, X1, X2, and X3 are all N; or, two of X1, X2, and X3 are selected from N, and the other is selected from CH.

[0035] A second aspect of this application provides a compound, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042] A third aspect of this application provides a pharmaceutical composition comprising the compound described in the first or second aspect of this application, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0043] The fourth aspect of this application provides the use of a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof described in the first or second aspect of this application, or a pharmaceutical composition described in the third aspect of this application, in the preparation of a medicament for treating immune-related diseases.

[0044] In some embodiments of this application, the immune-related disease is an ophthalmic posterior uveitis-related disease.

[0045] The fifth aspect of this application provides a method for treating an immune-related disease, the method comprising administering a therapeutically effective amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof described in the first or second aspect of this application, to a subject in need via the suprachoroidal space.

[0046] In some embodiments of this application, the immune-related disease is an ophthalmic posterior uveitis-related disease.

[0047] The beneficial effects of this application are:

[0048] This application provides a compound of formula (II) or formula (II'), its stereoisomer, or a pharmaceutically acceptable salt thereof, which, upon injection, is completely converted into the compound of formula (I) in the suprachoroidal space, and can exert a therapeutic effect on posterior uveitis; and can remain in the suprachoroidal space for more than 30 days after injection. The compound provided in this application can be used to prepare drugs for immune-related diseases, especially ophthalmic diseases related to posterior uveitis.

[0049] Of course, implementing any product or method of this application does not necessarily require achieving all of the advantages described above at the same time. Detailed Implementation

[0050] The technical solutions of this application will be clearly and completely described below with reference to the embodiments of this application. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. All other embodiments obtained by those skilled in the art based on this application are within the scope of protection of this application.

[0051] The first aspect of this application provides a compound of formula (II) or formula (II'), its stereoisomers, or a pharmaceutically acceptable salt thereof.

[0052]

[0053] Wherein, R is selected from C1-C 20 Alkyl, -C(O)-R1, C1-C 20 Heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 12 Aryl or 5-12 heteroaryl groups;

[0054] R1 is selected from C1-C1 that is unsubstituted or substituted by one or more Ra. 20 Alkyl, unsubstituted or substituted with one or more Ra C1-C 20 Heteroalkyl, unsubstituted or C substituted with one or more Ra 3- C8 cycloalkyl, unsubstituted or substituted by one or more Ra C6-C 12 aryl, unsubstituted or 5-12 heteroaryl groups substituted with one or more Ra, -OC 3- C8 cycloalkyl, -OC 2- C4 alkenyl, unsubstituted or substituted with one or more Ra groups 2- C4 alkenyl, C that is not substituted or is substituted by one or more Ra 1- C8 alkoxy, unsubstituted or substituted by one or more Ra-membered heterocyclic alkyl groups;

[0055] Ra is independently selected from C1-C each time it appears. 10 Alkyl, C 3- C8 cycloalkyl, unsubstituted or C6-C substituted with one or more Rb 12 Aryl, -OAc, methoxy, hydroxy, 3-8 membered heterocyclic alkyl, halogen, -NH- C6-C substituted with one or more methyl groups 12 Aryl group; Rb is selected from C1-C6 alkyl or methoxy groups;

[0056] Y is selected from -C(O)-LC(O)-, -C(O)-, -Ar-, Or -P(O)R3-;

[0057] L is selected from C1-C 20 Alkylene, C1-C 20 alkenyl, C1-C 20 Ethyne group, C1-C 20 Heteroalkyl, unsubstituted or substituted with one or more halogens, C6-C 12 5-12 membered heteroaryl, unsubstituted or substituted by one or more halogens;

[0058] Ar is selected from C6-C 12 arylene or 5-12 heteroarylene;

[0059] R3 is selected from C1-C 20 alkyl;

[0060] X1, X2, and X3 are each independently selected from CH or N each time they appear;

[0061] The heteroatom in the heteroaryl group, the heteroalkyl group, the heterocyclic alkyl group, the heteroalkylene group, and the heterocyclic aryl group is independently selected from O, N, or S.

[0062] The halogens described in this application are preferably F, Cl, or Br.

[0063] Since compound (I) is not suitable for direct administration into the suprachoroidal space, this application modifies the structure of compound (I) to obtain a series of oxygen derivatives as shown in formula (II) or (II'). Due to the increased molecular weight and hydrophobicity, compounds shown in formula (II) or (II') can remain in the suprachoroidal space for more than 30 days after injection. Pharmacokinetic experiments show that compound (II) or (II') dissolved in the suprachoroidal space can be completely converted into compound (I) and can have a therapeutic effect on posterior uveitis.

[0064] In some embodiments of this application, the compound represented by formula (II) is selected from:

[0065]

[0066] R1 is selected from C1-C1 that is unsubstituted or substituted by one or more Ra. 20 Alkyl, unsubstituted or C substituted with one or more Ra 3- C8 cycloalkyl, unsubstituted or substituted by one or more Ra C6-C 12 aryl, unsubstituted or 5-12 heteroaryl groups substituted with one or more Ra, -OC 3- C8 cycloalkyl, -OC2- C4 alkenyl, unsubstituted or substituted with one or more Ra groups 2- C4 alkenyl, C that is not substituted or is substituted by one or more Ra 1- C8 alkoxy, unsubstituted or substituted by one or more Ra-membered heterocyclic alkyl groups;

[0067] Ra is independently selected from C1-C each time it occurs. 10 Alkyl, C 3- C8 cycloalkyl, unsubstituted or C6-C substituted with one or more Rb 12 Aryl, -OAc, methoxy, hydroxy, 3-8 membered heterocyclic alkyl, halogen, -NH- C6-C substituted with two methyl groups 12 Aryl; Rb is selected from C1-C6 alkyl or methoxy.

[0068] In some embodiments of this application, the compounds represented by formula (II) or formula (III) are:

[0069] The -OC 2- The C4 alkenyl group is selected from -O-CH2-CH=CH2;

[0070] The unsubstituted or substituted C by one or more Ra 2- The C4 alkenyl group is selected from -CH=CH-CH3, -CH=C(CH3)2, or -CH=CH-C6-C. 12 Aryl.

[0071] In some embodiments of this application, the compound represented by formula (II') is selected from:

[0072]

[0073] in,

[0074] The L is selected from C1-C 20 Alkylene, C1-C 20 alkenyl, C1-C 20 Ethyne group, C1-C 20 Heteroalkyl, unsubstituted or C6-C substituted with two Cl groups 12 aryl; the C1-C 20 The heteroatom in the heteroalkylene group is selected from O;

[0075] The Ar is selected from C6-C. 12 The heteroatom in the 5-12-membered heteroaryl group is selected from N.

[0076] In some embodiments of this application, the compound represented by formula (II') is selected from:

[0077]

[0078] in,

[0079] R3 is selected from C1-C3 alkyl groups.

[0080] In some embodiments of this application, the compound represented by formula (II') is selected from:

[0081]

[0082] Wherein, X1, X2, and X3 are all N; or, two of X1, X2, and X3 are selected from N, and the other is selected from CH.

[0083] A second aspect of this application provides a compound, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from:

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090] A third aspect of this application provides a pharmaceutical composition comprising the compound described in the first or second aspect of this application, its stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.

[0091] The fourth aspect of this application provides the use of a compound, its stereoisomer, or a pharmaceutically acceptable salt thereof described in the first or second aspect of this application, or a pharmaceutical composition described in the third aspect of this application, in the preparation of a medicament for treating immune-related diseases.

[0092] In some embodiments of this application, the immune-related disease is an ophthalmic posterior uveitis-related disease.

[0093] The fifth aspect of this application provides a method for treating an immune-related disease, the method comprising administering a therapeutically effective amount of the compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof described in the first or second aspect of this application, to a subject in need via the suprachoroidal space.

[0094] In some embodiments of this application, the immune-related disease is an ophthalmic posterior uveitis-related disease.

[0095] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in human and animal tissues to the extent of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0096] The term "substituted by one or more Ra" means that one or more hydrogen atoms in a group are independently replaced by the corresponding number of substituents Ra.

[0097] The term "Ra is selected independently each time it appears" means that when a compound appears more than once in its composition or structure, its definition is independent in each case.

[0098] There are no particular limitations on the synthesis method of the compounds in this application; any method known to those skilled in the art can be used for synthesis. The following examples illustrate the synthesis process of the compounds in this application.

[0099] The compound represented by formula (III) provided in this application can be synthesized using the compound represented by formula (I):

[0100]

[0101] Specifically, it can be synthesized sequentially using the compound shown in formula (IV) and the compound shown in formula (V):

[0102]

[0103] The compound represented by formula (VI) provided in this application can be synthesized using the compound represented by formula (I):

[0104]

[0105] The compound represented by formula (VII) provided in this application can be synthesized from the compound represented by formula (IV) via the compound represented by formula (VIII):

[0106]

[0107] The compound represented by formula (IX) provided in this application can be synthesized using the compound represented by formula (I):

[0108]

[0109] The compound represented by formula (X) provided in this application can be synthesized using the compound represented by formula (I):

[0110]

[0111] The compound represented by formula (XI) provided in this application can be synthesized using the compound represented by formula (I):

[0112]

[0113] The following specific examples illustrate the synthesis process of the compounds of this application in more detail. Unless otherwise specified, "parts" and "%" refer to mass measurements.

[0114] Example 1: Synthesis of Compound 1

[0115] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl3-methylbutanoate

[0116] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 3-methylbutyrate

[0117]

[0118] Compound (I) (324 mg, 1.0 mmol), HATU (2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, 760 mg, 2.0 mmol), Et3N (triethylamine, 202 mg, 2.0 mmol), and isobutyric acid (167 mg, 2.0 mmol) were added to DMF (dimethylformamide, 3.0 mL), and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by column chromatography to give compound 1 (123 mg, yield: 32.3%, white solid).

[0119] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.58(s,1H),7.52(t,1H),6.75(dd,1.9Hz,1H),6.29(q,1H),3.66-3.52(m,2H),3.18 (d,1H),3.10(d,1H),2.63(d,2H),2.22(dd,2H),2.11(s,1H),2.05-1.90(m,3H),1.66(d,3H),1.52(dtt,2H),0.92(dd,6H).

[0120] Example 2: Synthesis of Compound 2

[0121]

[0122] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl propionate

[0123] Ethyl propionate (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)propionate was prepared by reacting compound (I) with propionic acid in a similar manner to that in Example 1 to give product compound 2.

[0124] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.59(s,1H),7.52(t,1H),6.75(dd,1.9Hz,1H),6.30(q,1H),3.61-3.53(m,2H),3.18( d,1H),3.09(d,1H),2.63(d,2H),2.36(p,2H),2.14-2.06(m,1H),1.95(dd,2H),1.66(d,3H),1.59-1.42(m,2H),1.05(t,3H).

[0125] Example 3: Synthesis of Compound 3

[0126] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl butyrate

[0127] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl butyrate

[0128]

[0129] Using a similar approach as in Example 1, compound (I) was reacted with n-butyric acid to obtain product compound 3.

[0130] 1H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.58(s,1H),7.52(t,1H),6.75(dd,1.9Hz,1H),6.29(q,1H),3.58(t,2H),3.18( d,1H),3.09(d,1H),2.63(d,2H),2.31(td,2H),2.11(t,1H),1.95(d,2H),1.66(d,3H),1.62-1.44(m,4H),0.90(t,3H).

[0131] Example 4: Synthesis of Compound 4

[0132] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl4-isobutylbenzoate

[0133] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)4-isobutylbenzoate ethyl ester

[0134]

[0135] Using a similar approach as in Example 1, compound (I) was reacted with 4-isobutylbenzoic acid to obtain product compound 4.

[0136] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.58(s,1H),7.51(t,1H),7.23-7.14(m,2H),7.05(dd,2H),6.71(dd,1H),6.30(q,1H),3.76(dq,1H) ,3.54(t,2H),3.17(d,1H),3.05(d,1H),2.62(d,2H),2.36(td,2H),2 .09(t,1H),1.91(d,2H),1.54(d,2H),1.40(d,3H),0.88-0.73(m,6H).

[0137] Example 5: Synthesis of Compound 5

[0138] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-acetoxybenzoate

[0139] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 2-acetoxybenzoate

[0140]

[0141] Using a similar approach as in Example 1, compound (I) was reacted with 2-acetoxybenzoic acid to obtain product compound 5.

[0142] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.63(s,1H),8.03(dd,1H),7.69(td, 1H),7.52(t,1H),7.40(td,1H),7.22(dd,1H),6.74(dd,1H),6.58(q,1H),3 .53(t,2H),3.23(d,1H),2.97(d,1H),2.55(d,2H),2.10(s,3H),2.07-1.99 (m,1H),1.93(d,1H),1.77(d,3H),1.67(d,1H),1.55(qd,1H),1.25(qd,1H).

[0143] Example 6: Synthesis of Compound 6

[0144] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-(6-methoxynaphthalen-2-yl)propanoate

[0145] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-(6-methoxynaphthyl-2-yl)propionate ethyl ester

[0146]

[0147] Using a similar approach as in Example 1, compound (I) was reacted with 2-(6-methoxynaphthalene-2-yl)propionic acid to obtain compound 6.

[0148] 1 H NMR(400MHz,DMSO-d6)δ12.00(d,1H),8.59(d,1H),7.74(dd,3H),7.52(t,1H),7.39( dt,1H),7.26(d,1H),7.12(dd,1H),6.75(dd,1H),6.30(q,1H),3.94(dq,1H),3.85(d, 3H),3.59-3.46(m,1H),3.16(d,1H),3.01(d,1H),2.57(d,1H),2.38(dd,1H),2.05(d d,1H),1.95-1.75(m,2H),1.70(d,1H),1.54(d,2H),1.51-1.46(m,3H),1.39(dt,2H)0

[0149] 98-0.84(m, 1H).

[0150] Example 7: Synthesis of Compound 7

[0151] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl pentanoate

[0152] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl valerate

[0153]

[0154] Using a similar approach as in Example 1, compound (I) was reacted with n-valeric acid to obtain compound 7.

[0155] 1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.59(s,1H),7.52(t,1H),6.75(dd,1H),6.29(q,1H),3.58(t,2H),3.18(d,1H),3.09( d,1H),2.63(d,2H),2.33(td,2H),2.14(d,1H),1.95(d,2H),1.66(d,3H),1.59-1.42(m,4H),1.37-1.22(m,2H),0.86(t,3H).

[0156] Example 8: Synthesis of Compound 8

[0157] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl octanoate

[0158] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl octanoate

[0159]

[0160] Using a similar approach as in Example 1, compound (I) was reacted with octanoic acid to obtain compound 8.

[0161] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.58(s,1H),7.52(t,1H),6.75(dd,1H),6.29(q,1H),3.58(t,2H),3.18(d,1H),3.09(d,1 H),2.62(d,2H),2.32(td,2H),2.10(d,1H),1.95(d,2H),1.65(d,3H),1.59-1.41(m,4H),1.33-1.13(m,8H),0.89-0.78(m,3H).

[0162] Example 9: Synthesis of Compound 9

[0163] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl hexanoate

[0164] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl hexanoate

[0165]

[0166] Using a similar approach as in Example 1, compound (I) was reacted with hexanoic acid to obtain compound 9.

[0167] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.58(s,1H),7.52(t,1H),6.75(dd,1H),6.29(q,1H),3.58(t,2H),3.18(d,1H),3.0 9(d,1H),2.62(d,2H),2.32(q,2H),2.11(s,1H),1.95(d,2H),1.66(d,3H),1.51(dt,4H),1.26(dt,4H),0.87-0.82(m,3H).

[0168] Example 10: Synthesis of Compound 10

[0169] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl decanoate

[0170] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl decanoate

[0171]

[0172] Using a similar approach as in Example 1, compound (I) was reacted with n-decanoic acid to obtain compound 10.

[0173] 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.58(s,1H),7.52(t,1H),6.75(dd,1H),6.29(q,1H),3.58(t,2H),3.18(d,1H),3.09( d,1H),2.62(d,2H),2.32(q,2H),2.11(s,1H),1.95(d,2H),1.65(d,3H),1.59-1.46(m,4H),1.23(d,12H),0.88-0.79(m,3H).

[0174] Example 11: Synthesis of Compound 11

[0175] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl nicotinate

[0176] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl) ethyl nicotinate

[0177]

[0178] Using a similar approach as in Example 1, compound (I) was reacted with nicotinic acid to obtain compound 11.

[0179] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),9.14(dd,1H),8.83(dd,1H),8.62(s,1H),8.34(dt,1H),7.56(ddd,1H),7.52(t,1H),6.74(dd,1H),6.60(q,1 H),3.55(q,2H),3.25(d,1H),3.00(d,1H),2.55(d,2H),2.12-1.98(m,1H) ,1.93(d,1H),1.83(d,3H),1.68(d,1H),1.57(qd,1H),1.28-1.14(m,1H).

[0180] Example 12: Synthesis of Compound 12

[0181] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclopropanecarboxylate

[0182] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclopropionate

[0183]

[0184] Using a similar approach as in Example 1, compound (I) was reacted with cyclopropionic acid to obtain compound 12.

[0185] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.60(s,1H),7.52(t,1H),6.75(dd,1H),6.29(q,1H),3.58(t,2 H),3.18(d,1H),3.11(d,1H),2.63(d,2H),2.10(t,1H),1.94(d,2H),1.57(t,2H),1.00-0.82(m,4H).

[0186] Example 13: Synthesis of Compound 13

[0187] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclopentyl carbonate

[0188] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)cyclopentyl ethyl carbonate

[0189]

[0190] Compound (I) (324 mg, 1.0 mmol), cyclopentyl chloroformate (149 mg, 1.0 mmol), and Et3N (202 mg, 2.0 mmol) were added to DMF (3.0 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by column chromatography to give compound 13 (120 mg, yield: 27.5%, white solid).

[0191] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.60(s,1H),7.52(t,1H),6.75(dd,1H),6.15(q,1H),5.07(dq,1H),3.64-3.54(m,2H) ,3.20(d,1H),3.07(d,1H),2.64(d,2H),2.17-2.05(m,1H),1.95(d,2H),1.89-1.78(m,2H),1.70(d,3H),1.66-1.52(m,8H).

[0192] Example 14: Synthesis of Compound 14

[0193] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclobutanecarboxylate

[0194] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)cyclobutylcarboxylate

[0195]

[0196] Using a similar approach as in Example 1, compound (I) was reacted with cyclobutane carboxylic acid to obtain compound 14.

[0197] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,1H),8.59(s,1H),7.53(t,1H),6.75(dd,1H),6.29(q,1H),3.50(q,2H),3.21(d,1H) ,3.14(d,1H),2.70-2.61(m,2H),2.44-2.29(m,4H),2.09(dq,2H),1.97-1.87(m,3H),1.75-1.59(m,3H),1.57(d,3H).

[0198] Example 15: Synthesis of Compound 15

[0199] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-hydroxybenzoate

[0200] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 2-hydroxybenzoate

[0201]

[0202] Using a similar approach as in Example 1, compound (I) was reacted with 2-hydroxybenzoic acid to obtain compound 15.

[0203] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),10.51(s,1H),8.63(s,1H),7.80(dd,1H),7.61-7.47(m,2H),7.01(dd,1H),6.96-6.88(m,1H),6.76(dd,1H), 6.62(q,1H),3.57(q,2H),3.25(d,1H),3.04(d,1H),2.56(d,2H),2.07(s, 1H),1.95(d,1H),1.84(d,3H),1.74(d,1H),1.60(tt,1H),1.28(ddd,1H).

[0204] Example 16: Synthesis of Compound 16

[0205] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl isobutyl carbonate

[0206] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)isobutyl ethyl carbonate

[0207]

[0208] Using a similar approach as in Example 13, compound (I) was reacted with isobutyl chloroformate to obtain compound 16.

[0209] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.61(s,1H),7.53(t,1H),6.77(dd,1H),6.18(q,1H),3.95(d,2H),3.65-3 .52(m,2H),3.08(d,1H),2.65(d,2H),2.20-2.05(m,1H),1.93(td,3H),1.73(d,3H),1.55(dqd,2H),0.90(d,6H).

[0210] Example 17: Synthesis of Compound 17

[0211] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)succinate

[0212] bis(R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl succinate

[0213]

[0214] Compound (I) (324 mg, 1.0 mmol), DMAP (4-dimethylaminopyridine, 13 mg, 0.1 mmol), and Et3N (202 mg, 2.0 mmol) were added to DCM (dichloromethane, 3.0 mL), followed by the addition of Boc2O (di-tert-butyl dicarbonate, 220 mg, 1.0 mmol). The mixture was stirred at room temperature for 5 min. A 10% aqueous acetic acid solution (1 mL) was added to the reaction mixture. The mixture was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to obtain intermediate B (212 mg, yield: 50%, white solid).

[0215] Intermediate B (212 mg, 0.5 mmol), HATU (380 mg, 1.0 mmol), Et3N (101 mg, 1.0 mmol), and succinic acid (118 mg, 1.0 mmol) were added to DCM (3.0 mL) and stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by column chromatography to give intermediate C (180 mg, yield: 19.3%, white solid).

[0216] Intermediate C (180 mg, 0.19 mmol) was added to DCM (2.0 mL), followed by the addition of trifluoroacetic acid (1.0 mL) and stirring at room temperature for 15 min. The reaction mixture was concentrated and purified by column chromatography to obtain compound 17 (100 mg, yield: 70.9%, white solid).

[0217] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,2H),8.60(s,2H),7.53(t,2H),6.74(dd,2H),6.29(q,2H),3.66-3.49(m,4H),3.18(d,2H ),3.08(d,2H),2.65(t,4H),2.46(q,4H),2.15-2.03(m,2H),1.99-1.88(m,2H),1.65(d,8H),1.53(qd,2H),1.15(qd,2H).

[0218] Example 18: Synthesis of Compound 18

[0219] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)adipate

[0220] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl adipic acid

[0221]

[0222] Using a similar approach as in Example 17, compound (I) was reacted with adipic acid to obtain compound 18.

[0223] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,2H),8.59(s,2H),7.53(t,2H),6.74(dd,2H),6.29(q,2H),3.66-3.49(m,4H),3.18( d,2H),3.08(d,2H),2.60(d,4H),2.36(q,4H),2.15-2.03(m,2H),1.99-1.88(m,4H),1.65(d,6H),1.61-1.42(m,8H).

[0224] Example 19: Synthesis of Compound 19

[0225] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)2,2'-oxydiacetate

[0226] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)2,2'-oxydiacetate

[0227]

[0228] Using a similar approach as in Example 17, compound (I) was reacted with diethylene glycol to obtain compound 19.

[0229] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,2H),8.58(s,2H),7.53(t,2H),6.75(dd,2H),6.38(q,2H),4.29(d,4H),3.56(q d,4H),3.18(d,2H),3.12(d,2H),2.59(d,4H),2.17-2.05(m,2H),1.93(td,4H),1.69(d,6H),1.57-1.42(m,4H).

[0230] Example 20: Synthesis of Compound 20

[0231] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-cyclobutylacetate

[0232] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-cyclobutyrate

[0233]

[0234] Using a similar approach as in Example 1, compound (I) was reacted with cyclobutylacetic acid to obtain compound 20.

[0235] 1H NMR(400MHz,DMSO-d6)δ11.97(d,1H),8.58(s,1H),7.52(t,1H),6.75(dd,1H),6.28(q,1H),3.57(ddt,2H),3.17(d,1H),3.09(d,1H) ,2.61(dd,3H),2.45(t,2H),2.09-2.02(m,3H),1.95(dd,2H),1.84-1.76(m,2H),1.70-1.67(m,2H),1.64(d,3H),1.59-1.45(m,2H).

[0236] Example 21: Synthesis of Compound 21

[0237] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-(oxetan-3-yl)acetate

[0238] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-(oxetane-3-yl)ethyl acetate

[0239]

[0240] Using a similar approach as in Example 1, compound (I) was reacted with 3-oxetaneacetic acid to obtain compound 21.

[0241] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.59(s,1H),7.52(t,1H),6.75(dd,1H),6.28(q,1H),4.66(dd,2H),4.30(td,2H),3.57(tt,2H),3.2 7(t,1H)3.17(d,1H),3.09(d,1H),2.82-2.72(m,2H),2.63(d,2H),2.09(dd,1H),2.02-1.89(m,2H),1.65(d,J=6.7Hz,3H),1.50(dtt,2H).

[0242] Example 22: Synthesis of Compound 22

[0243] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl oxetane-3-carboxylate

[0244] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)oxetane-3-carboxylic acid ethyl ester

[0245]

[0246] Using a similar approach as in Example 1, compound (I) was reacted with 3-oxetanecarboxylic acid to obtain compound 22.

[0247] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.59(s,1H),7.52(t,1H),6.76(dd,1H),6.37(q,1H),4.73(dt,2H),4.65(q,2H),3.97(tt,1 H),3.65-3.52(m,2H),3.20(d,1H),3.09(d,1H),2.63(d,2H),2.10(qd,1H),1.95(d,2H),1.69(d,3H),1.57(qd,1H),1.45(qd,1H).

[0248] Example 23: Synthesis of Compound 23

[0249] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl3,3-difluorocyclobutane-1-carboxylate

[0250] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)3,3-difluorocyclobutane-1-carboxylic acid ethyl ester

[0251]

[0252] Using a similar approach as in Example 1, compound (I) was reacted with 3,3-difluorocyclobutanecarboxylic acid to obtain compound 23.

[0253] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.60(s,1H),7.53(t,1H),6.76(dd,1H),6.33(q,1H),3.64-3.53(m,2H),3.19(d,1 H),3.11(ddt,2H),2.94-2.75(m,4H)2.63(d,2H),2.10(dp,1H),1.95(dt,2H),1.69(d,3H),1.57(qd,1H),1.45(qd,1H).

[0254] Example 24: Synthesis of Compound 24

[0255] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cycloheptanecarboxylate

[0256] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cycloheptanecarboxylate

[0257]

[0258] Using a similar approach as in Example 1, compound (I) was reacted with cycloheptaneformic acid to obtain compound 24.

[0259] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.61(s,1H),7.54(t,1H),6.77(dd,1H),6.30(q,1H),3.61(t,2H),3.31-3.18(m,3H),3. 16-3.07(m,1H),2.65(d,2H),2.23-2.06(m,1H),2.03-1.94(m,2H),1.89(tdd,2H),1.68(d,J=2.6Hz,3H),1.57-1.40(m,11H).

[0260] Example 25: Synthesis of Compound 25

[0261] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-methoxyacetate

[0262] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-methoxyethyl acetate

[0263]

[0264] Using a similar approach as in Example 1, compound (I) was reacted with 2-methoxyacetic acid to obtain compound 25.

[0265] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.60(s,1H),7.52(t,1H),6.76(dd,1H),6.38(q,1H),4.18-3.98(m,2H),3.66-3.52 (m,2H),3.33(s,3H),3.19(d,1H),3.11(d,1H),2.62(d,2H),2.11(t,1H),2.00-1.92(m,2H),1.70(d,3H),1.53(tdd,2H).

[0266] Example 26: Synthesis of Compound 26

[0267] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclohexanecarboxylate

[0268] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclohexanecarboxylate

[0269]

[0270] Using a similar approach as in Example 1, compound (I) was reacted with cyclohexanecarboxylic acid to obtain compound 26.

[0271] 1H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.59(s,1H),7.52(t,J=3.1Hz,1H),6.75(dd,J=3 .6,1.9Hz,1H),6.30(q,J=6.6Hz,1H),3.59(t,J=11.7Hz,2H),3.18(d,J=10.6Hz,1H),3 .09(d,J=10.5Hz,1H),2.63(d,J=6.4Hz,2H),2.18-2.05(m,1H),1.95(d,J=12.7Hz,2H) ,1.88-1.77(m,2H),1.68-1.64(m,2H),1.65(d,3H),1.53(ddd,3H),1.43-1.13(m,6H).

[0272] Example 27: Synthesis of Compound 27

[0273] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclopentanecarboxylate

[0274] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cyclopentanoate

[0275]

[0276] Using a similar approach as in Example 1, compound (I) was reacted with cyclopentanecarboxylic acid to obtain compound 27.

[0277] 1 H NMR (400MHz, DMSO-d6) δ11.98(s,1H),8.59(s,1H),7.52(t,1H),6.75(dd,1H),6.29(q,1H),3.59(t,2H),3.19(d,1H),3.09( d,1H),2.77(tt,1H),2.63(d,2H),2.18-2.05(m,1H),2.00-1.91(m,2H),1.90-1.70(m,4H),1.66(d,3H),1.63-1.45(m,6H).

[0278] Example 28: Synthesis of Compound 28

[0279] butyl((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)carbonate

[0280] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)butyl ethyl carbonate

[0281]

[0282] Using a similar approach as in Example 13, compound (I) was reacted with butyl chloroformate to obtain compound 28.

[0283] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.60(s,1H),7.52(t,1H),6.75(dd,1H),6.17(q,1H),4.18-4.10(m,2H),3.58(t,2H),3. 21(d,1H),3.07(d,1H),2.64(d,2H),2.10(d,1H),1.94(d,2H),1.71(d,3H),1.65-1.43(m,4H),1.39-1.26(m,2H),0.88(t,3H).

[0284] Example 29: Synthesis of Compound 29

[0285] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl tetrahydro-2H-pyran-4-carboxylate

[0286] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid ethyl ester

[0287]

[0288] Using a similar approach as in Example 1, compound (I) was reacted with tetrahydropyran-4-carboxylic acid to obtain compound 29.

[0289] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.60(s,1H),7.53(t,1H),6.77(dd,1H),6.34(q,1H),3.87 -3.78(m,2H),3.65-3.55(m,2H),3.38(s,1H),3.20(d,1H),3.10(d,1H),2.69-2.58(m,3H),2.20-

[0290] 2.06(m,1H),1.97(d,2H),1.84-1.72(m,2H),1.67(d,3H),1.64-1.45(m,5H).

[0291] Example 30: Synthesis of Compound 30

[0292] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl3-methoxypropanoate

[0293] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 3-methoxypropionate

[0294]

[0295] Using a similar approach as in Example 1, compound (I) was reacted with 3-methoxyacetic acid to obtain compound 30.

[0296] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.60(s,1H),7.53(t,1H),6.76(dd,1H),6.35(q,1H),3.57(t,4H),3.22(s,3H), 3.21-3.16(m,1H),3.16-3.09(m,1H),2.65-2.55(m,4H),2.15-2.06(m,1H),1.95(d,2H),1.68(d,3H),1.55(dqd,2H).

[0297] Example 31: Synthesis of Compound 31

[0298] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl tetrahydro-2H-pyran-3-carboxylate

[0299] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)tetrahydro-2H-pyran-3-carboxylic acid ethyl ester

[0300]

[0301] Using a similar approach as in Example 1, compound (I) was reacted with tetrahydropyran-3-carboxylic acid to obtain compound 31.

[0302] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.60(d,1H),7.53(t,1H),6.76(dd,1H ),6.34(p,1H),3.92-3.81(m,1H),3.68(dt,,1H),3.65-3.47(m,3H),3.40(dd ,1H),3.20(d,1H),3.11(d,1H),2.64(d,2H),2.62-2.57(m,1H),2.20-2.06(m ,1H),2.03-1.91(m,3H),1.78-1.70(m,1H),1.67(dd,3H),1.63-1.43(m,4H).

[0303] Example 32: Synthesis of Compound 32

[0304] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl4,4-difluorocyclohexane-1-carboxylate

[0305] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 4,4-difluorocyclohexane-1-carboxylate

[0306]

[0307] Using a similar approach as in Example 1, compound (I) was reacted with 4,4-difluorocyclohexanecarboxylic acid to obtain compound 32.

[0308] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.59(s,1H),7.53(t,1H),6.77(dd,1H),6.32(q,1H),3.68-3.54(m,2H),3.20(d,1H),3.11( d,1H),2.70(t,2H),2.64(d,2H),2.58(d,1H),2.20-2.08(m,1H),2.00(s,2H),1.89-1.79(m,3H),1.67(d,3H),1.64-1.43(m,5H).

[0309] Example 33: Synthesis of Compound 33

[0310] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)3,3'-oxydipropionate

[0311] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)3,3'-oxodipropionate

[0312]

[0313] Using a similar approach as in Example 17, compound (I) was reacted with di(2-carboxyethyl) ether to obtain compound 33.

[0314] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,2H),8.60(s,2H),7.51(t,2H),6.71(dd,2H),6.32(q,2H),3.68-3.61(m,4H),3.58-3.47(m,4 H),3.17(d,2H),3.07(d,2H),2.60(d,4H),2.56(dd,4H),2.09-2.00(m,2H),1.96-1.85(m,4H),1.65(d,6H),1.60-1.44(m,4H).

[0315] Example 34: Synthesis of Compound 34

[0316] allyl((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)carbonate

[0317] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)allyl ethyl carbonate

[0318]

[0319] Using a similar approach as in Example 13, compound (I) was reacted with allyl chloroformate to obtain compound 34.

[0320] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.62(s,1H),7.53(t,1H),6.77(dd,1H),6.21(t,1H),5.96(ddt,1H),4.68(dt, 2H),3.66-3.54(m,2H),3.22(d,1H),3.08(d,1H),2.65(d,2H),2.11(d,1H),1.95(t,2H),1.73(d,3H),1.55(dqd,2H).

[0321] Example 35: Synthesis of Compound 35

[0322] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl tetrahydro-2H-pyran-2-carboxylate

[0323] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)tetrahydro-2H-pyran-2-carboxylic acid ethyl ester

[0324]

[0325] Using a similar approach as in Example 1, compound (I) was reacted with 2-tetrahydropyranoic acid to obtain compound 35.

[0326] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.60(d,1H),7.53(t,1H),6.76(dd,1H ),6.34(p,1H),4.32-4.27(m,1H),3.68(dt,1H),3.65-3.47(m,2H),3.40(dd, 1H),3.20(d,1H),3.11(d,1H),2.68(d,2H),2.62-2.57(m,2H),2.20-2.06(m ,1H),2.03-1.91(m,2H),1.78-1.70(m,2H),1.67(dd,3H),1.63-1.43(m,4H).

[0327] Example 36: Synthesis of Compound 36

[0328] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl5-methylfuran-2-carboxylate

[0329] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 5-methylfuran-2-carboxylate

[0330]

[0331] Using a similar approach as in Example 1, compound (I) was reacted with 5-methylfuran-2-carboxylic acid to obtain compound 36.

[0332] 1 H NMR(400MHz, DMSO-d6)δ11.99(s,1H),8.61(s,1H),7.52(t,1H),7.24(d,1H),6.74(dd,1H),6.47(q,1H),6.33(dd,1H),3.65-3.48(m,2H),3.22(d, 1H),3.05(d,1H),2.56(d,2H),2.33(s,3H),2.31(d,1H),2.14-2.01(m,1 H),1.99-1.91(m,1H),1.77(d,3H),1.75-1.71(m,1H),1.59-1.49(m,1H).

[0333] Example 37: Synthesis of Compound 37

[0334] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2,4-dimethylbenzoate

[0335] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 2,4-dimethylbenzoate

[0336]

[0337] Using a similar approach as in Example 1, compound (I) was reacted with 2,4-dimethylbenzoic acid to obtain compound 37.

[0338] 1 H NMR(400MHz,DMSO-d6)δ11.97(s,1H),8.60(s,1H),7.78(d,1H),7.51(t,1H), 7.15(s,1H),7.09(dd,1H),6.74(dd,1H),6.52(q,1H),3.67-3.49(m,2H),3.2 0(s,1H),3.02(d,1H),2.58(d,2H),2.54(s,3H),2.31(s,3H),2.13-2.00(m,1 H),1.99-1.89(m,1H),1.78(d,3H),1.73(s,1H),1.59(qd,1H),1.32(qd,1H).

[0339] Example 38: Synthesis of Compound 38

[0340] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-phenylacetate

[0341] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-ethyl phenylacetate

[0342]

[0343] Using a similar approach as in Example 1, compound (I) was reacted with phenylacetic acid to obtain compound 38.

[0344] 1 H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.60(s,1H),7.52(t,1H),7.33-7.22(m,5H),6.74(dd,1H),6.32(q,1H),3.72(d,2H),3. 54(ddd,2H),3.15(d,1H),2.95(d,1H),2.57(dd,2H),2.07(ddt,1H),1.88(ddt,2H),1.67(d,3H),1.51(qd,1H),1.35(qd,1H).

[0345] Example 39: Synthesis of Compound 39

[0346] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl3-phenylpropanoate

[0347] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 3-phenylpropionate

[0348]

[0349] Using a similar approach as in Example 1, compound (I) was reacted with 3-phenylpropionic acid to obtain compound 39.

[0350] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.61(s,1H),7.53(t,1H),7.28-7.22(m,5H),6.76(t,1H),6.32(q,1H),3.56(q,2H),3.17( d,1H),3.05(d,1H),2.89(t,2H),2.64-2.60(m,2H),2.10(s,1H),1.93(t,2H),1.64(d,3H),1.63-1.50(m,1H),1.49-1.37(m,1H).

[0351] Example 40: Synthesis of Compound 40

[0352] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)decanedioate

[0353] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)sebacate

[0354]

[0355] Using a similar approach as in Example 17, compound (I) was reacted with sebacic acid to obtain compound 40.

[0356] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,2H),8.59(s,2H),7.52(t,2H),6.75(dd,2H),6.30(q,2H),3.66-3.50(m,4H),3.18(d,2H), 3.09(d,2H),2.62(d,4H),2.31(td,4H),2.16-2.05(m,2H),1.95(d,4H),1.66(d,6H),1.59-1.44(m,8H),1.26-1.20(m,8H).

[0357] Example 41: Synthesis of Compound 41

[0358] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(carbonate)

[0359] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))di(carbonate)

[0360]

[0361] Compound (I) (324 mg, 1.0 mmol), DMAP (13 mg, 0.1 mmol), and Et3N (202 mg, 2.0 mmol) were added to DCM (3.0 mL), and Boc2O (220 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 5 min. 10% aqueous acetic acid solution (1 mL) was added to the reaction mixture. The mixture was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness, and purified by column chromatography to give intermediate B (212 mg, yield: 50%, white solid).

[0362] Intermediate B (212 mg, 0.5 mmol), DMAP (244 mg, 2.0 mmol), and Et3N (253 mg, 2.5 mmol) were added to DCM (3.0 mL), followed by p-nitrophenyl chloroformate (202 mg, 1.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by column chromatography to give intermediate E (180 mg, yield: 61.2%, pale yellow solid).

[0363] Intermediate E (180 mg, 0.3 mmol), DMAP (244 mg, 2.0 mmol), and Et3N (253 mg, 2.5 mmol) were added to DCM (3.0 mL), followed by the addition of polyethylene glycol (150 mg, 1.0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by column chromatography to obtain intermediate F (80 mg, yield: 25.3%, white solid).

[0364] Intermediate F (80 mg, 0.076 mmol) was added to DCM (2.0 mL), followed by trifluoroacetic acid (1.0 mL) and stirring at room temperature for 15 min. The reaction mixture was concentrated and purified by column chromatography to give compound 41 (30 mg, yield: 46.3%, white solid).

[0365] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,2H),8.61(s,2H),7.52(t,2H),6.75(dd,2H),6.17(q,2H),4.31-4.15(m,4H),3. 70-3.43(m,12H),3.20(d,2H),3.08(d,2H),2.62(d,,4H),2.10(s,2H),1.94(d,4H),1.70(d,6H),1.54(ddt,4H).

[0366] Example 42: Synthesis of Compound 43

[0367] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-cyclohexylacetate

[0368] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-cyclohexylethyl acetate

[0369]

[0370] Using a similar approach as in Example 1, compound (I) was reacted with 2-cyclohexaneacetic acid to obtain compound 43.

[0371] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.59(s,1H),7.53(t,1H),6.76(dd,1H),6.29(q,1H),3.66- 3.53(m,2H),3.19(d,1H),3.10(d,1H),2.64(d,2H),2.22(dd,2H),2.12(d,3H),1.96(d,2H),1.72-

[0372] 1.51(m, 11H) 1.68(d, 3H).

[0373] Example 43: Synthesis of Compound 44

[0374] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-cyclohexylideneacetate

[0375] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-cyclohexylethyl acetate

[0376]

[0377] Using a similar approach as in Example 1, compound (I) was reacted with 2-cyclohexylacetic acid to obtain compound 44.

[0378] 1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.60(s,1H),7.53(t,1H),6.77(dd,1H),6.30(q,1H),5.53(dt,1H),3.64-3.54(m,2H) ,3.19(d,1H),3.11(d,1H),3.00(d,2H),2.63(d,2H),2.20-2.05(m,1H),2.04-1.88(m,7H),1.67(d,3H),1.60-1.45(m,6H).

[0379] Example 44: Synthesis of Compound 45

[0380] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl(E)-but-2-enoate

[0381] (E)-(R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)butyl-2-enoic acid ethyl ester

[0382]

[0383] Using a similar approach as in Example 1, compound (I) was reacted with crotonic acid to obtain compound 45.

[0384] 1 H NMR(400MHz,DMSO-d6)δ11.98(d,1H),8.59(s,1H),7.52(t,1H),6.96(dq,1H),6.75(dd,1H),6.34(q,1H),5.95(dq,1H),3.64-3.49(m, 2H),3.18(d,1H),3.05(d,1H),2.60(d,2H),2.17-2.04(m,1H),1.92(ddt,2H),1.85(dd,3H),1.68(d,3H),1.55(qd,1H),1.43(tt,1H).

[0385] Example 45: Synthesis of Compound 46

[0386] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl3-methylbut-2-enoate

[0387] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)3-methylbutyl-2-enoic acid ethyl ester

[0388]

[0389] Using a similar approach as in Example 1, compound (I) was reacted with 3,3-dimethylacrylic acid to obtain compound 46.

[0390] 1 H NMR(400MHz,DMSO-d6)δ11.98(s,1H),8.59(s,1H),7.51(t,1H),6.74(dd,1H),6.31(q,1H),5.73( p,1H),3.57(qd,2H),3.18(d,1H),3.06(d,1H),2.60(d,2H),2.15(d,3H),2.11-2.02(m,1H),1.98-

[0391] 1.89(m,2H),1.88(d,3H),1.67(d,3H),1.56(qd,1H),1.45(qd,1H).

[0392] Example 46: Synthesis of Compound 47

[0393] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl benzoate

[0394] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl benzoate

[0395]

[0396] Using a similar approach as in Example 1, compound (I) was reacted with benzoic acid to obtain compound 47.

[0397] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.62(s,1H),8.11-7.96(m,2H),7.83-7.60(m,1H),7.52(td,3H),6.74(dd,1H),6.57(q,1H),3.63-3. 48(m,2H),3.23(d,1H),3.01(d,1H),2.55(d,2H),2.07-1.99(m,1H), 1.93(dt,1H),1.82(d,3H),1.66(dt,1H),1.56(qd,1H),1.20(qd,1H).

[0398] Example 47: Synthesis of Compound 48

[0399] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl4-methylbenzoate

[0400] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 4-methylbenzoate

[0401]

[0402] Using a similar approach as in Example 1, compound (I) was reacted with 4-methylbenzoic acid to obtain compound 48.

[0403] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.62(s,1H),7.89(d,2H),7.52(t,1H),7.31(d,2H),6.74(dd,1H),6.55(q,1H),3.64-3.47(m,2H), 3.23(d,1H),3.00(d,1H),2.55(d,2H),2.33(s,3H),2.04(dp,1H),1.93(dt,1H),1.80(d,3H),1.66(dt,1H),1.57(qd,1H),1.21(qd,1H).

[0404] Example 48: Synthesis of Compound 49

[0405] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)carbonate

[0406] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)carbonate

[0407]

[0408] Compound (I) (324 mg, 1.0 mmol) and NaH (40 mg, 1.0 mmol) were added to DMF (3.0 mL), cooled to 0 °C, and CDI (N,N'-carbonyldiimidazole, 162 mg, 1.0 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and purified by column chromatography to give compound 49 (240 mg, yield: 71.2%, white solid).

[0409] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.60(s,2H),7.53(t,2H),6.76(dd,2H),6.24(q,2H),3.59(q,4H), 3.23(d,2H),3.07(d,2H),2.65(d,4H),2.18-2.09(m,2H),2.01-1.93(m,4H),1.77(d,6H),1.60(qd,4H).

[0410] Example 49: Synthesis of Compound 50

[0411] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl icosanoate

[0412] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl eicosanoate

[0413]

[0414] Using a similar approach as in Example 1, compound (I) was reacted with n-eicosanoic acid to obtain compound 50.

[0415] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.59(s,1H),7.52(t,1H),6.75(dd,1H),6.30(q,1H),3.65-3.51(m,2H),3.24-3.1 5(m,1H),3.09(d,1H),2.62(d,2H),2.32(td,2H),2.11(dtd,1H),1.94(dd,2H),1.66(d,3H),1.52(qd,4H),1.22(d,35H).

[0416] Example 50: Synthesis of Compound 51

[0417] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cinnamate

[0418] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl cinnamate

[0419]

[0420] Using a similar approach as in Example 1, compound (I) was reacted with cinnamic acid to obtain compound 51.

[0421] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.63(s,1H),7.77-7.67(m,3H),7.53(t,1H),7.42(dd,3H),6.77(dd,1H),6.72(d,1H),6.46(q,,1H),3.6 6-3.52(m,2H),3.23(d,1H),3.13(d,1H),2.60(d,2H),2.08(q,1H),1.9 5(dt,1H),1.90-1.80(m,1H),1.76(d,3H),1.59(qd,1H),1.46(qd,1H).

[0422] Example 51: Synthesis of Compound 52

[0423] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl1-hydroxy-2-naphthoate

[0424] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 1-hydroxy-2-naphthoate

[0425]

[0426] Using a similar approach as in Example 1, compound (I) was reacted with 2-hydroxynaphthoic acid to obtain compound 52.

[0427] 1 H NMR(400MHz,DMSO-d6)δ12.05(s,1H),11.89(s,1H),8.65(s,1H),8.33(d,1H), 7.92(d,1H),7.77-7.68(m,2H),7.62(t,1H),7.54(t,1H),7.40(d,1H),6.76(dd ,1H),6.71(q,1H),3.57(dtd,2H),3.27(d,1H),3.05(d,1H),2.53(d,2H),2.13 -2.01(m,1H),2.00-1.91(m,1H),1.89(d,3H),1.72-1.54(m,2H),1.22(qd,1H).

[0428] Example 52: Synthesis of Compound 55

[0429] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-((2,3-dimethylphenyl)amino)benzoate

[0430] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-((2,3-dimethylphenyl)amino)ethyl benzoate

[0431]

[0432] Using a similar approach as in Example 1, compound (I) was reacted with mefenamic acid to obtain compound 55.

[0433] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),9.24(s,1H),8.61(s,1H),7.87(dd,1H),7.52(t,1H) ,7.33(ddd,1H),7.13(d,2H),7.06(dd,1H),6.75(dd,1H),6.69-6.60(m,3H),3.63-3.48(m ,2H),3.24(d,1H),3.03(d,1H),2.48-2.43(m,2H),2.29(s,3H),2.11(s,3H),2.09-2.00(m ,1H),1.98-1.90(m,1H),1.83(d,3H),1.79-1.70(m,1H),1.56(qd,1H),1.35-1.24(qd,1H).

[0434] Example 53: Synthesis of Compound 56

[0435] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-isopropylbenzoate

[0436] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-isopropylbenzoate ethyl ester

[0437]

[0438] Using a similar approach as in Example 1, compound (I) was reacted with 2-isopropylbenzoic acid to obtain compound 56.

[0439] 1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.61(s,1H),7.71(dd,1H),7.59-7.4 5(m,3H),7.28(td,1H),6.77(dd,1H),6.53(q,1H),3.71(h,1H),3.60(dt,2H ),3.29-3.19(m,1H),3.07(d,1H),2.61(d,2H),2.19-2.04(m,1H),1.97(dt ,1H),1.86(dt,1H),1.80(d,3H),1.61(qd,1H),1.46(qd,1H),1.21(dd,6H).

[0440] Example 54: Synthesis of Compound 57

[0441] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl adamantane-1-carboxylate

[0442] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)adamantane-1-carboxylic acid ethyl ester

[0443]

[0444] Using a similar approach as in Example 1, compound (I) was reacted with adamantane carboxylic acid to obtain compound 57.

[0445] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.60(s,1H),7.53(t,1H),6.76(dd,1H),6.30(q,1H),3.59(t,2H),3.2 6-3.16(m,1H),3.08(d,1H),2.64(d,2H),2.17-2.04(m,1H),1.95(dt,5H),1.82(d,6H),1.68-1.50(m,11H).

[0446] Example 55: Synthesis of Compound 58

[0447] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-propylpentanoate

[0448] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-propylpentanoate ethyl ester

[0449]

[0450] Using a similar approach as in Example 1, compound (I) was reacted with 2-propylvaleric acid to obtain compound 58.

[0451] 1 H NMR (400MHz, DMSO-d6) δ12.00(s,1H),8.58(s,1H),7.53(t,1H),6.76(dd,1H),6.29(q,1H),3.69-3.56(m,2H),3.18(d,1H),3.11(d,1H),2.64( d,2H),2.36(tt,1H),2.19-2.06(m,1H),2.00-1.89(m,2H),1.66(d,3H) ,1.62-1.46(m,4H),1.44-1.32(m,2H),1.29-1.20(m,4H),0.84(dt,6H).

[0452] Example 56: Synthesis of Compound 59

[0453] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2,4-dichlorobenzoate

[0454] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 2,4-dichlorobenzoate

[0455]

[0456] Using a similar approach as in Example 1, compound (I) was reacted with 2,4-dichlorobenzoic acid to obtain compound 59.

[0457] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.62(s,1H),7.93(d,1H),7.81(d,1H),7.60-7.50(m,2H),6.77(dd,1H),6.57(q,1H),3.64-3.52(m, 2H),3.25(d,1H),3.04(d,1H),2.60(d,2H),2.16-2.04(m,1H),1.96( dt,1H),1.86-1.84(m,1H),1.82(d,3H),1.59(qd,1H),1.42(qd,1H).

[0458] Example 57: Synthesis of Compound 60

[0459] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-ethylbenzoate

[0460] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 2-ethylbenzoate

[0461]

[0462] Using a similar approach as in Example 1, compound (I) was reacted with 2-ethylbenzoic acid to obtain compound 60.

[0463] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.61(s,1H),7.82(dd,1H),7.60-7.46(m,2H),7.41-7.27(m,2H),6.76(dd,1H),6.54(q,1H),3.59(dtd,2 H),3.24(d,1H),3.06(d,1H),2.95(q,2H),2.59(d,2H),2.18-2.04(m,1 H),1.96(dt,1H),1.81(d,4H),1.60(qd,1H),1.39(qd,1H),1.16(t,3H).

[0464] Example 58: Synthesis of Compound 61

[0465] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-(4-isobutylphenyl)propanoate

[0466] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2-(4-isobutylphenyl)propionate ethyl ester

[0467]

[0468] Using a similar approach as in Example 1, compound (I) was reacted with 2-(4-isobutylphenyl)propionic acid to obtain compound 61.

[0469] 1 H NMR(400MHz,DMSO-d6)δ12.01(dt,1H),8.59(d,1H),7.52(dt,1H),7.18(dd,2H),7.09(d,1 H),7.03(d,1H),6.72(ddd,1H),6.31(q,1H),3.84-3.71(m,1H),3.62-3.39(m,2H),3.18(d ,1H),3.02(dd,1H),2.65-2.53(m,2H),2.38(dd,2H),2.16-1.97(m,1H),1.97-1.71(m,3H) ,1.69(d,2H),1.55(d,2H),1.41(dd,3H),1.16(qd,1H),0.83(dd,,3H),0.80-0.75(m,3H).

[0470] Example 59: Synthesis of Compound 62

[0471] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl tetradecanoate

[0472] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl tetradecanoate

[0473]

[0474] Using a similar approach as in Example 1, compound (I) was reacted with n-tetradecanoic acid to obtain compound 62.

[0475] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.59(s,1H),7.53(t,1H),6.76(dd,,1H),6.30(q,1H),3.64-3.52(m,2H),3.18(d,1H),3.10(d ,1H),2.62(d,2H),2.32(td,2H),2.12(ddh,1H),2.00-1.91(m,2H),1.66(d,3H),1.60-1.44(m,4H),1.28-1.21(m,20H),0.85(t,3H).

[0476] Example 60: Synthesis of Compound 63

[0477] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl palmitate

[0478] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl palmitate

[0479]

[0480] Using a similar approach as in Example 1, compound (I) was reacted with palmitic acid to obtain compound 63.

[0481] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.59(s,1H),7.52(t,1H),6.75(dd,1H),6.30(q,1H),3.65-3.53(m,2H),3.22-3.14(m,1H),3.14-3.04(m,1 H),2.62(d,2H),2.32(td,2H),2.17-2.06(m,1H),2.00-1.89(m,2H),1.6 6(d,,3H),1.62-1.41(m,4H),1.28-1.21(m,24H),0.85(t,J=6.7Hz,3H).

[0482] Example 61: Synthesis of Compound 64

[0483] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-bromobenzoate

[0484] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 2-bromobenzoate

[0485]

[0486] Using a similar approach as in Example 1, compound (I) was reacted with 2-bromobenzoic acid to obtain compound 64.

[0487] 1 H NMR(400MHz,DMSO-d6)δ12.03(s,1H),8.63(s,1H),7.85(dd,1H),7.81-7.75(m,1H),7.52(ddd,3H),6.81-6.74(m,1H),6.58(q ,1H),3.59(q,2H),3.25(d,1H),3.06(d,1H),2.61(d,2H),2.12(q,,1H),1.97(d,1H),1.83(d,4H),1.61(qd,1H),1.48(qd,1H).

[0488] Example 62: Synthesis of Compound 65

[0489] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2-methylbenzoate

[0490] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 2-methylbenzoate

[0491]

[0492] Using a similar approach as in Example 1, compound (I) was reacted with 2-methylbenzoic acid to obtain compound 65.

[0493] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.62(s,1H),7.88(dd,1H),7.53(t,1 H),7.49(td,1H),7.35(d,1H),7.30(t,1H),6.76(dd,1H),6.55(q,1H),3.68 -3.51(m,2H),3.24(d,1H),3.05(d,1H),2.60(d,2H),2.58(s,3H),2.09(dt t,1H),1.95(dd,1H),1.81(d,3H),1.75(t,1H),1.60(qd,1H),1.34(qd,1H).

[0494] Example 63: Synthesis of Compound 66

[0495] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl stearate

[0496] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl stearate

[0497]

[0498] Using a similar approach as in Example 1, compound (I) was reacted with stearic acid to obtain compound 66.

[0499] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.59(s,1H),7.53(t,1H),6.76(dd,1H),6.30(q,1H),3.65-3.53(m,2H),3.18(d,1H),3.10(d,1H), 2.63(d,2H),2.39-2.25(m,2H),2.12(td,1H),1.99-1.91(m,2H),1.66(d,3H),1.61-1.45(m,4H),1.28-1.18(m,28H),0.90-0.81(m,3H).

[0500] Example 64: Synthesis of Compound 67

[0501] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl2'-fluoro-[1,1'-biphenyl]-4-carboxylate

[0502] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)2'-fluoro-[1,1'-biphenyl]-4-carboxylic acid ethyl ester

[0503]

[0504] Using a similar approach as in Example 1, compound (I) was reacted with 2-fluorobiphenyl-4-carboxylic acid to obtain compound 67.

[0505] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,1H),8.63(s,1H),8.15-8.06(m,2H),7.71(dt,2H) ),7.59(td,1H),7.53(t,1H),7.48(dddd,1H),7.39-7.29(m,2H),6.76(dd,1H),6.6 1(q,1H),3.65-3.49(m,2H),3.25(d,1H),3.06(d,1H),2.57(d,2H),2.13-2.01(m,1 H),1.97-1.91(m,1H),1.83(d,3H),1.76-1.69(m,1H),1.59(qd,1H),1.25(qd,1H).

[0506] Example 65: Synthesis of Compound 68

[0507] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl4-octylbenzoate

[0508] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)4-octylbenzoate ethyl ester

[0509]

[0510] Using a similar approach as in Example 1, compound (I) was reacted with 4-octylbenzoic acid to obtain compound 68.

[0511] 1 H NMR(400MHz,DMSO-d6)δ12.01(s,1H),8.62(s,1H),7.91(d,2H),7.52(t,1H), 7.32(d,2H),6.74(dd,1H),6.56(q,1H),3.56(dddd,2H),3.28-3.18(m,1H),3 .01(d,1H),2.64(t,2H),2.55(d,2H),2.12-1.99(m,1H),1.94(dt,1H),1.80( d,3H),1.72-1.63(m,1H),1.62-1.53(m,3H),1.31-1.16(m,12H),0.84(t,3H).

[0512] Example 66: Synthesis of Compound 69

[0513] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)terephthalate

[0514] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)paraben

[0515]

[0516] Using a similar approach as in Example 17, compound (I) was reacted with the starting material p-benzoic acid to obtain compound 69.

[0517] 1 H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.62(s,2H),8.12(s,4H),7.52(t,2H),6.73(dd,2H),6.60(q,2H),3.54(tdd,4H),3.28-3.22( m,2H),2.97(dd,2H),2.54(s,2H),2.10-1.97(m,2H),1.96-1.90(m,2H),1.83(d,6H),1.68-1.60(m,2H),1.54(qd,2H),1.14(qd,2H).

[0518] Example 67: Synthesis of Compound 70

[0519] 2,2'-((((pyrazine-2,5-diylbis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl))bis(piperidine-1,4-diyl))diacetonitrile

[0520] 2,2'-((((pyrazine-2,5-diylbis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl)bis(piperidine-1,4-diyl)diacetonitrile

[0521]

[0522] Using a similar approach to that in Example 48 (Compound 49), Compound (I) was reacted with 2,5-dichloropyrazine to give Compound 70.

[0523] 1 H NMR(400MHz,DMSO-d6)δ12.00(s,2H),8.56(s,2H),8.10(s,2H),7.56(t,2H),6.74(dd,2H),6.67(q,2H),3.65-3.49(m ,4H),3.22(d,2H),3.11(d,2H),2.56(d,4H),2.05(d,2H),1.96-1.81(m,8H),1.73(d,2H),1.46(qd,2H),1.01(qd,2H).

[0524] Example 68: Synthesis of Compound 71

[0525] tris((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)benzene-1,3,5-tricarboxylate

[0526] Tris((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)phenyl-1,3,5-tricarboxylate

[0527]

[0528] Using a similar approach as in Example 17, compound (I) was reacted with isobenzoic acid to obtain compound 71.

[0529] 1 H NMR(400MHz,Chloroform-d)δ12.29(s,3H),8.86(s,3H),8.67(s,3H),7.37(t,3H),6.60(q,3H),6.52(dd,3H),3.79-3.66(m,3 H),3.56(t,3H),3.15(s,6H),2.35(d,6H),2.04(d,3H),1.99-1.92(m,3H),1.86(d,12H),1.74-1.68(m,3H),1.52-1.39(m,3H).

[0530] Example 69: Synthesis of Compound 72

[0531] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)2,5-dichloroterephthalate

[0532] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)2,5-dichloroparaben

[0533]

[0534] Using a similar approach as in Example 17, compound (I) was reacted with 2,5-dichloro-p-benzoic acid to obtain compound 72.

[0535] 1 H NMR(400MHz,DMSO-d6)δ12.01(t,2H),8.60(s,2H),8.06(s,2H),7.52(t,2H),6.75(dd,2H),6.58(q,2H),3.66-3.50(m,4H ),3.24(d,2H),3.04(d,2H),2.60(d,4H),2.17-2.04(m,2H),2.02-1.94(m,2H),1.83(d,8H),1.59(qd,2H),1.44(qd,2H).

[0536] Example 70: Synthesis of Compound 74

[0537] 2,2',2"-((((1R,1'R,1"R)-((1,3,5-triazine-2,4,6-triyl)tris(oxy))tris(ethane-1,1-diyl))tris(i midazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl))tris(piperidine-1,4-diyl))triacetonitrile

[0538] 2,2',2”-((((1R,1'R,1”R)-((1,3,5-triazine-2,4,6-triyl)tri(oxy))tri(ethane-1,1-diyl)tri(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl)tri(piperidine-1,4-diyl)triacetonitrile

[0539]

[0540] Using a similar approach to that in Example 48 (Compound 49), compound (I) was reacted with cyanuric trichlorotrichloromel to obtain compound 74.

[0541] 1 H NMR(400MHz,DMSO-d6)δ11.94(s,3H),8.53(s,3H),7.45(t,3H),6.60(dd,3H),6.53(q,3H),3.49(td,3H),3.28(t,3H),3.14-3.05(m, 3H),2.98(d,3H),2.49-2.34(m,6H),1.99-1.91(m,3H),1.84(d,3H),1.69(d,9H),1.62-1.52(m,3H),1.44(dt,3H),1.15-1.00(m,3H).

[0542] Example 71: Synthesis of Compound 75

[0543] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)isophthalate

[0544] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)isophthalate

[0545]

[0546] Using a similar approach as in Example 17, compound (I) was reacted with isophthalic acid to obtain compound 75.

[0547] 1 H NMR(400MHz,DMSO-d6)δ12.02(t,2H),8.61(s,2H),8.54(t,1H),8.27(dd,2H),7.67(t,1H),7.53(t,2H),6.73(dd,2H),6.58(q,2H),3.62-3.47(m ,4H),3.22(dd,2H),3.03-2.95(m,2H),2.46(d,4H),2.07-1.94(m,2H),1 .92-1.83(m,2H),1.81(d,6H),1.65(dt,2H),1.53(qd,2H),1.15(qd,2H).

[0548] Example 72: Synthesis of Compound 76

[0549] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)methylphosphonate

[0550] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)methyl phosphate

[0551]

[0552] Using a similar approach as in Example 17, compound (I) was reacted with methylphosphine dichloro to obtain compound 76.

[0553] 1H NMR (400) MHz,DMSO-d6)δ12.01(dt,2H),8.58(d,2H),7.52(dt,2H),6.73(ddd,2H),5.99 (p,1H),5.88-5.78(m,1H),3.60(dtd,2H),3.53-3.42(m,2H),3.21(d,2H),3.1 0-2.95(m,2H),2.58(d,2H),2.26(d,2H),2.18-2.07(m,1H),2.03-1.87(m,3H) ,1.79(d,4H),1.75-1.68(m,2H),1.65(d,4H),1.51(d,3H),1.23-1.11(m,2H).

[0554] Example 73: Synthesis of Compound 77

[0555] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)phthalate

[0556] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)phthalate

[0557]

[0558] Using a similar approach as in Example 17, compound (I) was reacted with phthalic acid to obtain compound 77.

[0559] 1 H NMR(400 MHz, DMSO-d6)δ12.01(t,2H),8.61(s,2H),7.76(dd,2H),7.67(dd,2H),7.53(t,2H),6.75(dd,2H),6.48(q,2H),3.55(dtd ,4H),3.19(dt,2H),3.06(d,2H),2.53(d,4H),2.03(dt,2H),1.99-1.88(m,2H),1.73(d,8H),1.52(dd,2H),1.31(dd,2H).

[0560] Example 74: Synthesis of Compound 78

[0561] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl1-naphthoate

[0562] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl 1-naphthoate

[0563]

[0564] Using a similar approach as in Example 1, compound (I) was reacted with 1-naphthoic acid to obtain compound 78.

[0565] 1 H NMR(400 MHz, DMSO-d6)δ12.01(s,1H),8.89(dd,1H),8.63(s,1H),8.20(dt,2H),8. 04(dd,1H),7.69(ddd,1H),7.65-7.59(m,2H),7.52(t,1H),6.75(dd,1H),6 .68(q,1H),3.58(dddd,2H),3.27(d,1H),3.05(d,1H),2.54(d,2H),2.06( ddq,1H),2.01-1.93(m,1H),1.88(d,3H),1.75-1.56(m,2H),1.35(qd,1H).

[0566] Example 75: Synthesis of Compound 79

[0567] 2,2'-((((pyrimidine-2,4-diylbis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl))bis(piperidine-1,4-diyl))diacetonitrile

[0568] 2,2'-((((pyrazine-2,4-diylbis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl)bis(piperidine-1,4-diyl)diacetonitrile

[0569]

[0570] Using a similar approach as in Example 48 (Compound 49), compound (I) was reacted with 2,4-dichloropyrimidine to obtain compound 79.

[0571] 1 H NMR(400MHz,DMSO-d6)δ11.92(dt,2H),8.55(d,2H),8.29(d,1H),7.47(t,1H),7.39(t,1H),6.64(dd,2H),6.59-6.50(m,3H),3.58-3.42(m,2H) ,3.30(s,1H),3.13(td,4H),2.74(d,1H),2.49-2.39(m,4H),1.91(td,4 H),1.78-1.66(m,7H),1.55-1.35(m,3H),1.09(pd,1H),0.80(dtd,1H).

[0572] Example 76: Synthesis of Compound 80

[0573] 2,2',2"-((((pyrimidine-2,4,6-triyltris(oxy))tris(ethane-1,1-diyl))tris(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl))tris(piperidine-1,4-diyl))triacetonitrile

[0574] 2,2',2”-((((pyrimidin-2,4,6-triyltri(oxo))tri(ethane-1,1-diyl))tri(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl)tri(piperidine-1,4-diyl)triacetonitrile

[0575]

[0576] Using a similar approach to that in Example 48 (Compound 49), Compound (I) was reacted with 2,4,6-trichloropyrimidine to give Compound 80.

[0577] 1H NMR(400MHz,DMSO-d6)δ11.94(s,3H),8.55(s,2H),8.53(s,1H),7.45(dt, 3H),6.63(dd,2H),6.55(q,2H),6.48(dd,1H),6.41(q,1H),5.99(s,1H),3 .61-3.36(m,6H),3.14-2.95(m,6H),2.43-2.26(m,3H),2.09-1.94(m,3H) ,1.92-1.83(m,3H),1.79-1.59(m,15H),1.56-1.40(m,3H),1.14(td,3H).

[0578] Example 77: Synthesis of Compound 81

[0579] 2,2'-(((((1,2,4,5-tetrazine-3,6-diyl)bis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl))bis(piperidine-1,4-diyl))diacetonitrile

[0580] 2,2'-(((((1,2,4,5-tetraazine-3,6-diyl)bis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl)diacetonitrile

[0581]

[0582] Using a similar approach to that in Example 48 (Compound 49), Compound (I) was reacted with dichlorotriazine to obtain Compound 81.

[0583] 1 H NMR(400MHz,DMSO-d6)δ12.03(s,2H),8.58(s,2H),7.54(t,2H),6.76(dd,2H),6.68(q,2H),3.65-3.49(m,4H),3 .23(d,2H),3.14(d,2H),2.54(d,4H),2.05(d,2H),1.95-1.83(m,8H),1.74(d,2H),1.48(qd,2H),1.03(qd,2H).

[0584] Example 78: Synthesis of Compound 82

[0585] bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)naphthalene-1,4-dicarboxylate

[0586] Bis((R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl)naphthalene-1,4-dicarboxylate

[0587]

[0588] Using a similar approach as in Example 17, compound (I) was reacted with 1,4-naphthalenedicarboxylic acid to obtain compound 82.

[0589] 1 H NMR(400MHz,DMSO-d6)δ12.01(t,2H),8.87(dt,2H),8.61(s,2H),8.14(s,2H),7.80(dt,2H),7.52(t,2H),6.79-6.72(m,2H),6.68(q,2H ),3.57(dt,4H),3.28(d,2H),3.05(d,2H),2.55(d,4H),2.06(s,2H),1.96(d,2H),1.88(d,6H),1.73(d,2H),1.62(td,2H),1.35(qd,2H).

[0590] Example 79: Synthesis of Compound 83

[0591] 2,2'-((((pyrimidine-4,6-diylbis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl))bis(piperidine-1,4-diyl))diacetonitrile

[0592] 2,2'-((((pyrazine-4,6-diylbis(oxy))bis(ethane-1,1-diyl))bis(imidazo[4,5-d]pyrrolo[2,3-b]pyridine-2,1(6H)-diyl)bis(piperidine-1,4-diyl)diacetonitrile

[0593]

[0594] Using a similar approach to that in Example 48 (Compound 49), compound (I) was reacted with 4,6-dichloropyrimidine to give compound 83.

[0595] 1 H NMR(400MHz,DMSO-d6)δ11.99(s,2H),8.58(s,2H),8.5 1 (s, 1 H), 7.5 1 (t,2H),6.35(s, 1 H), 6.8 1 -6.70(m, 4H), 3.6 1 -3.46(m,4H),3. 1 8(d,2H), 3.09(d,2H), 2.09- 1 .97(m,2H), 1 .95- 1 .86(m,2H), 1 .77(d,8H), 1 0.47(qd,2H), 0.94(qd,2H).

[0596] Example 80: Synthesis of Compound 84

[0597] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl heptadecanoate

[0598] (R)-1-(1-(4-(cyanomethyl)piperidin-1-yl)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2-yl)ethyl heptadecanoate

[0599]

[0600] Using a similar approach as in Example 1, compound (I) was reacted with heptadecanoic acid to obtain compound 84.

[0601] 1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),8.58(s,1H),7.52(t,1H),6.75(dd,1H),6.29(q,1H),3.65-3.52(m,2H),3.26(dt,1H),3.18(d,1H) ,3.09(d,1H),2.62(d,2H),2.14-2.05(m,1H),2.00-1.89(m,2H),1.6 5(d,3H),1.61-1.41(m,7H),1.22(d,25H),1.08(t,1H),0.99(t,1H).

[0602] Rabbit plasma hydrolysis experiment

[0603] The compound of this application was dissolved in DMSO (dimethyl sulfoxide) to prepare a 1 mM solution. 10 μL of the above solution and 20 μL of rabbit plasma were diluted to 1 mL with distilled water, and the resulting mixture was incubated at 37°C for 24 hours. 1 mL of acetonitrile was added to the mixture. The concentration of the compound of this application and the concentration of the compound of formula (I) in the mixture were determined by HPLC using external standard method. The hydrolysis ratio of the compound of this application after 24 hours and the formation ratio of the compound of formula (I) were calculated (based on 100% hydrolysis). The results are shown in Table 1 below.

[0604] Table 1 Results of rabbit plasma hydrolysis experiment

[0605]

[0606] In vivo metabolism experiments of compounds

[0607] 50 mg of the compound of this application and 50 mg of Tween 80 were suspended in 2 mL of distilled water and ground into a stable suspension. 50 μL of the suspension was injected into the suprachoroidal space of a rabbit eye using a microneedle. After culturing for 7 or 28 days, the injected rabbit eyeballs were removed; the posterior part of the eye tissue was excised, weighed, and homogenized with 19 times its weight in methanol. The homogenate was centrifuged, and the supernatant was collected. The concentrations of the compound of this application and the compound of formula (I) in the supernatant were determined using HPLC with external standard method. The remaining amount of the compound of this application and the tissue fluid concentration of the compound of formula (I) were calculated. The above data were repeated three times, and the average value was calculated. The results are shown in Table 2 below.

[0608] Table 2 Results of in vivo metabolism experiments of the compounds

[0609]

[0610] Note: "NA" means it does not exist.

[0611] As can be seen from the above results, the compound represented by formula (II) or formula (II'), its stereoisomer or its pharmaceutically acceptable salt provided in this application can be completely converted into the compound of formula (I) in the suprachoroidal space after injection, and can play a therapeutic role in posterior uveitis; and has a long residence time in the suprachoroidal space after injection.

[0612] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of this application.

Claims

1. A compound of formula (II) or formula (II'), its stereoisomer, or a pharmaceutically acceptable salt thereof, in, R is selected from C1-C 20 Alkyl, -C(O)-R1, C1-C 20 Heteroalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 12 Aryl or 5-12 heteroaryl groups; R1 is selected from C1-C1 that is unsubstituted or substituted by one or more Ra. 20 Alkyl, unsubstituted or substituted with one or more Ra C1-C 20 Heteroalkyl, unsubstituted or C substituted with one or more Ra 3- C8 cycloalkyl, unsubstituted or substituted by one or more Ra C6-C 12 aryl, unsubstituted or 5-12 heteroaryl groups substituted with one or more Ra, -OC 3- C8 cycloalkyl, -OC 2- C4 alkenyl, unsubstituted or substituted with one or more Ra groups 2- C4 alkenyl, C that is not substituted or is substituted by one or more Ra 1- C8 alkoxy, unsubstituted or substituted by one or more Ra-membered heterocyclic alkyl groups; Ra is independently selected from C1-C each time it appears. 10 Alkyl, C 3- C8 cycloalkyl, unsubstituted or C6-C substituted with one or more Rb 12 Aryl, -OAc, methoxy, hydroxy, 3-8 membered heterocyclic alkyl, halogen, -NH- C6-C substituted with one or more methyl groups 12 Aryl group; Rb is selected from C1-C6 alkyl or methoxy groups; Y is selected from -C(O)-LC(O)-, -C(O)-, -Ar-, Or -P(O)R3-; C6 replaces L from -C1C2 1 -Asia C 2 Fang 0 Subunit, alkyl group, C-substitution 1 -C or 20 Encapsulated by a single alkyl group or multiple C groups 1 -C halogen 20 5C- α ... 1 1-2C 20 The aryl group of the alkylene halide is unsubstituted or selected from C6-C by one or more halogens Ar. 12 arylene or 5-12 heteroarylene; R3 is selected from C1-C 20 alkyl; X1, X2, and X3 are each independently selected from CH or N each time they appear; The heteroatom in the heteroaryl group, the heteroalkyl group, the heterocyclic alkyl group, the heteroalkylene group, and the heterocyclic aryl group is independently selected from O, N, or S.

2. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (II) is selected from: R1 is selected from C1-C1 that is unsubstituted or substituted by one or more Ra. 20 Alkyl, unsubstituted or C substituted with one or more Ra 3- C8 cycloalkyl, unsubstituted or substituted by one or more Ra C6-C 12 aryl, unsubstituted or 5-12 heteroaryl groups substituted with one or more Ra, -OC 3- C8 cycloalkyl, -OC 2- C4 alkenyl, unsubstituted or substituted with one or more Ra groups 2- C4 alkenyl, C that is not substituted or is substituted by one or more Ra 1- C8 alkoxy, unsubstituted or substituted by one or more Ra-membered heterocyclic alkyl groups; The Ra is independently selected from C1-C each time it occurs. 10 Alkyl, C 3- C8 cycloalkyl, unsubstituted or C6-C substituted with one or more Rb 12 Aryl, -OAc, methoxy, hydroxy, 3-8 membered heterocyclic alkyl, halogen, -NH- C6-C substituted with two methyl groups 12 Aryl; Rb is selected from C1-C6 alkyl or methoxy.

3. The compound according to claim 1 or 2, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The -OC 2- The C4 alkenyl group is selected from -O-CH2-CH=CH2; The unsubstituted or substituted C by one or more Ra 2- The C4 alkenyl group is selected from -CH=CH-CH3, -CH=C(CH3)2, or -CH=CH-C6-C. 12 Aryl.

4. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (II') is selected from: in, The L is selected from C1-C 20 Alkylene, C1-C 20 alkenyl, C1-C 20 Ethyne group, C1-C 20 Heteroalkyl, unsubstituted or C6-C substituted with two Cl groups 12 aryl; the C1-C 20 The heteroatom in the heteroalkylene group is selected from O; The Ar is selected from C6-C. 12 The heteroatom in the 5-12-membered heteroaryl group is selected from N.

5. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein, The compound represented by formula (II') is selected from: in, R3 is selected from C1-C3 alkyl groups.

6. The compound according to claim 1, its stereoisomers, or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (II') is selected from: Wherein, X1, X2, and X3 are all N; or, two of X1, X2, and X3 are selected from N, and the other is selected from CH.

7. A compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

8. A pharmaceutical composition comprising the compound of any one of claims 1-7, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. The use of any compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8 in the preparation of a medicament for treating immune-related diseases; preferably, the immune-related disease is posterior uveitis-related ophthalmological disease.

10. A method for treating an immune-related disease, the method comprising administering a therapeutically effective amount of any one of claims 1-7, its stereoisomers or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 8 to a subject in need of suprachoroidal administration; preferably, the immune-related disease is an ophthalmic posterior uveitis-related disease.

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