AHR AGONISTS

Abstract

The present disclosure relates to certain AHR agonist compounds, their method of making, and to pharmaceutical compositions comprising the compounds and to methods of using the compounds to treat immune-mediated diseases, such as psoriasis and atopic dermatitis.

Claims

1. A compound of formula: ##STR00521## wherein: ring A is a 5-membered or 6-membered carbocycle; ring B is a phenyl, or a 5-membered or 6-membered heteroaryl having 1 or 3 heteroatoms, wherein each heteroatom of the heteroaryl is independently selected from N, S, and O; R is H or C.sub.1-3 alkyl; X is H, halo, C.sub.1-3 alkyl optionally substituted with one or more halo, or a C.sub.1-3 alkoxyl; Y is H, C.sub.1-4 alkyl, or C.sub.3-4 cycloalkyl, wherein the C.sub.1-4 alkyl is a primary or secondary alkyl; and Z is CH or N, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

2. The compound of claim 1, wherein R is H, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

3. The compound of claim 1, wherein ##STR00522## is selected from ##STR00523## a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

4. The compound of claim 1, having formula: ##STR00524## wherein: X is H or halo; Y is H or C.sub.1-3 alkyl; and W is CH or N, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

5. The compound of claim 1, wherein ##STR00525## is selected from the group consisting of: ##STR00526## a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

6. The compound of claim 1, wherein ring A is phenyl, or a pharmaceutically acceptable salt of each thereof.

7. The compound of claim 1, wherein ring A is ##STR00527## a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

8. The compound of claim 1, having the formula: ##STR00528## wherein: X is H or halo; Y is H or C.sub.1-3 alkyl; and W is CH or N, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

9. The compound of claim 1, wherein Z is N, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

10. The compound of claim 1, wherein Z is CH, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

11. The compound of claim 4, wherein W is N, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

12. The compound of claim 1, wherein X is F, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

13. The compound of claim 1, wherein Y is methyl, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

14. The compound of claim 1, selected from the table below, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof: TABLE-US-00015

15. The compound of claim 1, selected from the following table, or a pharmaceutically acceptable salt thereof: TABLE-US-00016

16. The compound of claim 1, having the formula of: ##STR00609## or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, having the formula of: ##STR00610## a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

18. The compound of claim 1, having the formula of: ##STR00611## or a pharmaceutically acceptable salt of each thereof.

19. The compound of claim 1, having the formula of: ##STR00612## a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

20. The compound of claim 1, selected from Table 2, 2A, and 3, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

21. A method of treating a disease or disorder selected from psoriasis, atopic dermatitis, ulcerative colitis, Crohn's disease, graft-versus-host disease, rheumatoid arthritis, and multiple sclerosis in a patient in need thereof, comprising administering to the patient an effective amount of a compound of claim 1, a stereoisomer or mixture of stereoisomers thereof, or a pharmaceutically acceptable salt of each thereof.

22. A compound of the formula: ##STR00613## or a salt thereof, wherein R.sup.0 is C.sub.1-3 alkyl.

23. A compound of the formula: ##STR00614## or a salt thereof, wherein R.sup.0 is C.sub.1-3 alkyl.

24. A process for preparing a compound of claim 23, comprising contacting a compound of formula: ##STR00615## with molecular hydrogen under conditions sufficient to provide the compound of claim 23.

Description

EXAMPLE 1

N-(5-Fluoropyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide

[0347] ##STR00444##

[0348] [1,2,4]Triazolo[4,3-a]quinoline-4-carboxylic acid (100 mg, 0.447 mmol) and 5-fluoropyrimidine-2-amine (80 mg, 0.672 mmol) were dissolved in DCM (5 mL). To this mixture, pyridine (180 mg, 2.26 mmol) was added followed by phosphoryl chloride (350 mg, 2.24 mmol). The reaction mixture was stirred at ambient temperature for 18 hrs. After this time, the reaction mixture was concentrated under reduced pressure, and the residue was triturated with DMF at 20? C. for 5 min. The solid was filtered and washed with DMF to give N-(5-fluoropyrimidin-2-yl)-[1,2,4]triazolo[4,3-a]quinoline-4-carboxamide as a white solid (77 mg, 48.0%). ES/MS (m/z): 309.1 (M+H).

EXAMPLE 2

N-(5-Fluoropyrimidin-2-yl)imidazo[1,2-a]quinoline-4-carboxamide

[0349] ##STR00445##

[0350] Imidazo[1,2-a]quinoline-4-carboxylic acid was reacted with 5-fluoropyrimidine-2-amine using a procedure analogous to that of Example 1 to give N-(5-fluoropyrimidin-2-yl)imidazo[1,2-a]quinoline-4-carboxamide as white solid (166 mg, 95%). ES/MS (m/z): 308.3 (M+H).

EXAMPLE 3

(R)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide Or (S)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide (Enantiomer 1) and

EXAMPLE 4

(R)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide Or (S)-6-Methyl-N-(pyridin-2-yl)-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide (Enantiomer 2)

[0351] ##STR00446##

[0352] 6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid (Preparation 2) (300 mg, 0.80 mmol) and pyridin-2-amine (120 mg, 1.6 mmol) were dissolved in dichloromethane (5 mL). To this mixture, pyridine (220 mg, 2.77 mmol) was added followed by phosphoryl chloride (200 mg, 1.3 mmol). The reaction mixture was stirred at ambient temperature for 18 hrs. After this time, the reaction mixture was poured into saturated aqueous NaCl (10 mL) and extracted with ethyl acetate (20 mL?3). The organic phases were combined and dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. This residue was purified via silica gel chromatography (4 g, 0-80% ethyl acetate in petroleum ether) to provide a crude product. The crude product is subsequently subject to chiral separation on a preparatory column under the following conditions to give the enantiomers:

[0353] Separation Condition A: [0354] Column: DAICEL CHIRALPAK AD 250?30 mm I.D., 10 ?m [0355] Mobile phase A: CO.sub.2 [0356] Mobile phase B: Ethanol (0.1% NH40H) [0357] Gradient: 40% B [0358] Flow rate: 80 mL/Min

[0359] Analysis was done by Supercritical Fluid Chromatography (SFC) under the following condition to give the Retention Time (RT): [0360] Column: Chiralpak OJ-3 50?4.6 mm I.D., 3 ?m [0361] Mobile phase A: CO.sub.2 [0362] Mobile phase B: Ethanol (0.05% DEA)

[0363] Gradient: a) 0-2.5 min: 5% B95% A ramping to 40% B60% A; [0364] b) 2.5 min-3.0 min: hold at 40% B60% A; [0365] c) 3.0 min-4.0 min: 40% B60% A ramping to 5% B95% A.

[0366] Flow rate: 4 ml/min

[0367] Column temperature: 35? C.

[0368] Automated backpressure regulator (ABPR) pressure: 1500 psi

[0369] Enantiomer 1 Retention time: 1.458 min

[0370] Enantiomer 2 Retention time: 1.566 min

[0371] Enantiomer 1 and enantiomer 2 are obtained at the above retention times (RT), and each dried to provide white solids. Enantiomer 1: (16.0 mg, 6.7%). ES/MS (m/z): 294.1 (M+H). Enantiomer 2: (17.6 mg, 7.4%). ES/MS (m/z): 294.1 (M+H).

[0372] The compounds in Table 1A were prepared using suitable starting material under conditions analogous to those of Examples 3 and 4. The starting material may be commercialized available or may be synthesized by referencing examples herein provided and common knowledge. The reaction time may be adjusted, for example, by monitoring with chromatography or similar means, to allow for reaction completion. Moreover, the separation and analytical conditions used are the same as those described for Examples 3 and 4.

TABLE-US-00008 TABLE 1A Examples 5 to 8 Ex. ES/MS (m/z) No. Chemical Name Structure (M + H) RT (min) 5 (S)-N-(5- Fluoropyrimidin-2-yl)- 6-methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4]triazolo [4,3-a]pyridine-4- carboxamide [00447] 313.1 1.602 6 (R)-N-(5- Fluoropyrimidin-2-yl)- 6-methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4]triazolo [4,3-a]pyridine-4- carboxamide [00448] 313.1 1.769 7 6-Methyl-N-(pyrimidin- 2-yl)-7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00449] 295.1 1.629 8 6-Methyl-N-(pyrimidin- 2-yl)-7,8-dihydro-6H- cyclopenta[e][1,2,4]triazolo [4,3-a]pyridine-4- carboxamide (enantiomer 2) [00450] 295.1 1.783

[0373] The compounds in Table 1B were prepared using suitable starting material under conditions analogous to those of Examples 3 and 4. The starting material may be commercialized available or may be synthesized by referencing examples herein provided and common knowledge. The reaction time may be adjusted, for example, by monitoring with chromatography or similar means, to allow for reaction completion. The crude product is subsequently subject to chiral separation on a preparatory column under Separation Condition A. Separation Condition A:

[0374] Column: DAICEL CHIRALPAK AD 250?30 mm I.D., 10 ?m

[0375] Mobile phase A: CO.sub.2

[0376] Mobile phase B: Ethanol (0.1% NH40H)

[0377] Gradient: 40% B

[0378] Flow rate: 80 mL/Min

[0379] Retention times are analyzed using an analytical column under the following condition, and the retention times are provided in Table 1B:

[0380] Column: (S,S)-Welk-0-1.8 50?4.6 mm I.D., 1.8 m

[0381] Mobile phase A: COS

[0382] Mobile phase B: 40 ethanol (0.05% DEA)

[0383] Flow rate: 2.8 mL/min

[0384] Column temperature: 35? C.

[0385] ABPR pressure: 1500 psi.

TABLE-US-00009 TABLE 1B Examples 9 to 12 ES/MS Ex. (m/z) RT No. Chemical Name Structure (M + H) (min) 9 6-Methyl-N-(pyridin-2-yl)-7,8- dihydro-6H- cyclopenta[e]imidazo[1,2- a]pyridine-4-carboxamide (enantiomer 1) [00451] 293.0 1.614 10 6-Methyl-N-(pyridin-2-yl)-7,8- dihydro-6H- cyclopenta[e]imidazo[1,2- a]pyridine-4-carboxamide (enantiomer 2) [00452] 293.0 2.230 11 6-Methyl-N-(pyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e]imidazo[1,2- a]pyridine-4-carboxamide (enantiomer 1) [00453] 294.1 3.231 12 6-Methyl-N-(pyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e]imidazo[1,2- a]pyridine-4-carboxamide (enantiomer 2) [00454] 294.1 2.296

[0386] The compounds in Table 1C were prepared using suitable starting material under conditions analogous to those of Examples 3 and 4. The starting material may be commercialized available or may be synthesized by referencing examples herein provided and common knowledge. The reaction time may be adjusted, for example, by monitoring with chromatography or similar means, to allow for reaction completion. The crude product is subsequently subject to chiral separation on a preparatory column to give the enantiomers under conditions analogous to Separation Condition A (with necessary variation in the mobile phase (e.g. MeOH, EtOH, isopropanol, ACN or 1:1 mixtures thereof) used and gradient (e.g. 35% B, 40% B, 55% B, or 60% B) to optimize the performance). The analytical conditions used are as follows and the retention times are provided in Table 1C:

[0387] Column: AD-3 50?4.6 mm I.D., 3p m

[0388] Mobile phase A: CO.sub.2

[0389] Mobile phase B: isopropanol (0.05% DEA)

[0390] Gradient: a) 0-2.5 min: 5% B95% A ramping to 40% B60% A; [0391] b) 2.5 min-3.0 min: hold at 40% B60% A; [0392] c) 3.0 min-4.0 min: 40% B60% A ramping to 5% B95% A.

[0393] Flow rate: 4 ml/min

[0394] Column temperature: 35? C.

[0395] Automated backpressure regulator (ABPR) pressure: 1500 psi.

TABLE-US-00010 TABLE 1C Examples 13 and 14 Ex. ES/MS (m/z) No. Chemical Name Structure (M + H) RT (min) 13 N-(5-Fluoropyrimidin- 2-yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e]imidazo[1,2- a]pyridine-4- carboxamide (enantiomer 1) [00455] 312.1 2.282 14 N-(5-Fluoropyrimidin- 2-yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e]imidazo[1,2- a]pyridine-4- carboxamide (enantiomer 2) [00456] 312.1 2.445

[0396] For clarity, enantiomer 1 above refers to the enantiomer that eludes out first from the stationary phase of the preparatory column; and enantiomer 2 above refers to the enantiomer that eludes out second from the stationary phase of the preparatory column.

[0397] Each compound described in Examples 1-14 are referred to as Compounds 1-14, respectively.

[0398] Compound 15 of Example 15 in Table 2 below can be synthesized according to the Schemes 1 and 3 described above with reference to conditions described for Examples 3 and 4 and separated using conditions similar to those described for Examples 3-14.

TABLE-US-00011 TABLE 2 Example 15 Ex. No. Chemical Name Structure 15 N-(5-Fluoropyrimidin-2-yl)-7,8- dihydro-6H- cyclopenta[e][1,2,4]triazolo[4,3- a]pyridine-4-carboxamide [00457]

[0399] The compounds 16 to 57 of Table 2A below were synthesized according to the Schemes 1-3 described above with reference to conditions described for Examples 3 and 4 and separated on a preparatory column under conditions analogous to Separation Condition A (with necessary variation in the type of column, mobile phase and gradient as specified in Table 2A).

TABLE-US-00012 TABLE 2A Examples 16 to 57 Variation ES/MS from Ex. (m/z) Separation No Chemical Name Structure (M + H) Condition A 16 17 N-(4-Fluorophenyl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(4-Fluorophenyl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00458] or [00459] 310.9 311.0 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Gradient: Isocratic 40% B 18 19 6-Methyl-N-phenyl- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) 6-Methyl-N-phenyl- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00460] or [00461] 292.9 293.0 Column: DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 20 21 N-(2-methoxyphenyl)- 6-methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) N-(2-methoxyphenyl)- 6-methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00462] or [00463] 323.2 323.2 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 22 23 N-(5-Fluorothiazol-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(5-Fluorothiazol-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00464] or [00465] 318.0 318.1 Gradient: Isocratic 50% B Flow Rate: 120 mL/min 24 25 6-Methyl-N-(thiazol-2- yl)-7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) 6-Methyl-N-(thiazol-2- yl)-7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00466] or [00467] 300.1 300.1 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 45% B 26 27 6-Methyl-N-(5- (trifluoromethyl)pyrimidin- 2-yl)-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) 6-Methyl-N-(5- (trifluoromethyl)pyrimidin- 2-yl)-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00468] or [00469] 363.1 363.1 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 55% B 28 29 6-Methyl-N-(5- methylpyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4]tria zolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) 6-Methyl-N-(5- methylpyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4]tria zolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00470] or [00471] 309.2 309.4 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 30 31 6-Methyl-N-(oxazol-2- yl)-7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) 6-Methyl-N-(oxazol-2- yl)-7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00472] or [00473] 284.1 284.1 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 32 33 N-(Isoxazol-3-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e]imidazo [1,2-a]pyridine-4- carboxamide (enantiomer 1) N-(Isoxazol-3-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e]imidazo [1,2-a]pyridine-4- carboxamide (enantiomer 2) [00474] or [00475] 284.2 284.3 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 55% B 34 35 6-Methyl-N-(5- (trifluoromethyl)95yridine- 2-yl)-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) 6-Methyl-N-(5- (trifluoromethyl)pyridin- 2-yl)-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00476] or [00477] 362.1 362.3 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 45% B 36 37 N-(3-Fluoropyridin-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) N-(3-Fluoropyridin-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00478] or [00479] 312.5 312.5 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 38 39 N-(Isothiazol-5-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(Isothiazol-5-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00480] or [00481] 300.1 300.0 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 40 41 N-(Isothiazol-3-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(Isothiazol-3-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00482] or [00483] 300.3 300.2 Column: DAICEL CHIRALCEL OX (250 mm *3 0 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 42 43 N-(5-Fluoropyridin-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(5-Fluoropyridin-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4 ]triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00484] or [00485] 312.2 312.1 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 50% B 44 45 N-(Isoxazol-5-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) N-(Isoxazol-5-yl)-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00486] or [00487] 284.1 284.0 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 45% B 46 47 N-(5-Chloropyrimidin- 2-yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) N-(5-Chloropyrimidin- 2-yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00488] or [00489] 328.9 328.9 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 48 49 N-(5- Methoxypyrimidin-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(5- Methoxypyrimidin-2- yl)-6-methyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00490] or [00491] 325.1 325.1 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 ACN/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 50 51 N-(5-Fluoropyrimidin- 2-yl)-6-isopropoxy-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(5-Fluoropyrimidin- 2-yl)-6-isopropoxy-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00492] or [00493] 357.2 357.2 Column: DAICEL CHIRALCEL OX (250 mm * 30 mm, 10 ?m) Mobile phase B: 1:1 Isopropanol/Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 52 53 N-(5-Fluoropyrimidin- 2-yl)-1,6-dimethyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) N-(5-Fluoropyrimidin- 2-yl)-1,6-dimethyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00494] or [00495] 327.4 327.4 Mobile phase B: Isopropanol (0.1% NH.sub.4OH) Gradient: Isocratic 35% B Flow Rate: 60 mL/min 54 55 N-(5-Fluoropyrimidin- 2-yl)-1-isopropyl-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) N-(5-Fluoropyrimidin- 2-yl)-1-isopropyl-6- methyl-7,8-dihydro- 6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00496] or [00497] 355.5 355.3 Column: DAICEL CHIRALCEL IBN (250 mm * 30 mm, 10 ?m) Mobile phase B: Ethanol (0.1% NH.sub.4OH) Gradient: Isocratic 35% B 56 57 6-Ethyl-N-(5- fluoropyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) 6-Ethyl-N-(5- fluoropyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) [00498] or [00499] 327.1 327.0 Column: DAICEL CHIRALCEL AY-H (250 mm * 30 mm, 10 ?m) Mobile phase B: Ethanol (0.1% NH.sub.4OH) Gradient: Isocratic 45% B

[0400] The compounds 58 to 68 of Table 3 below were synthesized according to the Schemes 1-3 described above with reference to conditions described for Examples 3 and 4 and separated on a preparatory column under conditions analogous to Separation Condition A (with necessary variation in the mobile phase and gradient as specified in Table 3).

TABLE-US-00013 TABLE 3 Examples 58-68 Variation ES/MS from Ex. (m/z) Separation No. Chemical Name Structure (M + H) Condition A 58 59 N-(5-Fluoropyrimidin- 2-yl)-6-isopropyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) N-(5-Fluoropyrimidin- 2-yl)-6-isopropyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00500] or [00501] 341.0 341.2 Mobile phase B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 40% B 60 6-(sec-butyl)-N-(5- Fluoropyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2/2) [00502] or [00503] or [00504] or [00505] 355.2 Separation 1: Column: DAICEL CHIRALCEL OX 250 ? 30 mm I.D., 10 ?m Mobile phase B: 1:1 ACN/EtOH (0.1% NH.sub.4OH) Gradient: Isocratic 55% B; Separation 2: Column: DAICEL CHIRALCEL OX 250 ? 30 mm I.D., 10 ?m Mobile phase B: 1:1 ACN/EtOH (0.1% NH.sub.4OH) Gradient: Isocratic 55% B 61 62 6-Methyl-N-(2-methyl- 2H-1,2,3-triazol-4-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) 6-Methyl-N-(2-methyl- 2H-1,2,3-triazol-4-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00506] or [00507] 298.1 298.2 Column: DAICEL CHIRALCEL OX 250 ? 30 mm I.D., 10 ?m phase Mobile B: Methanol (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 63 6-Methyl-N-(1-methyl- 1H-pyrazol-3-yl)-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00508] or [00509] 297.2 Column: DAICEL CHIRALCEL OX 250 ? 30 mm I.D., 10 ?m Mobile phase B: 1:1 ACN/MeOH (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 64 65 6-Cyclobutyl-N-(5- fluoropyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) 6-Cyclobutyl-N-(5- fluoropyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00510] or [00511] 353.0 353.0 Column: DAICEL CHIRALCEL OX 250 ? 30 mm I.D., 10 ?m Mobile phase B: 1:1 ACN/MeOH (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 66 67 6-Cyclopropyl-N-(5- fluoropyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 2) 6-Cyclopropyl-N-(5- fluoropyrimidin-2-yl)- 7,8-dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00512] 339.3 339.1 Column: DAICEL CHIRALCEL OX 250 ? 30 mm I.D., 10 ?m Mobile phase B: 1:1 ACN/MeOH (0.1% NH.sub.4OH) Gradient: Isocratic 60% B 68 N-(5-Fluoropyrimidin- 2-yl)-6-propyl-7,8- dihydro-6H- cyclopenta[e][1,2,4] triazolo[4,3-a]pyridine-4- carboxamide (enantiomer 1) [00513] or [00514] 341.1 Column: DAICEL CHIRALCEL OX 250 ? 30 mm I.D., 10 ?m Mobile phase B: 1:1 ACN/MeOH (0.1% NH.sub.4OH) Gradient: Isocratic 60% B

EXAMPLE 69

(S)N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide

[0401] ##STR00515##

Step 1

Methyl (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate

[0402] ##STR00516##

[0403] Phosphoryl chloride (POCl.sub.3) (740 g) was added to a solution of methyl (5S)-5-methyl-2-oxo-1,5,6,7-tetrahydrocyclopenta[b]pyridine-3-carboxylate (100 g) and DMF (705 mg). The mixture was stirred at 100? C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove POCl.sub.3. The residue was diluted with water (4.00 L, 5 V) and extracted with EtOAc (1.60 L?3). The combined organic layers were washed with saturated aqueous NaCl (800 mL, 1 V), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give methyl (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (985 g) as a brown solid.

Step 2

(5S)-2-Chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0404] ##STR00517##

[0405] Sodium hydroxide NaOH (232 g) was added to a solution of methyl (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate (328 g) in H.sub.2O (984 mL) and THE (984 mL). Methanol (984 mL, 3 V) was added at 25-30? C. The mixture was stirred at 25? C. for 0.5 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The pH of mixture was adjusted to approximately 2-3 with 3 M HCl (10 V) at 5-10? C. Solid was gradually separated out of the mixture and filtered to give (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (550 g, 67.5%) as a white solid.

Step 3

(5S)-2-Hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid

[0406] ##STR00518##

[0407] N.sub.2H.sub.4.H.sub.2O (3.32 kg) was added to a solution of (5S)-2-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (275 g) in dioxane (1.65 L, 6 V). The mixture was stirred at 80? C. for 16 hrs. The reaction mixture was concentrated under reduced pressure to remove N.sub.2H.sub.4.H.sub.2O. The residue was diluted with MeCN (2.20 L, 4 V) then filtered and removed the insoluble. The combined organic layers were concentrated under reduced pressure to give (5S)-2-hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (1.30 kg, crude) as a brown solid.

Step 4

(S)-6-Methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid

[0408] ##STR00519##

[0409] A solution of (5S)-2-hydrazino-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (1.30 kg) in formic acid (5.20 L, 4 V) was stirred at 100? C. for 12 hrs. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with ice water (3.25 L, 2.5 V) and stirred at 0? C. for 1 hr. The mixture was filtered and washed with water (3.90 L, 3 V), and filtered to give (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid (360 g, 64%) as a brown solid.

Step 5

(S)N-(5-Fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide

[0410] ##STR00520##

[0411] A mixture of pyridine (1.11 kg) and 5-fluoropyrimidin-2-amine (296 g) was added to a solution of (S)-6-methyl-7,8-dihydro-6H-cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxylic acid (412 g) in DCM (2.47 L, 6 V). POCl.sub.3 (402 g) was added dropwise into the mixture at 25? C. The mixture was stirred at 25? C. for 0.5 hr. The reaction mixture was quenched by addition H.sub.2O (2.00 L, 5 V) at 25? C., and then extracted with DCM (2.46 L, 2 V?3). The combined organic layers were washed with saturated aqueous NaCl (410 mL, 1 V), dried over Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with DCM in EtOAc (I/O to 1/1) to give (S)N-(5-fluoropyrimidin-2-yl)-6-methyl-7,8-dihydro-6H cyclopenta[e][1,2,4]triazolo[4,3-a]pyridine-4-carboxamide (365 g, 61.7% yield, 99.6 purity) as an off-white solid.

hAHR Nuclear Translocation Assay

[0412] The purpose of this assay is to measure the ability of compounds to bind to, activate, and induce the translocation of AhR into the nucleus of a cell for transcription. Stable cell lines were established using Jump-In? T-REx? HEK293 Retargeting Kit (Life Technologies). Human AhR cDNA was cloned into the pJTI R4 CMV-TO EGFP vector. The EGFP was cloned to the C-terminal of AHR to form AhR-EGFP chimera. The pJTI R4 CMV-TO AhR-EGFP vector was transfected using FuGENE? HD into Jump-In? T-REx? HEK293 cells. Transfected cells were selected using 2.5 mg/ml G418 for 10 to 14 days, then expanded, harvested, and suspended in freeze media (FBS with 8% DMSO) at 2?10.sup.7 cells/ml, and aliquots were stored in liquid nitrogen. One day before the assay date, cells were thawed and resuspended in DMEM with 5% FBS in the presence of 1 ?g/ml Doxycycline and plated into ploy-L-Lysine coated CELLCARRIER-384 ULTRA Microplates (Perkin Elmer) at 12,000 to 15,000 cells per well and incubated at 37? C. and 5% CO.sub.2 overnight. On the assay date, compound was serially diluted (1:2) into 384-well nunc plates with DMSO using acoustic dispensing (ECHO?). The dose response was a 20-point curve. Compound was resuspended in 40 ?l of DMEM plus 0.1% BSA. The culture media was damped and 25 ?l of DMEM plus 0.1% BSA was added, then 25 ?L of compound in DMEM plus 0.1% BSA was added into cell plates. Cells were incubated compounds at 37? C. and 5% CO.sub.2 for 45 minutes. The final DMSO concentration was 0.2%. The media was damped after 45 minutes incubation. The cells were fixed with 40 ?l of cold MeOH (?20? C.) for 20 minutes. The MeOH was damped and 50 ?L of DPBS containing 1 ?g/mL Hochst was added into the cell plates. The intensity of EGFP was quantitated by using Opera PHENIX? or OPERETTA? high content image system (Perkin Elmer) with 20? Water Objective and five field per well. The ratio of EGFP fluorescent intensity in nuclear over cytosol was analyzed using a 4-parameter nonlinear logistic equation to determine the potency of AhR agonists.

[0413] Table 3 shows the hAHIR nuclear translocation assay data for certain compounds of examples above. The designation A refers to EC.sub.50<=1 nM; B refers to 1 nM<EC.sub.50<=10 nM; C refers to 10 nM<EC.sub.50<=50 nM; and D refers to EC.sub.50>50 nM. - indicates activity not tested.

TABLE-US-00014 TABLE 3 hAHR Nuclear Translocation Assay EC.sub.50 Values Example No. Rel EC.sub.50 (nM) 1 3.1 2 0.585 3 5.37 4 D 5 5.79 6 5.74 7 11.1 8 25.3 9 3.37 10 1.32 11 1.58 12 9.8 13 0.495 14 1.66 15 16 A 17 A 18 A 19 A 20 D 21 D 22 A 23 B 24 B 25 B 26 B 27 B 28 C 29 C 30 C 31 C 32 B 33 D 34 B 35 B 36 B 37 B 38 B 39 B 40 A 41 B 42 B 43 B 44 D 45 C 46 B 47 B 48 C 49 C 50 D 51 D 52 D 53 D 54 D 55 D 56 B 57 B 58 B 59 C 60 C 61 B 62 C 63 C 64 B 65 B 66 B 67 B 68 C

[0414] Certain compounds of the present disclosure are novel agonist of the aryl hydrocarbon receptor (AHR), as demonstrate by hAHR Nuclear Translocation Assay illustrated above. Additional compounds of Formula I-1, I-2, I-3, II-1, II-2, II-3, II-1A, III-1, III-2, III-3, III-1A, IV-1, IV-2, IV-3, IV-1A, V-1, V-2, V-3, or V-4, can be shown to be AHR agonists using the same or similar assay techniques described above. These compounds and the examples provided herein, are believed to be useful in the treatment of immune-mediated diseases (IMD), in particular psoriasis and atopic dermatitis, among others.