EA038607B1 - Aryl, heteroaryl and heterocyclic compounds for treating complement-mediated disorders - Google Patents

Abstract

Provided are compounds, methods of use and methods of making complement factor D inhibitors comprising Formula I, or a pharmaceutically acceptable salt or a compositions thereof, wherein R12 or R13 on the A group is aryl, heteroaryl, or heterocyclic (R32). The inhibitors described herein target factor D and inhibit or modulate complement cascade at an early and necessary point in the alternative complement pathway and reduce factor D's ability to modulate classical and lectin complement pathways. Inhibitors of factor D described herein are capable of reducing excessive activation of complement associated with certain autoimmune, inflammatory and neurodegenerative diseases as well as ischemia-reperfusion injuries and cancer.

Description

Link to related claims

This application claims priority under U.S. Provisional Application No. 61 / 944.189, filed February 25, 2014, U.S. Provisional Application No. 62 / 022.916, filed July 10, 2014, and U.S. Provisional Application No. 62 / 046,783, filed September 5, 2014. The entirety of each of these applications is incorporated herein by reference for all purposes.

State of the art

The complement system is a part of the innate immune system that does not adapt to changes during the life of the host, but is recruited and used by the adaptive immune system. For example, it helps or complements the ability of antibodies and phagocytic cells to remove pathogens. This complex regulatory pathway allows a rapid response to pathogenic organisms, protecting host cells from destruction. More than thirty proteins and protein fragments make up the complement system. These proteins act through opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (tearing the membranes of foreign cells), and agglutination (clustering and binding pathogens together).

The complement system has three pathways: classical, alternative, and lectin. Complement factor D plays an early and central role in activating the alternate complement cascade pathway. Activation of the alternative complement pathway is initiated by spontaneous hydrolysis of the thioether bond in C3 to give C3 (H ₂ O), which binds to factor B to form the C3 (H ₂ O) B complex. Complement factor D acts by cleaving factor B at the C3 (H ₂ O) B complex to form Ba and Bb. The Bb fragment remains linked to C3 (H ₂ O) to form the alternative C3 pathway of the C3 (H ₂ O) Bb convertase. In addition, C3b obtained from any of the C3 convertases also binds to factor B to form C3bB, which cleaves factor D to a later step of the alternative C3 convertase pathway, C3bBb. This latter form of the alternative C3 convertase pathway can provide important downstream amplification along all three designated complement pathways, ultimately leading to the recruitment and assembly of additional factors in the complement cascade pathway, including cleavage of C5 into C5a and C5b. C5b acts to assemble factors C6, C7, C8 and C9 into a membrane attack complex that can destroy pathogenic cells by lysis of the cell.

Dysfunction or over-activation of complement has been associated with certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer. For example, activation of the alternative complement cascade pathway promotes the production of C3a and C5a, both potent anaphylatoxins that also play a role in a number of inflammatory disorders. Thus, in some cases, it is desirable to reduce the response of the complement pathway, including the alternative pathway of complement. Some examples of complement mediated disorders include age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis, and rheumatoid arthritis.

Age-related macular degeneration (AMD) is the leading cause of vision loss in industrialized countries. Based on a number of genetic studies, there is evidence of a link between the complement cascade and macular degeneration. Individuals with mutations in the gene encoding complement factor H have a five-fold increased risk of developing macular degeneration, and individuals with mutations in other complement factor genes also have an increased risk of developing AMD. Individuals with mutant factor H also have elevated levels of C-reactive protein, a marker of inflammation. Without adequate functioning of factor H, the alternative pathway of the complement cascade is over-activated, resulting in cell damage. Thus, inhibition of the alternative pathway is desirable.

Paroxysmal nocturnal hemoglobinuria (PNH) is a benign, hematological disease characterized by the expansion of hematopoietic stem cells and the offspring of mature blood cells that are deficient in some surface proteins. PNH erythrocytes are unable to modulate their superficial complement activation, resulting in the typical hallmark of PNH: chronic complement-mediated intravascular anemia. Currently, only one product, the anti-C5 monoclonal antibody eculizumab, has been approved in the United States for the treatment of PNH. However, many of the patients treated with eculizumab remain anemic and many patients still require blood transfusions. In addition, eculizumab treatment requires lifelong intravenous injections. Thus, there is an unmet need for the development of new inhibitors of the complement pathway.

Factor D is an attractive target for inhibition or regulation of the complement cascade due to its early and important role in the alternative complement pathway, as well as its potential role in signal amplification in the classical and lectin complement pathways. Inhibition of factor D effectively interrupts the pathway and suppresses the formation of a membrane attacking complex.

While initial attempts have been made to develop factor D inhibitors, there are currently no small molecule factor D inhibitors in clinical trials.

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Examples of factor D inhibitors or prolyl compounds are described in the following disclosures.

U.S. Patent No. 6653340 BioCryst Pharmaceuticals titled Compounds useful in the complement, coagulant and kallikrein pathways and methods for their preparation describes fusion bicyclic ring compounds that are potential inhibitors of factor D. The development of factor D inhibitor BCX1470 was discontinued due to the lack of specificity and short half-life of the compound. ...

PCT Patent Publication WO 2012/093101 Novartis entitled Indole Compounds or their Analogs Suitable for the Treatment of Age-Related Macular Degeneration describes several factor D inhibitors.

PCT patent publications WO 2014/002057 by Novartis entitled Pyrrolidine derivatives and their use as complement pathway modulators and WO 2014/009833 entitled Complement pathway modulators and their use describe additional heterocyclic substituted factor D inhibitors. Additional factor D inhibitors are described in Novartis PCT Patent Publications WO 2014/002051, WO 2014/002052, WO 2014/002053, WO 2014/002054, WO 2014/002058, WO 2014/002059 and WO 2014/005150.

Bristol-Myers Squibb PCT Patent Publication WO 2004/045518 titled Urea-associated open chain proliferation modulators with androgen receptor function describes urea and thiourea-associated open chain proliferation compounds for the treatment of androgen receptor-associated conditions such as age-related diseases, such as sarcopenia.

In PCT Patent Publication Japan Tobacco Inc. WO 1999/048492 entitled Amide derivatives and antagonists of nociceptin describes compounds with a proline-like nucleus and aromatic substituents linked to the proline nucleus via amide bonds useful in the treatment of pain.

In PCT Patent Publication Ferring B.V. and Yamanouchi Pharmaceutical Co. LTD. WO 1993/020099 entitled CCK and / or gastrin receptor ligands describes compounds with a proline-like nucleus and heterocyclic substituents linked to the proline nucleus via amide bonds for the treatment of, for example, stomach upset or pain.

PCT Patent Publication Alexion Pharmaceuticals WO 1995/029697 entitled Methods and Compositions for the Treatment of Glomerulonephritis and Other Inflammatory Diseases discloses antibodies against the C5 complement pathway for the treatment of glomerulonephritis and inflammatory conditions involving pathological activation of the complement system. Alexion Pharmaceutical's anti-C5 antibody eculizumab (Soliris®) is currently the only complement specific antibody on the market and represents the first and only approved treatment for paroxysmal nocturnal hemoglobinuria (PNH).

Compounds that mediate the complement pathway, and, for example, act as inhibitors of factor D, are required for the treatment of disorders in the recipient, including humans, associated with improper regulation of the complement cascade.

The essence of the invention

It has been found that a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a composition thereof, wherein R ¹² or R ¹³ on group A is aryl, heteroaryl, or heterocycle, is an excellent inhibitor of factor D complement.

In one embodiment, the invention provides a method of treating a dysfunctional disorder, including overactive complement pathway, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, as described in more detail below.

In one embodiment of the invention, the disorder is associated with an alternative pathway of the complement cascade. In yet another embodiment of the invention, the disorder is associated with the classical complement pathway. In an additional embodiment of the invention, the disorder is associated with the lectin complement pathway. Factor D inhibitors disclosed herein can thus attenuate or inhibit the deleterious activity of complement in a recipient by administering an effective amount in a suitable manner to a recipient in need thereof.

Specific embodiments of the present invention are directed to specific disease indications. In one embodiment, a method of treating paroxysmal nocturnal hemoglobinuria (PNH) comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method for treating age-related macular degeneration (AMD), which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method for treating rheumatoid arthritis which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating multiple sclerosis which comprises administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In other embodiments, an active compound as claimed herein can be used to treat or prevent a disorder in a recipient mediated by complement factor D or an excessive or detrimental amount of the C3 amplification loop of the complement pathway. As examples, the present invention includes methods for treating or preventing complement-related disorders that are induced by antibody-antigen interactions, a component of an immune or autoimmune disorder, or ischemic injury. The invention also provides methods for reducing inflammation or immune response, including an autoimmune response that is mediated or influenced by factor D.

The present invention relates to compounds of the formula I o ^ Q ³ /

Q ² \ /

IX) = ° ^A (I) and their pharmaceutically acceptable salts and compositions with them, in which

Q ¹ is N (R1) or C (R1R1);

Q ² is C (R ² R ² '), C (R ² R ² ) -C (R ² R ² '), S, O, N (R ² ) or C (R ² R2 ² ') O;

Q ³ represents N (R ³ ), S or C (R ³ R ³ );

X ¹ and X ² independently represent N, CH, or CZ, or X ¹ and X ² together represent C = C; and where Q ¹ , Q ² , Q ³ , X ¹ and X ² are selected so as to result in stable connections.

Non-limiting ring examples

9-Q ³

I \ 4

L are shown below (any of which may be otherwise substituted with R ¹ , R ¹ , R ² , R ² , R ³ and R ³ ) as described in more detail below.

where q is 0, 1, 2, or 3 and r is 1, 2, or 3.

R and R 'are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycle-3 038607 loalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, where each group may be optionally substituted, or any other group of substituents herein that provides desired properties. In some embodiments, the ring comprises one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon may be present as an enantiomer or mixtures of enantiomers, including a racemic mixture. Where the ring contains more than one stereocenter, all enantiomers and diastereomers are included in the invention as separate examples.

Z is F, Cl, NH2, CH3, CH2D, CHD2, or CD3.

R ¹ , R ¹ , R ² , R ² , R ³ and R ^{3 are} independently selected in each specific case, as necessary, and only when lead to stable compounds, from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C1- C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C2-C6-alkynyl, C2-C6-alkanoyl, C1-C6-thioalkyl, hydroxyC1-C6-alkyl, aminoC1-C6-alkyl, -C0-C4-alkyl-NR ⁹ R ¹⁰ , -C (O) OR ⁹ , -OC (O) R ⁹ , -NR ⁹ C (O) R ¹⁰ , -C (O) NR ⁹ R ¹⁰ , -OC (O) NR ⁹ R ¹⁰ , —NR ⁹ C (O) OR ¹⁰ , C1 — C ₂ haloalkyl and C ₁ —C ₂ haloalkoxy, where R ⁹ and R ^{10 are} independently selected at each occurrence from hydrogen, C ₁ - C ₆ -alkyl, (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl) and -O-C ₀ -C ₄ -alkyl ( C ₃ -C ₇ -cycloalkyl).

In alternative embodiments, R ¹ and R ¹ or R ³ and R ³ can be taken together to form a 3-6 membered carbocyclic spiro ring or a 3-6 membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N , O or S; R ² and R ² can be taken together to form a 3-6 membered carbocyclic spiro ring; or R ² and R ² can be taken together to form a 3-6 membered heterocyclic spiro ring; each of the spiro-ring may be unsubstituted or substituted with one or more substituents independently selected from halogen (and in particular, F), hydroxy, cyano, -COOH, _C1-C4 alkyl (including, in particular, methyl ), C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C1-C ₄ -alkoxy, C ₂ -C ₄ -alkanoyl, hydroxyC1-C ₄ -alkyl, (mono- and di-C1C _{4 -alkylamino} ) C ₀ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O-C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ C ₂ -haloalkyl; and C ₁ -C ₂ -haloalkoxy.

In alternative embodiments, R ¹ and R ² may be taken together to form a 3-membered carbocyclic ring; R ¹ and R ² can be taken together to form a 4-6 membered carbocyclic or aryl ring, or a 4-6 membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O and S; or R ² and R ³ , when bonded to adjacent carbon atoms, can be taken together to form a 3-6 membered carbocyclic or aryl ring, or a 3-6 membered heterocyclic or heteroaryl ring; each of the rings may be unsubstituted or substituted with one or more substituents independently selected from halogen (and in particular, F), hydroxy, cyano, -COOH, _C1-C4 alkyl (including, in particular, methyl), C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C 1 C ₄ alkoxy, C ₂ -C ₄ alkanoyl, _{gidroksiS1-C4} alkyl, (mono- and di-C ₁ -C ₄ alkylamino ) C ₀ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -OQ-Q-alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₂ -halogenoalkyl and C ₁ -C ₂ -haloalkoxy.

In alternative embodiments, R ¹ and R ¹ , R ² and R ^2, or R ³ and R ³ may be taken together to form a carbonyl group. In alternative embodiments, R ¹ and R ² or R ² and R ³ can be taken together to form a carbon-carbon double bond.

A represents a group selected from

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R ^{4 is} selected from -CHO, -CONH2, C2-C ₆ -alkanoyl, hydrogen, -SO2NH2, -QCH ^ F, -CH (CF3) NH2, Ci-Cb-alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -C (O) C ₀ -C ₂ -alkyl (C ₃ -C ₇ -cycloalkyl),

each of R ⁴ other than hydrogen, —CHO, and —CONH2 is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanimino, C ₁ -C ₂ alkyl, _{C 1 C 2} alkoxy, - C ₀ -C ₂ -alkyl (mono- and di- _{C 1} -C ₄ -alkylamino), C _{1 -C 2} -haloalkyl and _{C 1 -C 2} -haloalkoxy.

R ⁵ and R ^{6 are} independently selected from -CHO, -C (O) NH ₂ , -C (O) NH (CH ₃ ), C ₂ -C ₆ -alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, -COOH , -SO ₂ NH ₂ , vinyl, C ₁ -C ₆ -alkyl (including methyl), C ₂ -C ₆ alkenyl, C ₁ -C ₆ -alkoxy, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -C (O) C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -P (O) (OR ⁹ ) 2, -OC (O) R ⁹ , -C (O) OR ⁹ , C (O) N (CH2CH2R ⁹ ) (R ¹⁰ ), -NR ⁹ C (O) R ¹⁰ , phenyl or 5-6 membered heteroaryl.

Each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or optionally substituted. For example, R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano, and —COOH may be substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanimino, C ₁ -C ₂ -alkyl, C ₁ -C ₄ -αlkoksi, -C ₀ -C ₂ alkyl (mono- and _di-C1-C4 alkylamino), C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ -galogenalkoksi.

R ⁶ represents hydrogen, halogen, hydroxyl, C1-C4 alkyl, -c0-C4-alkyl (C3-C7-cycloalkyl) or C ₁ -C ₄ -alkoxy; or R ⁶ and R ⁶ can be taken together to form an oxo, vinyl or imino group.

R ⁷ is hydrogen, C ₁ -C ₆ -alkyl or —C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl).

R ⁸ and R ^{8 are} independently selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ alkyl, —C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₆ alkoxy, and (C1- C ₄ -alkylamino) C ₀ -C ₂ -alkyl; or R ⁸ and R ⁸ taken together form an oxo group; or R ⁸ and R ⁸ can be taken together with the carbon atom to which they are attached to form a 3-membered carbocyclic ring.

R ^{16 is} absent or may include one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, -C ₀ -C ₄ alkyl (mono- and di-C ₁ -C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₂ - haloalkyl and _C1-C2 haloalkoxy.

R ¹⁹ represents hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkanoyl, -SO2C1-C6-alkyl, (mono- and di-C1-C6-alkylamino) C1-C4-alkyl, - C0-C4-alkyl (C3-C7-cycloalkyl), -C0-C4-alkyl (C3-C7-heterocycloalkyl), -C0-C4-alkyl (aryl), C0-C4-alkyl (heteroaryl), and where R ¹⁹ other than hydrogen is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, —COOH, and —C (O) OC1-C4 alkyl.

X ¹¹ represents N or CR ¹¹ .

X ¹² represents N or CR ¹² .

X ¹³ represents N or CR ¹³ .

X ¹⁴ is N or CR ¹⁴ .

At most 2 of X ¹¹ , X ¹² , X ¹³ and X ¹⁴ are N.

One of R ¹² and R ^{13 is} selected from R ³¹ and the other of R ¹² and R ^{13 is} selected from R ³² . In an alternative embodiment, R ¹² and R ^{13 are} each independently selected from the residue R ³² .

R ^{31 is} selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, C ₁ -C ₂ -halogenoalkyl,

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C1-C2 haloalkoxy, C1-C ₆ alkyl, -C ₀ -C4 alkyl (C ₃ -C ₇ cycloalkyl), _C2-C6 alkenyl, _C2-C6 alkanoyl, _C1-C6 alkoxy _C2-C6 -alkeniloksi, -C (O) OR ^9, C 1 -C 6 thioalkyl, -c0 -C 4 alkyl-NR ⁹ R ^10, -C (O) NR ⁹ R ^10, -SO2R ^9, -SO2NR9R ¹⁰ , -OC (O) R ⁹ and -C (NR ⁹ ) NR ⁹ R ¹⁰ , each of R ³¹ other than hydrogen, halogen, hydroxyl, nitro, cyano, C1-C ₂ -halogenoalkyl and C ₁ -C ₂ -haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -CONH2 C ₁ -C ₂ -halogenoalkyl and C ₁ -C ₂ -gαlogenoalkoxy, and each of R ^{31 is} also optionally substituted with one substituent selected from phenyl and a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein phenyl or 4-7-membered heterocycle is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, (mono- and di-C ₁ -C ₆ alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -α-alkyl ether, -C ₀ -C ₄ -alkyl) (C ₃ -C ₇ cycloalkyl) C 1 C ₂ -haloalkyl and C ₁ -C ₂ -galogenalkoksi;

R ^{32 is} selected from aryl; saturated or unsaturated heterocycle (for example, a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S), where the heterocycle is linked through a carbon atom in the heterocyclic ring to the ring A carbon atom at position R ¹² or R ¹³ ; and heteroaryl (eg, a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S), wherein the aryl, heterocycle, or heteroaryl ring may be optionally substituted.

R ¹¹ , R ¹⁴ and R ^{15 are} independently selected at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O (PO) (OR ⁹ ) 2, - (PO) (OR ⁹ ) 2, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -αlkenyl, C ₂ -C ₆ -alkynyl, C ₂ -C _6- alkenyl (aryl), C _{2 -C 6-} alkenyl (cycloalkyl), C ₂ -C _6- alkenyl (heterocycle) , C ₂ -C ₆ -alkenyl (heteroaryl), C ₂ -C ₆ -alkynyl, C _{2 to} C ₆ alkynyl (aryl), C ₂ -C ₆ -alkynyl (cycloalkyl), C ₂ -C ₆ -αlkinil (heterocycle ), C ₂ -C ₆ -alkynyl (heteroaryl), C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -thioαalkyl, -C ₀ -C ₄ -alkyl (mono- and di -C1-C ₆ -alkylamino), -C ₀ C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -C ₀ -C ₄ -alkoxy (C ₃ -C ₇ -cycloalkyl), C1-C ₂ -haloalkyl and C1-C2 haloalkoxy.

L is a bond or is selected from formulas

where R ¹⁷ is hydrogen, C ₁ -C ₆ -alkyl or -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), and R ¹⁸ and R ^{18 are} independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1, 2, or 3.

B is monocyclic or bicyclic carbocyclic; monocyclic or bicyclic carbocyclo-oxy group; a monocyclic, bicyclic or tricyclic heterocyclic group having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and from 4 to 7 ring atoms in the ring; C ₂ -C ₆ alkenyl; C ₂ -C ₆ -alkynyl; - (C ₀ -C ₄ -alkyl) (aryl); - (C ₀ -C ₄ -alkyl) (heteroaryl); or - (C ₀ -C ₄ -alkyl) (biphenyl).

Each of B is unsubstituted or substituted with one or more substituents independently selected from R ³³ and R ³⁴ , and 0 or 1 substituent is selected from R ³⁵ and R ³⁶ .

R ^{33 is} independently selected from halogen, hydroxyl, -COOH, cyano, C1-C6-alkyl, C2-C6-alkanoyl, C1-C6-alkoxy, -C0-C4-alkyl-NR ⁹ R ¹⁰ , -SO2R ⁹ , C1-C ₂ -haloalkyl and C ₁ -C ₂ -haloalkoxy;

R ^{34 is} independently selected from nitro, C2-C6-alkenyl, C2-C6-α-alkyl, C1-C6-thioalkyl, -JC3-C7 cycloalkyl, -B (OH) 2, -JC (O) NR ⁹ R ²³ , -JOSO2OR ²¹ , -C (O) (CH2) _1-4 S (O) R ²¹ , -O (CH ₂ ) 1- ₄ S (O) NR ²¹ R ²² , -JOP (O) (OR ²¹ ) (OR ²² ) , -JP (O) (OR ²¹ ) (OR ²² ), -JOP (O) (OR ²¹ ) R ²² , JP (O) (OR ²¹ ) R ²² , -JOP (O) R ²¹ R ²² , -JP (O) R ²¹ R ²² , -JSP (O) (OR ²¹ ) (OR ²² ), -JSP (O) (OR ²¹ ) (R ²² ), -JSP (O) (R ²¹ ) (R ²² ), -JNR ⁹ P (O) (NHR ²¹ ) (NHR ²² ),

-JNR ⁹ P (O) (OR ²¹ ) (NHR ²² ), JNR ⁹ P (O) (OR ²¹ ) (OR ²² ), -JC (S) R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S ( O) NR ¹⁰ R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR ⁹ COR ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC (O) NR ²¹ SO2R ²² , -JC (NH2) NR ²² , -JC (NH2) NR ⁹ S (O) 2R ²² , -JOC (O) NR ²¹ R ²² , -JNR ²¹ C (O) OR ²² , -JNR ²¹ OC (O) R ²² , - (CH2 ) i-4C (O) NR ²¹ R ²² , -JC (O) R ²⁴ R ²⁵ , -JNR ⁹ C (O) R ²¹ , -JC (O) R ²¹ , -JNR ⁹ C (O) NR ¹⁰ R ²² , —CCR ²¹ , - (CH2) 1-4OC (O) R ²¹ and —JC (O) OR ²³ ; each of R ³⁴ may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, —B (OH) ₂ , —Si (CH ₃ ) ₃ , —COOH, —CONH2, -P (O) (OH) ₂ , C ₁ -C ₆ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₆ -alkoxy, -C ₀ -C ₂ alkyl (mono- and _di-C1-C4 alkylamino), C ₁ -C ₆ alkyl esters, _C1-C4 alkylamino, _C1-C4 -gidroksilalkila, C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ haloalkoxy.

R ^{35 is} independently selected from naphthyl, naphthyloxy, indanyl, (4-7 membered heterocycloalkyl) C0-C4 alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms, independently selected from N, O and S, and containing from 4 to 7 ring atoms in each ring; each R ³⁵ is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C ₆ alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ -αalkoxy, (mono- and di-C ₁ -C ₆ -alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -αalkyl ether, -C ₀ -C ₄

- 6,038607 alkyl (C ₃ -C ₇ -cycloalkyl), -SO2R ⁹ , C1-C2-haloalkyl and C1-C2-haloalkoxy.

R ^{36 is} independently selected from tetrazolyl, (phenyl) C0-C2 alkyl, (phenyl) C1-C2 alkoxy, phenoxy and 5 or 6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, B and S, each of R ³⁶ is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ -alkoxy, (mono and di-C1-C ₆ -alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -alkylether, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl) , -SO2R ⁹ , -OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ , -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , C ₁ -C ₂ -halogenoalkyl and C1-C ₂ -haloalkoxy.

R ²¹ and R ^{22 are} independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ -haloalkyl, C ₁ -C ₆ -alkoxy, (C ₃ -C ₇ -cycloalkyl ) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, -C1C ₄ -alkylOS (O) OC1-C ₆ -alkyl, -C1-C ₄ -alkylOS (O) C1-C ₆ - alkyl, -C ₁ -C ₄ -alkylC (O) OC ₁ -C ₆ -alkyl, (4-7 membered heterocycloalkyl) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and each of R ²¹ and R ²² may be optionally substituted.

R ^{23 is} independently selected at each occurrence from C ₁ -C ₆ -alkyl, C ₁ -C ₆ -haloalkyl, (aryl) C ₀ -C ₄ -alkyl, (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ - alkyl, (phenyl) C ₀ -C ₄ -alkyl, (4-7 membered heterocycloalkyl) C ₀ -C ₄ -alkyl having 1, 2, or 3 heteroatoms independently selected from N, O and S, and (5 - or a 6-membered unsaturated or aromatic heterocycle) C ₀ -C ₄ -alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and each R ²³ may be optionally substituted.

R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic heterocycloalkyl group or a 6-10 membered bicyclic heterocyclic group having fused, spiro or bridged rings, and each of R ²⁴ and R ²⁵ may optionally be substituted.

J is independently selected at each occurrence from a covalent bond, C ₁ -C ₄ alkylene, —OC ₁ -C ₄ alkylene, C ₂ C 4 alkenylene, and C 2 -C 4 alkynylene.

Also disclosed are pharmaceutical compositions comprising a compound or salt of Formula I together with a pharmaceutically acceptable carrier.

Discloses methods of treating or preventing disorders mediated by factor D of the complement cascade, including but not limited to age-related macular degeneration (AMD), retinal degeneration, other ophthalmic diseases (e.g., geographic atrophy), paroxysmal nocturnal hemoglobinuria (PNH) , multiple sclerosis (MS), arthritis, including rheumatoid arthritis (RA), respiratory disease or cardiovascular disease, comprising administering a therapeutically effective amount of a compound or salt of Formula I to a recipient, including a human, in need of such treatment.

In another embodiment, the invention provides an effective amount of an active factor D inhibiting compound for the treatment of an inflammatory or immune disorder, including an autoimmune disorder that is mediated or influenced by factor D. In an alternative embodiment, a compound of formula I can be used to treat a disorder mediated by complement, regardless of whether it acts through factor D.

The present invention includes at least the following features:

(a) a compound of Formula I as described herein, and pharmaceutically acceptable salts and prodrugs thereof (each and all of their subgenera and species, considered separately and specifically described);

(b) Formula I as described herein and pharmaceutically acceptable salts and prodrugs thereof for use in the treatment or prevention of disorders mediated by complement and, for example, factor D cascade, including age-related macular degeneration (AMD), degeneration retina, paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS) and rheumatoid arthritis (RA), and other disorders described hereinafter;

(c) the use of formula I and its pharmaceutically acceptable salts and prodrugs in the manufacture of a medicament for use in the treatment or prevention of disorders mediated by complement and, for example, cascade factor D, including age-related macular degeneration (AMD), retinal degeneration, paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis (MS) and rheumatoid arthritis (RA) and other disorders described later herein;

(d) a method for preparing a medicament intended for therapeutic use for the treatment or prevention of treatment or prevention of disorders mediated by factor D of the complement cascade, including age-related macular degeneration (AMD), retinal degeneration, paroxysmal nocturnal hemoglobinuria (PNH), multiple sclerosis ( MS) and rheumatoid arthritis (RA) and other disorders described herein below, characterized in that the formula I described herein is used upon receipt;

(e) a pharmaceutical composition comprising an amount effective for treating a recipient

- 7,038607 of Formula I, or a pharmaceutically acceptable salt or prodrug thereof, together with a pharmaceutically acceptable carrier or diluent;

(f) Formula I, as described herein, in substantially pure form, including substantially isolated from other chemical compounds (eg, at least 90 or 95%);

(g) methods for preparing compounds of Formula I and their salts, compositions, dosage forms; and (h) methods for preparing therapeutic products that contain an effective amount of Formula I as described herein.

Detailed description of the invention

I. Terminology

Connections are described using standard nomenclature. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Compounds in any of the formulas described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers such as rotamers, as if each were specifically described. Formula I includes all subgeneric groups of Formula I, such as Formula IA and Formula IB, and also includes pharmaceutically acceptable salts of a compound of Formula I unless otherwise clearly contradicted by the context in which the phrase is recited. Formula I also includes all subgeneric groups of formula I, such as formulas IC - ID and formulas II - XXX, and also includes pharmaceutically acceptable salts of all subgeneric groups of formula I, such as formulas IA-ID and formula II - XXX, unless otherwise clearly contradicted the context in which this phrase is given.

The terms a and an do not mean limiting the number, but rather mean the presence of at least one of those described. The term either means and / or. Specification of ranges of values is intended only to be used as an abbreviated way of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each individual value is included in the description as if it were individually indicated herein. The end values of all ranges are included within the range and are independently combined. All methods described herein can be performed in a suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples or illustrative expressions (eg, such as) is intended only to better illustrate the invention and is not intended to limit the scope of the invention unless otherwise stated. Unless otherwise indicated, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The present invention includes compounds of formula I and the use of compounds with at least one desired isotopic substitution of an atom in an amount that is higher than the natural isotope content, i. E. enriched. Isotopes are atoms that have the same atomic number but different mass numbers, i.e. the same number of protons, but a different number of neutrons.

Examples of isotopes that may be included in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, C ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F ³¹ P , ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I, respectively. The invention includes isotopically modified compounds of formula I. In one embodiment of the invention, isotopically labeled compounds can be used in metabolic studies (with ¹⁴ C), kinetic studies of reactions (with, for example, ² H or ³ H), in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or in the radioactive treatment of patients. In particular, a compound labeled with ¹⁸ F may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this invention and their prodrugs can generally be prepared by following the procedures described in the Schemes or in the Examples, and the formulations described below can be prepared by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent.

As a general example, and not limited to, isotopes of hydrogen such as deuterium ( ² H) and tritium ( ³ H) can be used at any position in the described structures to achieve the desired result. Alternatively or in addition, carbon isotopes, for example ¹³ C and ¹⁴ C, can be used. In one embodiment of the invention, isotopic substitution is the replacement of hydrogen with deuterium at one or more positions of the molecule to improve drug efficacy, for example, pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, deuterium can be bonded to carbon at the site of bond cleavage during metabolism (kinetic isotope effect of α-deuterium) or near or near the site of bond cleavage (kinetic isotope effect of βdeuterium).

Isotopic substitutions, for example, deuterium substitutions, can be partial or complete. Partial substitution with deuterium means that at least one hydrogen is substituted with deuterium. In some

8,038607 embodiments of the invention are isotopically enriched by 90, 95, or 99% or more in the isotope at any position of interest. In one embodiment of the invention, at the desired position, deuterium is 90%, 95%, or 99% enriched. Unless otherwise indicated, the enrichment at any position is above the natural level and is sufficient to alter the detectable property of the drug in the human body.

In one embodiment of the invention, the substitution of a hydrogen atom for a deuterium atom occurs within the substituent of the R group in the region of the LB fragment. In one embodiment of the invention, the substitution of a hydrogen atom for a deuterium atom occurs within an R group selected from any of R ¹⁸ , R ¹⁸ , R ³³ , R ³⁴ , R ³⁵ and / or R ³⁶ . In one embodiment of the invention, the substitution of a hydrogen atom for a deuterium atom occurs within the substituent of the R group in the region of the A-carbonyl moiety. In one embodiment of the invention, the substitution of a hydrogen atom for a deuterium atom occurs in R ⁴ , R ⁵ , R ⁶ , R ⁶ , R ⁷ , R ⁸ , R ⁸ ', R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁹ , R ²¹ , R ²² , R ²³ , R ³¹ and R ³² . In other embodiments, certain substituents on the proline ring are selectively deuterated. For example, in one embodiment of the invention, the substitution of a hydrogen atom for a deuterium atom occurs at R, R ', R ¹ , R ¹ , R ² , R ^2' , R ³ and / or R ^{3 '} . In one embodiment of the invention, for example, when any of the substituents R on the proline ring is methyl or methoxy, the alkyl moiety is optionally deuterated, for example CD ₃ or OCD ₃ . In some other embodiments, when two substituents on the proline ring are combined to form a cyclopropyl ring, the unsubstituted methylene carbon is deuterated.

The substitution of a hydrogen atom for a deuterium atom occurs within the R group when at least one of the variables in the R group is hydrogen (eg ² H or D) or alkyl (eg CD ₃ ). For example, when any of the R groups is or contains, for example, by substitution, methyl or ethyl, the alkyl residue is usually deuterated, eg CD ₃ , CH ₂ CD ₃ or CD ₂ CD ₃ .

The compound of the present invention can form a solvate with solvents (including water). Thus, in one embodiment, the invention includes a solvated form of the active compound. The term solvate refers to a molecular complex of a compound of the present invention (including its salts) with one or more solvent molecules. Examples of solvents include water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term hydrate refers to a molecular complex containing a compound of the invention and water. Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be isotopically substituted, eg D ₂ O, d ₆ -acetone, d ₆ DMSO. The solvate can be in liquid or solid form.

A dash (-) that is not between two letters or characters is used to indicate the attachment point of the surrogate. For example, - (C = O) NH ₂ is carbon-bonded to the keto (C = O) group.

The term substituted as used herein means that any one or more hydrogen atoms on a specified atom or group are replaced by a moiety selected from the specified group, provided that the normal valence of the specified atom is not exceeded. For example, when a substituent is oxo (i.e., = O), then two hydrogen atoms on the atom are replaced. When an oxo group replaces two hydrogen atoms in an aromatic moiety, the corresponding partially unsaturated ring replaces the aromatic ring. For example, a pyridyl group substituted with an oxo group is pyridone. Combinations of substituents and / or variables are only permissible if such combinations result in stable compounds or useful synthesis intermediates.

A stable compound or stable structure refers to a compound resulting in a compound that can be isolated and formulated into a dosage form with a shelf life of at least one month.

Any suitable group may be present at the substituted or optionally substituted position which forms a stable molecule and leads to the desired object of the invention and includes, but is not limited to, for example, halogen (which may independently be F, Cl, Br or I); cyano; hydroxyl; nitro; azido; alkanoyl (such as a C ₂ -C ₆ alkanoyl group); carboxamide; alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy such as phenoxy; alkylthio, including those having one or more thioether linkages; alkylsulfinyl; alkylsulfonyl groups including those having one or more sulfonyl bonds; aminoalkyl groups, including groups having one or more N atoms; aryl (eg phenyl, biphenyl, naphthyl, or the like, each ring being either substituted or unsubstituted aromatic); arylalkyl having, for example, 1 to 3 separate or fused rings and 6 to about 14 or 18 ring carbon atoms, benzyl being an example of an arylalkyl group; arylalkoxy, for example, having from 1 to 3 separate or fused rings with benzyloxy, which is an example of an arylalkoxy group; or a saturated, unsaturated or aromatic heterocyclic group having from 1 to 3 separate or condensed rings with one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, pyrazinyl, pyrimidinyl, furanyl,

- 9 038607 pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl and pyrrolidinyl. Such heterocyclic groups can be further substituted, eg, hydroxy, alkyl, alkoxy, halogen and amino. In some embodiments, the optionally substituted includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH2, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ -alkynyl, -C ₁ -C _6- alkoxy, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ -alkylether, (mono- and di-C1-C ₆ -alkylamino) C ₀ -C ₂ - alkyl, C ₁ -C ₂ -halogenoalkyl, hydroxyC _{1 -C 6} -alkyl, ester, carbamate, urea, sulfanilamide, -C ₁ -C ₆ -alkyl (heterocyclo), C ₁ -C ₆ -alkyl (heteroaryl), - C ₁ -C ₆ -alkyl (C ₃ -C ₇ -cycloalkyl), O-C ₁ -C ₆ -alkyl (C ₃ -C ₇ -cycloalkyl), B (OH) ₂ , phosphate, phosphonate and C ₁ -C _2- haloalkoxy.

Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms, or from 1 to about 4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8 carbon atoms. In some embodiments, the alkyl is CrC ₂ , C ₁ -C _3, or C1-G6. Specific ranges as used herein indicate an alkyl group having each member of the range described as a species in its own right. For example, the term C ₁ -C ₆ alkyl, as used herein, indicates a straight or branched chain alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and means that each is described as its own. view. For example, the term C ₁ -C ₄ -alkyl as used herein indicates a straight or branched alkyl group having 1, 2, 3 or 4 carbon atoms and means that each is described as a species in its own right. When C ₀ -C _n -alkyl is used herein in combination with another group, for example, (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl or -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), then the specified group, in this case cycloalkyl, is either directly linked by a single covalent bond (C0alkyl), or attached by an alkyl chain, in this case with 1, 2, 3 or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms such as in —O — C0 — C4 alkyl (C ₃ —C ₇ cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, nhexyl, 2-methylpentane, 3-methylpentane, 2,2-dimethylbutane and 2,3-dimethylbutane. In one embodiment, the alkyl group is optionally substituted as described above.

Alkenyl is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may be in a stable position on the chain. Non-limiting examples are C ₂ -C ₈ alkenyl, C ₂ -C ₆ alkenyl and C ₂ -C ₄ alkenyl. Specific ranges as used herein indicate an alkenyl group having each member of the range described as a distinct species as described above for the alkyl moiety. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described above.

Alkynyl is a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that can be at any stable position on the chain, for example C ₂ -C ₈ alkynyl or C ₂ -C ₆ alkynyl. Specific ranges as used herein indicate an alkynyl group having each member of the range described as a species in itself, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexenyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5hexynyl. In one embodiment, the alkynyl group is optionally substituted as described above.

Alkylene means a divalent saturated hydrocarbon. Alkylenes, for example, can represent a 1 to 8 carbon residue, a 1 to 6 carbon residue, or a specified number of carbon atoms, for example, C ₁ -C ₄ alkylene, C ₁ -C ₃ alkylene or C ₁ -C ₂ - alkylene.

Alkenylene is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes, for example, can be from 2 to 8 carbon residues, from 2 to 6 carbon residues, or the number of carbon atoms indicated, for example C ₂ -C ₄ alkenylene.

Alkynylene is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkenylenes, for example, can represent a 2 to 8 carbon residue, a 2 to 6 carbon residue, or a specified number of carbon atoms, for example C2-C4 alkynylene.

Alkoxy is an alkyl group as defined above covalently linked through an oxygen bridge (—O—). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, npropoxy, iso-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy. Likewise, an alkylthio or thioalkyl group is an alkyl group as defined above, with the indicated

- 10 038607 number of carbon atoms, covalently linked through a sulfur bridge (-S-). In one embodiment, the alkoxy group is optionally substituted as described above.

Alkenyloxy is an alkenyl group, as defined, covalently linked to the group it replaces through an oxygen bridge (—O—).

Alkanoyl is an alkyl group as defined above covalently linked through a carbonyl (C = O) bridge. Carbon of the carbonyl group included in the number of carbon atoms, i.e. S2alkanoil represents a group CH ₃ (C = O) -. In one embodiment, the alkanoyl group is optionally substituted as described above.

Alkyl ether is an alkyl group, as defined herein, covalently linked through an ether bond. The ether bond can be in one orientation or another, for example, a group of the formula --O (C = O) alkyl or a group of the formula - (C = O) Oalkyl.

The amide or carboxamide is —C (O) NR ^a R ^b , where R ^a and R ^{b are} each independently selected from hydrogen, alkyl, for example C1-C6 alkyl, alkenyl, for example C2-C6 alkenyl, alkynyl, for example , C2-C6 alkynyl, -C0-C4-alkyl (C3-C7-cycloalkyl), -C0-C4-alkyl (C3-C7-heterocycloalkyl), -C0-C4 alkyl (aryl) and -C0-C4-alkyl ( heteroaryl); or together with the nitrogen to which they are attached, R ^a and R ^b may form a _{C3-C7-heterocyclic} ring. In one embodiment, R ^a and R ^{b are} each independently optionally substituted as described above.

A carbocyclic group, carbocyclic ring, or cycloalkyl is a saturated or partially unsaturated (i.e., non-aromatic) group containing all carbon atoms in the ring. A carbocyclic group typically contains 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms. Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom, which may have two substituents, may have a cycloalkyl group that is attached as a spiro group. Examples of carbocyclic rings include cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl, and cyclopropyl rings. In one embodiment, the carbocyclic ring is optionally substituted as described above. In one embodiment, cycloalkyl is a partially unsaturated (i.e., non-aromatic) group containing all carbon atoms in the ring. In another embodiment, cycloalkyl is a saturated group containing all carbon atoms in the ring.

A carbocyclic oxy group is a monocyclic carbocyclic ring or a mono- or bicyclic carbocyclic group, as defined above, attached to the group it substitutes via an oxygen, —O—, linker.

Haloalkyl means both branched and unbranched alkyl groups substituted with 1 or more halogen atoms up to the maximum number of halogen atoms allowed. Examples of haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2fluoroethyl, and penta-fluoroethyl.

Haloalkoxy means a haloalkyl group as defined herein attached via an oxygen bridge (oxygen from an alcohol radical).

Hydroxyalkyl is an alkyl group, as previously described, substituted with at least one hydroxyl substituent.

Aminoalkyl is an alkyl group, as previously described, substituted with at least one amino acid substituent.

Halo or halogen means independently any of fluorine, chlorine, bromine and iodine.

Aryl means an aromatic group containing only carbon in the aromatic ring or rings. In one embodiment, the aryl groups contain from 1 to 3 separate or fused rings and from 6 to about 14 or 18 ring atoms without a heteroatom as a ring member. When indicated, such aryl groups may be further substituted with carbon atoms or non-carbon atoms or groups. Such substitution may include condensing with a 5 to 7 membered saturated cyclic group which optionally contains 1 or 2 heteroatoms independently selected from N, O and S to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one embodiment, the aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one embodiment, the aryl group is optionally substituted as described above.

The term heterocycle or heterocyclic ring, as used herein, refers to a saturated or partially unsaturated (i.e., having one or more double and / or triple bonds in the ring without aromaticity) carbocyclic radical of from 3 to about 12 or more, typically from 3, 5, 6, 7 to 10 ring atoms, in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, and the remaining ring atoms are C, where one or more ring atoms are optionally substituted independently by one or more substituents described above. A heterocycle can be a monocycle having 3

- 11 038607 up to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, P and S), or a bicycle having 6 to 10 ring members (4 to 9 atoms carbon and from 1 to 6 heteroatoms selected from N, O, P and S), for example: the bicyclo system [4.5], [5.5], [5.6] or [6.6]. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Heterocycles are described in Paquette, Leo A .; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7 and 9; The Chemistry of Heterocyclic Compounds, A series of Monographs (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19 and 28; and J. Am. Chem. Soc. (1960) 82: 5566. Examples of heterocyclic rings include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, tioksanil, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oksepanil, tiepanil, oxazepinyl, diazepinyl , thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianil, dithiolanyl, dihydropyranyl, dihydrothienyl, tetrahydrofuranyl, dihydroisoquinylamide -oxa-5-azabicyclo [2.2.2] octane, 3-oxa-8azabicyclo [3.2.1] octane, 8-oxa-3-azabicyclo [3.2.1] octane, 6-oxa-3-azabicyclo [3.1.1 ] heptane, 2-oxa-5azabicyclo [2.2.1] heptane, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, 3H-indolyl, quinolizinyl, N -pyridylurea and pyrrolopyrimidine. Spiro residues are also included within the scope of this definition. Examples of the heterocyclic group in which 1 or 2 ring carbon atoms are substituted with oxo (= O) residues are pyrimidinonyl and 1,1-dioxothiomorpholinyl. Heterocyclic groups herein are optionally substituted independently by one or more substituents described herein.

A heterocyclicoxy group is a monocyclic heterocyclic ring or bicyclic heterocyclic group, as previously described, linked to the group it substitutes via an oxygen, —O—, linker.

Heteroaryl indicates a stable monocyclic aromatic ring that contains 1 to 3 or, in some embodiments, 1 to 2 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system, containing at least one 5-7 membered aromatic ring that contains from 1 to 3 or in some embodiments from 1 to 2 heteroatoms selected from N, O and S, with the remaining ring atoms being carbon. In one embodiment, the only heteroatom is nitrogen. In one embodiment, the only heteroatom is oxygen. In one embodiment, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, the bicyclic heteroaryl groups are 9-10 membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5-7 membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In one embodiment, the total number of S and O atoms in the heteroaryl group is not more than 2. In another embodiment of the invention, the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl (in including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, pyrroliazolyl , quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl , quinoxalinyl, naphthyridinyl, tetrahydrofuranyl and furopyridinyl. Heteroaryl groups are optionally substituted independently with one or more substituents described herein. Heteroaryloxy is a heteroaryl group, as described, linked to the group it replaces via an oxygen, —O—, linker.

Heterocycloalkyl is a saturated ring group. It can have, for example, 1, 2, 3 or 4 heteroatoms independently selected from N, S and O, with the remaining ring atoms being carbon. In a typical embodiment, nitrogen is a heteroatom. Monocyclic heterocycloalkyl groups generally have 3 to 8 ring atoms or 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl.

The term mono- and / or dialkylamino indicates secondary or tertiary alkylamino groups, where the alkyl groups are independently selected alkyl groups as defined herein. The point of attachment of the alkylamino group is at nitrogen. Examples of mono and di

12,038607 alkylamino groups include ethylamino, dimethylamino and methylpropylamino.

Dosage form means the unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, solutions, emulsions, implants, particles, spheres, creams, ointments, suppositories, inhalation forms, transdermal forms, buccal forms, sublingual forms, topical forms, gel, mucosal forms, and the like. ... The dosage form can also include an implant, such as an optical implant.

Pharmaceutical compositions are compositions containing at least one active agent, such as a compound or salt of formula I, as well as at least one other substance, such as a carrier. Pharmaceutical combinations are combinations of at least two active agents that can be combined in one dosage form or provided together as separate dosage forms with instructions so that the active agents are to be used together to treat any disorder described herein.

Pharmaceutically acceptable salts include derivatives of the disclosed compounds in which the parent compound has been modified to form inorganic and organic, non-toxic acid or base addition salts. Salts of the compounds of the present invention can be synthesized from the parent compound, which contains a basic or acidic residue, by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as Na, Ca, Mg or K hydroxide, carbonate, bicarbonate, and the like), or by reacting the free base forms of these compounds with a stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water, or in an organic solvent, or a mixture of the two. Typically non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical where practicable. The salts of the compounds of the present invention further include the solvates of the compounds and the salt compound.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound, derived, for example, from non-toxic inorganic or organic acids. For example, common non-toxic acid salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymalic, phenylacetic, glutamic, benzoic, salicylic, mesyl, esyl, esyl, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC- (CH ₂ ) _p -COOH, where n is 0-4, and the like. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., P. 1418 (1985).

The term carrier, as used in pharmaceutical compositions / combinations of the invention, refers to a diluent, excipient or carrier with which the active compound is provided.

Pharmaceutically acceptable excipient means an excipient that is suitable for the preparation of a pharmaceutical composition / combination that is generally safe, non-toxic and neither biologically nor otherwise suitable for administration to a host, and includes, in one embodiment, an excipient that is acceptable for use in veterinary medicine, as well as for pharmaceutical purposes for humans. A pharmaceutically acceptable excipient, as used herein, includes one or more of such excipients.

The patient or host or subject is a human or non-human animal in need of modulation of the complement factor D pathway. Typically, the host is a human. A patient or host or subject also refers to, for example, mammals, primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.

Prodrug, as used herein, means a compound that, when administered to a host in vivo, is converted to the parent drug. As used herein, the term parent drug means any of the chemical compounds described herein that are useful in the treatment of any of the disorders described herein, or for the control or amelioration of the underlying cause or symptoms associated with any physiological or pathological disorder described herein. , the owner is usually a human. Prodrugs can be used to achieve any desired effect, including to improve the properties of the parent drug or to improve the pharmaceutical or pharmacokinetic properties of the parent drug. The existence of a prodrug strategy provides a choice

- 13 038607 in modulating conditions for in vivo formation of the parent drug, all of which are considered to be included in this document. Non-limiting examples of prodrug strategies include covalent attachment of removable groups or removable portions of groups, for example, but not limited to, acylation, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxyl derivatives, sulfoxy or sulfone derivatives, carbonylation or anhydride, among others.

The provision of a compound of formula I with at least one additional active agent means a compound of formula I and additional active agent (s) presented simultaneously in one dosage form, presented in parallel as separate dosage forms, or presented in separate dosage forms for administration separated by a certain interval time, which is within the time in which both the compound of formula I and at least one additional active agent are in the patient's blood. In some embodiments, the compound of Formula I and the additional active agent should not be prescribed to the patient by the same healthcare professional. In some embodiments, the additional active agent or agents should not require a prescription. The administration of a compound of formula I or at least one additional active agent can be by any suitable route, for example, in oral tablets, in oral capsules, in oral solutions, by inhalation, injection, suppository or topical contact.

A therapeutically effective amount of a pharmaceutical composition / combination of the present invention means an amount effective when administered to a patient in order to provide a therapeutic benefit such as amelioration of symptoms, eg, an amount effective to reduce symptoms of macular degeneration. In one embodiment, the therapeutically effective amount is an amount sufficient to prevent a significant increase or will significantly decrease the detectable level of complement factor D in the patient's blood, serum, or tissues.

II. Detailed description of active connections

In accordance with the present invention, a compound of formula I is claimed

as well as its pharmaceutically acceptable salts and compositions. Formula I can be considered as having a central core, a substituent LB and a substituent (C = O) A. It has been found that a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein R ¹² or R ¹³ on group A is aryl, heteroaryl or heterocycle is an excellent inhibitor of factor D complement, and therefore can be used in an effective amount for treating a host in need of complement factor D modulation.

Non-limiting examples of compounds falling under formula I with variations in variables, eg, A, B, R1-R ³ and L, are shown below. The description includes all combinations of these definitions resulting in stable compounds.

Formulas II-XXX.

In one aspect, the invention includes compounds and salts of formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII , XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX and XXX, which are within the scope of Formula I. The variables shown in Formulas IIXXX have the definitions set forth in the Summary section for Formula I or any definitions set forth herein description.

- 14 038607

- 15 038607

Formula XXIX Formula XXX

In these embodiments, it should be understood that where R ¹ or R ^{3 is} attached to a carbon atom, there may be two independent attachments, as in R ² / R 2, and these formulas are to be construed as including all such variations.

In addition, the invention includes compounds and salts of formula I, and pharmaceutically acceptable compositions thereof, and any of their subformulas (II-XXX), in which at least one of the following conditions occurs in the embodiments described below.

Aryl, heteroaryl and heterocyclic substituents R ¹² and R ¹³ .

It has surprisingly been found that a compound of Formula I, a pharmaceutically acceptable salt thereof or a composition wherein R ¹² or R ¹³ on group A is aryl, heteroaryl or heterocycle is an excellent inhibitor of factor D complement.

One of R ¹² and R ^{13 is} selected from R ³¹ and the other of R ¹² and R ^{13 is} selected from R ³² . In another embodiment of the invention, each of R ¹² and R ¹³ can be independently selected from R ³² .

R ^{31 is} selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, C1-C2-haloalkyl, C1-C2-haloalkoxy, C1-C6-alkyl, -C0-C4-alkyl (C3-C7-cycloalkyl) C2-C6-alkenyl, C2-C6 alkanoyl, C1-C6-alkoxy, C2 -C6 alkenyloxy, -C (O) OR ^9, _C1-C6 thioalkyl, -C ₀ -C ₄ alkyl-NR ⁹ R ¹⁰ , -C (O) NR ⁹ R ¹⁰ , -SO2R ⁹ , -SO2NR ⁹ R ¹⁰ , -OC (O) R ⁹ and -C (NR ⁹ ) NR ⁹ R ¹⁰ , each of R ³¹ , which is different from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C2-haloalkyl and C1-C2-haloalkoxy, is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, -COOH, -CONH2 , C1-C2-haloalkyl and C1-C2-haloalkoxy, and of which each R ^{31 is} also optionally substituted with one substituent selected from phenyl and a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein the phenyl or 4-7chlenny heterocycle is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C ₆ alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkanoyl , C ₁ -C ₆ -alkoxy, (mono- and di-C ₁ -C ₆ -alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -alkyl ether, -C ₀ -C ₄ -alkyl) (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₂ haloalkyl and C ₁ -C ₂ -haloalkoxy;

R ^{32 is} selected from aryl; saturated or unsaturated heterocycle (for example, a 5-6 membered ring having 1, 2, or 3 heteroatoms independently selected from N, O, and S), where the heterocycle is linked through a carbon atom in the heterocyclic ring to the ring A carbon atom at position R ¹² or R ¹³ ; and heteroaryl (eg, a 5-6 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S), wherein the aryl, heterocycle, or heteroaryl ring may be optionally substituted.

Non-limiting examples of R ³² are

- 16 038607

Non-limiting options R ¹² / R ¹³ .

In one embodiment, R ¹² is R ³² .

In one embodiment, R ¹³ is R ³² .

In one embodiment, R ¹² is R ³² which is aryl.

In one embodiment, R ¹² is optionally substituted aryl.

In one embodiment, R ¹² is an optionally substituted saturated or unsaturated heterocycle linked through a carbon atom in the heterocyclic ring to the carbon atom of Ring A at the R ¹² position.

In one embodiment, R ¹² is optionally substituted heteroaryl.

In one embodiment, R ¹³ is optionally substituted aryl.

In one embodiment, R ¹³ is an optionally substituted saturated or unsaturated heterocycle linked through a carbon atom in the heterocyclic ring to the ring A carbon at the R ¹³ position.

In one embodiment, R ¹³ is optionally substituted heteroaryl.

In one embodiment, R ¹² is R ³² , which is a (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2, or 3 heteroatoms independently selected from N, O and S, where (5- or 6-membered unsaturated heterocycle) is attached through a carbon atom to a CR ¹² or CR ¹³ carbon atom.

In one embodiment, R ¹² is R ³² , which is (4-7 membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O and S, where (4-7 membered heterocycloalkyl) attached through a carbon atom to a CR ¹² carbon atom or

- 17 038607

CR ¹³ .

In one embodiment, R ¹³ is R ³² which is aryl.

In one embodiment, R ¹³ is R ³² , which is a (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2, or 3 heteroatoms independently selected from N, O and S, where (5- or 6-membered unsaturated heterocycle) is attached through a carbon atom to a CR ¹² or CR ¹³ carbon atom.

In one embodiment, R ¹³ is R ³² which (4-7 membered heterocycloalkyl) has 1, 2, or 3 heteroatoms independently selected from N, O and S, where (4-7 membered heterocycloalkyl) is bonded through a carbon atom with a carbon atom CR ¹² or CR ¹³ .

In one embodiment, the invention relates to compounds of Formula I wherein one of R ¹² and R ¹³ is H and the other of R ¹² and R ¹³ is R ³² , wherein R ^{32 is} selected from aryl, which may optionally be substituted; (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (5- or 6-membered unsaturated heterocycle) is attached through a carbon atom to carbon CR ¹² or CR ¹³ , where (5- or 6-membered unsaturated or aromatic heterocycle) may be optionally substituted; and (4-7 membered heterocycloalkyl) having 1, 2, or 3 heteroatoms independently selected from N, O and S, where (4-7 membered heterocycloalkyl) is bonded through a carbon atom to a CR ¹² or CR ¹³ carbon atom, and (47 -membered heterocycloalkyl) may be optionally substituted.

In another embodiment, the invention relates to compounds of Formula I, wherein

R ¹ , R ¹ ', R ² and R ³ ' are all hydrogen;

R ² represents fluorine, and R ³ represents hydrogen, -C ₀ -C ₄ alkyl (C ₃ -C ₇ -cycloalkyl) or -O-C ₀ -C ₄ -alkul _(C-3 -S7 tsikloalkul);

R ⁵ represents hydrogen, halogen or _C1-C2 alkyl;

R ¹¹ , R ¹³ , R ¹⁴ and R ¹⁵ , if present, are independently selected at each occurrence from hydrogen, halogen, hydroxyl, amino, C ₁ -C ₄ alkyl, C1-C ₄ alkoxy, —C ₀ -C ₂ -alkyl (mono- and di-C ₁ -C ₂ -alkylamino), trifluoromethyl and trifluoromethoxy;

X ¹² represents CR ¹² ; and

R ^{12 is} selected from aryl, which may be optionally substituted; (5- or 6-membered unsaturated or aromatic heterocycle) having 1, 2 or 3 heteroatoms independently selected from N, O and S, where (5- or 6-membered unsaturated heterocycle) is attached through a carbon atom to carbon CR ¹² or CR ¹³ , where (5- or 6-membered unsaturated or aromatic heterocycle) may be optionally substituted; and (4-7 membered heterocycloalkyl) having 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein (4-7 membered heterocycloalkyl) is bonded through a carbon atom to a CR ¹² or CR ¹³ carbon atom, and (4-7 membered heterocycloalkyl) may optionally be substituted.

In one embodiment, the invention relates to compounds of Formula I wherein m is 0 or 1;

R ² is halogen, R2 'is hydrogen or halogen, and R ³ is hydrogen, halogen, —C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl) or —O — C ₀ -C ₄ - alkyl (C ₃ -C ₇ -cycloalkyl);

R ⁶ is -C (O) C ₁ -C ₄ -alkyl, -C (O) NH ₂ , -C (O) CF ₃ , -C (O) (C ₃ -C ₇ -cycloalkyl) or -ethyl (cyanoimino);

one of R ¹² and R ¹³ is selected from hydrogen, halogen, _C1-C4 alkyl, _C1-C4 alkoxy, trifluoromethyl and trifluoromethoxy; and the other of R ¹² and R ¹³ is R ³² , where

R ^{32 is} selected from aryl; saturated or unsaturated heterocycle (for example, a 5-6 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S), the heterocycle being linked through a carbon atom in the heterocyclic ring to the carbon atom of ring A at position R ¹² or R ¹³ ; and heteroaryl (eg, a 5-6 membered ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S), wherein the aryl, heterocycle, or heteroaryl ring may be optionally substituted.

In one embodiment, the invention relates to compounds of Formula I wherein one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R ¹² and R ¹³ is R ³² , where

R ^{32 is} selected from aryl, heteroaryl, or heterocycle linked to ring A through a carbon atom of the heterocycle;

In one embodiment, R ³² may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, —B (OH) ₂ , —Si (CH ₃ ) ₃ , —COOH, -CONH2, -P (O) (OH) ₂ , C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, -C ₀ -C ₂ -alkyl (mono- and diC ₁ -C ₄ -alkylamino), C ₁ -C ₆ -alkulefiar, C ₁ -C ₄ -alkulamino, _C1-C4 -gidroksilalkila, C ₁ -C ₂ -haloalkyl and C1-C2 haloalkoxy.

Remnant of the central nucleus.

The remainder of the central core in formula I is shown below:

- 18 038607

The remainder, I y. ' at

Central ^ - ^: _o - /

Kernels - x;

) = O

And where Q ¹ represents N (R1) or C (R1R1);

Q ² is C (R ² R ² '), C (R ² R ² ') -C (R ² R ² '), S, O, N (R ² ) or C (R ² R ² ') O ;

Q ³ represents N (R ³ ), S or C (R ³ R ³ );

X ¹ and X ² independently represent H, CH or CZ, or X ¹ and X ² together represent C = C; and where Q1, Q2, Q3, X1 and X2 are selected such that stable compounds are obtained.

Non-limiting ring examples

X are shown below (any of which may be otherwise substituted with R1, R1 ', R2, R2', R3 and R3 ') as described in more detail below.

where q is 0, 1, 2, or 3 and r is 1, 2, or 3.

R and R 'are independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, heteroarylalkyl, where each group may be optionally substituted, or any other substituent group herein that provides the desired properties. In some embodiments, the ring contains one or more chiral carbon atoms. The invention includes embodiments in which the chiral carbon may be present as an enantiomer or mixtures of enantiomers, including a racemic mixture. Where the ring contains more than one stereocenter, all enantiomers and diastereomers are included as specific examples in the invention.

Z is F, Cl, NH ₂ , CH ₃ , CH ₂ D, CHD _2, or CD ₃ .

R ¹ , R ¹ , R ² , R ² , R ³ and R ^{3 are} independently selected in each case depending on the circumstances and only when stable compounds are obtained from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C ₁ -C ₆ -αalkyl, C ₂ -C ₆ -αalkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -αalkoxy, C ₂ -C ₆ -alkynyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ -thioalkyl, hydroxyC1-C ₆ -alkyl, aminoC1-C ₆ -alkyl, -C ₀ -C ₄ -alkyl-NR ⁹ R ¹⁰ , -C (O) OR ⁹ ,

- 19 038607

-OC (O) R ⁹ , -NR ⁹ C (O) R ¹⁰ , -C (O) NR ⁹ R ¹⁰ , -OC (O) NR ⁹ R ¹⁰ , -NR ⁹ C (O) OR ¹⁰ , C1- C ² haloalkyl and _{C 1} -C ² haloalkoxy, where R ⁹ and R ^{10 are} independently selected at each occurrence from hydrogen, C _{1 -C 6} -alkyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C4-alkyl, -C ₀ -C ₄ -alkyl (C3-C ₇ -cycloalkyl) and -O-C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl).

Non-limiting options for the central core.

In alternative embodiments, R ¹ and R ¹ or R ³ and R ³ can be taken together to form a 3-6 membered carbocyclic spiro ring or a 3-6 membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N , O or S; R ² and R ² can be taken together to form a 3-6 membered carbocyclic spiro ring; or R ² and R ² can be taken together to form a 3-6 membered heterocyclic spiro ring;

each of the rings may be unsubstituted or substituted with one or more substituents independently selected from halogen (and in particular, F), hydroxy, cyano, -COOH, _C1-C4 alkyl (including, in particular, methyl), C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C1-C ₄ -alkoxy, C ₂ -C ₄ -alkanoyl, hydroxy-C _{1 -C 4} -alkyl, (mono- and di-C ₁ -C ₄ -alkylamino ) C ₀ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O-C ₀ -C ₄ -alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ -haloalkyl and C 1 C ₂ -galogenalkoksi.

In alternative embodiments, R ¹ and R ² may be taken together to form a 3-membered carbocyclic ring; R ¹ and R ² can be taken together to form a 4-6 membered carbocyclic or aryl ring or a 4-6 membered heterocyclic or heteroaryl ring containing 1 or 2 heteroatoms independently selected from N, O and S; or R ² and R ³ , when bonded to adjacent carbon atoms, can be taken together to form a 3-6 membered carbocyclic or aryl ring or a 3-6 membered heterocyclic or heteroaryl ring;

each ring may be unsubstituted or substituted with one or more substituents independently selected from halogen (in particular, F), hydroxy, cyano, -COOH, _C1-C4 alkyl (including, in particular, methyl), C ₂ -C ₄ -alkenyl, C ₂ -C ₄ -alkynyl, C ₁ -C ₄ -alkoxy, C ₂ -C ₄ -alkanoia, hydroxyC1-C ₄ -alkyl, (mono- and di-C ₁ -C ₄ -alkylamino) C ₀ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O-C ₀ -C ₄ -alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ -haloalkyl and _C1-C2 -galogenalkoksi.

In one embodiment, the core residue is proline.

In one embodiment of the invention, the core residue is 4fluoroproline.

In one embodiment, R ¹ , R ¹ , R ² , R ³ and R ³ , if present, are all hydrogen; and R ² is fluoro.

In one embodiment, R ¹ , R ¹ , R ² and R ³ , if present, are all hydrogen; and R ² is fluoro, and R ³ is —C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) or —O — C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl).

In one embodiment, R ¹ and R ² taken together form a 3-6 membered cycloalkyl group and R ¹ , R ² , R ³ and R ³ , where present, are all hydrogen.

In one embodiment, R ¹ , R ¹ , R ³ and R ³ , if present, are all hydrogen, and R ² and R ² taken together form a 5 or 6 membered heterocycloalkyl group having 1 or 2 atoms oxygen.

In one embodiment, R ¹ is hydrogen and R ² is fluoro.

In one embodiment, R ¹ and R ^{2 are} linked to form a 3-membered ring.

The disclosure includes compounds of formula I in which the central pyrrolidine is substituted vinyl, for example:

In one embodiment of the invention, a compound of Formula I has the structure:

F

In one embodiment of the invention, the central pyrrolidine is modified by the addition of a second heteroatom to the pyrrolidine ring, such as N, O, S, or Si, for example:

Another modification within the scope of the invention is the attachment of a substituent -20 038607 a on the central ring of pyrrolidine at R ⁷ or R ⁸ to form a 5- or 6-membered heterocyclic ring, for example:

Examples of compounds having the modifications described above include:

Substituents L-B of the central nucleus.

Substituents L-B of the central nucleus in formula I are given below:

L is a bond or is selected from the formulas:

where R ¹⁷ is hydrogen, C ₁ -C ₆ -alkyl or -C ₀ -C ₄ -alkyl ( _{C 3 -C 7} -cycloalkyl) and R ¹⁸ and R ^{18 are} independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0, 1, 2, or 3.

B is monocyclic or bicyclic carbocyclic; monocyclic or bicyclic carbocyclic oxy group; a monocyclic, bicyclic or tricyclic heterocyclic group having 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, and from 4 to 7 ring atoms in the ring; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl; - (C ₀ -C ₄ -alkyl) (aryl); - (C ₀ -C ₄ alkyl) (heteroaryl); or - (C ₀ -C ₄ -alkyl) (biphenyl).

Each of B is unsubstituted or substituted with one or more substituents independently selected from R ³³ and R ³⁴ , as well as 0 or 1 substituents selected from R ³⁵ and R ³⁶ :

R ^{33 is} independently selected from halogen, hydroxyl, -COOH, cyano, C1-C6-α-alkyl, C2-C6-alkanoyl, C1-C6-alkoxy, -C0-C4-alkyl-NR ⁹ R ¹⁰ , -SO2R ⁹ , C1-C2- haloalkyl and C1-C2-haloalkoxy; R ^{34 is} independently selected from nitro, C2-C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ thioαalkyl, -JC ₃ -C ₇ -cycloalkyl, -B (OH) ₂ , -JC (O ) NR ⁹ R ²³ , -JOSO2OR ²¹ , -C (O) (CH2) 1-4S (O) R ²¹ , -O (CH2) _1-4 S (O) NR ²¹ R ²² , -JOP (O) ( OR ²¹ ) (OR ²² ), -JP (O) (OR ²¹ ) (OR ²² ), -JOP (O) (OR ²¹ ) R ²² , JP (O) (OR ²¹ ) R ²² , -JOP (O) R ²¹ R ²² , -JP (O) R ²¹ R ²² , -JSP (O) (OR ²¹ ) (OR ²² ), -JSP (O) (OR ²¹ ) (R ²² ), -JSP (O) (R ²¹ ) (R ²² ), -JNR ⁹ P (O) (NHR ²¹ ) (NHR ²² ), -JNR ⁹ P (O) (OR ²¹ ) (NHR ²² ),

JNR ⁹ P (O) (OR ²¹ ) (OR ²² ), -JC (S) R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S (O) NR ¹⁰ R ²² , -jnr ⁹ so2nr ¹⁰ r ²² , - jso2nr ⁹ cor ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC (O) NR ²¹ SO2R ²² , -JC (NH2) NR ²² , -JC (NH2) NR ⁹ S (O) 2R ²² , -JOC (O) NR ²¹ R ²² , -JNR ²¹ C (O) OR ²² , -JNR ²¹ OC (O) R ²² , - (CH2) 1-4C (O) NR ²¹ R ²² , -JC (O ) R ²⁴ R ²⁵ , -JNR ⁹ C (O) R ²¹ , -JC (O) R ²¹ , -JNR ⁹ C (O) NR ¹⁰ R ²² , -CCR ²¹ , - (CH2) 1-4OC (O) R ²¹ and -JC (O) OR ²³ ; each of R ³⁴ may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, —B (OH) 2, —Si (CH ₃ ) ₃ , —COOH, —CONH2, -P (O) (OH) ₂ , C ₁ -C ₆ -alkyl, -C ₀ -C ₄ alkyl (C ₃ -C ₇ -cycloalkyl), C1-C ₆ -alkoxy, -C ₀ -C ₂ -alkyl (mono- and di-C ₁ -C ₄ -alkylamino), C ₁ -C ₆ alkyl ester, a _C1-C4 alkylamino, _C1-C4 -gidroksilalkila, C1-C ₂ -haloalkyl and C 1 C ₂ -galogenalkoksi;

R ^{35 is} independently selected from naphthyl, naphthyloxy, indanyl, (4-7 membered heterocycloalkyl) C0-C4 alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms, independently selected from N, O and S, and containing from 4 to 7 ring atoms in each ring; each of R ^{35 is} unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C6 alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C1-C ₆ alkoxy , (mono- and di-C ₁ -C ₆ -alkylamino) C ₀ -C ₄ -alkyl, C1-C ₆ -alkyl ether, -C ₀ -C ₄ alkyl (C ₃ -C ₇ -cycloalkyl), -SO ₂ R ⁹ , C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ -haloalkoxy; and

R ^{36 is} independently selected from tetrazolyl, (phenyl) C ₀ -C ₂ -alkyl, (phenyl) C ₁ -C ₂ -alkoxy, phenoxy, and 5-21 038607 or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms, independently selected from N, O, B and S, each of R ^{36 is} unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C6-α-alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -αalkoxy, (mono and di-C1-C ₆ -alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -alkylether, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -SO2R ⁹ ,

-OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ , -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , C ₁ -C ₂ -halogenoalkyl and C _1-2 haloalkoxy.

J is independently selected at each occurrence from a covalent bond, C1-C ₄ -alkylene, -OC ₁ -C ₄ -alkylene, C _{2 to} C ₄ alkenyl and C ₂ -C ₄ -alkynyl.

In one embodiment of the invention, -L-B- is

where R ²⁶ and R ^{27 are} independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C _6- alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy , C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ alkyl (mono- and _di-C1-C6 alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) -C ₀ -C ₄ -alkoxy (C ₃ -C ₇ -cycloalkyl), C1-C ₂ -haloalkyl, C1-C ₂ -haloalkoxy and C1-C ₂ -haloalkylthio.

Non-limiting options L-B.

In another embodiment, -L-B- is

where R ¹⁸ and R ^{18 are} independently selected from hydrogen, halogen, hydroxymethyl and methyl; and m is 0 or 1; and

R ²⁶ , R ²⁷ and R ^{28 are} independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkanoyl, C1-C6-α-alkoxy, C1-C6-thioalkyl , (mono- and di-C1-C6-alkylamino) C0-C4 alkyl, (C3-C7-cycloalkyl) C0-C4-alkyl, (aryl) C0-C4-alkyl-, (heteroaryl) C0-C4-alkyl- and -C0-C4 alkoxy (C3-C7 cycloalkyl); each of which R ²⁶ , R ²⁷ , R ²⁸ , other than hydrogen, halogen, hydroxyl, nitro, cyano, is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, C1-C ₂ alkoxy, C ₁ -C ₂ -haloalkyl, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ -alkyl and C ₁ -C ₂ -haloalkoxy; and

R ²⁹ is hydrogen, C ₁ -C ₂ -alkyl, C1-C ₂ -haloalkyl or Si (CH ₃ ) ₂ C (CH ₃ ) ₃ .

In one embodiment, m is 0.

In one embodiment, the invention further comprises compounds and salts of Formula I wherein B is 2-fluoro-3-chlorophenyl. In another embodiment, another carbocyclic, aryl, heterocyclic or heteroaryl group is used, such as 2 bromo-pyridin-6-yl, 1- (2,2,2-trifluoroethyl) -1H-pyrazol-3-yl, 2,2- dichlorocyclopropylmethyl or 2-fluoro-3trimethylsilylphenyl.

In another embodiment, B is phenyl, pyridyl, or indanyl, each of which is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C _6- alkenyl, C ₂ -C ₆ -αalkanoyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ -thioalkyl, (mono- and di-C1-C ₆ -alkylamino) C ₀ -C ₄ -alkyl, (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl, -C 0 -C 4 -alkoxy (C 3 -C 7 -cycloalkyl), (phenyl) C 0 -C 2 -alkyl, (pyridyl) C 0 -C 2 -alkyl; each of substituents other than hydrogen, halogen, hydroxyl, nitro, cyano is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, C ₁ C ₂ -alkyl, C ₁ -C ₂ -alkoxy, - OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ , -Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , C ₁ -C ₂ -haloalkyl and C1-C2 haloalkoxy.

In another embodiment of the invention B represents a phenyl or pyridyl substituted with 1, 2 or 3 substituents selected from chloro, bromo, hydroxy, -SCF _{3, C1-C2-alkyl, C1-C2} alkoxy, trifluoromethyl, phenyl, and trifluoromethoxy, each of the substituents other than chlorine, bromine, hydroxyl, —SCF ₃ , may be optionally substituted.

- 22 038607

In some embodiments, B is a 2-fluoro-3-chlorophenyl or 2-fluoro-3-trifluoromethoxyphenyl group.

In one embodiment of the invention B represents a pyridyl, optionally substituted by halogen, _C1-C2 alkoxy and trifluoromethyl.

In one embodiment of the invention B represents a phenyl substituted with 1, 2 or 3 substituents independently selected from halogen, _{C1-C2-alkyl, C1-C2} alkoxy, trifluoromethyl, and optionally substituted phenyl.

In one embodiment, R ^{23 is} independently selected at each occurrence from (C ₃ -C ₇ cycloalkyl) C ₀ -C 4 alkyl, (phenyl) C ₀ -C 4 alkyl, (4-7 membered heterocycloalkyl) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle) C0-C4-alkyl having 1, 2, or 3 heteroatoms independently selected from N, O and S.

In one embodiment, B is selected from

- 23 038607

- 24 038607

- 25 038607 where R ²⁷ represents hydrogen, methyl or trifluoromethyl; R ²⁸ is hydrogen or halogen; and R ²⁹ is hydrogen, methyl, trifluoromethyl, or —Si (CH ₃ ) ₂ C (CH ₃ ) ₃ .

Deputy (C = O) A of the central nucleus.

The substituent (C = O) A of the central nucleus in formula I is shown below:

A represents a group selected from

R ^{4 is} selected from -CHO, -CONH2, C2-C6-alkanoyl, hydrogen, -SO2NH2, -C (CH2) 2F, -CH (CF3) NH2, C _r C ₆ alkyl, -C ₀ -C ₄ -alkyl ( C ₃ -C ₇ -cycloalkyl), -C (O) C ₀ -C ₂ -alkyl (C ₃ -C ₇ -cycloalkyl),

each of R ⁴ other than hydrogen, —CHO, and —CONH2 is unsubstituted or substituted with one or more of amino, imino, halogen, hydroxyl, cyano, cyanimino, Cl — C ₂ alkyl, C ₁ —C ₂ alkoxy, - C ₀ -C ₂ alkyl (mono- and _di-C1-C4 alkylamino), C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ -gαlogenalkoksi.

R ⁵ and R ^{6 are} independently selected from -CHO, -C (O) NH2, -C (O) NH (CH3), C2-C6-alkanoia, hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -SO2NH2, vinyl, C1-C6-α-alkyl (including methyl), C2-C6-alkenyl, C1-C6-α-alkoxy, -C0-C4-alkyl (C3-C7-cycloalkyl), -C (O) C0-C4-alkyl (C3 -C7-cycloalkyl), -P (O) (OR ⁹ ) 2, -OC (O) R ⁹ , -C (O) OR ⁹ , -C (O) N (CH ₂ CH ₂ R ⁹ ) (R ¹⁰ ), -NR ⁹ C (o) r ¹⁰ , phenyl, or a 5- or 6-membered heteroaryl.

Each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or optionally substituted. For example, R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano, and —COOH may be substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanimino, C ₁ -C ₂ -alkyl, C ₁ -C ₄ -alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C _{1 to} C ₄ -alkylamino), C ₁ -C ₂ -galogenalkila and C ₁ -C ₂ -galogenalkoksi.

R ⁶ is hydrogen, halogen, hydroxyl, C ₁ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl) or C ₁ -C ₄ -alkoxy; or R ⁶ and R ⁶ can be taken together to form an oxo, vinyl or imino group.

R ⁷ is hydrogen, C ₁ -C ₆ -alkyl or —C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl).

R ⁸ and R ^{8 are} independently selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ -αalkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ cycloalkyl), C ₁ -C ₆ -α alkoxy and (C ₁ -C ₄ -alkylamino) C ₀ -C ₂ -alkyl; or R ⁸ and R ⁸ taken together form an oxo group; or R ⁸ and R ⁸ can be taken together with the carbon atom to which they are attached to form a 3-membered carbocyclic ring.

- 26 038607

R ^{16 is} absent or may include one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C _6- alkoxy, -C0-C4 alkyl (mono- and di-C ₁ -C ₆ -alkylamino), -C ₀ -C4-alkyl (C ₃ -C ₇ -cycloalkyl), C1-C ₂ -halogenoalkyl and C1-C2haloalkoxy ...

R ¹⁹ represents hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkanoyl, -SO2C1-C6-alkyl, (mono- and di-C1-C6-alkylamino) C1-C4-alkyl, - C0-C4-alkyl (C3-C7-cycloalkyl), -C0-C4-alkyl (C3-C7-heterocycloalkyl), -C0-C4-alkyl (aryl), C0-C4-alkyl (heteroaryl), and where R ¹⁹ other than hydrogen is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, —COOH, and —C (O) OC1 — C4 alkyl.

X ¹¹ represents N or CR ¹¹ .

X ¹² represents N or CR ¹² .

X ¹³ represents N or CR ¹³ .

X ¹⁴ is N or CR ¹⁴ .

At most 2 of X ¹¹ , X ¹² , X ¹³ and X ¹⁴ represent N.

R ¹¹ , R ¹⁴ and R ^{15 are} independently selected at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O (PO) (OR ⁹ ) 2, - (PO) (OR ⁹ ) 2, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₂ -C _6- alkenyl (aryl), C _{2 -C 6-} alkenyl (cycloalkyl), C ₂ -C _6- alkenyl (heterocycle) , C ₂ -C ₆ -alkenyl (heteroaryl), C ₂ -C ₆ -alkynyl, C ₂ C ₆ alkynyl (aryl), C ₂ -C ₆ -alkynyl (cycloalkyl), C ₂ -C ₆ -alkynyl (heterocycle ), C ₂ -C ₆ -alkynyl (heteroaryl), C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -thioalkyl, -C ₀ -C ₄ -alkyl (mono- and di -C1-C ₆ -alkylamino), -C ₀ C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -C ₀ -C ₄ -alkoxy (C ₃ -C ₇ -cycloalkyl), C1-C ₂ -haloalkyl and C ₁ -C ₂ nalkoxy halo.

In one embodiment, R ⁵ and R ^{6 are} independently selected from —CHO, —C (O) NH2, —C (O) NH (CH ₃ ), C ₂ -C ₆ alkanoyl, and hydrogen.

In one embodiment, each of R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanimino, C ₁ -C ₂ alkyl, C1-C4 alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C ₁ -C ₄ -alkylamino), C1-C ₂ -haloalkyl and C 1 C ₂ -galogenalkoksi.

In one embodiment, R ⁸ and R ^{8 are} independently hydrogen or methyl.

In one embodiment, R ⁸ and R ⁸ are hydrogen.

In one embodiment, R ⁷ is hydrogen or methyl.

In one embodiment, R ⁷ is hydrogen.

Formula variants IA, IB, IC and ID

To further illustrate the invention, various embodiments of formulas IA, IB, IC and ID are disclosed. They are presented by way of example to show some of the variations among the presented compounds within the scope of the invention, and can be applied to any of formulas I-XXX.

In one aspect, the present disclosure includes compounds and salts of Formula IA:

where R ⁶ , R ¹³ and B may have any of the definitions set forth herein for this variable.

In another aspect, the present disclosure includes compounds and salts of formulas IB, IC and ID.

In formulas IA, IB, IC and ID, variables can include any of the definitions set forth herein, which results in a stable connection. In some embodiments, the following conditions apply for formulas IB and IC.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is heteroaryl.

In some embodiments of the invention, structures are provided comprising the formulas

- 27 038607

IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl,

R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is heteroaryl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is heteroaryl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ is H and B is heteroaryl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R 6 is an amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m = 0, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 0, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 1, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is

- 28 038607 is heteroaryl.

In some embodiments of the invention, structures are provided comprising the formulas

IB and IC, where m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl,

R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is heteroaryl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 1, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is heteroaryl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ is H and B is heteroaryl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 1, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m = 1, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is heteroaryl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 1, R ¹ is H, R ² is

F, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising Formulas IB and IC, wherein m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 1, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is R ³² , R ³² is heteroaryl, R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is R ³² , R ³² is heteroaryl , R ¹³ is H and B is phenyl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 1, R ¹ is H, R ² is F, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, structures are provided comprising Formulas IB and IC, where m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is alkanoyl, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, the invention provides structures comprising formulas IB and IC, where m = 1, R ¹ is H, R ² is F, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

In some embodiments, structures are provided comprising formulas IB and IC, where m = 1, R ¹ and R ^{2 are} joined to form a 3-membered ring, R ⁶ is an amide, R ¹² is H, R ¹³ is R ³² , R ³² is heteroaryl and B is phenyl.

- 29 038607

Variants of Formula VII.

To further illustrate the invention, various embodiments of Formula VII are provided. In one aspect, the disclosure includes compounds and salts of Formula VII:

R ² ; , ^{r3 r2} t \ /

where '

R ¹ , R ² , R ² and R ^{3 are} independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, -C0-C2 alkyl-NR ⁹ R ¹⁰ , -C0-C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -O-C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C1-C ₂ -haloalkyl and C1-C ₂ -haloalkoxy;

R ⁸ and R ^{8 are} independently selected from hydrogen, halogen and methyl;

R ⁵ is hydrogen, hydroxyl, cyano, -COOH, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ alkanoyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -C (O) C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₂ -haloalkyl or C1-C2-haloalkoxy;

R ⁶ is —C (O) CH ₃ , —C (O) NH ₂ , —C (O) CF ₃ , —C (O) (cyclopropyl), or —ethyl (cyanoimino); and

R ¹¹ and R ¹⁴ are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C ₁ -C ₆ alkyl, C2 -C6 alkenyl, C2 -C6 alkanoyl, C1 -C6 alkoxy, C1 -C6 thioalkyl , -C0-C4-alkyl (mono- and di-C1C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -OC ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₂ -haloalkyl and C1-C2-haloalkoxy.

Prodrugs of Formula I are also included within the scope of this disclosure.

Pharmaceuticals

The compounds described herein can be administered as a pure chemical, but can also be administered as a pharmaceutical composition that includes an effective amount for a host in need of treatment of a selected compound of Formula I as described herein. Accordingly, the invention relates to pharmaceutical compositions containing an effective amount of a compound or pharmaceutically acceptable salt of Formula I together with at least one pharmaceutically acceptable carrier. The pharmaceutical composition may contain a compound or salt of formula I as the only active agent or, in an alternative embodiment of the invention, formula I and at least one additional active agent. In some embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg a compound of Formula I, and optionally about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of an additional active agent in a unit dosage form. Examples are dosage forms with at least 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750 mg of active substance or a salt thereof. The pharmaceutical composition may also comprise a molar ratio of a compound of Formula I to an additional active agent. For example, the pharmaceutical composition may contain a molar ratio of about 0.5: 1, about 1: 1, about 2: 1, about 3: 1, or about 1.5: 1 to about 4: 1 of another anti-inflammatory agent.

The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, by means of an implant, including an ophthalmic implant, transdermally, via buccal administration, rectally, as an ophthalmic solution, by injection, including ophthalmic injection, by intravenous, intra-aortic, intracranial, or other means in unit dosage forms containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition can be formulated in any pharmaceutically acceptable form, eg, an aerosol, cream, gel, tablet, capsule, tablet, syrup, transdermal patch, or ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate amounts of active ingredients, eg, an effective amount to achieve the desired purpose.

Carriers include excipients and diluents and must be of sufficient purity and low enough toxicity to be suitable for administration to the patient being treated. The carrier can be inert or it can have its own pharmaceutical benefits. The amount of carrier used in combination with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound.

Classes of carriers include, but are not limited to, binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, fragrances, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers can be listed in more than one class, for example, vegetable oil can be used as a lubricant in some formulations and as a diluent in others. Examples of pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, maltose, gelatin; talc and vegetable oils. Optional active agents can be included in the pharmaceutical composition that do not substantially interfere with the activity of the compound of the present invention.

Pharmaceutical compositions / combinations can be formulated for oral administration. These compositions may contain any amount of an active compound of Formula I to achieve the desired result, for example from 0.1 to 99% by weight (wt%) of a compound of Formula I, and typically at least about 5% by weight of a compound of Formula I. Some embodiments contain from about 25 wt% to about 50 wt% or from about 5 wt% to about 75 wt% of a compound of Formula I.

The factor D complement inhibitors of the present invention can be administered, for example, either systemically or topically. Systemic administration includes, for example, oral, transdermal, subdermal, intraperitoneal, subcutaneous, transnasal, sublingual, or rectal. Local administration for ocular administration includes: local, intravitreal, periocular, transscleral, retrobulbar, perioscleral, subepiscleral, or via an intraocular device. Inhibitors can be delivered by a delayed delivery device implanted intravitrally or transscleral, or by other known means of topical delivery to the eye.

Treatment methods

The compounds and pharmaceutical compositions disclosed herein can be used to treat or prevent a disorder mediated by complement, and in particular a pathway that is modulated by complement factor D. In some embodiments, the disease is an inflammatory disease, an immune disease, an autoimmune disease, or complement factor D-related diseases in a host. In one embodiment of the invention, the disease is an ocular disease. Complement-mediated diseases that can be treated or prevented with the compounds and compositions of the present invention include, but are not limited to, the inflammatory effects of sepsis, systemic inflammatory response syndrome (SIRS), ischemia / reperfusion injury (I / R injury), psoriasis, myasthenia gravis. , systemic lupus erythematosus (SLE), paroxysmal nocturnal hemoglobinuria (PNH), hereditary angioedema, multiple sclerosis, trauma, burns, capillary leak syndrome, obesity, diabetes, Alzheimer's dementia, stroke, schizophrenia, epilepsy, diabetes, age-related macular retinopathy, asthma, allergies, acute respiratory distress syndrome (ARDS), atypical hemolytic uremic syndrome (aHUS), hemolytic uremic syndrome (HUS), cystic fibrosis, myocardial infarction, lupus nephritis, Crohn's disease, rheumatoid arthritis, atherosclerosis, rejection , prevention of fetal loss, biomaterial reactions (e.g., during hemodialysis, implants), glomerulonephritis C3, abdominal aortic aneurysms, neuromyelitis optics (NMO), vasculitis, neurological disorders, Guillain-Barré syndrome, traumatic brain injury, Parkinson's disease, diseases with inappropriate or unwanted activation of complement, complications of hemodialysis, altograft rejection IL-2-induced toxicity during IL-2 therapy, inflammatory diseases, inflammatory autoimmune diseases, adult respiratory distress syndrome, thermal injury, including burns or frostbite, myocarditis, postischemic reperfusion conditions, balloon angioplasty, post-hemodialysis syndrome in cardiopulmoral circulation circulation, hemodialysis, renal ischemia, mesenteric artery reperfusion after aortic reconstruction, complex immune diseases and autoimmune diseases, SLE nephritis, proliferative nephritis, liver fibrosis, hemolytic anemia, tissue regeneration and neuron th regeneration. In addition, other known complement-related diseases are lung diseases and disorders such as shortness of breath, hemoptysis, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and heart attacks, pneumonia, fibrogenic dust diseases, inert dusts and minerals (e.g. silicon, coal dust, beryllium and asbestos), pulmonary fibrosis, organic dust diseases, chemical injury (due to irritating gases and chemicals, e.g. chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia and hydrochloric acid), smoke injury, thermal injury (e.g. burns, frostbite), bronchospasm, hypersensitive pneumonitis, parasitic diseases, Goodpasture syndrome, pulmonary vasculitis, pauci-immune vasculitis, inflammation associated with the immune complex, uveitis (including Behcet's disease and other subtypes of uveitis) , antiphospholipid syndrome, arthritis, autoimmune heart disease, inflammatory bowel disease, ischemic reperfu sionic trauma, Barracker-Simons syndrome, hemodialysis, systemic lupus erythematosus, erythematous lupus erythematosus, transplantation, diseases of the central nervous system and other neurodegenerative conditions, gloma

- 31 038607 rollonephritis (including proliferative membrane glomerulonephritis), skin diseases with blistering (including bullous pemphigoid, pemphigus and epidermolysis bullosa), ocular cicatricial pemphigoid, MPGN II, uveitis, macular degeneration, diabetic retinopathy retinitis, macular edema, Behcet's uveitis, multifocal choroiditis, Vogt-Koyangi-Harad syndrome, intermediate uveitis, shot retinochorioditis, sympathetic ophthalmia, ocular dicatricial pemphigoid, pemphigus, ischemic venous neuropathy and ocular retinal occlusion.

In some embodiments, complement-mediated diseases include ophthalmic diseases (including early or neovascular age-related macular degeneration and geographic atrophy), autoimmune diseases (including arthritis, rheumatoid arthritis), respiratory diseases, cardiovascular diseases. In other embodiments, the compounds of the present invention are useful in the treatment of diseases and disorders associated with fatty acid metabolism, including obesity and other metabolic disorders.

In one embodiment, the invention relates to a method of treating paroxysmal nocturnal hemoglobinuria (PNH), which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating age-related macular degeneration (AMD), which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method for treating rheumatoid arthritis which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating multiple sclerosis which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method for treating myasthenia gravis, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating atypical hemolytic uremic syndrome (aHUS), which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method for treating C3 glomerulonephritis which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method of treating an abdominal aortic aneurysm which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In another embodiment, the invention provides a method for treating neuromyelitis optic (NMO), which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

In some embodiments, the present invention provides methods for treating or preventing an inflammatory or complement disorder by administering to a host in need thereof an effective amount of a compound of Formula I of the invention. In some embodiments, the present invention provides methods for treating or preventing an inflammatory disorder, more generally an immune disorder, an autoimmune disorder, or complement factor D related diseases, by providing an effective amount of a compound or pharmaceutically acceptable salt of Formula I to a factor D mediated patient inflammatory disorder. A compound or salt of Formula I may be provided as the only active agent, or may be provided together with one or more additional active agents.

In one embodiment, the invention provides a method of treating a disorder associated with dysfunction in the complement cascade, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, the invention provides a method of inhibiting the activation of an alternative complement pathway in a subject, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier. In one embodiment, the invention provides a method of modulating factor D activity in a subject, which comprises administering an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier.

Prevention, as used herein, means that the likelihood of symptom onset in a patient who is prophylactically administered with a compound is reduced as compared to the likelihood of symptom onset in patients who are not administered the compound, or the severity of symptoms in a patient who is prophylactically administered is reduced by compared to the severity

- 32,038607 symptoms experienced by patients with the disorder or condition to which the compound was not administered. In an alternative embodiment of the invention, an effective amount of a compound of formula

I is used for the prevention or prophylaxis of complement factor D disorders.

An effective amount of a pharmaceutical composition / combination of the invention may be an amount sufficient to (a) inhibit the progression of a complement mediated disorder, including an inflammatory, immune, including autoimmune, disorder, or factor D-related disease; (b) initiating regression of an inflammatory, immune, including autoimmune, disorder, or factor D-related disease; or (c) initiating an inflammatory, immune, including autoimmune, disorder, or factor D-related disease from treatment.

An effective amount of a compound or pharmaceutical composition described herein also provides a sufficient amount of active agent that, when administered to a patient, provides clinical benefit. Such an amount can be experimentally determined, for example, by assessing the concentration of the agent in the blood, or theoretically, by calculating the bioavailability.

Combination therapy

In one embodiment of the invention, the compound or salt of the formula I may be presented in combination or alternation with at least one additional inhibitor of the complement system or a second active compound with a different biological mechanism of action. In one embodiment of the invention, a compound or salt of Formula I may be presented in combination with a complement C5 inhibitor or a C5 convertase inhibitor. In another embodiment, a compound or salt of Formula I may be present in combination with eculizumab. In one embodiment of the invention, a compound or salt of Formula I may be present in combination with additional factor D inhibitors.

In one embodiment, a compound or salt of Formula I may be co-presented with a compound that inhibits an enzyme that metabolizes protease inhibitors. In one embodiment, a compound or salt of Formula I may be co-presented with ritonavir.

In non-limiting embodiments, a compound or salt of Formula I can be provided together with a protease inhibitor, soluble complement regulator, therapeutic antibody (monoclonal or polyclonal), complement component inhibitors, receptor or siRNA agonists.

Non-limiting examples of active agents in these categories.

Protease inhibitors: Plasma-derived C1-INH concentrates such as Cetor® (Sanquin), Berinert-P® (CSL Behring, Lev Pharma) and Cinryze®; and recombinant human C1 inhibitors such as Rhucin®.

Soluble complement regulators: soluble complement receptor 1 (TP10) (Avant Immunotherapeutics); sCR1-sLe ^x / TP-20 (Avant Immunotherapeutics); MLN-2222 / CAB-2 (Millenium Pharmaceuticals); Mirococept (Inflazyme Pharmaceuticals).

Therapeutic Antibodies: Eculizumab / Soliris (Alexion Pharmaceuticals); Pexelizumab (Alexion Pharmaceuticals); Ofatumumab (Genmab A / S); TNX-234 (Tanox); TNX-558 (Tanox); TA106 (Taligen Therapeutics); Neutrazumab (G2 Therapies); Anti-properdin (Novelmed Therapeutics); HuMax-CD38 (Genmab A / S).

Complement component inhibitors: Compstatin / POT-4 (Potentia Pharmaceuticals); ARC1905 (Archemix).

Receptor agonists: PMX-53 (Peptech Ltd.); JPE-137 (Jerini); JSM-7717 (Jerini).

Others: recombinant human MBL (rhMBL; Enzon Pharmaceuticals).

In one embodiment, the present invention provides a method for treating or preventing age-related macular degeneration (AMD) by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention. In one embodiment, the compositions of the present invention are administered in combination with an anti-VEGF agent. Non-limiting examples of anti-VEGF agents include, but are not limited to, aflibercept (Eylea®; Regeneron Pharmaceuticals); ranibizumab (Lucentis®: Genentech and Novartis); and pegaptanib (Macugen®; OSI Pharmaceuticals and Pfizer); Bevacizumab (Avastin; Genentech / Roche); anecortan acetate, squalamine lactate, and corticosteroids, including but not limited to triamcinolone acetonide.

In another embodiment, a compound of Formula I can be combined with a second agent for treating an ocular disorder.

Examples of the types of therapeutic agents that can be used in combination for ophthalmic applications include anti-inflammatory drugs, antimicrobial agents, anti-angiogenesis agents, immunosuppressants, antibodies, steroids, ocular antihypertensive drugs, and combinations thereof. Examples of therapeutic agents include amikacin, anecortan acetate, anthracenedione, anthracycline, azole, amphotericin B, bevacizumab, camptothecin, cefuroxime, chloramphenicol, chlorhexidine, chlorhexidine digluconate, clotrimazole, clotrimazole, cephalostaziponazine flucytosine, fluoropyrimidines, fluoroquinolines, gatifloxacin, glycopeptides, imidazoles, itraconazole, ivermectin, ketoconazole, levofloxacin, macrolides, miconazole, miconazole nitrate, moxifloxacin, natamycinisin, neomycinol, analogs polyimycin B, propamidine isethionate, pyrimidine nucleoside, ranibizumab, squalamine lactate, sulfonamides, triamcinolone, triamcinolone acetonide, triazoles, vancomycin, vascular endothelial growth factor (VEGF) inhibitors, VEGF antibodies, VEGF antibodies, alkalostolamide fragments, VEGF antibodies , latanopros t, bimatoprost, brimonidine, dorzolamide, acetazolamide, pilocarpine, ciprofloxacin, azithromycin, gentamicin, tobramycin, cefazolin, voriconazole, ganciclovir, sidofovir, foscarnet, diclofenac, nepafenacomalon, ketorofexorolacin, phyclofenac, nepafenacolon, ketoroforolacin tacrolimus; and combinations thereof. Examples of eye diseases that can be treated in accordance with the compositions and methods described herein include amoebic keratitis, fungal keratitis, bacterial keratitis, viral keratitis, onchocercian keratitis, bacterial keratoconjunctivitis, viral keratoconjunctivitis, dystrophic corneal diseases , Sjogren's syndrome, Stevens-Johnson syndrome, autoimmune diseases of dry eyes, environmental diseases of dry eyes, neovascular diseases of the cornea, treatment and prevention of corneal transplant rejection, autoimmune uveitis, infectious uveitis, anterior uveitis, posterior uveitis (including toxoplasmosis), panuveitis, inflammatory disease of the vitreous body or retina, prevention and treatment of endophthalmitis, macular edema, macular degeneration, age-related macular degeneration, proliferative and non-proliferative diabetic retinopathy, hypertensive retinopathy, autoimma retinal disease, primary and metastatic intraocular melanoma, other intraocular metastatic tumors, open-angle glaucoma, angle-closure glaucoma, pigmentary glaucoma, and combinations thereof.

A compound of Formula I, or a combination of Formula I and another active agent, may be administered to the ophthalmic section by injection into the vitreous chamber, subretinal space, subchoroidal space, episclera, conjunctiva, sclera, anterior chamber, and cornea, and sections therein (e.g. subepithelial, intrastromal, endothelial).

In an alternative embodiment of the invention, a compound of Formula I, or a combination of Formula I and another active agent, can be administered to the ophthalmic section by binding to mucosal permeable particles to treat a condition localized in the vitreous chamber, subretinal space, subchoroidal space, episclera, conjunctiva, sclera or anterior chamber, and the cornea, and sections in them (eg, subepithelial, intrastromal, endothelial). Mucosal permeable particles are known in the art and are described, for example, in Kala Pharmaceuticals published PCT application WO 2013166436, which is incorporated herein in its entirety.

In other embodiments, the invention provides a composition comprising a compound of Formula I suitable for topical administration to the eye. The pharmaceutical composition comprises a plurality of coated particles containing a particle core, comprising a compound of Formula I, wherein Formula I comprises at least about 80% by weight of the particle core, and the coating comprises one or more surface altering agents, wherein one of the more surface altering agents comprises at least at least one poloxamer, poly (vinyl alcohol) or polysorbate. One or more surface-modifying agents are present on the outer surface of the particle core with a density of at least 0.01 molecules / nm. One or more surface-modifying agents are present in the pharmaceutical composition in an amount of from about 0.001% to about 5% by weight. The plurality of coated particles have an average smallest cross-sectional size of less than about 1 micron. The pharmaceutical composition also includes one or more ophthalmologically acceptable carriers, additives and / or diluents.

Those of skill in the art would understand that particles suitable for use in the methods disclosed herein can exist in various forms, including but not limited to spheroids, rods, discs, pyramids, cubes, cylinders, nanospirals, nanosprings, nanorings, rod-shaped particles, arrow-shaped particles, droplet-shaped particles, tetrapod-shaped particles, prismatic particles and many other geometric and non-geometric shapes. In some embodiments, the particles described herein are spherical.

In one embodiment, the present invention provides a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need of

34 038607 this, an effective amount of a composition containing a compound of the present invention. In one embodiment, the present invention relates to a method of treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention, in combination or alternation with additional inhibitors of the complement system or other active compound with a different biological mechanism of action. In another embodiment, the present invention relates to a method for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH) by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention in combination or alternation with eculizumab.

In one embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention. In one embodiment, the present invention provides a method for treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention in combination or alternation with an additional inhibitor of the complement system. In another embodiment, the present invention relates to a method for treating or preventing rheumatoid arthritis by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention in combination or alternation with methotrexate.

In some embodiments, a compound of Formula I is administered in combination or alternation with at least one anti-rheumatoid arthritis drug selected from: salicylates, including aspirin (Anacin, Ascriptin, Aspirin Bayer, Ecotrin) and salsalate (Mono-Gesic, Salgesic) ; non-steroidal anti-inflammatory drugs (NSAIDs); non-selective inhibitors of cyclooxygenase enzymes (COX-1 and COX-2), including diclofenac (Cataflam, Voltaren), ibuprofen (Advil, Motrin), ketoprofen (Orudis), naproxen (Aleve, Naprosyn), piroxicam (Feldene), etodolac , indomethacin, oxaprozin (Daypro), nabumetone (Relafen), and meloxicam (Mobic); selective inhibitors of cyclooxygenase-2 (COX-2), including celecoxib (Celebrex); disease-modifying antirheumatic drugs (DMARDs), including azathioprine (Imuran), cyclosporine (Sandimmune, Neoral), gold salts (Ridaura, Solganal, Aurolate, Myochrysine), hydroxychloroquine (Plaquenil), leflunomide (Arava), methotrexate) (Rheumeniciline) (Cuprimine) and sulfasalazine (Azulfidine); biological medicines including abatacept (Orencia), etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), and anakinra (Kineret); corticosteroids, including betamethasone (Celestone Soluspan), cortisone (Cortone), dexamethasone (Decadron), methylprednisolone (SoluMedrol, DepoMedrol), prednisolone (Delta-Cortef), prednisone (Deltasone, Orasortone), and triamcinolone); (Aristocortone); gold salts including Ridaura; Aurothioglucose (Solganal); Aurolat; Myohrizin; or any combination of them.

In one embodiment, the present invention relates to a method for treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention. In one embodiment, the present invention provides a method for treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention in combination or alternation with additional inhibitors of the complement system. In another embodiment, the present invention relates to a method for treating or preventing multiple sclerosis by administering to a subject in need thereof an effective amount of a composition containing a compound of the present invention in combination or alternation with corticosteroids. Examples of corticosteroids include, but are not limited to, prednisone, dexamethasone, solumedrol, and methylprednisolone.

In one embodiment, a compound of formula I is combined with at least one multiple sclerosis drug selected from: Aubagio (teriflunomide), Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Sorahope (glatiramer acetate), Extavia (interferon beta-1b), Gilenya (Fingolimod), Lemtrada (alemtuzumab), Novantrone (mitoxantrone), Plegridy (peginterferon beta-1a), Rebif (interferon beta-1a), Tecfidera (dimethyl fumarate), Sol -Medrol (methylprednisolone), high-dose oral Deltazone (prednisone), N.R. Acthar Gel (ACTH) and combinations thereof.

In one aspect, the compound or salt of Formula I can be presented in combination or alternation with an immunosuppressive agent or anti-inflammatory agent.

In one embodiment of the present invention, a compound described herein can be administered in combination or alternation with at least one immunosuppressive agent. The immunosuppressant agent can be, but are not limited to, a calcineurin inhibitor such as cyclosporin or ascomycin, such as Cyclosporin A (NEORAL®), FK506 (tacrolimus), pimecrolimus, an mTOR inhibitor, such as rapamycin or a derivative thereof, such as Sirolimus

- 35 038607 (Rapamune®), Everolimus (Certican®), temsirolimus, zotarolimus, biolimus-7, biolimus-9, rapalog, eg, Ridaforolimus, azathioprine, Campat 1H, S1P receptor modulator, eg, fingolimod or its analog anti-IL-8 antibody, mycophenolic acid or its salt, e.g. sodium salt, or its prodrug, e.g. Mycophenolate Mofetil (CELLCEPT®), OKT3 (ORTHOCLONE OKT3®), Prednisone, ATGAM®, THYMOGLOBULIN®, Brequinar Sodium, OKT4, T10B9.A-3A, 33B3.1, 15-deoxypergualin, tresperimus, Leflunomide ARAVA®, CTLAI-Ig, anti-CD25, anti-IL2R, Basiliximab (SIMULECT®), Daclizumab (ZENAPAX®), mizorbine, methotrexine, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus, Elidel®), CTLA41g (Abatacept), belatacept, LFA31g, etanercept (marketed as ENBREL® from Immunex), adalimumab (LFA®), infliximab (REMICADE antibodies) -1, natalizumab (Antegren®), Enlimomab, gavilimomab, antithymocyte immunoglobulin, siplizumab, Alefacept efalizumab, pentase, mesalazine, asacol, codeine phosphate, benor ilat, fenbufen, naprozin, diclofenac, etodolac and indomethacin, aspirin and ibuprofen.

Examples of anti-inflammatory agents include methotrexate, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate, fluoromethalone acetate, fluoromethalonic alcohol, lotoprendol etabonate, medrisone, prednisolone acetate, prednisolone sodium phosphate, difluprednate, rimexolone sodium phosphate, difluprednate, rimexolone, acetrocortisolone, hydrocortrophomethane , piroxicam, meloxicam, flubiprofen, naproxan, ketoprofen, tenoxicam, diclofenac sodium, ketotifen fumarate, diclofenac sodium, nepafenac, bromfenac, flurbiprofen sodium, suprofen, celecoxib, naproxen, combinations of rofecoxib and any of their glucocorticoids. In one embodiment, a compound of formula I is combined with one or more non-steroidal anti-inflammatory drugs (NSAIDs) selected from naproxen sodium (Anaprox), celecoxib (Celebrex), sulindac (Clinoril), oxaprozin (Daypro), salsalate (Disalcid), diflunisal ( Dolobid, piroxicam (Feldene), indomethacin (Indocin), etodolac (Lodine), meloxicam (Mobic), naproxen (Naprosyn), nabumetone (Relafen), ketorolac tromethamine (Toradol), naproxen / esomeprazole (Vimenovo) and diclofenovo and their combinations.

Vi. Method for preparing compounds of formula I

Abbreviations

(Vos) 2O di-tert-butyl dicarbonate ACN Acetonitrile AcOEt, EtOAc ethyl acetate SNzON, MeON Methanol CsF Cesium fluoride Cui Copper iodide DCM, CH2CI2 Dichloromethane DIEA, DIPEA Ν, Ν-diisopropylethylamine DMA Ν, Ν -dimethyl acetamide DMF Ν, Ν-dimethylformamide DMSO Dimethyl sulfoxide DPPA Diphenylphosphorylazide Et ₃ N, TEA Triethylamine EtOAc Ethyl acetate EtOH Ethanol HATU 1- [Bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3 oxide hexafluorophosphate HCl Hydrochloric acid TnNEt Ν, Ν-diisopropylethylamine K2CO3 Potassium carbonate LiOH Lithium hydroxide MTBE Methyl tertiary butyl ether Na ₂ SO4 Sodium sulfate NaCl Sodium chloride NaH Sodium hydride

- 36 038607

NaHCO ₃ Bicarbonate of soda NEt ₃ Trimethylamine Pd (OAc) ₂ Palladium acetate Pd (dppf) Cl ₂ [1, G-B _is (d _and phenylphosphino) ferrocene] dichloro palladium (P) Pd (PPh ₃ ) ₂ Cl ₂ Bis (triphenylphosphine) palladium (P) dichloride Pd (PPh ₃ ) ₄ Tetrakis (triphenylphosphium) yalladium (0) Pd ₂ (dba) ₃ Tris (dibeisylideneacetone) dipalladium (0) PPh ₃ Triphenylphosphine K.T. Room temperature tBuOK Potassium tert-butoxide TEA Trimethylamine TFA trifluoroacetic acid Tf ₂ O trifluoromethanesulfonic anhydride TFA Trifluoroacetic acid THF T etrahydrofuran TMSBr Bromotrimethylsilane fe Retention time Zn (CN) ₂ Zinc cyanide

General ways

All non-aqueous reactions were carried out under dry argon or nitrogen gas using anhydrous solvents. The progress of the reactions and the purity of the target compounds were determined using one of the two methods of liquid chromatography (LC) below. The structure of the starting materials, intermediate and final products was confirmed by standard analytical techniques, including NMR spectroscopy and mass spectrometry.

Method A LC.

Instrument: Waters Acquity Ultra Performance LC Column: ACQUITY UPLC VEN C18 2.1x50 mm, 1.7 μm.

Column temperature: 40 ° C.

Mobile phase: solvent A: H ₂ O + 0.05% FA; Solvent B: CH3CN + 0.05% FA.

Flow rate: 0.8 ml / min.

Gradient: 0.24 min @ 15% B, 3.26 min gradient (from 15-85% B), then 0.5 min @ 85% V.

Detection: UV (PDA), ELS and MS (SQ in EI mode).

Method B LC.

Instrument: Shimadzu LC-2010A HT Column: Athena, C18-WP, 50x4.6 mm, 5 microns.

Column temperature: 40 ° C.

Mobile phase: solvent A: H2O / CH3OH / FA = 90/10 / 0.1; solvent B: H2O / CH3OH / FA = 10/90 / 0.1 Flow rate: 3 ml / min.

Gradient: 0.4 min @ 30% B, 3.4 min gradient (30-100% B), then 0.8 min @ 100% V.

Detection: UV (220/254 nm).

Example 1. General synthesis route.

The compound of the present invention can be obtained, for example, from a central core. In one embodiment of the invention, for example, the central core of Structure 1 is an N-protected amino acid, where X ¹ is nitrogen and PG = protecting group. In one embodiment, the central core is attached to an amine to provide an amide of Structure 2 (where LB includes a C (O) N residue). The Co of Structure 2 can then be deprotected to give Structure 3. Structure 3 is attached to Structure 4 (A-COOH) to form a second amide bond, forming a compound within Formula I. The chemistry is illustrated in Route 1.

- 37 038607

Structure 1, 1-Q ¹

Route 1 qi ^ ^q - ¹ activation Q ¹ ^ ^Q \ 'COpH 1 ₁ delete

------------ ^Q 'X ----------- accession | pg amine PG

Structure 2 ^ Qi _h A-COOH

IX%. / ^{B *} (Structure 4) ot '~ ^L ' q1 / ^L ----------- ^U ^ X ^{1 * * *}

Structure 3

Formula I

Alternatively, the central core of Structure 5 is reacted with a heterocyclic or heteroaryl compound to provide a compound of Structure 6. In one embodiment of the invention, Structure 6 is deprotected to provide a carboxylic acid of Structure 7. In one embodiment, Structure 7 is coupled to an amine to provide a compound of Formula I. This chemistry is illustrated on Route 2.

Route 2 l ^prnsoe '- ° ^pg

Q- _X 1 II dyneine 'Λ ~ γΤ removal __ / o ---- * -χ ¹ II ———

О = (/ О PG; А

Gl

Structure 5 Structure 6

Structure? Formula!

In an alternative embodiment, Structure 8 is deprotected to provide an amine which is Structure 9. Structure 9 is then coupled to form an amide which is Structure 6. Structure 6 is deprotected to provide a carboxylic acid which is Structure 7 Structure 7 is then attached to form the amide which falls under Formula I. The chemistry is illustrated in Route 3.

Route 3

In an alternative embodiment, a heteroaryl or aryl residue 4-1 is attached to the central core to give 4-2. The protected acid, 4-2, is deblocked to form the carboxylic acid, 4-3. The carboxylic acid is then added to form the amide (LB), which is 4-4. The heteroaryl or aryl residue, A ', can then be further used to add substituents at positions X ¹¹ , X ¹² , X ¹³ and X ¹⁴ to give compounds of Formula I. This chemistry is illustrated in Route 4.

- 38 038607

Route 4

In an alternative embodiment, Structure 5-1 is coupled to an acid, Structure 5-2, to give Structure 5-3. The carboxylic acid, Structure 5-3, is deblocked to give the carboxylic acid, which is Structure 5-4. A carboxylic acid of Structure 5-4 is coupled to an amine to form the amide product (L-B), which is a compound within Formula I. This chemistry is illustrated in Route 5.

Q ¹

Ql ' ^Q \ A-COOH

X ^{2 J} Structure 5-2

-χ ¹ '

Route 5

About Structure. 5-1

A

O

HE

Structure 5-4

Structure 5-3 L!

activation of Q ¹ \ _

CO _g H I χ2

- ° <x assignment J — O amine /

A

Formula I

In an alternative embodiment, the heteroaryl compound of Structure 10 is acylated to provide a compound of Structure 11 in which LG is a leaving group. By way of example, the leaving group can be a halide such as a bromide. Structure 11 is attached to Structure 12 to form Structure 13. In some embodiments, LG1 is a leaving group. In some embodiments, LG1 is a halide. Structure 13 is attached to an aryl, heteroaryl, or heterocyclic compound to form Structure 14. In some embodiments, Structure 13 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis (triphenylphosphine) palladium (0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 14 is treated with an organic acid such as, but not limited to, trifluoroacetic acid to give Structure 15. Structure 15 is coupled to Structure 3 from Route 1 to provide a compound within Formula I. This chemistry is illustrated in Route 6.

- 39 038607

Route 6

In an alternative embodiment, the heteroaryl compound of Structure 17 is acylated to provide a compound of Structure 18 in which LG is a leaving group. By way of example, the leaving group can be a halide such as a bromide. Structure 18 is coupled to the activated ester, Structure 12 from Route 6, in which LG ₁ may be halogen, to give Structure 19.

Structure 19 is attached to an aryl, heteroaryl, or heterocyclic compound to form Structure 20. In some embodiments, Structure 19 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis (triphenylphosphine) palladium (0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 20 is treated with an organic acid such as, but not limited to, trifluoroacetic acid to provide Structure 21. Structure 21 is coupled to Structure 3 from Route 1 to provide a compound within Formula I. This chemistry is illustrated in Route 7.

Route 7

- 40 038607

In an alternative embodiment, the heteroaryl compound of Structure 8-1 is acylated to provide a compound of Structure 8-2 in which LG is a leaving group. By way of example, the leaving group can be a halide such as a bromide. Structure 8-2 is attached to Structure 8-3 to give Structure 8-4. In some embodiments, LG ₁ is a leaving group. In some embodiments, LG ₁ is a halide.

Structure 8-4 is attached to an aryl, heteroaryl, or heterocyclic compound to give Structure 8-5. In some embodiments, Structure 8-4 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis (triphenylphosphine) palladium (0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 8-5 is treated with an organic acid such as, but not limited to, trifluoroacetic acid to provide Structure 8-6. Structure 8-6 is coupled to Structure 3 from Route 1 to give a compound within Formula I. This chemistry is illustrated in Route 8.

Route 8

In an alternative embodiment, the heteroaryl compound of Structure 9-1 is acylated to provide a compound of Structure 9-2 in which LG is a leaving group. By way of example, the leaving group can be a halide such as a bromide. Structure 9-2 is attached to an activated ester, Structure 9-3, in which LG1 can be a halide, to give Structure 9-4. Structure 9-4 is attached to an aryl, heteroaryl, or heterocyclic compound to give Structure 9-5. In some embodiments, Structure 9-4 is treated with an aryl, heteroaryl, or heterocyclic boronic acid, an organometallic catalyst, a base, and an organic solvent. In some embodiments, the organometallic catalyst is tetrakis (triphenylphosphine) palladium (0). In some embodiments, the base is cesium carbonate. In some embodiments, the organic solvent is DMF. Structure 9-5 is treated with an organic acid such as, but not limited to, trifluoroacetic acid to provide Structure 9-6. Structure 9-6 is coupled to Structure 3 from Route 1 to provide a compound within Formula I. This chemistry is illustrated in Route 9.

- 41 038607

Route 9

In an alternative embodiment, Structure 10-1 is coupled to an amine to form the amide (L-B) and Structure 10-2. Structure 10-2 is coupled to an amine to give compounds within Formula I. This chemistry is illustrated in Route 10.

Route 10

Vos

Vos

Vos

Example 2. Examples of central synthons

Z ^A represents halogen.

In one embodiment of the invention, deuterated L-proline synthons are disclosed. Deuterated synthons include, but are not limited to, for example, the following compounds:

- 42 038607

Structure A can be treated with deuterium oxide to form Structure B. See Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491 and WO 2014/037480 (p. 103). Structure B can be restored to give Structure C. See Barraclough, P. et al. Tetrahedron Lett. 2005, 46, 4653-4655; Barraclough, P. et al. Org. Biomol. Chem. 2006, 4, 1483-1491. Structure C can be treated under Mitsunobu reaction conditions to give Structure D. Structure B can be processed with DAST to give Structure E. See WO 2014/037480. Structure A can be treated with sodium borodeuteride to give Structure F. See Dormoy, J. -R .; Castro, B. Synthesis 1986, 81-82. Compound F can be used to prepare Structure K. See Dormoy, J. -R .; Castro, B. Synthesis 1986, 81-82. Structure B can be treated with a deuterated reducing agent, eg sodium borodeuteride, to give Structure G. Structure G can be treated with DAST to give Structure H. Structure F can be used to obtain Structure K. See Dormoy, J. -R .; Castro, B. Synthesis 1986, 81-82. Structure G can be used to prepare Structure I. Structure J can be prepared in accordance with Hruby, V. J. et al. J. Am. Chem. Soc. 1979, 101, 202-212. Structures A-J can be used to prepare compounds of Formula I.

Example 3. Obtaining central-L-B synthons

Routes 1a, 1b and 1c.

On Route 1a 5- (1,1-dimethylethyl) 5-azaspiro [2,4] heptane-4,5-dicarboxylic acid ester, (4S) -, CAS 209269-08-9, can be prepared as described in Tandon, M. et al. Bioorg. Med. Chem. Lett. 1998, 8, 1139-1144. In Step 2, a protected azaspiro [2,4] heptane is coupled to an amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; the remainder of the L-B. In one embodiment, the amine is (3-chloro-2fluorophenyl) methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment of the invention, the condensing agent is HATU. In Step 3, the protecting group is removed. In one embodiment of the invention, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In Route 1b, (4S) -4-oxazolidinecarboxylic acid hydrochloride is treated with an amine safener. In one embodiment, the amine safener is di-tert-butyl dicarbonate. In another embodiment, 3- (1,1-dimethylethyl) 3,4-oxazolidinedicarboxylic acid ester, (4S) -, is commercially available from JPM2 Pharmaceuticals. In one embodiment of the invention, the reaction is carried out in an organic solvent in the presence of a base. In one embodiment of the invention, the organic solvent is acetonitrile. In one embodiment, the base is 4-dimethylaminopyridine (DMAP). In Step 2, a protected 4-oxazolidinecarboxylic acid is coupled to an amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; the remainder of the L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment of the invention, the condensing agent is HATU. In Step 3, the protecting group is removed. In one embodiment of the invention, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In Route 1c, (S) -5- (tert-butoxycarbonyl) -5-azaspiro [2,4] heptane-6-carboxylic acid, CAS 1129634-44-1, is commercially available from Ark Pharm. In Step 2, a carboxylic acid is added to an amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; the remainder of the L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment of the invention, the condensing agent is HATU. In Step 3, the protecting group is removed. In one embodiment of the invention, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

Routes 2a, 2b, 2c and 2d

amine addition

Stage 1 amine addition

Stage 1

2c

amine addition

Stage 1

Stage 2

Vos

amine addition

Stage 1

In Route 2a, commercially available Boc-L-proline is coupled to an amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; the remainder of the L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment of the invention, the condensing agent is HATU. In Step 3, the Boc protecting group is removed. In one embodiment of the invention, the starting material enters

- 44 038607 in the reaction with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In Route 2b, commercially available (1R, 3S, 5R) -2 - [(tert-butoxy) carbonyl] -2-azabicyclo [3.1.0] hexane-3-carboxylic acid from Enamine is coupled to an amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; the remainder of the L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment of the invention, the condensing agent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment of the invention, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In Route 2c, a commercially available (2S, 4R) -1- (tert-butoxycarbonyl) -4-fluoropyrroligin-2carboxylic acid from Manchester Organics is coupled to an amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; the remainder of the L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment of the invention, the condensing agent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment of the invention, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane.

In Route 2d, a commercially available (S) -1- (tert-butoxycarbonyl) indoline-2-carboxylic acid from Chem-Impex is coupled to an amine in the presence of an organic solvent, a base and a condensing reagent to form an amide bond; the remainder of the L-B. In one embodiment, the amine is (3-chloro-2-fluorophenyl) methanamine. In one embodiment of the invention, the organic solvent is DMF. In one embodiment, the base is diisopropylethylamine. In one embodiment of the invention, the condensing agent is HATU. In Step 2, the Boc protecting group is removed. In one embodiment of the invention, the starting material is reacted with an acid in the presence of an organic solvent. In one embodiment of the invention, the acid is 4N. hydrochloric acid. In one embodiment of the invention, the organic solvent is dioxane. This chemistry is illustrated in Figure 2.

Additional starting materials that can readily be converted to Central-E-B Cintones include, but are not limited to: (S) -1- (tert-butoxycarbonyl) -2,3-dihydro-EH-pyrrole-2carboxylic acid, CAS 90104- 21-5, available from Ark Pharm; cyclopent-1-ene-1,2-dicarboxylic acid, CAS 3128-15-2, purchased from Ark Pharm; imidazole, 1H-imidazole-1,2-dicarboxylic acid, 1- (1,1-dimethylethyl) 2-ethyl ester, CAS 553650-00-3, commercially available from the FCH Group; Boc-Eoctahydroindole-2-carboxylic acid, which can be purchased from Chem Impex.

Compound

can be obtained in accordance with the methods described in WO

2004/111041; (S) -Boc-5-oxopyrrolezgin-2-carboxylic acid is available from Aldrich Chemical Co .; (1S, 2S, 5R) -3- (tert-butoxycarbonyl) -3-azabicyclo [3.3.0] hexane-2-carboxylic acid is available from Ark Pharm; (S) -3-Boc-thiazolygine-2-carboxylic acid is available from Alfa Aesar; (2S, 4R) -1- (tert-butoxycarbonyl) -4-chloropyrrolidine-2-carboxylic acid available from Arch Bioscience; (1S, 3aR, 6aS) 2- (tert-butoxycarbonyl) octahydrocyclopenta [c] pyrrole-1-carboxylic acid available from Ark Pharm; 1,2-pyrrolidinedicarboxylic acid, 3 - [[(phenylmethoxy) carbonyl] amino] -, 1- (1,1-dimethylethyl) ester, (2S, 3R) can be prepared as described in WO 2004/007501. The Cbz group can be removed and the amino group can be alkylated to give the centralized compounds of the present invention.

Compound n ^OH can be prepared as described in Braun, JV; Heymons, Albrecht Berichte der Deutschen Chemischen Gesellschaft [Abteilung] B: Abhandlungen (1930) 63B, 502-7.

Compounds (2S, 3S, 4S) -4-fluoro-3-methoxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester and (2R, 3R, 4R) -3-fluoro-4-methoxypyrrolidine-1,2 The α-dicarboxylic acid 1-tert-butyl ester can be prepared as a mixture according to Novartis WO 2012/093101 and the regioisomers may ultimately be separated from each other by being attached to form the central core-LB synthons. Compound (S) -Boc-5-oxopyrroligine-2-carboxylic acid is available from Aldrich Chemical Co.

Example 4. Synthesis of aryl, heteroaryl and heterocyclic compounds of formula I.

Synthesis of (2S, 4R) -1- (2- (3-acetyl-5- (2-methoxypyrigin-5-yl) -Sh-indol-1-yl) acetyl) -N- (2'-chloro-2fluoro- [1, T-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide (27).

Scheme 1

1- (5-Bromo-III-indol-3-yl) ethanone (2) was prepared from 5-bromoindole according to the procedure described by MacKay et al. (MacKay, JA; Bishop, R .; Rawal, VH Org. Lett. 2005, 7, 3421-3424.) Tert-Butyl 2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate (3).

A mixture of 3.9 g (16.4 mmol) of 1- (5-bromo-1H-indol-3-yl) ethanone, 2.63 ml (18.02 mmol) of tert-butyl bromoacetate and 2.50 g (18.02 mmol) potassium carbonate in anhydrous acetonitrile (80 ml) was heated under reflux for 5 h. The reaction mixture was then cooled to rt. and the solvent was removed under reduced pressure. The residue was dissolved in a 1: 1 mixture of CH ₂ Cl ₂ and water (100 ml: 100 ml). The two layers were separated and the organic layer was washed with water (2x100 ml). Finally, the organic layer was dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was stirred with 50 ml of heptane for 30 min, cooled in an ice bath and filtered, washing the solid with cold heptane (10 ml). This creamy solid was dried under high vacuum to provide 5.6 g of tert-butyl 2- (3-acetyl-5-bromo1H-indol-1-yl) acetate.

tert-Butyl-2- (3-acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetate (4).

A mixture of 351 mg (1 eq.) 3, (2-methoxypyrimidin-5-yl) boronic acid (230 mg, 1.5 eq.), Cesium carbonate (650 mg, 2 eq.) In DMF (15 ml) and water ( 1.5 ml) was purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.05 eq.) Was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product (7: 3 mixture of acid and ester) was used directly in the next synthesis step.

2- (3-Acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetic acid (5).

Took tert-butyl-2- (3-acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetate (crude product of the above reaction) in 4N. HCl in dioxane (20 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. After completion of the reaction, the solvent was removed under reduced pressure. The rest of the material was used directly in the next stage of the synthesis.

(2S, 4R) -1- (2- (3-Acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetyl) -N- (2'-chloro-2-fluoro [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide (27).

Compound 5 (100 mg, 1 eq.) From the previous step was dissolved in DMF (10 ml) and iPr ₂ NEt (0.269 ml, 5 eq.) Was added, followed by the addition of (2S, 4R) -N- (3-chloro- (2S, 4R) -N- (6-chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide (111 mg, 1 eq.) At 5 ° C. Then, at the same temperature, HATU (263 mg , 2.1 eq.) And the reaction mixture was stirred for 3 h at rt.After completion of the reaction monitored by HPLC, the reaction mixture was added to water (50 ml + 10 g NaCl) and extracted with DCM (2x25 ml The organic layer was washed sequentially with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with DCM / CH3OH) to give 7.1H NMR (400 MHz, DMSO-d ₆ , 300K): (main rotamer) δ 2.13-2.3 (m, 1H), 2.45 (s , 3H), 2.68-2.70 (m, 1H), 3.95-4.05 (m, 4H), 4.16-4.24 (m, 1H), 4.78 (t, J = 8 Hz, 1H), 5.28 (d J = 20 Hz, 1H), 5.45 (d, J = 20 Hz, 1H), 5.50 -5.63 (m, 1H), 7.04-7.08 (m, 1H), 7.20-7.24 (m, 1H), 7.37-7.61 (m, 7H), 7 , 75-7.78 (m, 1H), 7.94-7.98 (m,

- 46 038607

1H), 8.31 (s, 1H), 8.88 (s, 1H), 8.97 (s, 1H); 19F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ 126.64, -175.79. LC (method A): tR = 2.16 min. LC / MS (EI) m / z: [M + H] + calc. for C ₃₄ H ₂₈ CIF ₂ N ₅ O ₄ , 643;

found 644.

Scheme 2

2'-Chloro-2-fluoro- [1,1'-biphenyl] -3-amine hydrochloride (10).

A mixture of 8 (30 g), 9 (60 g), K ₂ CO ₃ (91 g) and Pd (dppf) ₂ Cl ₂ (19.25 g) in a solvent (dioxane 400 ml, H2O 100 ml) was flushed with argon in a vessel high pressure for 5 min and stirred for 15 h at 100 ° C. The solvent was removed under reduced pressure and the resulting residue was purified by flash column chromatography. The purified material was then dissolved in MeOH and treated with HCl / MeOH. The solvent was removed and the remaining solid was washed with IPA-heptane (1/1) to give 10.

(2S, 4R) -tert-Butyl-2 - ((2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) carbamoyl) -4-fluoropyrrolidine-1 carboxylate (12).

To an ice-cold solution of 11 (530 mg) in 20 ml of CH ₂ Cl _{2 was} added dropwise with stirring 1-chloro-N, N, 2-trimethyl-1-propenylamine (0.333 ml, 1.1 eq.). Stirring was continued for 3 h at this temperature, then solid 10 (640 mg, 1.1 eq.) And then 1.12 ml iPr ₂ NEt (3 eq.) Were added. The cooling bath was removed and the reaction mixture was stirred overnight at rt. After completion of the reaction, monitored by HPLC, the reaction mixture was added to water (20 ml) and was extracted with DCM (2x25 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (ISCO eluted with Hexanes / EtOAC) to give 12.

(2S, 4R) -N- (2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (6).

We took (2S, 4R) -tert-butyl-2 - ((2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) carbamoyl) -4-fluoropyrrolidine-1carboxylate 12 (700 mg) at 4N. HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at rt. within 3 hours. After completion of the reaction, monitored by HPLC, the solvent was removed under reduced pressure. The remaining residue 6 was used directly in the next synthesis step (preparation 7).

Example 5. Additional syntheses of aryl, heteroaryl and heterocyclic compounds of formula I.

Scheme 1

- 47 038607

Stage 1. 1- (5-Bromo-1H-indol-3-yl) ethanone.

The title compound was prepared from 5-bromoindole following the procedure described by MacKay et al. (MacKay, J. A .; Bishop, R .; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)

Step 2. tert-Butyl-2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate.

A mixture of 1- (5-bromo-1H-indol-3-yl) ethanone (3.9 g, 16.4 mmol), tert-butyl bromoacetate (2.63 ml, 18.02 mmol) and potassium carbonate (2.50 g, 18.02 mmol) in anhydrous acetonitrile (80 ml) was heated under reflux for 5 h. The reaction mixture was then cooled to rt. and the solvent was removed under reduced pressure. The residue was dissolved in a 1: 1 mixture of DCM and water (100 ml: 100 ml). The two layers were separated and the organic layer was washed with water (2x100 ml). Finally, the organic layer was dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was stirred with 50 ml of heptane for 30 min, cooled in an ice bath and filtered, washing the solid with cold heptane (10 ml). This creamy solid was dried under high vacuum to provide 5.6 g of tert-butyl 2- (3-acetyl-5-bromo-1Nindol-1-yl) acetate.

Step 3. tert-Butyl-2- (3-acetyl-5- (pyridazin-4-yl) -1H-indol-1-yl) acetate.

A mixture of tert-butyl-2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate (351 mg, 1 eq.), 4- (4,4,5,5-tetramethyl1,3,2 -dioxaborolan-2-yl) pyridazine (250 mg, 1.5 eq), cesium carbonate (700 mg, 2 eq), DMF (15 ml) and water (1.5 ml) were purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.05 eq.) Was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 4. 2- (3-Acetyl-5- (pyridazin-4-yl) -1H-indol-1-yl) acetic acid.

Took tert-Butyl-2- (3-acetyl-5- (pyridazin-4-yl) -1H-indol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (20 ml), and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 5. (2S, 4R) -1- (2- (3-Acetyl-5- (pyridazin-4-yl) -1H-indol-1-yl) acetyl) -N- (2'-chloro-2- fluoro [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide (20).

2- (3-Acetyl-5- (pyridazin-4-yl) -1H-indol-1-yl) acetic acid (100 mg, 1 eq.) Was dissolved in DMF (10 ml) and DIEA (0.269 ml, 5 eq.) followed by the addition of (2S, 4R) -N (3-chloro- (2S, 4R) -N- (6-chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (111 mg, 1 eq. .) at a temperature of 5 ° C. Then, at the same temperature, HATU (263 mg, 2.1 eq.) was slowly added and the reaction mixture was stirred for 3 h at rt.The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x25 ml) The organic layer was sequentially washed with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated at The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give 20. 1H NMR (400 MHz, DMSO-d ₆ , 300 K): (main rotamer) δ 2.13-2.30 (m, 1H) , 2.45 (s, 3H), 2.58-2.68 (m, 1H), 3.95-4.05 (m, 1H), 4.13-4.22 (m, 1 H), 4.75 (t, J = 8 Hz, 1H), 5.28 (d, J = 20 Hz, 1H), 5.45 (d, J = 20 Hz, 1H), 5.50-5.63 (m, 1H), 7.06-7.10 (m, 1H), 7.31-7.49 (m , 4H), 7.51-7.61 (m, 1H), 7.65-7.80 (m, 1H), 7.92-8.03 (m, 2H), 8.35 (s, 1H), 8.61 (s 1H), 9.23 (d, 1H) , 9.61 (s, 1H), 9.97 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ -126.74, -175.78. LC (method A): t _R = 2.58 min. LC / MS (EI) m / z: [M + H] ⁺ 614.

Scheme 2

Step 1. 2'-Chloro-2-fluoro- [1,1'-biphenyl] -3-amine hydrochloride.

A mixture of 3-bromo-2-fluoroaniline (30 g), (2-chlorophenyl) boronic acid (60 g), K2CO3 (91 g) and Pd (dppf) ₂ Cl ₂ (19.25 g) in a solvent (dioxane 400 ml , H ₂ O 100 ml) was purged with argon in a pressure vessel for 5 min and stirred for 15 h at 100 ° C. The solvent was removed under reduced pressure and the remaining residue was purified using flash column chromatography. The purified 48 038607 material was then dissolved in MeOH and treated with HCl / MeOH. The solvent was removed and the remaining solid was washed with IPA-heptane (1/1) to give the title compound.

Step 2. (2S, 4R) -tert-Butyl-2 - ((2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) carbamoyl) -4-fluoropyrrolidine-1-carboxylate.

To an ice-cold solution of (2S, 4R) -1- (tert-butoxycarbonyl) -4-fluoropyrrolidine-2-carboxylic acid (530 mg) in DCM (20 ml) was added dropwise with stirring 1-chloro-N, N, 2 -trimethyl-1-propenylamine (0.333 ml, 1.1 eq.). Stirring was continued for 3 h at this temperature and then solid 2'-chloro-2-fluoro- [1,1'-biphenyl] -3-amine hydrochloride (640 mg, 1.1 eq.) Was added followed by DIEA ( 1.12 ml, 3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water (20 ml) and extracted with

DCM (2x25 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with hexanes / EtOAc) to give (2S, 4R) -tert-butyl-2 - ((2'-chloro-2-fluoro- [1,1'-biphenyl] -3 -yl) carbamoyl) -4fluoropyrrolidine-1-carboxylate.

Step 3. (2S, 4R) -N- (2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2 carboxamide hydrochloride.

We took (2S, 4R) -tert-butyl-2 - ((2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) carbamoyl) -4-fluoropyrrolidine-1carboxylate (700 mg) in 4n. HCl in dioxane (25 ml), and the resulting reaction mixture was stirred at rt. within 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next stage of the synthesis.

Scheme 3

Step 1. 5-Bromo-1H-indole-3-carboxamide.

A mixture of 5-bromo-1H-indole-3-carbonitrile (10 g) in TFA (160 ml) and sulfuric acid (40 ml) was stirred at room temperature for 4 hours. The reaction mixture was then poured onto ice and the precipitated solid the material was collected by filtration, washed with water and dried in vacuo to give 5 bromo-1 H-indole-3-carboxamide.

Step 2. tert-Butyl-2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate.

A mixture of 5-bromo-1H-indole-3-carboxamide (9.8 g, 41.66 mmol), mpem-butyl bromoacetate (6.67 ml, 1.1 eq.) And potassium carbonate (6.32 g, 1, 1 eq.) In anhydrous acetonitrile (100 ml) was heated under reflux for 5 h. The reaction mixture was then cooled to rt. and the solvent was removed under reduced pressure. The residue was dissolved in a mixture of DCM and water. The two layers were separated and the organic layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated. The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give tert-butyl 2- (5-bromo-3carbamoyl-1H-indazol-1-yl) acetate.

Scheme 4

gtadnch 3

Step 1. tert-Butyl-2- (3-carbamoyl-5- (1H-pyrazol-4-yl) -1H-indazol-1-yl) acetate.

A mixture of tert-butyl-2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate (211 mg, 1 eq.), 4- (4,4,5,5- 49 038607 tetramethyl-1 , 3,2-dioxaborolan-2-yl) -III-pyrazole (140 mg), cesium carbonate (391 mg, 2 eq.), DMF (10 ml) and water (1.0 ml) were purged with argon in a pressure vessel in within 5 minutes. Then tetrakis (triphenylphosphine) palladium (0) (35 mg) was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (1H-nyrazol-4-yl) -1H-indazol-1-yl) acetic acid.

Took tert-butyl-2- (3-carbamoyl-5- (1H-pyrazol-4-yl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3.1- (2 - ((2S, 4R) -2 - ((2'-Chloro-2-fluoro- [1,1'-biphenyl) carbamoyl) -4-fluoropyrrolidin-1-yl) -2oxoethyl) -5- (1H-pyrazol-4-yl) -1H-indazole-3-carboxamide (1).

2- (3-Carbamoyl-5-1H- (pyrazol-4-yl) -1H-indazol-1-yl) acetic acid (100 mg, 1 eq.) Was dissolved in DMF (10 ml) and DIEA (0.269 ml , 5 eq.) Followed by the addition of (2S, 4R) N- (3-chloro- (2S, 4R) -N- (6-chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (111 mg, 1 eq.) At a temperature of 5 ° C. Then, at the same temperature, HATU (263 mg, 2.1 eq.) Was added slowly and the reaction mixture was stirred for 3 h at rt.The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x25 ml) The organic layer was washed sequentially with aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give 1.1H NMR (400 MHz, DMSOd ₆ , 300K): (main rotamer) δ 2.01-2.21 (m, 1H) , 2.49-2.55 (m, 1H), 3.80-3.92 (m, 1H), 4.08-4.21 (m, 1H), 4.61 (t, 1H), 5.47-5.62 (m, 3 H), 7.05 (t, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.31-7.40 (m, 4H), 7.49-7.62 (m, 5H), 7.77 (m, 1H), 8.21 (s , 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ -126.75, -175.87. LC (method A): tR = 1.79 min. LC / MS (EI) m / z: [M + H] ⁺ 604.

Scheme 5

stage 3

Step 1. tert-Butyl-2- (3-carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetate.

A mixture of tert-butyl 2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate (211 mg), pyrimidine-5ylboronic acid (82 mg), cesium carbonate (391 mg, 2 eq.), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (40 mg) was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid.

Took tert-butyl-2- (3-carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3.1- (2 - ((2S, 4R) -2 - ((2'-Chloro-2-fluoro- [1,1'-biphenyl) carbamoyl) -4-fluoropyrrolidin-1-yl) -2oxoethyl) -5- (pyrimidin-5-yl) -1H-indazole-3-carboxamide (2).

2- (3-Carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid (45 mg, 1 eq.) From the previous step was dissolved in DMF (10 ml) and DIEA (0 , 12 ml, 5 eq.) Followed by the addition of (2S, 4R) -N- (3-chloro- (2S, 4R) -N- (6-chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (50

- 50 038607 mg, 1 eq.) At 5 ° С. Then, at the same temperature, HATU (118 mg, 2.1 eq.) Was added slowly and the reaction mixture was stirred for 3 h at rt. The reaction mixture was then added to water (25 ml + 5 g solid NaCl) and extracted with DCM (2x15 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (10 ml), water (10 ml) and brine (10 ml), then dried over Na 2 SO 4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give 2.Ή NMR (400 MHz, DMSOd6, 300K): (main rotamer) δ 2.11-2.29 (m, 1H), 2.51-2.62 (m , 1H), 3.89-4.08 (m, 1H), 4.18-4.30 (m, 1H), 4.76 (t, 1H), 5.48-5.76 (m, 3H), 7.06 (t, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.37-7.48 (m, 4H), 7.57 (m, 1H), 7.72-7.88 (m, 2H), 7.86 (t, 1H), 8.47 (s, br, 1H), 9.15 ( s, 2H), 9.21 (s, 1H), 9.99 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main) δ -126.69, -175.86. LC (method A): tR = 1.82 min. LC / MS (EI) m / z: [M + H] ⁺ 616.

Scheme 6

Step 1. tert-Butyl-2- (3-carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indαzol-1-yl) acetate.

A mixture of tert-butyl-2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate (316 mg), 2- (pyrrolidin-1-yl) -5 (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (271 mg), cesium carbonate (350 mg, 2 eq), DMF (10 ml) and water (1.5 ml) were purged with argon in a pressure vessel in within 5 minutes. Then tetrakis (triphenylphosphine) palladium (0) (57 mg) was added under argon and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indαzol-1-yl) acetic acid.

Took tert-Butyl-2- (3-carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3.1 - (2 - ((2 S, 4R) -2 - ((2'-Chloro-2-fluoro- [1,1'-biphenyl) carbamoyl) -4-fluoropyrrolidin-1 -yl) -2oxoethyl ) -5- (2-pyrrolidin-1-yl) -1 H-indαzole-3-carboxamide (10).

2- (3-Carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid (110 mg, 1 eq.) Was dissolved in DMF (10 ml) and DIEA (0.3 ml) was added followed by the addition of (2S, 4R) -N- (3-chloro- (2S, 4R) -N- (6-chloropyridin-2-yl) -4-fluoropyrrolidin-2- carboxamide (110 mg, 1 eq.) at 5 ° C. Then, at the same temperature, HATU (118 mg) was added slowly and the reaction mixture was stirred for 3 h at rt.The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x20 ml) The organic layer was sequentially washed with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give 10. NMR (400 MHz, DMSO-d ₆ , 300 K): (main rotamer) δ 1.96 (m, 4H), 2.07-2.25 (m, 1H), 2.49-2.62 (m, 1H), 3.53 (m, 4H), 3.78 -3.92 (m, 1H), 4.18-4.27 (m, 1H), 4.66 (t, 1H) , 5.45-5.51 (m, 1H), 5.58-5.69 (m, 2H), 7.04 (t, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.32-7.48 (m, 4H), 7.53-7.69 (m, 4H), 7.95 (m, 1H), 8.24 (s, 1H), 9.97 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ -126.70, -175.88. LC (method A): t _R = 2.33 min. LC / MS (EI) m / z: [M + H] ⁺ 685.

- 51 038607

Scheme 7

Step 1. tert-Butyl-2- (3-carbamoyl-5- (6-fluoropyridin-3-yl) -1H-indazol-1-yl) acetate.

A mixture of tert-butyl 2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate (211 mg), 6-fluoropyridine-3ylboronic acid (135 mg), cesium carbonate (350 mg, 2 eq. ), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (50 mg) was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (6-fluoropyridin-3-yl) -1H-indazol-1-yl) acetic acid.

Took tert-butyl-2- (3-carbamoyl-5- (6-fluoropyridin-3-yl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3.1 - (2 - ((2S, 4R) -2 - ((2'-Chloro-2-fluoro- [1,1'-biphenyl) carbamoyl) -4-fluoropyrrolidin-1-yl) -2oxoethyl) -5- (6-fluoropyridin-3-yl) -1H-indazole-3-carboxamide (12).

2- (3-Carbamoyl-5- (6-fluoropyridin-3-yl) -1H-indazol-1-yl) acetic acid (110 mg, 1 eq.) Was dissolved in DMF (10 ml) and DIEA (0, 3 ml) followed by the addition of (2S, 4R) -N (3-chloro- (2S, 4R) -N- (6-chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (110 mg, 1 eq. .) at 5 ° C. Then, at the same temperature, HATU (118 mg) was slowly added and the reaction mixture was stirred for 3 h at rt.The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and ext was reacted with DCM (2x20 ml). The organic layer was sequentially washed with aqueous NaHCO ₃ (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue purified by flash column chromatography (eluted with DCM / MeOH) to give 12.1H NMR (400 MHz, DMSO-d ₆ , 300K): (main rotamer) δ 2.10-2.32 (m, 1H), 2.49-2.65 (m, 1H), 3.88-4.06 (m, 1H), 4.18-4.29 (m, 1H), 4.73 (t, 1H), 5.955.74 (m, 3H), 7.05 (t, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.31-7.48 (m, 5H), 7.46 (m, 1H), 8.27 (m, 1H), 8.39 (s, 1H), 8.55 (s, 1H), 9.98 (s, 1H) ; ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ -125.25, -175.87. LC (method A): t _R = 2.43 min. LC / MS (EI) m / z: [M + H] ⁺ 633.

Scheme 8

Step 1. (1R, 3S, 5R) -tert-Butyl-3 - ((6-bromopyridin-2-yl) carbamoyl) -2-azabicyclo [3.1.0] hexane-2carboxylate.

To an ice-cold solution of (1R, 3S, 5R) -mpem-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-2carboxylic acid (1.5 g) in DCM (20 ml) was added dropwise with stirring 1-χλορ- Ν, Ν, 2trimethyl-1-propenylamine (998 mg, 1.1 eq.). Stirring was continued for 3 h at this temperature and then solid 6-bromopyridin-2-amine (1.3 g, 1.1 eq.) Was added followed by DIEA (3.34 ml, 3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20

- 52,038607 ml), then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (eluted with hexanes / EtOAc) to give (1R,

3S, 5R) -tert-butyl-3 - ((6-bromopyridin-2-yl) carbamoyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate.

Step 2. (1R, 3S, 5R) -N- (6-bromopyridin-2-yl) -2-azabicyclo [3.1.0] hexane-3-carboxamide hydrochloride.

We took (1R, 3S, 5R) -tert-butyl-3 - ((6-bromopyridin-2-yl) carbamoyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate (500 mg) in 4N. HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next synthesis step.

Scheme 9

stage 3 *

Step 1. tert-Butyl-2- (3-carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetate.

A mixture of tert-butyl-2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate (211 mg), pyrimidine-5ylboronic acid (135 mg), cesium carbonate (350 mg, 2 eq.), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (50 mg) was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid.

Took tert-butyl-2- (3-carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3. 1- (2 - ((1R, 3S, 5R) -3 - ((6-Bromopyridin-2-yl) carbamoyl) -2-azabicyclo [3.1.0] hexan-2-yl-2oxoethyl) 5 - (pyrimidin-5-yl) -1 H-indazole-3-carboxamide (4).

2- (3-Carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid (110 mg) obtained in the previous step was dissolved in DMF (20 ml) and DIEA (0, 3 ml) followed by the addition of (17R, 3S, 5R) -N- (6-bromopyridin-2-yl) -2-azabicyclo [3.1.0] hexane-3-carboxamide hydrochloride (126 mg) at 5 ° C. Then HATU (350 mg) was added slowly at the same temperature and the reaction mixture was stirred for 3 h at rt. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x20 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give 4.1H NMR (400 MHz, DMSO-d ₆ , 300K): (main rotamer) δ 0.75 (m, 1H), 1.02 (m, 1H) , 1.85 (m, 1H), 2.16-2.35 (m, 2H), 3.80 (m, 1H), 4.42 (m, 1H), 5.54 (d, 1H), 5.86 (d, 1H), 7.32 (t, 1H ), 7.48 (br s, 1H), 7.68-7.88 (m, 4H), 8.03 (d, 1H), 8.46 (s, 1H), 9.23 (s, 2H), 10.76 (s, 1H); LC (method A): tR = 1.42 min. LC / MS (EI) m / z: [M + H] ⁺ 561.

- 53 038607

Scheme 10

herding 3

Step 1. tert-Butyl-2- (3-carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indazol-1-yl) acetate.

A mixture of tert-butyl-2- (5-bromo-3-carbamoyl-III-indazol-1-yl) acetate (316 mg), 2- (pyrrolidin-1-yl) -5 (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (271 mg), cesium carbonate (350 mg), DMF (10 ml) and water (1.5 ml) were purged with argon in a pressure vessel for 5 minutes ... Then tetrakis (triphenylphosphine) palladium (0) (57 mg) was added under argon and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid.

Took tert-butyl-2- (3-carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next synthesis step.

Stage 3. 1- (2 - ((1R, 3S, 5R) -3 - ((6-Bromopyridin-2-yl) carbamoyl) -2-azabicyclo [3.1.0] hexan-2-yl-2oxoethyl) 5- ((2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indazole-3-carboxamide (11).

2- (3-Carbamoyl-5- (2-pyrrolidin-1-yl) pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid (131 mg) obtained in the previous step was dissolved in DMF (20 ml) and DIEA (0.25 ml) was added followed by the addition of (1R, 3S, 5R) -N- (6-bromopyridin-2-yl) -2-azabicyclo [3.1.0] hexane-3carboxamide hydrochloride (110 mg) at 5 ° C. Then HATU (240 mg) was added slowly at the same temperature and the reaction mixture was stirred for 3 h at rt. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x20 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give 11.1H NMR (400 MHz, DMSO-d6, 300K): (main rotamer) δ 0.74 (m, 1H), 1.01 (m, 1H ), 1.25 (m, 1H), 1.86-1.98 (m, 5H), 2.13-2.38 (m, 2H), 3.56 (m, 4H), 3.80 (m, 1H), 4.42 (m, 1H), 5.51 ( d, 1H), 5.82 (d, 1H), 7.19 (d, J = 6.8 Hz, 1H), 7.40 (br s, 1H), 7.64-7.72 (m, 4H), 8.01 (d, 1H), 8.27 ( s, 1H), 8.66 (s, 2H), 10.75 (s, 1H); LC (method A): tR = 1.82 min. LC / MS (EI) m / z: [M + H] +630.

Br N— / 4 N HCl in disksan A stage 2 || θ

HCl

DIEADCBe ^e C "KT gtash-i 1

Step 1. (2S, 4R) -1-tert-Butyl-2 - ((6-bromopyridin-2-yl) carbamoyl) -4-fluoropyrrolidine-1-carboxylate.

To an ice-cold solution of (2S, 4R) -1-tert-butoxycarbonyl) -4-fluoropyrrolidine-2-carboxylic acid (1.59 g) in DCM (20 ml) was added dropwise with stirring 1-chloro-N, N, 2-trimethyl-1-propenylamine (998 mg, 1.1 eq.). Stirring was continued for 3 h at this temperature and then solid 6-bromopyridin-2-amine (1.3 g, 1.1 eq.) Was added followed by DIEA (3.34 ml, 3 eq.). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture is then

Scheme 11

H ₇ N N. L g Ng ^{1 F}

NO I 4 'b

Bat. ... N ^J Boss

54 038607 was added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO 4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (eluted with hexanes / EtOAc) to give (2S, 4R) -tert-butyl-2 - ((6-bromopyridin-2-yl) carbamoyl) -4-fluoropyrrolidine-1-carboxylate.

Step 2. (2S, 4R) -N- (6-bromopyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride.

We took (2S, 4R) -1-tert-Butyl-2 - ((6-bromopyridin-2-yl) carbamoyl) -4-fluoropyrrolidine-1-carboxylate (1.5 g) in 4N. HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at rt. within 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next stage of the synthesis.

Scheme 12

Step 1. tert-Butyl-2- (3-carbamoyl-5- (4-morpholinophenyl) -1H-indazol-1-yl) acetate.

A mixture of tert-butyl 2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate (316 mg), (4-morpholinophenyl) boronic acid (224 mg), cesium carbonate (585 mg, 2 eq. ), DMF (20 ml) and water (2 ml) were purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (45 mg) was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (4-morpholinophenyl) -1H-indazol-1-yl) acetic acid.

Took tert-butyl-2- (3-carbamoyl-5- (4-morpholinophenyl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3.1- (2 - ((2S, 4R) -2 - ((6-Bromopyridin-2-yl) carbamoyl) -4-fluoropyrrolidin-1-yl) -2-oxoethyl) 5- (4-morpholinophenyl) -1 H-indazole-3-car boxamide (3).

2- (3-Carbamoyl-5- (4-morpholinophenyl) -1H-indazol-1-yl) acetic acid (177 mg, 1 eq.) From the previous step was dissolved in DMF (10 ml) and DIEA (0.25 ml) followed by the addition of (2S, 4R) -N- (6-bromopyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (118 mg, 1 eq.) at 5 ° C. Then HATU (248 mg) was added slowly at the same temperature and the reaction mixture was stirred for 3 h at rt. The reaction mixture was then added to water (50 ml + 10 g solid NaCl) and extracted with DCM (2x20 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with DCM / MeOH) to give 3.Ή NMR (400 MHz, DMSO-d ₆ , 300 K): (main rotamer) δ 2.07-2.22 (m, 1H), 2.49-2.61 ( m, 1H), 3.12-3.18 (m, 4H), 3.73-3.78 (m, 4H), 3.86-4.09 (m, 1H), 4.13-4.25 (m, 1H), 4.66 (t, J = 8.4 Hz, 1H), 5.42-5.48 (m, 1H), 5.58-5.70 (m, 2H), 7.04 (t, J = 6.4 Hz, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.35-7.52 (m , 1H), 7.50-7.58 (d, J = 8.4 Hz, 2H), 7.63-7.75 (m, 4H), 8.02 (d, J = 8 Hz, 1H), 8.32 (s, 1H), 10.99 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main) δ -175.70. LC (method A): t _R = 1.82 min. LC / MS (EI) m / z: [M + H] ⁺ 650.

- 55 038607

Scheme 13> - <<f \ f P

Ci f. ; = (F.> - <

KN-c, / Cl> = <Ci

-. pH HCl ...., HN — 4 j 4HKIt№aw! HN- (i mL W --------- <T UCH ^w _{_____,:} Mr. WW • NPIN q ^l -nb in ^{«.., Ν γ A. hoc ™} « " ²

Cl

DEA, DCM, 0 ° C to rt.

stage 1

Step 1. (1R, 3S, 5R) -tert-Butyl-3 - ((2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) carbamoyl) -2-azabicyclo [3.1. 0] hexane-2-carboxylate.

To an ice-cold solution of (1R, 3S, 5R) -tert-butoxycarbonyl) -2-azabicyclo [3.1.0] hexane-2carboxylic acid (1.13 g) in DCM (20 ml) was added dropwise with stirring 1-χλορ- Ν, Ν, 2trimethyl-1-propenylamine (731 mg, 1.1 eq.). Stirring was continued for 3 hours at this temperature and then solid 2'-chloro-2-fluoro- [1,1'-biphenyl] -3-amine hydrochloride (1.3 g, 1 eq.) Was added followed by the addition of DIEA ( 2.45 ml). The cooling bath was removed and the reaction mixture was stirred overnight at rt. The reaction mixture was then added to water (20 ml) and extracted with DCM (2x25 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluted with hexanes / EtOAc) to give (1R, 3S, 5R) -tert-Butyl-3 - ((2'-chloro-2-fluoro [1,1'-biphenyl] -3yl) carbamoyl) -2-azabicyclo [3.1.0] hexane-2-carboxylate.

Stage 2. Hydrochloride (1R, 3S, 5R) -N- (2'-Chloro-2-fluoro- [1,1'-biphenyl] -3-yl) -2-azabicyclo [3.1.0] hexane-3- carboxamide.

We took (1 R, 3S, 5R) -tert-butyl-3 - ((2'-chloro-2-fluoro- [1,1 '-biphenyl] -3-yl) carbamoyl) -2-azabicyclo [3.1.0 ] hexane-2-carboxylate (700 mg) in 4N. HCl in dioxane (25 ml) and the resulting reaction mixture was stirred at rt. within 3 hours. The solvent was removed under reduced pressure and the remaining residue was used directly in the next stage of the synthesis.

Scheme 14

HCI stage 3

Step 1. tert-Butyl-2- (3-carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetate.

A mixture of tert-butyl 2- (5-bromo-3-carbamoyl-1H-indazol-1-yl) acetate (211 mg), pyrimidin-5-ylboronic acid (82 mg), cesium carbonate (391 mg, 2 eq. ), DMF (9 ml) and water (1.0 ml) were purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (40 mg) was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid.

Took tert-butyl-2- (3-carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetate (crude from the above reaction) in 4N. HCl in dioxane (5 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3. 1- (2 - ((1R, 3S, 5R) -3 - ((2'-Chloro-2-fluoro- [1,1 '-biphenyl] -3-yl) carbamoyl) azabicyclo [3.1.0 ] hexan-2-yl) -2-oxoethyl) -5- (pyrimidin-5-yl) -1H-indazole-3-carboxamide (6).

2- (3-Carbamoyl-5- (pyrimidin-5-yl) -1H-indazol-1-yl) acetic acid (131 mg, 1 eq.)

- 56 038607 of the next step was dissolved in DMF (10 ml) and DIEA (0.33 ml, 5 eq.) Was added, followed by the addition of hydrochloride (1R, 3S, 5R) -N- (2'-chloro-2-fluoro- [ 1,1'-biphenyl] -3-yl) 2-azabicyclo [3.1.0] hexane-3-carboxamide (131 mg, 1 eq.) At 5 ° C. Then HATU (350 mg, 2.1 eq.) Was added slowly at the same temperature and the reaction mixture was stirred for 3 h at rt. The reaction mixture was then added to water (25 ml + 5 g solid NaCl) and extracted with DCM (2x15 ml). The organic layer was washed sequentially with an aqueous solution of NaHCO ₃ (10 ml), water (10 ml) and brine (10 ml), then dried over Na ₂ SO 4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluting with DCM / MeOH) to give 6. ¹ H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 0.73 (m, 1H) , 1.07 (m, 1H), 1.26 (m, 1H), 1.90 (m, 1H), 2.28-2.35 (m, 2H), 3.78-3.83 (m, 1H), 4.54 (m, 1H), 5.52 (d, 1H), 5.84 (d, 1H), 7.07 (t, J = 6.4 Hz, 1H), 7.27 (t, J = 8.0 Hz, 1H), 7.35-7.58 (m, 4H), 7.55 (d, 1H), 7.72-7.84 ( m, 4H), 8.47 (s, 1H), 9.72 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300K): (main) δ -126.54. LC (method A): tR = 1.96 min. LC / MS (EI) m / z: [M + H] ⁺ 610.

Scheme 15

Pd (dppf) CI ₂

Pd _z dba ₃

Zn (CN) ₂ , DMF

Stage-1. 5-Chloro-3-iodo-1H-pyrazolo [3,4] pyridine.

Iodine (37.2 g, 1.5 eq.) And potassium hydroxide (13 , 7 g, 2.5 eq.) At 0 ° С. The reaction mixture was stirred at rt. for 12 h and then diluted with 10% aqueous sodium thiosulfate solution (250 ml) and extracted with EtOAc. The combined organic extracts were washed with brine and then dried. The resulting solid (15 g) was slurried with MTBE, filtered and dried.

Stage-2. tert-Butyl 2- (5-chloro-3-iodo-1H-pyrazolo [3,4] pyridin-1-yl) acetate.

To a mixture of 5-chloro-3-iodo-1H-pyrazolo [3.4] pyridine (14 g, 1 eq.) And potassium carbonate (8.3 g, 1.2 eq.) In DMF (140 ml) was added drops of tert-butyl bromoacetate (8.9 ml, 1.2 eq.) at rt. and the resulting mixture was stirred at 50 ° C for 3 hours. The reaction mixture was then poured into water and extracted with EtOAc; the combined organic extracts were concentrated under reduced pressure. The resulting material was taken to the next stage without additional purification.

Stage-3. tert-Butyl 2- (5-chloro-3-cyano-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate.

A mixture of tert-butyl 2- (5-chloro-3-iodo-1H-pyrazolo [3.4] pyridin-1-yl) acetate (12.5 g, 1 eq.), Zn (CN) 2 (4, 5 g, 1.2 eq.), Pd (dppf) Cl ₂ (2.6 g, 0.1 eq.), Pd ₂ (dba) ₃ (2.9 g, 0.1 eq.), Water ( 25 ml) and DMF (125 ml) were stirred at 100 ° C for 5 h under nitrogen atmosphere. The reaction mixture was diluted with EtOAc and then washed sequentially with water, saturated aqueous NaHCO ₃ and brine. The combined organic layer was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography (hexane / EtOAc) to give the title compound.

Stage-4. tert-Butyl 2- (3-carbamoyl-5-chloro-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate.

A mixture of tert-butyl 2- (5-chloro-3-cyano-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate (5.7 g, 1 eq.), Acetaldoxime (2.3 g , 2 eq.), Pd (OAc) ₂ (0.22 g, 0.05 eq.) And PPh ₃ (0.54 g, 0.1 eq.) In aqueous ethanol (143 ml, H ₂ O / EtOH (29 ml / 114 ml) was heated to 90 ° C for 3 h under nitrogen atmosphere The reaction mixture was filtered through Celite and the solvent was removed under reduced pressure The crude residue was purified by column chromatography on silica gel (hexane / EtOAc) to give the indicated in the title of the compound (3.5 g).

Scheme 16

- 57 038607

Step 1. 2- (3-Carbamoyl-5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c] pyridin-1-yl) acetic acid.

A mixture of tert-butyl-2- (3-carbamoyl-5-chloro-1H-pyrazolo [3,4-c] pyridin-1-yl) acetate (311 mg, 1 mmol), pyrimidin-5-ylboronic acid (248 mg , 2 mmol), K ₃ PO ₄ (634 mg, 3 mmol), dioxane (9 ml) and water (1 ml) were degassed and replenished with argon three times. To this mixture was added Pd (PPh ₃ ) ₄ (58 mg, 0.05 mmol) under argon atmosphere and the reaction mixture was heated in an oil bath at 85 ° C overnight. Added to the solution additional Pd (PPh ₃ ) ₄ (58 mg, 0.05 mmol) and the reaction mixture was kept at 85 ° C for an additional 24 h. The reaction mixture was cooled to rt. and the volatiles were removed under reduced pressure. The remaining residue was acidified with 10% aqueous citric acid (10 ml) and extracted with ethyl acetate (20 ml). Discard the organic layer and evaporate the aqueous phase to dryness. The remaining solid was loaded onto a silica gel plug and washed with methanol. The methanol solution was concentrated and coevaporated with toluene. The resulting solid was dried under high vacuum and used in the next step without further purification.

Stage 2.1 - (2 - ((2S, 4R) -2 - ((2'-Chloro-2-fluoro- [1,1'-biphenyl] -3-yl) carbamoyl) -4-fluoropyrrolidin-1 yl ) -2-oxoethyl) -5- (pyrimidin-5-yl) -1H-pyrazolo [3,4-c] pyridine-3-carboxamide (19).

To a mixture of 2- (3-carbamoyl-5- (pyrimidin-5-yl) -III-pyrazolo [3,4-c] pyridin-1-yl) acetic acid (77 mg, 0.26 mmol), HATU (120 mg, 0.32 mmol, 1.2 eq.), hydrochloride (2S, 4R) -N- (2'-chloro-2-fluoro- [1,1'biphenyl] -3-yl) -4-fluoropyrrolidine- 2-carboxamide (96 mg, 0.26 mmol) and DMF (2.5 ml) were added DIEA (0.15 ml, 0.86 mmol) at RT. The reaction mixture was stirred for 30 min at rt. and then the volatiles were removed under reduced pressure. The remaining residue was subjected to preparative HPLC to obtain 40.9 mg of the title product. Ή NMR (400 MHz, DMSO-d ₆ , 300 K): (main rotamer) δ 2.17-2.25 (m, 1H), 2.49-2.57 (m, 1H), 3.86-3.99 (m, 1H), 4.13-4.22 (m, 1H), 4.73 (t, J = 8.4 Hz, 1H), 5.57-5.61 (m, 1H), 5.65-5.84 (m, 2H), 6.99 (t, J = 6.4 Hz, 1H), 7.14 ( t, J = 8.0 Hz, 1H), 7.28-7.42 (m, 4H), 7.507.58 (m, 1H), 7.83-7.92 (m, 2H), 8.58 (s, 1H), 9.15 (s, 1H) , 9.23 (s, 1H), 9.38 (s, 2H), 9.95 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ , 300K): (main rotamer) δ -126.77, -175.85. LC (method A): t _R = 2.47 min. LC / MS (EI) m / z: [M + H] ⁺ 617.

Scheme 17

stage 3

Step 1. tert-Butyl-2- (3-acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetate.

A mixture of tert-butyl 2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate (351 mg, 1 eq.), (2-methoxypyrimidin-5-yl) boronic acid (230 mg, 1 , 5 eq.), Cesium carbonate (650 mg, 2 eq.), DMF (15 ml) and water (1.5 ml) were purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.05 eq.) Was added under an argon atmosphere and the pressure vessel was sealed and heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was used directly in the next synthesis step.

Step 2. 2- (3-Acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetic acid.

Took crude tert-butyl-2- (3-acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetate (top) in 4N. HCl in dioxane (20 ml) and the resulting reaction mixture was stirred at rt. within 4 hours. The solvent was removed under reduced pressure and the remaining material was used directly in the next stage of the synthesis.

Stage 3. (2S, 4R) -1 - (2- (3-Acetyl-5- (2-methoxypyrimidin-5-yl) -1 N-indol-1-yl) acetyl) -N- (2'-chloro2 -fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide (27).

2- (3-Acetyl-5- (2-methoxypyrimidin-5-yl) -1H-indol-1-yl) acetic acid (100 mg, 1 eq.) From the previous step was dissolved in DMF (10 ml) and added to DIEA (0.269 ml, 5 eq.) Followed by the addition of (2S, 4R) -N- (3-chloro- (2S, 4R) -N- (6-chloropyridin-2-yl) -4-fluoropyrrolidine-2 hydrochloride

- 58 038607 carboxamide (111 mg, 1 eq.) At 5 ° C. Then HATU (263 mg, 2.1 eq.) Was added slowly at the same temperature and the reaction mixture was stirred for 3 h at rt. The reaction mixture was then added to water (50 ml + 10 g NaCl) and extracted with DCM (2x25 ml). The organic layer was washed sequentially with an aqueous NaHCO ₃ solution (20 ml), water (20 ml) and brine (20 ml), then dried over Na ₂ SO 4 and concentrated under reduced pressure. The remaining residue was purified by flash column chromatography (eluting with DCM / MeOH) to give 27. ¹ H NMR (400 MHz, DMSO-d6, 300 K): (major rotamer) δ 2.13-2.3 (m, 1H) , 2.45 ( s, 3H), 2.68-2.70 (m, 1H), 3.95-4.05 (m, 4H), 4.16-4.24 (m, 1 H), 4.78 (t, J = 8 Hz, 1H), 5.28 (d, J = 20 Hz, 1H), 5.45 (d, J = 20 Hz, 1H), 5.50-5.63 (m, 1H), 7.04-7.08 (m, 1H), 7.20-7.24 (m, 1H), 7.37-7.61 ( m, 7H), 7.75-7.78 (m, 1H), 7.94-7.98 (m, 1H), 8.31 (s, 1H), 8.88 (s 1H), 8.97 (s 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ -126.64, -175.79. LC (method A): tR = 2.16 min. LC / MS (EI) m / z: [M + H] ⁺ 644.

Scheme 18. Synthesis of (2S, 4R) -1 - (2- (3-acetyl-5- (4-acetylpiperazin-1 -yl) -1Н-indol-1 -yl) acetyl) -N- (2'chloro- 2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide (16)

Stage 1. 1- (5-Bromo-1H-indol-3-yl) ethanone.

1- (5-Bromo-1H-indol-3-yl) ethanone was prepared from 5-bromoindole according to the procedure described by MacKay et al. (MacKay, J. A .; Bishop, R .; Rawal, V. H. Org. Lett. 2005, 7, 3421-3424.)

Step 2. tert-Butyl-2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate.

A mixture of 1- (5-bromo-1H-indol-3-yl) ethanone (3.9 g, 16.4 mmol), tert-butyl bromoacetate (2.63 ml (18.02 mmol) and potassium carbonate (2.50 g, 18.02 mmol) in anhydrous acetonitrile (80 ml) was heated under reflux for 5 h. The reaction mixture was then cooled to rt and the solvent was removed under reduced pressure. The residue was dissolved in a 1: 1 mixture of DCM and water ( 100 ml: 100 ml) Two layers were separated and the organic layer was washed with water (2x100 ml) Finally, the organic layer was dried (Na ₂ SO ₄ ) and concentrated.The resulting residue was stirred with 50 ml of heptane for 30 min, cooled in an ice bath and the filtered solid residue, washed with cold heptane (10 ml). The solid residue was dried under high vacuum to give tert-butyl 2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate (5.6 g ).

Step 3. tert-Butyl 4- (3-acetyl-1- (2- (tert-butoxy) -2-oxoethyl) -1H-indol-5-yl) piperazine-1carboxylate.

A mixture of tert-butyl 2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate (379 mg), tert-butylpiperazine-1 carboxylate (223 mg, 1.2 eq.), Cesium carbonate (489 mg, 1.4 eq.), (S) - (-) - 2,2-bis (biphenylphosphino) -1,1binaftyl (40 mg) and toluene (8 ml) were purged with argon for 5 min. Then, tris (dibenzylideneacetone) dipalladium (0) (40 mg) was added under an argon atmosphere and the reaction mixture was heated at 100 ° C. overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (EtOAc gradient in hexanes) to give tert-butyl-4- (3-acetyl-1- (2- (tert-butoxy) -2-oxoethyl) -1H-indol-5-yl) piperazine-1-carboxylate (89 mg).

Step 4. TFA salt of tert-butyl 2- (3-acetyl-5- (piperazin-1-yl) -1H-indol-1-yl) acetate.

- 59 038607 tert-Butyl-4- (3-acetyl-1- (2- (tert-butoxy) -oxoethyl-III-indol-5-yl) piperazine-1-carboxylate (65 mg) was dissolved in 5% TFA ( 0.5 ml) in DCM (10 ml) at 0-5 ° C and the resulting reaction mixture was stirred at 0-5 ° C for 24 hours. The solvent was then removed under reduced pressure and the remaining material was used directly in the next synthesis step.

Step 5. tert-Butyl-2- (3-acetyl-5- (4-acetylpiperazin-1-yl) -1H-indol-1-yl) acetate.

TFA salt of tert-butyl 2- (3-acetyl-5- (piperazin-1-yl) -1H-indol-1-yl) acetate c Step 4 was dissolved in DCM (4 ml) and DIEA (0.14 ml , excess) followed by the addition of AcCl (0.02 ml, 1 eq.) at 0-5 ° C. After stirring for 10 min, the reaction mixture was diluted with EtOAc (10 ml) and water (4 ml). The EtOAc layer was separated, washed with brine (15 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness under reduced pressure. The rest of the material was used directly in the next step.

Step 6. 2- (3-Acetyl-5- (4-acetylpiperazin-1-yl) -1H-indol-1-yl) acetic acid.

tert-Butyl 2- (3-acetyl-5- (4-acetylpiperazin-1-yl) -III-indol-1-yl) acetate from the previous step was dissolved in DCM (5 ml) and TFA (1 ml) was added. The reaction mixture was stirred overnight at rt. Then, the solvent was removed under reduced pressure, and the remaining material was used directly in the next stage of the synthesis.

Stage 7. (2S, 4R) -1 - (2- (3-Acetyl-5- (4-acetylpiperazin-1 -yl) -1 N-indol-1-yl) acetyl) -N- (2'-chloro -2fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide.

DIEA (0.13 ml, 3 eq. ) and then (2S, 4R) -N- (3-chloro- (2S, 4R) -N- (6chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (108 mg, 1.1 eq.) Then HATU (120 mg, 1.2 eq.) Was added slowly and the reaction mixture was stirred for 18 h at rt The reaction mixture was then added to water (10 ml) and extracted with EtOAc (2x15 ml). The organic layer washed sequentially with aqueous NaHCO ₃ (10 ml), water (10 ml) and brine (10 ml), then dried over Na2SO4 and concentrated under reduced pressure.The remaining residue was purified by flash column chromatography (eluted with DCM / CH3OH) with obtaining the title compound.1H NMR (400 MHz, DMSO-d ₆ , 300K): (main rotamer) δ 2.18 (s, 3H), 2.24-2.41 (m, 1H), 2.50 (s, 3H), 2.64 -2.78 (m, 1H), 3.08-3.19 (m, 4H), 3.69-3.80 (m, 4H), 3.91-4.09 (m, 1H), 4.16-4.27 (m, 1H), 4.78 (t, J = 8 Hz, 1H), 5.16 (d, J = 17 Hz, 1H), 5.26 (d, J = 17 Hz, 1H), 5.45-5.61 (m, 1H), 7.04-7.08 (m, 1H), 7.18-7.25 (m , 1H), 7.38-7.47 (m, 4H), 7.51-7.56 (m, 1H), 7.86-7.90 (s, 1H), 7.93-7.98 (m, 1H), 8.12 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ -128.56, -178.51. LC (method A): tR = 2.30 min. LC / MS (EI) m / z: [M + H] ⁺ 664.

Scheme 19. (2S, 4R) -1 - (2- (3-Acetyl-5- (4-methylsulfonylpiperazin-1 -yl) -1 N-indol-1 -yl) acetyl) -N (2'-chloro- 2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide (33)

Step 1. tert-Butyl-2- (3-acetyl-5 - (4- (methylsulfonyl) piperazin-1-yl) -1 H-indol-1-yl) acetate.

The TFA salt of tert-butyl 2- (3-acetyl-5- (piperαzin-1-yl) -1H-indol-1-yl) acetate (90 mg) was dissolved in DCM (4 ml). DIEA (0.14 ml) was added to this solution, followed by methylsulfonyl chloride (0.06 ml) at 0-5 ° C. After stirring for 10 min, the reaction mixture was diluted with EtOAc (10 ml) and water (4 ml). The separated organic layer was washed with brine (15 ml), dried (Na ₂ SO ₄ ) and evaporated to dryness under reduced pressure. The rest of the material was used directly in the next step.

Step 2. 2- (3-Acetyl-5- (4- (methylsulfonyl) piperazin-1-yl) -1H-indol-1-yl) acetic acid.

tert-Butyl 2- (3-acetyl-5 - (4- (methylsulfonyl) piperazin-1-yl) -1 H-indol-1-yl) acetate was dissolved in DCM (5 ml) and TFA (1 ml) was added ... The reaction mixture was stirred overnight at rt. and then the solvent was removed under reduced pressure. The rest of the material was used directly in the next step.

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Stage 3. (2S, 4R) -1 - (2- (3 - Acetyl-5 - (4- (methylsulfonyl) piperazin-1 -yl) -1 N-indol-1 -yl) acetyl) -N (2 ' -chloro-2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide.

DIEA (0.17 ml, 4 eq. ) followed by (2S, 4R) -N- (3-chloro- (2S, 4R) -N- (6chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (102 mg, 1.1 eq. Then HATU (120 mg, 1.2 eq.) Was added slowly and the reaction mixture was stirred for 18 h at rt The reaction mixture was then added to water (10 ml) and extracted with EtOAc (2x15 ml). the layer was washed sequentially with aqueous NaHCO ₃ (10 ml), water (10 ml) and brine (10 ml), then dried over Na ₂ SO ₄ and concentrated under reduced pressure.The resulting residue was purified by HPLC to give the title compound . ¹ H NMR (400 MHz, DMSO-d _6,

300 K): (main rotamer) δ 2.18 (s, 3H), 2.27-2.42 (m, 1H), 2.50 (s, 3H), 2.67-2.80 (m, 1H), 2.98 (s, 3H), 3.52 ( m, 8H), 3.95-4.29 (m, 2H), 4.78 (t, J = 8 Hz, 1H), 5.21 (d, J = 18 Hz, 1H), 5.35 (d, J = 18 Hz, 1H), 5.42-5.63 (m,

1H), 7.04-7.08 (m, 1H), 7.14-7.20 (m, 1H), 7.22-7.29 (m, 1H), 7.30-7.42 (m, 3H), 7.43-7.51 (m, 3H), 7.93- 7.96 (m, 1H); 8.15 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO ^, 300 K): (main rotamer) δ -128.49, -178.41. LC (method A): tR = 2.09 min. LC / MS (EI) m / z: [M + H] 698.

Scheme 20. Synthesis of (2S, 4R) -1- (2- (3-acetyl-5- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -1H-indol-1yl) acetyl) -N- (2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide (28)

Step 1. tert-Butyl-2- (3-acetyl-5- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -1H-indol-1yl) acetate.

A mixture of tert-butyl 2- (3-acetyl-5-bromo-1H-indol-1-yl) acetate (113 mg, 0.32 mmol), 1- (4- (4,4,5,5 tetramethyl-1 , 3,2-dioxaborolan-2-yl) -5,6-dihydropyridin-1 (2H) -yl) ethanone (80 mg, 0.32 mmol), cesium carbonate (209 mg, 0.64 mmol) and DMF ( 10 ml) was purged with argon in a pressure vessel for 5 min. Then tetrakis (triphenylphosphine) palladium (0) (18 mg, 0.016 mmol) was added under an argon atmosphere and the pressure vessel was sealed and heated at 90 ° C overnight. The reaction mixture was cooled to rt. and the solvent was removed under reduced pressure. The remaining crude product was used directly in the next synthesis step.

Step 2. 2- (3-Acetyl-5- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -1H-indol-1-yl) acetic acid.

Took tert-butyl-2- (3-acetyl-5- (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -1H-indol-1-yl) acetate in 4N. HCl in dioxane (10 ml) and the resulting reaction mixture was stirred at rt. for 4 hours. The solvent was then removed under reduced pressure, and the remaining material was used directly in the next stage of the synthesis.

Stage 3. (2S, 4R) -1 - (2- (3-Acetyl-5 - (1-acetyl-1,2,3,6-tetrahydropyridin-4-yl) -1 N-indol-1 yl) acetyl ) -N- (2'-chloro-2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide.

The title compound was prepared from 2- (3-acetyl-5- (1-acetyl-1,2,3,6-tetrahydropyridin4-yl) -Sh-indol-1-yl) acetic acid (100 mg, 0.29 mmol) and (2S, 4R) -N- (3-chloro- (2S, 4R) N- (6-chloropyridin-2-yl) -4-fluoropyrrolidine-2-carboxamide hydrochloride (110 mg, 0.29 mmol) in a manner similar to that described above for (2S, 4R) -1 - (2- (3-acetyl-5- (4-acetylpiperazin-1 -yl) -1H-indol-1 -yl) acetyl) -N- (2 ' chloro-2-fluoro- [1,1'-biphenyl] -3-yl) -4-fluoropyrrolidine-2-carboxamide. 1H NMR (400 MHz, DMSO-d ₆ , 300 K): (main rotamer) δ 2.05- 2.07 (s, 3H), 5 2.31-2.38 (m, 1H), 2.50 (s, 3H), 2.50-2.70 (m, 3H), 3.73-3.79 (m, 2H), 4.01-4.31 (m, 4H) , 4.85 (t, J = 8.4 Hz, 1H), 5.28-5.50 (m, 2H), 5.64 (d, J = 52.8 Hz, 1H), 6.18 (s, 1H), 7.16 (t, J = 6.8 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.41-7.68 (m, 6H), 8.04 (t, J = 7.6 Hz, 1H), 8.30 (d, J = 8 Hz, 1H), 8.35 ( s, 1H), 10.05 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d6, 300 K): (main rotamer) δ -126.64, -175.81 LC (method A): t _R = 2.07 min. LC / MS (EI) m / z: [M + H] ⁺ 659.

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Example 6 Non-limiting Examples of Compounds of Formula I

Table 1 depicts illustrative compounds of formula I with characteristic data. The analysis of Example 7 was used to determine the IC50 of the compounds. Other standard assays for factor D inhibition are also available. Three *** are used to designate compounds with IC50 less than 1 micromolar; two ** indicate a compound with an IC50 between 1 micromolar and 10 micromolar, and one * indicates a compound with an IC50 greater than 10 micromolar.

Table 1

Structure

RT min (Method carboxamide carboxamide carboxamide carboxamide l- (2 - ((2S, 4R) -2- (2 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (1 H-pyrazole -4-yl) -1Nindazol-3l- (2 - ((2S, 4R) -2- (2 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyrimidine-5 - yl) -1Nindazol-3l- (2 - ((2S, 4R) -2- (6bromopyridine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5- (4morpholinophenyl) III-indazole1 - (2 - (( lR, 3S, 5R) -3- (6bromopyridine-2ylcarbamoyl) -2azabicycloGZ. 1.0] hexan-2-yl) -2-oxoethyl) 5- (pyrimidin-5-yl) 1H-indazole-3

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l- (2 - ((2S, 4R) -2- (6-bromopyridine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyrimid in-5-yl) -1Nindazole-3carboxamide *** 1.30 (A ) 567

l- (2 - ((lR, 3S, 5R) -3- (2'- *** 1.96 (A) 610 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -2azabicyclo [3.1.0] hexan-2-yl) -2-oxoethyl) 5 - (pyrimidin-5-yl) III-ind azole-3 carboxamide l- (2 - ((lR, 3S, 5R) -3- (2'- *** 2.15 (A) 610 chlorine -2-fluorobiphenyl3 -ylcarbamoyl) -2azabicyclo [3.1.0] hexan-2-yl) -2-oxoethyl) 5 - (pyrimidin-2-yl) ΙΗ-ind azole-3 carboxamide l- (2 - ((lR , 3S, 5R) -3- (2- *** 1.74 (A) 584 fluoro-3 (trifluoromethoxy) phen ylcarbamoyl) -2azabicyclo [3.1.0] hexan-2-yl) -2-oxoethyl) 5 - ( pyrimidin-5-yl) III-ind azole-3 carboxamide

1- (2 - ((28.4K) -4-fluoro- *** 1.64 (A) 590

2- (2-fluoro-3 (trifluoromethoxy) phen ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyrimid in-5-yl) -1Nindazole-3carboxamide l- (2 - ((2S, 4R) - 2- (2'- *** 2.33 (A) 685 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5- (2 (pyrrolidin-1yl) pyrimidin-5-yl) III -ind azole-3 carboxamide

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l- (2 - ((lR, 3S, 5R) -3- (6- *** 1.82 (A) 630 bromopyridine-2ylcarbamoyl) -2azabicyclo [3.1.0] hexan-2-yl) -2-oxoethyl) 5 - (2- (pyrrolidin-1 yl) pyrimidin-5-yl) 1 N-ind azole-3 carboxamide l- (2 - ((2S, 4R) -2- (2'- *** 2.43 (A) 633 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5- (6fluoropyridin-3-yl) 1 H-indazole-3 carboxamide l- (2 - ((lR, 3S, 5R ) -3- (2'- *** 2.53 (A) 627 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -2azabicyclo [3.1.0] hexan-2-yl) -2-oxoethyl) 5 - (6-fluoropyridine -3 yl) -1 N-ind azole-3 carboxamide (2S, 4R) -l- (2- (3- *** 2.04 (A) 565 acetyl- 5 - (pyr im d in5-yl) -1 H -ind ol-1 yl) acetyl) -N- (6bromopyridin-2-yl) -4fluoropyrrolidin-2-carboxamide (lR, 3S, 5R) -2- (2- (3- *** 2.63 (A) 608 acetyl-5 - (pyrimidin5-yl) -1 N-ind ol-1 yl) acetyl) -1P- (2'chlor-2-fluorobiphenyl3-yl) -2azabicyclo [3.1.0] hexan-3 -carboxamide (2S, 4R) -l- (2- (3- *** 2.30 (A) 664 acetyl-5- (4acetylpiperazin-1 yl) -1 N-ind ol-1 yl) acetyl) -H- (2'chloro-2-fluorobiphenyl3 -yl) -4fluoropyrrolidine-2carboxamide

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tetrahydropyridine-4yl) -1 N-ind azole-3 carboxamide

1R, 3S, 5R -2- 2- (3acetyl-5- (pyrimidin5-yl) -1 N-ind ol-1 yl) acetyl) -M- (6orompyridin-2-yl) -2azabicycloGZ. 1.01hex an-3 -carboxamide

1- 2- (2S, 4R -2- 3chloro-2fluorobenzylcarbamoyl) -4-fluoropyrrolidin1-yl) -2-oxoethyl) -5 (pyrimidin-5-yl) -1Нpyrazolo | 3,4с I pyridin-3 carboxamide l- (2 - ((2S, 4R) -2- (2chloro-2-fluorobiphenyl3-ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyrimidin-5-yl) -1Hpyrazolo! 3,4c] pyridine- 3 carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (2 chloro-2-fluorobiphenylZyl) -4fluoropyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (2methoxypyrimidin-5yl) -1 N-ind ol-1yl) acetyl) -H- (6bromopyridin-2-yl) -4fluoropyrrolidine-2carboxamide ll- (2- ((2S, 4R) -2- (6bromopyridine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5- (1 methyl-1,2,3,6- 65 038607

(2S, 4R) -1- (2- (3- *** 2.24 (A) 520 acetyl-5- (pyrid azin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (6chloropyridine -2-yl) -4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (6- *** 2.23 (A) 522 chloropyridin-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) - 5 (pyridazin-4-yl) -1Nindazole-3carboxamide l- (2 - ((2S, 4R) -2- (6- *** 1.60 (A) 567 bromopyridine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2- oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3- *** 2.42 (A) 683 acetyl-5- (2 (pyrrolidin-1yl) pyrimidine- 5-yl) 1 N-ind ol-1 yl) acetyl) -M- (2'chlor-2-fluorobiphenyl3-yl) -4fluoropyrrolidin-2carboxamide (2S, 4R) -l- (2- (3- *** 2.16 (A) 644 acetyl-5- (2methoxypyrimidin-5yl) -1H-indole-1yl) acetyl) -M- (2'chlor-2-fluoro- [1, H biphenyl] -3-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3- *** 2.07 (A) 659 acetyl-5 - (1-acetyl1,2,3,6tetrahydropyridin-4yl) -1 N-ind ol-1 yl) acetyl ) -M- (2'chlor-2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide

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l- (2 - ((2S, 4R) -2- (2'- *** 2.01 (A) 646 chloro-2-fluorobiphenyl3 -ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5- (2methoxypyrimidine -5yl) -1 N-ind azole-3 carboxamide l- (2 - ((2S, 4R) -2- (6- *** 1.43 (A) 553 chloropyridine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2- oxoethyl) -5- (2methoxypyrimidine-5yl) -1 N-ind azole-3 carboxamide (2S, 4R) -l- (2- (3- *** 2.21 (A) 698 acetyl-5- (4 (pyrimidine- 2yl) piperazin-1 -yl) 1 N-ind ol-1 yl) acetyl) -M- (2'chlor-2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (3 - *** 2.43 (A) 716 acetyl-5- (4- (5fluoropyrimidin-2yl) piperazin-1-yl) 1 N-ind ol-1 yl) acetyl) -M- (2'chlor-2-fluorobiphenyl3- yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (3- *** 2.09 (A) 698 acetyl-5- (4 (methylsulfonyl) piperazin-1-yl) -1Nindol-1-yl ) acetyl) -M (2-chloro-2fluorobiphenyl-3-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (3- * 3.91 (B) 619 acetyl-5- (pyridazin4-yl) - 1H-indol-1 yl) acetyl) -M- (2 (benzo [b] thiazol2yl) phenyl) -4fluoropyrrolidine-2carboxamide

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(2S, 4R) -1- (2- (3- ** 2.33 (B) 557 acetyl-5- (pyrid azin4-yl) -1 N-indol-1 yl) acetyl) -M (benzo [c1 ] thiazol-2-ylmethyl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (3- ** 2.89 (B) 562 acetyl-5- (pyridazin4-yl) -1 Н-indol- 1 yl) acetyl) -K- (4,7difluoro-2,3-dihydro1 H-ind en-1 -yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (3- ** 2.08 (B ) 487 acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-M (pyridin-3 yl) pyrrolidine-2carboxamide (2S, 4R) -l- ( 2- (3- *** 2.03 (B) 501 acetyl-5 - (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-H (pyridin-2-ylmethyl) pyrrolidine- 2carboxamide

1- (2 - ((28.4K) -4-fluoro- ** 2.77 (B) 503

2- (pyridin-3ylmethylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3- ** 0.58 (B ) 501 acetyl-5 - (pyrid azin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-X (pyridin-4-ylmethyl) pyrrolidine-2carboxamide

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l- (2 - ((2S, 4R) -2- (2 (benzo [c1] thiazol-2yl) phenylcarbamoyl) 4-fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (rup dazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-I (6 (trifluoromethyl) benzo [ 0] isoxazole-3yl) pyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (4,7difluoro-2,3-dihydro1 H-ind en-1 ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2- oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl (acetyl) -N - (3 chlorobenzyl) -4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (3chlorobenzylcarbamoyl) -4-fluoropyrrolidin1-yl) -2-oxoethyl) -5 (pyrid az in-4-yl) - 1Nindazole-3carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (3-chloro5-fluorobenzyl) -4fluoropyrrolidine- 2carboxamide 1- (2 - ((28.4H) -4-fluoro2- (pyridin-3ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide

3.49 (B) 621

3.24 (B) 595 ** 2.69 (B) 564 *** 2.78 (B) 534 *** 2.48 (B) 536 *** 2.98 (B) 552

3.34 (B) 489

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1- (2 - ((28,4R) -2- (2ethyl-3OXOISOINDOLIN-5ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R ) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (2-ethyl3-oxoisoindolin-5 yl) -4fluoropyrrolidine-2carboxamide 1 - (2 - ((28,4R) -2 (benzo [O] thiazol-6ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide 1 - (2- ( (28,4R) -2 ((lR, 2S) -2 (benzyloxy) cyclopentylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide 1 - (2 - ((28,4R) -2 (benzo [P] thiazol-2ylmethylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l - (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -X- (2,3dimethyl-1 N-indol5 yl) -4fluoropyrrolidine-2carboxamide

1.97 (B) 571

2.49 (H) 569

2.03 (B) 545

2.81 (B) 586

2.15 (B) 559

2.91 (B) 553

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carboxamide methylimidazo 2,1 b] pyridin-5yl) pyridin-2yl) pyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-Ncarboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -K (benzo [a] thiazol-6-yl) 4-fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -4 ^ Top2- (4- (6methylimidazo [2.1 L] pyridin-5yl) thiazol-2ylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 (pyridazine -4-yl) -1Нindazol-3 (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 Н-indol-1 yl) acetyl) -4-fluoro-P4- ( 5,6,7,8 tetrahydronaphthalen2-yl) thiazol-2yl) pyrrolidine-2carboxamide

1- (2 - ((28.4K) -4-fluoro2- (4- (5,6,7,8tetrahydronaphthalen2-yl) thiazol-2ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4 -yl) -1Nindazol-3- 71 038607

carboxamide

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l- (2 - ((2S, 4R) -2- (2,3- ** 2.55 (B) 555 dimethyl-1 N-ind ol-5 ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyrid azin-4yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3- * 2.29 (B) 571 acetyl-5 - (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-M (2- (2oxooxazolid in-3 yl) phenyl) pyrrolidine -2-carboxamide l- (2 - ((2S, 4R) -4 ^ Top- * 1.63 (B) 573

2- (2- (2oxooxazolid in-3 yl) phenylcarbamoyl) p irrolidin-1 -yl) -2oxoethyl) -5 (pyridazine-4yl) -1Nindazole-3carboxamide (2S, 4R) -1- (2- (3- *** 2.63 (B) 521 acetyl-5- (pyrid azin4-yl) - lH-indol-1 yl) acetyl) -M- (5chloropyridin-3-yl) -4fluoropyrrolidine-2carboxamide

- (2 - ((2S, 4R) -2- (5- ** 2.34 (B) 523 chloropyridine-3ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridaz in-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3- *** 2.79 (B) 565 acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -K- (5bromopyr idin-3-yl) -4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (5- (3,4- * 3.61 (B) 640 dichlorophenyl) -1,3,4thiadiazole-2ylcarbamoyl ) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide

- 73 038607

carboxamide

1- (2 - ((28,4R) -4-φτop2- (2- (5-methyl-lHpyrazol-1yl) phenylcarbamoyl) p irrolidin-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) - 1Nindazol-3 (benzyloxy) cyclohexyl) -4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (4 (aminomethyl) phenyl rbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyrid azin-4-yl) -1Нindazol-32S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 Н-indol-1 yl) acetyl) -Н - ((18,28) 2S , 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -M- (2,2dimethyl-2,3oenzofuran-6-yl) -4fluoropyrrolidine-2carboxamide carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-M (2- (5-methyl-1Hpyrazol-1yl) phenyl ) pyrrolidine

-2-carboxamide

- (2 - ((28,4R) -2- (6 (benzyloxy) pyridin2-ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide

- 74 038607

l- (2 - ((2S, 4R) -2- (2,2dimethyl-2,3dihydrobenzofuran-6ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -H - ((1 S, 2S) 2 (benzyloxy) cyclopentyl) - 4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2 ((lS, 2S) -2 (benzyloxy) cyclohex silcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl ) -1Nindazole-3carboxamide l- (2 - ((2S, 4R) -4 ^ _TO p2 (methylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (lR , 3S, 5R) -2- (2- (3acetyl-5- (2methoxypyrimidin-5yl) -1 N-indol-1yl) acetyl) -M- (2'chlor-2-fluorobiphenyl3-yl) -2azabicyclo [3.1. 0] hexan-3 -carboxamide (lR, 3S, 5R) -2- (2- (3acetyl-5- (2methoxypyrimidin-5yl) -1 N-indol-1yl) acetyl) -M- (6bromopyridin-2-yl ) -2azabicyclo [3.1.0] hexan-3-carboxamide *** 2.92 (B) 558

3.33 (B) 584

3.38 (B) 600

2.10 (B) 426 *** 2.36 (A) 638 *** 1.91 (A) 591

- 75 038607

carboxamide carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-I methylpyrrolidine-2carboxamide

2S, 4R) -1- (2- (3acetyl-5- (2cyanopyrimid in-5 yl) -1 N-ind ol-1yl) acetyl) -M- (6bromopyridin-2-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3acetyl-5- (2fluoropyrimidin-5 yl) -1 N-ind ol-1yl) acetyl) -K- (6bromopyridin-2-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) - l- (2- (3acetyl-5- (2methylpyrimidin-5yl) -1 N-ind ol-1yl) acetyl) -M- (6bromopyridin-2-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2 - (3acetyl-5- (pyridazin4-yl) - Sh-indol-1 yl) acetyl) -M- (4 (aminomethyl) phenyl) 4-fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (lHindazol-6ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazol-32S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -X- (6chloropyrazin-2-yl) -4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (6chloropyrazine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) - 2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazol-3- 76 038607

1- (2 - ((2 S, 4R) -2- (5-bromopyr-idin-3 ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide l- ( 2 - ((2S, 4R) -4-φτop2- (4-fluoro-3- (6,7,8,9tetrahydro5Н [1,2,4] triazolo [4,3а] azepin-3 yl) phenylcarbamoyl) p irrolidine -1 -yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazol-3carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1H-ind ol-1 yl) acetyl) -4-fluoro-Н (4-fluoro-3- (6,7,8,9tetrahydro5Н [1,2,4] triazolo [4,3а] azepin-3 yl) phenyl) pyrrolidine - 2-carboxamide l- (2 - ((2S, 4R) -2- (3chlor-2 (trifluoromethyl) phenyl carbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole -3carboxamide l- (2 - ((2S, 4R) -2- (3- (2.4d ichl orphenyl) -1Hpyrazole-4ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazine-4 -yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-indol-1 yl) acetyl) -M- (3-chloro2- (1 Η-1,2,4-triazol-1 yl) phenyl) -4fluoropyrrolidine-2carboxamide ** 2.40 (B) 567

2.59 (H) 641

2.78 (H) 639

3.24 (B) 590

2.62 (B) 622

2.31 (B) 587

- 77 038607

l- (2 - ((2S, 4R) -2- (3chlor-2- (1H-1,2,4triazol-1yl) phenylcarbamoyl) 4-fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyrid azine- 4-yl) -1Nindazol-3carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-M ( 5-methyl-2 (trifluoromethyl) [1,2,4] triazole [1,5а] pyrimidine-7yl) pyrrolidine-2carboxamide l- (2 - ((2S, 4R) -4-φτop2- (2- (4- methyl-4Н1,2,4-triazol-Zyl) phenylcarbamoyl) p irrolidin-1 -yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- ( 3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (3 - (2chlorophenyl) -1,2,4thiadiazol-5-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3acetyl-5- (2chlorophenyl) -1Nindol-1 -yl) acetyl) -K (6-bromopyridine-2yl) -4fluoropyrrolidine-2carboxamide

- (2 - ((2 S, 4R) -2- (6bromopyridine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) - 5 - (2methyl pyrimidin- 5 1.94 (B) 589

2.46 (B) 610

2.42 (B) 569 *** 3.29 (B) 604 *** 2.45 (A) 599 *** 1.40 (A) 583 yl) - 1H-indazole-3 carboxamide

- 78 038607

fluorophenyl) 4,5,6,7tetrahydrobenzoHa] thiazol-7yl) pyrrolidine-2carboxamide

1- (2 - ((28,410-4-fluoro2- (2- (pyridin-2yl) isoindolin-4ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1 (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-K (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-K (2- (pyridin2yl) isoindolin-4yl) pyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (2methylpyrimidine-5yl) -1H-indole-1yl) acetyl) -M- (2 chloro-2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (2 chloro-2-fluorobiphenyl3-ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5- (2methylpyrimidin-5yl) -1 H-ind azole-3 carboxamide

- 79 038607

indazole-lcarboxamide fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -2- (5 bromopyrimidine-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-X (naphthalene-2yl) pyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-X1S, 2S -2hydroxycyclohexyl) pyrrolidine-2carboxamide l- (2 - ((2S, 4R) -4 ^ Topcarboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -Н- (5bromopyrimidine-2l- (2 - ((2S, 4R) - 4 ^ Top2- (2- (4-fluorophenyl) 4,5,6,7-tetrahydroenzoHa] thiazol-7ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridaz in-4-yl) -1Nindazole -3 (trifluoromethyl) benzo

a] isoxazole-3ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyrid azin-4-yl) -1H- 80 038607 l- (2 - ((2S, 4R) -4 ^ Top-

indazole-eindazol-j 2S, 4R) -l- (2- (5- (2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nacetamidopyrimidin5-yl) -3 -acetyl -1Nindol-1 -yl) acetyl) -M (6-bromopyridin-2fluoropyrrolidine-2carboxamide ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-32S, 4R) -l - (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (5- (3,4dichlorophenyl) -1,3,4thiadiazol-2-yl) -4fluoropyrrolidine -2carboxamide carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (5- (2chlorophenyl) -1,3,4thiadiazol-2- yl) -4fluoropyrrolidine-2carboxamide carboxamide l- (2 - ((2S, 4R) -2- (5- (2chlorophenyl) -1,3,4thiadiazole-2carboxamide l- (2 - ((2S, 4R) -2- ( 3- (2chlorophenyl) -1,2,4thiadiazole-52- (5-methyl-2 (trifluoromethyl) G1,2,41triazole [1,5а] pyrimidin-7ylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 ( pyridazin-4-yl) -1Н- 81 038607

carboxamide (2S, 4R) -l- (2- (3acetyl-5- (3chlorophenyl) -1Nindol-1-yl) acetyl) -N (6-bromopyridine-2fluoropyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (6methylpyridin-3 -yl) 1 N-ind ol-1carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro - ^ (8-methoxy-6methylchroman-4yl) pyrrolidine-2carboxamide l - (2 - ((2S, 4R) -4 ^ Top2- (1- (2-fluoro-5methylphenyl) -2oxopiperidin-3 ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl ) -1Nindazol-3yl) acetyl) -M- (6romopyridin-2-yl) -4fluoropyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (6methylpyridazin-4yl) -1 N-ind ol-1 yl) acetyl) -M- (2 chloro-2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide

1- (2 - ((2S, 4R) -44to _P 2- (8-methoxy-6methylchroman-4ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazol-3- 82 038607

carboxamide trifluorobenzoHa] G1,31d ioxol-52S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-H (1- ( 2-fluoro-5methylphenyl) -2oxopiperidin-3 yl) pyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -Н- (3-chlorocarboxamide

2S, 4R) -1- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-H (trifluoromethyl) phenyl) -4-fluoropyrrolidine2-carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (6oropyrazin-2-yl) -4fluoropyrrolidine-2carboxamide

1- 2- (2S, 4R) -2- (6romopyrazin-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazol-3yl) pyrrolidine-2carboxamide l- (2 - ((2S, 4R) -4 ^ Top2-2,2,6trifluorobenzo [alG1,31d ioxol-5ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazol-3- 83 038607

1- (2 - ((28.4Κ) -4-φτορ- * 2.77 (B) 538

2- (naphthalene-2ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (lR, 3S, 5R) -2- (2- (3- *** 1.74 (A) 573 acetyl-5- (2methylpyrimidin-5yl) -1 N-ind ol-1 yl) acetyl) -M- (6bromopyridin-2-yl) -2azabicyclo [3.1.0] hexan-3 -carboxamide ( lR, 3S, 5R) -2- (2- (3- *** 2.21 (A) 622 acetyl-5- (2methylpyrimidin-5yl) -1 N-ind ol-1 yl) acetyl) -M- (2 ' chloro-2-fluorobiphenyl3-yl) -2azabicyclo [3.1.0] hexan-3 -carboxamide (lR, 3S, 5R) -2- (2- (3- *** 1.71 (A) 560 acetyl-5- ( 2methylpyrimidin-5yl) -1 N-ind ol-1 yl) acetyl) -M- (3-chloro2-fluorobenzyl) -2azabicyclo [3.1.0] hexan-3 -carboxamide (2S, 4R) -l- (2- (3- *** 1.64 (A) 566 acetyl-5- (2methylpyrimidine-5yl) -1 N-ind ol-1 yl) acetyl) -M- (3-chloro2-fluorobenzyl) -4fluoropyrrolidine-2carboxamide (2S, 4R ) -l- (2- (3- *** 1.80 (A) 582 acetyl-5- (2methoxypyrimidin-5yl) -1 N-ind ol-1 yl) acetyl) -M- (3-chloro2-fluorobenzyl) - 4fluoropyrrolidine-2carboxamide

- 84 038607

(2S, 4R) -l- (2- (3- *** 1.53 (A) 535 acetyl-5- (2methylpyrimidin-5yl) -1 N-ind ol-1 yl) acetyl) -M- (6chloropyridin-2 -yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (5- (2- *** 1.95 (A) 671 acetamidopyrimidin5 -yl) -3 -acetyl-1Nindol-1 -yl) acetyl) - M (2'-chloro-2fluorobiphenyl-3-yl) -4fluoropyrrolidine-2carboxamide

1- (2 - ((2S, 4R) -44to _P - ** 3.38 (B) 503

2- (pyridin-2ylmethylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3- ** 1.51 (B ) 573 acetyl-5 - (pyrid azin4-yl) -1 H-ind ol-1 yl) acetyl) -4-fluoro-H (1- (1-methyl- 1Hpyrazol-4yl) piperid in-3 yl) pyrrolidine- 2carboxamide

1- (2 - ((28.4V) -4-fluoro- * 2.37 (B) 575

2- (1- (1-methyl- 1Hpyrazol-4yl) piperid in-3 ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R) - l- (2- (3- ** 2.10 (B) 526 acetyl-5 - (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-M (1H-indazol-6yl) pyrrolidine-2carboxamide

- 85 038607

143

144

145

(2S, 4R) -l- (2- (3- * 1.59 (B) 494 acetyl-5 - (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-H (( lR, 2R) -2hydroxycyclopentyl) pyrrolidine-2carboxamide (2S, 4R) -l- (2- (3- * 1.43 (B) 503 acetyl-5 - (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-H (6-hydroxypyridin2-yl) pyrrolidine-2carboxamide

1- (2 - ((28,4R) -4 ^ Top- * 1.66 (B) 496

2 - ((lR, 2R) -2hydroxycyclopentyl carbamoyl) pyrrolidi n-1 -yl) -2-oxoethyl) -5 (pyrid azin-4-yl) -1Nindazol-3

146

147

148

carboxamide

1- (2 - ((28,4R) -2- (3- (3- * 3.47 (B) 606 chlorophenyl) -1,2,4thiadiazole-5ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyrid azin-4-yl) -1Нindazole-3carboxamide (2S, 4R) -l- (2- (3- * 3.67 (B) 604 acetyl-5 - (pyridazin4-yl) -1 Н-ind ol-1 yl) acetyl) -I- (3 - (3 chlorophenyl) -1,2,4thiadiazol-5-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3- *** 1.49 (A) 580 acetyl-5- (6methylpyrrolidine-3 yl) -1 N-ind ol-1 yl) acetyl) -M- (6bromopyridin-2-yl) -4fluoropyrrolidine-2carboxamide

- 86 038607

(2S, 4R) -1- (2- (3 acetyl-5- (2methylpyrimidine-5yl) -1 N-ind ol-1yl) acetyl) -M- (2,2 'dichlorobiphenyl-3 yl) 4-fluoropyrrolidine- 2carboxamide (2S, 4R) -1- (2- (3 acetyl-5- (2methylpyrimidin-5yl) -1 N-ind ol-1yl) acetyl) -M- (2 'chloro-2,4', 5'trifluorobiphenyl -3 yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (3 acetyl-5- (6methylpyridin-3 -yl) 1 N-ind ol-1yl) acetyl) -K- (2 'chlorine -2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide

1- (2 - ((28.4K) -4-fluoro2- (2-methyl-3-oxo-3,4dihydro-2Hbenzo [b] [1,4] oxazin5ylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 (pyrid azin-4-yl) -1Nindazol-3carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-ind ol-1 yl) acetyl) - 4-fluoro-M (2-methyl-3-oxo-3,4 dihydro-2Hbenzo [L] [1,4] oxazin5-yl) pyrrolidine-2carboxamide

1- (2 - ((28.4K) -4-fluoro2- (4hydroxypyridin-2ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamidem *** 2.17 ( A) 644 *** 2.22 (A) 664 *** 1.91 (A) 627

1.97 (B) 573

2.31 (B) 571

2.17 (B) 505

- 87 038607

1- (2 - ((28,4Κ) -4-φτορ- *

2- (1- (1-methyl-1Hpyrazol-3-yl) -2oxopyrrolidin-3 ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R ) -l- (2- (3- * acetyl-5 - (pyrid azin4-yl) -1 N-ind ol-1 yl) acetyl) -M- (3 - (2,4dichlorophenyl) - 1Hpyrazol-4-yl ) -4fluoropyrrolidine-2carboxamide

1- (2 - ((28.4N) -4-fluoro- *

2- (pyridin-4ylmethylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide

1- (2 - ((2 8,4В) -4-fluoro 5 (pyridazin-4-yl) -1Nindazol-3carboxamide l- (2 - ((2S, 4R) -2- (l- (2chlorophenyl) -2oxopiperidin-3 ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) - 5 (pyrid az in-4-yl) -1Nindazol-3carboxamide (2 S, 4R) -1- (2- (3 acetyl-5- (pyrid azin4-yl) -1 N-indol-1 yl) acetyl ) -4-fluoro-H (1 - (2-fluorophenyl) -3 methyl- 1H-pyrazole-5yl) pyrrolidine-2carboxamide

1.19 (B) 575

2.98 (B) 620

0.37 (B) 503

2.49 (B) 586 ** 2.46 (B) 619 ** 2.36 (B) 584

- 88 038607

(2R, 4S) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-indol-1 yl) acetyl) -M- (1 - (2chlorophenyl) -2oxopiperid in-3-yl ) 4-fluoropyrrolidine-2carboxamide (2S, 4R) -1- (2- (3 acetyl-5 - (pyridazin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-M (1- ( 5-fluoro-3methylbenzofuran-2yl) ethyl) pyrrolidine 2-carboxamide (2S, 4R) -1- (2- (3 acetyl-5- (2methylpyrimidin-5yl) -1 N-ind azol-1 yl) acetyl) -M- (2'chloro-2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3acetyl-5- (2methyl pyrimidin-5 yl) -1 H-indol-1yl) acetyl) -M - (3 - (3 chloropyridin-2yl) -2fluorophenyl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3acetyl-5- (2methylpyrimid in-5 yl) -1 N-indazol-1 yl) acetyl) -M- (6bromopyridin-2-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-indol-1 yl) acetyl) -M- (2chloropyridin-3-yl) -4fluoropyrrolidine-2carboxamide *** 2.85 (B) 617 ** 3.52 (B) 586 *** 2.23 (A) 629 *** 1.65 (A) 629 *** 1.75 ( A) 580

2.26 (B) 521

- 89 038607

167

168

169

170

171

172

(2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-H (1- (1 -methyl-1NK pyrazole -3-yl) -2, Ν oxopyrrolidin-3 yl) pyrrolidine-2carboxamide

1- (2 - ((2 S, 4R) -2- (2cyclohexyl-5-oxo2,5-dihydro-1Hpyrazole-3ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl ) -1Nindazole-3carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-indol-1 yl) acetyl) -4-fluoro-M (5-methyl- 4-phenyl-1H-pyrazol-3yl) pyrrolidine-2carboxamide 1- (2 - ((28.4L) -4-fluoro2- (5-methyl-4-phenyl1H-pyrazol-3ylcarbamoyl) pyrrolidin-1-yl) -2oxoethyl) -5 (pyrid azin-4-yl) -1Nindazol-3carboxamide (2S, 4R) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1H-indol-1 yl) acetyl) -M - (1,5dimethyl-6-oxoν 4,5,6,7-tetrahydro-1Hpyrazolo [3.4b] pyridin-3-yl) -4fluoropyrrolidine-2carboxamide

1- (2 - ((28,4R) -4-φτop2 - ((lS, 2S) -2hydroxycyclohexyl carbamoyl) pyrrolidi n-1 -yl) -2-oxoethyl) -5 (pyrid azin-4-yl) - 1Nindazole-32.15 (B) 573

2.20 (H) 576

2.88 (B) 566

2.58 (H) 568

1.26 (B) 573

1.54 (B) 510 carboxamide

- 90 038607

173

174

175

178

176

177

(2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-M (3-methyl-2-oxo-2, 3 dihydropyrimidin-4yl) pyrrolidine-2carboxamide l- (2 - ((2S, 4R) -4-φτop2- (6hydroxypyridin-2ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazol -3carboxamide (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-K (5-hydroxypyridin2-yl) pyrrolidine- 2carboxamide l- (2 - ((2S, 4R) -4-φτop2- (5hydroxypyridin-2ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide (2S, 4R ) -l- (2- (3acetyl-5 - (pyrid azin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-K (4-hydroxypyridin-2yl) pyrrolidine-2carboxamide l- ( 2 - ((2S, 4R) -2- (4chloropyrimidin-2ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide

2.17 (B) 518

1.71 (H) 505

2.25 (B) 503

1.06 (B) 505

2.08 (B) 503

3.26 (B) 524

- 91 038607

indazole-j indazole-j carboxamide chloropyridine-j ylcarbamoyl) -4fluoropyrrolidin-1 yl) -2-oxoethyl) -5 (pyridazin-4-yl) -1Нcarboxamide

1- (2- (2S, 4R -4-fluoro 2- (S) -1- (5-fluoro-3methylbenzofuran-2yl) ethylcarbamoyl) pyrrolidin-1 -yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Н1- (2 - ((2S, 4R) -44to _P 2- (5-iodopyrimidin-2ylcarbamoyl) pyrroli din-1-yl) -2oxoethyl) -5 (pyridazin-4-yl) -1Nindazole-3carboxamide l- (2 - ((2S, 4R) -2- (2carboxamide (2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 H-ind ol-1 yl) acetyl) -M- (4chloropyrimidin-2-yl) 4-fluoropyrrolidine-2carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -4-fluoro-H (2- (4-methyl-4H-1, 2,4triazol-3yl) phenyl) pyrrolidine

-2-carboxamide

2S, 4R) -l- (2- (3acetyl-5- (pyridazin4-yl) -1 N-ind ol-1 yl) acetyl) -K- (5- (2chlorophenyl) -1,2,4 oxad iazol-3 -yl) -4fluoropyrrolidine-2carboxamide l- (2 - ((2S, 4R) -4 ^ Top2 - ((R) -l- (5 ^ _TO p-3methylbenzofuran-2yl) ethylcarbamoyl) pyrrolidin-1 -yl) - 2oxoethyl) -5 (pyridazin-4-yl) -1Nindazol-3- 92 038607

(2S, 4R) -l- (2- (3acetyl-5- (2 *** 1.79 (A) 630 hydroxypyrimidin5 -yl) -1 N-ind ol-1 yl) acetyl) -M- (2'chloro- 2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3- *** 2.16 (A) 687 acetyl-5- (2- (2methoxyethylamino) pyrimidin-5-yl) - 1Nindol-1-yl) acetyl) -M (2'-chloro-2 fluorobiphenyl-3-yl) -4fluoropyrrolidine-2carboxamide (2S, 4R) -l- (2- (3- *** 2.08 (A) 643 acetyl -5- (2 (methylamino) pyrimid in-5 -yl) -1 N-ind ol-1 yl) acetyl) -M- (2'chlor-2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide (lR, 3S, 5R) -2- (2- (3acetyl-5- (2methylpyrimidine-5yl) -1 N-ind azol-1 yl) acetyl) -M- (2'chlor-2-fluorobiphenyl3-yl) -2azabicyclo [3.1.0 ] hexan-3 -carboxamide (lR, 3S, 5R) -2- (2- (3acetyl-5- (2methylpyrimidine-5yl) -1 N-ind azol-1 yl) acetyl) -M- (6bromopyridine-2- yl) -2azabicyclo [3.1.0] hexan-3 -carboxamide (2S, 4R) -1- (2- (3 acetyl-5- (2 (trifluoromethyl) pyrim idin-5-yl) -1 H-ind ol1 -yl) acetyl) -M- (2chloro-2-fluorobiphenyl3-yl) -4fluoropyrrolidine-2carboxamide

2.37 (A) 623

1.90 (A) 574

2.64 (A) 682

- 93 038607

Example 7. Human Factor D Analysis.

Human Factor D (purified from human serum, Complement Technology, Inc.) at a final concentration of 80 nM is incubated with test compound at various concentrations for 5 minutes at room temperature in 50 mM Tris, 1M NaCl, pH 7.5. Synthetic substrate ZL-Lys-SBzl and DTNB (Ellman's reagent) are added to a final concentration of 100 μM each. The increase in color is recorded at OD ₄₀₅ nm on a microplate in kinetic mode for 30 min with 30 second time points on a spectrofluorimeter. _{IC 50} values are calculated by non-linear regression from percent inhibition of factor D complement activity versus test compound concentration.

Example 8. Analysis of hemolysis.

Hemolysis assays have been previously described by G. Ruiz-Gomez, et al., J. Med. Chem. (2009) 52: 6042-6052. In a red blood cell (RBC) assay, rabbit erythrocytes (purchased from Complement Technologies) are washed using GVB Buffer (0.1% gelatin, 5 mM Veronal, 145 mM NaCl, 0.025% NaN ₃ , pH 7.3) plus 10 mM the final Mg-EGTA. The cells are used at a concentration of 1 x 10 ⁸ cells / ml. Prior to hemolysis assay, the optimal concentration of Normal Human Serum (NHS), which is required to achieve 100% lysis of rabbit red blood cells, is determined by titration. NHS (Complement Technologies) was incubated with the inhibitor for 15 min at 37 ° C, rabbit erythrocytes in buffer were added and incubated for another 30 min at 37 ° C. The positive control (100% lysis) consists of serum and RBC and the negative control (0% lysis) contains only Mg-EGTA buffer and RBC. Samples were centrifuged at 2000 rpm for 5 min and supernatants were collected. The absorbance of the supernatant is measured at 405 nm using a UV / visible spectrophotometer. The percentage of lysis in each sample is calculated relative to the positive control (100% lysis).

Example 9. Non-limiting Examples of Compounds of Formula I.

table 2

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- 97 038607

- 98 038607

- 99 038607

- 100 038607

- 101 038607

- 102 038607

- 103 038607

- 104 038607

- 105 038607

- 106 038607

- 107 038607

- 108 038607

- 109 038607

- 110 038607

- 111 038607

- 112 038607

- 113 038607

- 114 038607

- 115 038607

- 116 038607

- 117 038607

- 118 038607

- 119 038607

- 120 038607

- 121 038607

- 122 038607

- 123 038607

This description has been disclosed with reference to embodiments of the invention. However, it will be apparent to one of ordinary skill in the art that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. Accordingly, the description is to be considered in an illustrative and not restrictive sense, and all such modifications are to be included within the scope of the invention.

Part B. Inclusion of the text of priority documents.

In order to provide full priority right to previously filed priority applications, the text of US Provisional Application 62 / 046,783, filed September 5, 2014, is incorporated herein by reference and the relevant portions are reproduced below. Where terms overlap, the term used in the claims shall be deemed to refer to the terms provided in Part A above, unless otherwise indicated or clear from the text of the claim, however, the entire disclosure is deemed to be part of the invention for all disclosed purposes. ...

The present invention relates to compounds of formula I

and their pharmaceutically acceptable salts.

In formula I, the variables, for example. A, B, L, X ¹ , X ² , Q ¹ , Q ² and Q ³ have the following meanings:

Q ¹ is N (R1) or C (R1R1);

Q ² is C (R ² R ² '), C (R ² R ² ') -C (R ² R ² ') or C (R ² R ² ') O;

Q ³ represents N (R ³ ), S or C (R ³ R ³ ');

(a) X ¹ and X ^{2 are} independently N or CH, or (b) X ¹ and X ² together are C = C; R ¹ , R ¹ , R ² , R ² , R ³ and R ^{3 are} independently selected at each occurrence from (c) and (d):

(c) hydrogen, halogen, hydroxyl, nitro, cyano, amino, C ₁ -C ₆ -αalkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ -alkynyl, C ₂ - C ₆ -alkanoyl, C ₁ -C ₆ -thioalkyl, hydroxyC1-C ₆ -alkyl, aminoC1-C ₆ -alkyl, -C ₀ -C ₄ -alkyl NR ⁹ R ¹⁰ , -C (O) OR ⁹ , -OC (O) R ⁹ , -NR ⁹ C (O) R ¹⁰ , -C (O) NR ⁹ R ¹⁰ , -OC (O) NR ⁹ R ¹⁰ , -NR ⁹ C (O) OR ¹⁰ , C1-C2 haloalkyl and C1-C2-haloalkoxy, where R ⁹ and R ^{10 are} independently selected at each occurrence from hydrogen, C1-C6-alkyl and (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl;

(d) -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl) and -O-C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl).

In addition, any one of the following rings (e), (f), (g), (h), (i), or (j) may be present:

(e) R ¹ and R ¹ or R ³ and R ³ can be taken together to form a 3-6 membered carbocyclic spiro ring or a 3-6 membered heterocyclic spiro ring containing 1 or 2 heteroatoms independently selected from N , O or S;

(f) R ² and R ² can be taken together to form a 3-6 membered carbocyclic spiro ring, (g) R ² and R ² can be taken together to form a 3-6 membered heterocyclic spiro ring, each of the spiro rings ( e), (f) and (g) is unsubstituted or substituted with one or more halogen or methyl substituents;

(h) R ¹ and R ² can be taken together to form a 3-membered carbocyclic ring;

(i) R ¹ and R ² can be taken together to form a 4-6 membered carbocyclic ring or a 46 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from N, O and S.

(j) R ² and R ³ , when bonded to adjacent carbon atoms, can be taken together to form a 36 membered carbocyclic ring or a 3-6 membered heterocyclic ring; each ring (g), (h) and (i) may be unsubstituted or substituted with 1 or more substituents independently selected from halogen, hydroxyl, cyano, —COOH, C ₁ -C ₄ -αalkyl, C ₂ -C ₄ -alkenyl C1-C ₄ alkoxy, C ₂ -C ₄ alkanoyl, _{gidroksiS1-C4} alkyl, (mono- and di-C ₁ -C ₄ alkylamino) C ₀ -C ₄ alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ cycloalkyl), -O-C ₀ -C ₄ -αalkyl (C ₃ -C ₇ -cycloalkyl), C1-C ₂ -halogenoalkyl and C ₁ -C ₂ -halogenoalkoxy;

A is a heterocyclic group selected from (k) and (l), where (k) is

and (l) is

124 038607

X4 is B (OH) and Y is CHR ⁹ ; or X4 is CHR ⁹ and Y is B (OH).

R4 is (m) or (n):

(m) -CHO, -CONH2 or _C2-C6 alkanoyl;

(n) hydrogen, -SO2NH2, -C (CH2) F, -CH (CF ₃ ) NH2, C ₁ -C ₆ -alkyl, -C ₀ -C4-alkyl (C ₃ -C ₇ -cycloalkyl), -C (O) C ₀ -C ₂ -alkyl (C ₃ -C ₇ -cycloalkyl),

each of R4 other than hydrogen, -CHO and -CONH2 is unsubstituted or substituted by one or more of amino, imino, halogen, hydroxyl, cyano, cyanimino, C ₁ -C ₂ -alkyl, C ₁ -C ₂ -alkoxy, - C ₀ -C ₂ alkyl (mono- and _di-C1-C4 alkylamino) C1-C ₂ -haloalkyl and C ₁ -C ₂ -galogenalkoksi;

R ⁵ and R ^{6 are} independently selected from (o) and (p):

(o) -CHO, -C (O) NH2, -C (O) NH (CH3) or C2-C6 alkanoyl;

(p) hydrogen, hydroxyl, halogen, cyano, nitro, -COOH, -SO2NH2, vinyl, C ₁ -C ₆ -alkyl, C ₂ -C _6- alkenyl, C ₁ -C _6- alkoxy, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -C (O) C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -P (O) (OR ⁹ ) 2, -OC (O ) R ⁹ , —C (O) OR ⁹ , —C (O) N (CH2CH ₂ R ⁹ ) (R ¹⁰ ), —NR ⁹ C (O) R ¹⁰ , phenyl or 5-6 membered heteroaryl.

Each R ⁵ and R ⁶ other than hydrogen, hydroxyl, cyano and -COOH is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, imino, cyano, cyanoimino, C ₁ -C ₂ -alkyl, C1 -C ₄ -alkoxy, -C ₀ -C ₂ alkyl (mono- and _di-C1-C4 alkylamino), C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ -gαlogenαlkoksi.

R ⁶ is hydrogen, halogen, hydroxyl, C ₁ -C ₄ alkyl, or _{C 1 -C 4} alkoxy; or R ⁶ and R ⁶ can be taken together to form an oxo, vinyl or imino group.

R ⁷ is hydrogen, C ₁ -C ₆ -alkyl or -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl.

R ⁸ and R ^{8 are} independently selected from hydrogen, halogen, hydroxyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, and ( _{C 1 C 4} alkylamino) C ₀ -C ₂ alkyl, or R ⁸ and R ⁸ , taken together form an oxo group.

R ¹⁶ represents 0 or 1 or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -αalkyl, C ₂ -C ₆ -αalkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, -C ₀ -C ₄ alkyl (mono- and di- _{C 1} -C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C _{1 -C 2} -haloalkyl and C1-C2 haloalkoxy.

R ¹⁹ represents hydrogen, C1-C6-alkyl, C2-C6-α-alkenyl, C2-C6-alkanoyl, -SO2C1-C6-alkyl, (mono- and di-C1-C6-alkylamino) C1-C4-alkyl, - C0-C4 alkyl (C3-C7 cycloalkyl) each of R ¹⁹ other than hydrogen is substituted with 0 or 1 or more substituents independently selected from halogen, hydroxyl, amino, -COOH and -C (O) OC1- C4 alkyl.

X ¹¹ represents N or CR ¹¹ .

X ¹² represents N or CR ¹² .

X ¹³ represents N or CR ¹³ .

X ¹⁴ is N or CR ¹⁴ .

X ¹⁵ represents N or CR ¹⁵ .

At most 2 of X ¹¹ , X ¹² , X ¹³ , X ¹⁴ and X ¹⁵ are N.

R ¹¹ , R ¹⁴ and R ^{15 are} independently selected at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O (PO) (OR ⁹ ) 2, - (PO) (OR ⁹ ) 2, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -αalkoxy, C ₁ -C ₆ thioalkyl, -C ₀ -C ₄ -alkyl (mono- and di-C1- C ₆ alkylamino), -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ - 125 038 607 alkoxy (C ₃ -C ₇ cycloalkyl) C1-C2 haloalkyl and C1-C2-haloalkoxy.

R ¹² and R ^{13 are} independently selected from (q), (r) and (s):

(q) hydrogen, halogen, hydroxyl, nitro, cyano, amino, -COOH, C ₁ -C ₂ -haloalkyl and C1-C2 haloalkoxy, (r) C ₁ -C ₆ -alkyl, C ₂ -C _6- alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, C ₂ -C _6- alkenyloxy, -C (O) OR ^{B 9} , C1-C6thioalkyl, -C0-C4-alkyl NR ⁹ R ^{10 * * *} , -C (O) NR ⁹ R ¹⁰ , -SO2R ⁹ R ¹⁰ , -SO2NR9R ¹⁰ , -OC (O) R ⁹ and -C (NR ⁹ ) NR ⁹ R ¹⁰ , each of (r) is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH2 C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ -haloalkoxy, and each of (r) is also optionally substituted with one substituent selected from phenyl and a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; wherein phenyl or a 47-membered heterocycle is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ - alkanoyl, C ₁ -C ₆ -alkoxy, (mono- and di-C ₁ -C ₆ -alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -alkyl ether, -C ₀ -C ₄ -alkyl) ( C ₃ -C ₇ cycloalkyl), C ₁ -C ₂ haloalkyl and C 1 -C 2 haloalkoxy;

(s) -C ₂ -C ₆ -alkynyl, -C ₂ -C ₆ -alkynyl R ²³ , C2-C6-alkanoyl, -JC3-C7-cycloalkyl, -B (OH) 2, -JC (O) NR ⁹ R ²³ , -JOSO2OR ²¹ , -C (O) (CH2) i-4S (O) R ²¹ , -O (CH2) i-4S (O) NR ²¹ NR ²² , JOP (O) (OR ²¹ ) (OR ²² ), -JP (O) (OR ²¹ ) (OR ²² ), -JOP (O) (OR ²¹ ) R ²² , -JP (O) (OR ²¹ ) R ²² , JOP (O) R ²¹ R ²² , -JP (O) R ²¹ R ²² , -JSP (O) (OR ²¹ ) (OR ²² ), -JSP (O) (OR ²¹ ) (R ²² ), -JSP (O) (R ²¹ ) (R ²² ), -JNR ⁹ P (O) (NHR ²¹ ) (NHR ²² ), -JNR ⁹ P (O) (OR ²¹ ) (NHR ²² ), -JNR ⁹ P (O) (OR ²¹ ) (OR ²² ), -JC (S) R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S (O) NR ¹⁰ R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR ⁹ COR ²² , -O (CH2) 1-4SO2NR ²¹ R ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC (O) NR ²¹ SO2R ²² , -JC (NH2) NR ²² , -JC (NH2) NS (O) 2R ²² , -JOC (O ) NR ²¹ R ²² , -JOC (O) NR ²⁴ R ²⁵ , -JNR ⁹ C (O) OR ¹⁰ , -JNR ⁹ C (O) OR ²³ , -JNR ²¹ OC (O) R ²² , - (CH2) _1-4 C (O) NR ²¹ R ²² , -JC (O) R ²⁴ R ²⁵ , -JNR ⁹ C (O) R ²¹ , -JC (O) R ²¹ , -JNR ⁹ C (O) NR ⁹ R ¹⁰ , -JNR ⁹ C (O) NR ¹⁰ R ²³ , -JNR ⁹ C (O) NR ²⁴ R ²⁵ , -CCR ²¹ , - (CH2) 1-4OC (O) R ²¹ , -JC (O) OR ²³ , -C2-C4-alkyl R ^{2 3} , —C2 — C4 alkenyl R ²³ , —C2 — C4 alkynyl R ^23, and —J paracyclophane.

J is independently selected at each occurrence from a covalent bond, C1-C ₄ -alkylene, -OC ₁ -C ₄ -alkylene, C ₂ C ₄ alkenyl and C ₂ -C ₄ -alkynyl.

R ²¹ and R ^{22 are} independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C1-C6 alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, -C1-C4 alkylOC (O) OC1-C ₆ -alkyl, -C ₁ -C ₄ -alkylOS (O) C ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkylC (O) OC ₁ -C ₆ -alkyl, (4-7 membered heterocycloalkyl) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S.

R ^{23 is} independently selected at each occurrence from (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, (4-7 membered heterocycloalkyl) C ₀ -C ₄ - alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected of N, O and S.

R ²⁴ and R ²⁵ taken together with the nitrogen atom to which they are attached form a 4 to 7 membered monocyclic heterocycloalkyl group or a 6 to 10 membered bicyclic heterocyclic group having fused, spiro or bridged rings.

Each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B (OH) ₂ , -Si (CH ₃ ) ₃ , -COOH, -CONH2 , -P (O) (OH) ₂ , C ₁ -C ₆ -alkyl, C1-C ₆ -alkoxy, -C ₀ -C ₂ -alkyl (mono- and di-C1-C ₄ -alkylamino), C1- _{C 6} alkyl ether, C ₁ -C ₄ alkylamino, C 1 -C 4 hydroxylalkyl, C ₁ -C ₂ haloalkyl and _{C 1 -C 2} haloalkoxy.

L is either (t), (u) or (v):

(t) is a group of the formula

where R ¹⁷ is hydrogen or C ₁ -C ₆ -alkyl, and R ¹⁸ and R ¹⁸ 'are independently selected from hydrogen, halogen and methyl; and m is 0,1,2 or 3; and (u) is a bond, (v) or a group of the formula

B is a monocyclic or bicyclic carbocyclic or carbocyclic-oxy group, or a monocyclic, bicyclic or tricyclic heterocyclic group having 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, and 4 to 7 ring atoms per ring or B represents a C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl group.

Each of B is unsubstituted or substituted with one or more substituents independently selected from (w) and (x), and 0 or 1 substituent selected from (y) and (z):

- 126 038607 (w) halogen, hydroxyl, -COOH, cyano, C1-C ₆ -alkyl, C2-C ₆ -alkanoyl, C1-C ₆ -alkoxy, -C ₀ -C ₄ -alkyl

NR9R ¹⁰ , —SO2R ⁹ , C ₁ -C ₂ haloalkyl and C ₁ -C ₂ haloalkoxy;

(x) nitro, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -thioalkyl, -JC ₃ -C ₇ -cycloalkyl, -B (OH) ₂ , -JC (O) NR ⁹ R ²³ , -JOSO2OR ²¹ , -C (O) (CH2) 1-4S (O) R ²¹ , -O (CH2) i-4S (O) NR ²¹ R ²² , -JOP (O) (OR ²¹ ) (OR ²² ), -JP (O) (OR ²¹ ) (OR ²² ), -JOP (O) (OR ²¹ ) R ²² , -JP (O) (OR ²¹ ) R ²² , JOP (O) R ²¹ R ²² , -JP (O) R ²¹ R ²² , -JSP (O) (OR ²¹ ) (OR ²² ), -JSP (O) (OR ²¹ ) (R ²² ), -JSP (O) (R ²¹ ) (R ²² ), -JNR ⁹ P (O) (NHR ²¹ ) (NHR ²² ), -JNR ⁹ P (O) (OR ²¹ ) (NHR ²² ),

-JNR ⁹ P (O) (OR ²¹ ) (OR ²² ), -JC (S) R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S (O) NR ¹⁰ R ²² , -JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR ⁹ COR ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , -JC (O) NR ²¹ SO2R ²² , -JC (NH2) NR ²² , -JC (NH2) NS (O) 2R ²² ,

-JOC (O) NR ²¹ R ²² , -JNR ²¹ C (O) OR ²² , -JNR ²¹ OC (O) R ²² , - (CH2) 1-4C (O) NR ²¹ R ²² , -JC (O) R ²⁴ R ²⁵ , -JNR ⁹ C (O) R ²¹ , -JC (O) R ²¹ , -JNR ⁹ C (O) NR ¹⁰ R ²² , -CCR ²¹ , - (CH2) 1-4OC (O) R ²¹ and -JC (O) OR ²³ ; each of (x) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B (OH) ₂ , -Si (CH ₃ ) ₃ , -COOH, -CONH2 , -P (O) (OH) ₂ , C ₁ -C ₆ -alkyl, C _{1 -C 6} -alkoxy, -C ₀ -C ₂ -alkyl (mono- and di-C ₁ -C ₄ -alkulamino), C -alkulefira ₁ -C _6, C 1 C ₄ alkylamino, Q-Qgidroksilalkila, C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ -galogenalkoksi;

(y) naphthyl, naphthyloxy, indanyl, (4-7 membered heterocycloalkyl) C ₀ -C ₄ -alkyl containing 1 or 2 heteroatoms selected from N, O and S, and a bicyclic heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and containing from 4 to 7 ring atoms in each ring; each of (y) is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, (mono and di-C ₁ -C ₆ -alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -alkylether, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl ), -SO2R ⁹ S2galogenalkila C1 and _C1-C2 -galogenalkoksi; and (z) tetrazolyl, (phenyl) C ₀ -C ₂ -alkyl, (phenyl) C 1 -C ₂ -alkoxy, phenoxy and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, B and S, each of (z) unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, (mono- and di-C ₁ -C ₆ alkylamino) C ₀ -C ₄ -alkyl, C ₁ -C ₆ -alkyl ether, -C ₀ -C ₄ -alkyl ( C ₃ -C ₇ -cycloalkyl), -SO2R ⁹ , -OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ , Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , C ₁ -C ₂ -halogenoalkyl and C1- C ₂ -halogenoalkoxy.

Either X ² is nitrogen or at least one of (d), (e), (g), (i), (l), (n), (p), (s), (v), ( x) and (y) is present. Also disclosed is a pharmaceutical composition comprising a compound or salt of Formula I together with a pharmaceutically acceptable carrier.

Also disclosed are methods of treating or preventing disorders mediated by the complement of the factor D cascade, such as age-related macular degeneration and retinal degeneration, comprising administering a therapeutically effective amount of a compound or salt of Formula I to a patient in need of such treatment.

Priority document terminology

Connections are described using standard nomenclature. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless clearly contradicted by context, each compound name includes the free acid or free base form of the compound, as well as all pharmaceutically acceptable salts of the compound.

The term Formula I encompasses all compounds that satisfy Formula I, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts of these compounds. Formula I includes all subgeneric groups of Formula I, such as Formula IA and IB, and also includes pharmaceutically acceptable salts of the compounds of Formula I, unless clearly contradicted by the context in which the phrase is used.

The terms a and an do not mean limiting the amount, but rather mean the presence of at least one of those described. The term either means and / or. An open transition phrase containing comprises an intermediate transition phrase consisting essentially of and a closed phrase consisting of. Claims made by one of these three transitional phrases or an alternative transitional phrase, such as containing or inclusive, may be written by means of some other transitional phrase, unless explicitly excluded by the context or art. Specification of ranges of values is intended only to be used as an abbreviated way of referring individually to each individual value falling within the range, unless otherwise indicated herein, and each individual value is included in the description as if it were individually indicated herein. The ends of all ranges are included within the range and are independently combined. All methods described herein can be performed in a suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any or all examples or illustrative expressions (eg, such as) is intended only to better illustrate the invention and is not intended to limit the scope of the invention unless otherwise stated. None of the expressions in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless otherwise indicated, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Compounds of Formula I include all compounds of Formula I having isotopic substitutions at any position. Isotopes include those atoms that have the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include ^P C, ¹³ C, and ¹⁴ C. Although the compounds of Formula I require moderate to high levels of deuteration (replacement of hydrogen with deuterium) at certain positions, Formula I includes including embodiments in which other positions are enriched in isotopes.

Active agent means a compound (including a compound described herein), an element or a mixture that, when administered to a patient, alone or in combination with another compound, element or mixture, leads directly or indirectly to a physiological effect on the patient. An indirect physiological effect can occur through a metabolic or other indirect mechanism.

A dash (-) that is not between two letters or characters is used to indicate the attachment point of the surrogate. For example, - (C = O) NH2 is carbon-bonded to the keto (C = O) group.

Alkyl is a branched or linear saturated aliphatic hydrocarbon group having a specified number of carbon atoms, typically from 1 to about 12 carbon atoms. The term C ₁ -C ₆ -alkyl as used herein indicates an alkyl group having from 1, 2, 3, 4, 5 or 6 carbon atoms. Other embodiments include alkyl groups having 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 or 2 carbon atoms, e.g., C ₁ -C ₈ alkyl, C ₁ -C ₄ alkyl, and C ₁ - C ₂ -alkyl. When C ₀ -Cn alkyl is used herein in combination with another group, for example (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl or -C ₀ -C ₄ alkyl (C ₃ -C ₇ cycloalkyl ), then the specified group, in this case cycloalkyl, is either directly linked by a single covalent bond (C0alkyl), or is attached by an alkyl chain having the indicated number of carbon atoms, in this case 1, 2, 3 or 4 carbon atoms. Alkyls can also be attached via other groups such as heteroatoms such as in —O — C ₀ —C ₄ alkyl (C ₃ —C ₇ cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, tert-butyl, npentyl, and sec-pentyl.

Alkenyl is a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds that can occur at any stable point along the chain having the indicated number of carbon atoms. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

Alkynyl is a straight or branched aliphatic hydrocarbon group having one or more double carbon-carbon triple bonds that can occur at any stable point along the chain having the indicated number of carbon atoms.

Alkylene means a divalent saturated hydrocarbon. Alkylenes include groups having from 1 to 8 carbon atoms, from 1 to 6 carbon atoms, or the indicated number of carbon atoms, for example, C ₁ -C ₄ alkylene.

Alkenylene is a divalent hydrocarbon having at least one carbon-carbon double bond. Alkenylenes include groups having 2 to 8 carbon atoms, 2 to 6 carbon atoms, or the indicated number of carbon atoms, for example C ₂ -C ₄ alkenylene.

Alkynylene is a divalent hydrocarbon having at least one carbon-carbon triple bond. Alkynylenes include groups having from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or the indicated number of carbon atoms, for example, C2-C4 alkynylene.

Alkoxy means an alkyl group as defined above with the indicated number of carbon atoms covalently bonded to the group it substitutes via an oxygen bridge (—O—). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy and 3-methylpentoxy. Likewise, an alkylthio or thioalkyl group is an alkyl group as defined above with the indicated number of carbon atoms covalently linked to the group it substitutes via a sulfur bridge (—S—).

Alkenyloxy is an alkenyl group, as defined above, with the indicated number of carbon atoms, covalently linked to the group it replaces via an oxygen bridge (—O—).

Alkanoyl is an alkyl group, as defined above, with the indicated number of carbon atoms, covalently linked to the group it replaces through a carbonyl bridge (C = O). The carbon of the carbonyl group is one of the carbon atoms, that is, C ₂ alkanoyl is a CH3 (C = O) - group.

An alkyl ether is an alkyl group, as defined herein, covalently linked to the group it substitutes via an ester bond. The ester bond can be in one orientation or another, for example, a group of the formula -O (C = O) alkyl or a group

- 128 038607 of the formula - (C = O) Oalkyl.

A carbocyclic group is a saturated, unsaturated or partially unsaturated (eg aromatic) group containing all carbon ring atoms. A carbocyclic group typically contains 1 ring of 3 to 7 carbon atoms or 2 fused rings each containing 3 to 7 carbon atoms. A carbocyclic ring is a saturated, unsaturated or partially unsaturated (eg aromatic) ring containing carbon ring atoms. The carbocyclic ring typically contains 1 ring of 3 to 7 carbon atoms, or the carbocyclic group may contain 1 carbocyclic ring or 2 fused carbocyclic rings, each of which contains 3 to 7 carbon atoms. Examples of carbocyclic rings include phenyl, cyclohexenyl, cyclohexyl, and cyclopropyl rings.

A carbocyclic oxy group is a monocyclic carbocyclic ring or mono- or bicyclic carbocyclic group, as defined above, attached to the group it substitutes via an oxygen, —O—, linker.

Cycloalkyl is a saturated hydrocarbon ring group having a specified number of carbon atoms. Monocyclic cycloalkyl groups generally have from 3 to about 8 carbon atoms in the ring, or from 3 to 7 (3, 4, 5, 6, or 7) carbon atoms in the ring. Cycloalkyl substituents may be pendant from a substituted nitrogen atom or carbon atom, or a substituted carbon atom, which may have two substituents, may have a cycloalkyl group that is attached as a spiro group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Haloalkyl means both branched and unbranched alkyl groups having the specified number of carbon atoms, substituted by 1 or more halogen atoms, up to the maximum number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

Haloalkoxy means a haloalkyl group as defined herein attached via an oxygen bridge (oxygen from an alcohol radical).

Hydroxyalkyl is an alkyl group, as previously described, substituted with at least one hydroxyl substituent.

Aminoalkyl is an alkyl group, as previously described, substituted with at least one amino substituent. Halo or halogen is any of fluorine, chlorine, bromine and iodine atoms.

Aryl are aromatic groups containing only carbon in the aromatic ring or rings. Typical aryl groups contain 1 to 3 separate, fused or pendant rings and 6 to about 18 ring atoms, with no heteroatom as a ring member. When indicated, such aryl groups may be further substituted with carbon atoms or non-carbon atoms or groups. Such substitution may include condensing with a 5 to 7 membered saturated cyclic group which optionally contains 1 or 2 heteroatoms independently selected from N, O and S to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and biphenyl.

A heterocyclic ring is a saturated, unsaturated or partially unsaturated (e.g. aromatic) ring containing from 1 to 4 heteroatoms in the ring independently selected from N, O and S, or when indicated, N, O, S and B, with the remainder carbon ring atoms. The heterocyclic group may contain 1 heterocyclic ring, 1 ring with 3 to 7 ring atoms, or 2 fused rings, each of which contains 3 to 7 ring atoms, with at least one ring that is a heterocyclic ring.

A heterocyclyloxy group is a monocyclic heterocyclic ring or bicyclic heterocyclic group, as previously described, linked to the group it substitutes via an oxygen, —O—, linker.

Heteroaryl is a stable monocyclic aromatic ring containing the indicated number of ring atoms, which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms selected from N, O and S, with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5 to 7-membered aromatic ring containing 1 to 3, or in some embodiments, 1 to 2 heteroatoms selected from N, O and S, with the remaining ring the atoms are carbon. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, the bicyclic heteroaryl groups are 9 to 10 membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5-7 membered aromatic ring is fused to a second aromatic or non-aromatic ring. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. Especially preferred

- 129 038607 so that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include, but are not limited to, oxazolyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo [d] oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxinil, furanyl, imidazolyl, indolyl, and isoxazolyl. Heteroaryloxy is a heteroaryl group, as described, linked to the group it replaces through an oxygen bridge.

Heterocycloalkyl is a saturated ring group having 1,2,3 or 4 heteroatoms independently selected from N, S and O, with the remaining ring atoms being carbon. Monocyclic heterocycloalkyl groups generally have 3 to 8 ring atoms or 4 to 6 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolinyl.

The term mono- and / or dialkylamino indicates secondary or tertiary alkylamino groups, where the alkyl groups are independently selected from alkyl groups as defined herein containing the indicated number of carbon atoms. The point of attachment of the alkylamino group is at nitrogen. Examples of mono and dialkylamino groups include ethylamino, dimethylamino, and methylpropylamino.

The term substituted as used herein means that any one or more hydrogen atoms on a specified atom or group are replaced by a selected one from the specified group, provided that the normal valence of the specified atom is not exceeded. When the substituent is oxo (i.e., = O), then 2 hydrogen atoms on the atom are replaced. When the oxo group is replaced by aromatic moieties, the corresponding partially unsaturated ring is replaced by the aromatic ring. For example, a pyridyl group substituted with an oxo group is pyridone.

Combinations of substituents and / or variables are only permissible if such combinations result in stable compounds or useful synthesis intermediates. A stable compound or stable structure means a compound that is stable enough to withstand isolation from the reaction mixture and subsequent processing into an effective therapeutic agent. Unless otherwise indicated, substituents are named in the basic structure. For example, it should be understood that when aminoalkyl is indicated as an optional substituent, the point of attachment of that substituent to the core structure is at the alkyl portion.

Suitable groups that may be present at a substituted or optionally substituted position include, but are not limited to, eg, halogen; cyano; hydroxyl; nitro; azido; alkanoyl (including a C ₂ -C ₆ alkanoyl group); carboxamide; alkyl groups (including cycloalkyl groups) having from 1 to about 8 carbon atoms or from 1 to about 6 carbon atoms; alkenyl and alkynyl groups, including groups having one or more unsaturated bonds and from 2 to about 8 or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen bonding and from 1 to about 8 or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups, including those having one or more thioether linkages and from 1 to 8 carbon atoms or from 1 to 6 carbon atoms; alkylsulfinyl groups, including those having one or more sulfinyl bonds and from 1 to about 8 carbon atoms or from 1 to about 6 carbon atoms; an alkylsulfonyl group including having one or more sulfonyl linkages and from 1 to about 8 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups, including groups having one or more N atoms and from 1 to about 8, or from 1 to about 6 carbon atoms; aryl containing 6 or more carbon atoms and one or more rings (eg, phenyl, biphenyl, naphthyl, or the like, each ring being either substituted or unsubstituted aromatic); arylalkyl having 1 to 3 separate or fused rings and 6 to about 18 carbon atoms in the ring with benzyl exemplifying an arylalkyl group; arylalkoxy having from 1 to 3 separate or condensed rings and from 6 to about 18 carbon atoms in the ring with benzyloxy exemplifying an arylalkoxy group; or a saturated, unsaturated or aromatic heterocyclic group having 1 to 3 separate or fused rings with 3 to about 8 ring members and one or more N, O or S atoms, e.g. coumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl , pyrazinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, triazinyl, oxazolyl, isoxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl, and piperazinyl. Such heterocyclic groups can be further substituted with, for example, hydroxy, alkyl, alkoxy, halogen and amino. In some embodiments, the optionally substituted includes one or more substituents independently selected from halogen, hydroxyl, amino, cyano, —CHO, —COOH, —CONH2, Cl — C ₆ alkyl, C ₂ -C ₆ alkenyl, Cl -C ₆ -alkoxy, C ₂ -C ₆ -alkanoyl, Cl-C ₆ -alkylether, (mono- and di-C1-C ₆ -alkylamino) C ₀ -C ₂ alkyl, C ₁ -C ₂ -halogenoalkyl and C1 -C ₂ -halogenoalkoxy.

Dosage form means the unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, solutions, emulsions, creams, ointments, suppositories, inhalation forms, transdermal forms, and the like.

- 130 038607

Pharmaceutical compositions are compositions containing at least one active agent, such as a compound or salt of Formula I, as well as at least one other substance, such as a carrier. The pharmaceutical compositions optionally contain one or more additional active agents. If indicated, the pharmaceutical compositions meet U.S. standards. FDA's GMP (Good Manufacturing Practice) for medicinal products for humans or non-humans. Pharmaceutical combinations are combinations of at least two active agents that can be combined in a single dosage form or provided together as separate dosage forms with instructions so that the active agents are to be used together to treat a disease such as hepatitis C.

The term pharmaceutically acceptable salts includes derivatives of the disclosed compounds in which the parent compound is modified by the formation of inorganic and organic non-toxic acid or base addition salts. Salts of the compounds of the present invention can be synthesized from the parent compound, which contains a basic or acidic residue, by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (e.g. hydroxide, carbonate, bicarbonate Na, Ca, Mg or K, etc.), or by reacting the free base form of these compounds with stoichiometric amount of the corresponding acid. Such reactions are usually carried out in water, or in an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred where practical. Salts of the compounds of the present invention further include solvates of the compounds and campound salts.

Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; etc. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound, derived, for example, from non-toxic inorganic or organic acids. For example, common salts of non-toxic acids include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymalic, phenylacetic, glutamic, benzoic, salicylic, mesyl, esyl, esyl, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC (CH ₂ ) _p -COOH, where n is 0-4 and the like. Lists of additional suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., P. 1418 (1985).

The term carrier, as used in pharmaceutical compositions / combinations of the invention, refers to a diluent, excipient or carrier with which the active compound is provided.

The term pharmaceutically acceptable excipient means an excipient that is suitable for the preparation of a pharmaceutical composition / combination, which is generally safe, non-toxic and neither biologically or otherwise undesirable, and includes an excipient that is acceptable for veterinary as well as pharmaceutical purposes for a person. A pharmaceutically acceptable excipient, as used herein, includes one or more of such excipients.

The patient is a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition such as a disease or disorder, prophylactic treatment or treatment for prevention, or diagnostic treatment. In some embodiments, the patient is a human patient.

Giving means serving, introducing, selling, distributing, transferring (for profit or not), manufacturing, compounding or dispersing.

Preparation of a compound of Formula I with at least one additional active agent means a compound of Formula I and additional active agent (s) are provided simultaneously in one dosage form, are provided simultaneously as separate dosage forms, or are provided, in separate dosage forms for administration, separated by a period of time , which is in the interval of time in which the compound of Formula I and at least one additional active agent is in the blood stream of the patient. In some embodiments, the compound of Formula I and the additional active agent should not be prescribed to the patient by the same healthcare professional. In some embodiments of the invention, the additional active agent or agents do not require a prescription. The administration of a compound of Formula I or at least one additional active agent can be by any suitable route, for example in oral tablets, in oral capsules,

- 131 038607 in oral solutions, by inhalation, injection, suppository or local contact.

Treatment, as used herein, includes providing a compound of Formula I, either as the sole active agent or together with at least one additional active agent, sufficient to: (a) prevent a disease or symptom of a disease in a patient who may be predisposed to the disease, but it has not yet been established that he is susceptible to it (e.g., including diseases that may be associated with or caused by the primary disease (as in macular degeneration, which may result in the context of factor D activation); (b) inhibit the disease, i.e. delay its progression, and (c) alleviate the disease, i.e. induce regression of the disease. one additional active agent for a patient with or susceptible to a condition mediated by fa ctor D complement.

The term therapeutically effective amount of a pharmaceutical composition / combination of the present invention means an amount effective when administered to a patient to provide a therapeutic benefit such as ameliorating symptoms, eg, an amount effective to reduce symptoms of macular degeneration. A therapeutically effective amount is also an amount sufficient to prevent a significant increase or a significant decrease in the detectable level of factor D complement in the patient's blood, serum, or tissues.

Chemical description

In addition to the compounds of Formula I recited in the Summary of the Invention section, the present invention also includes compounds in which the variables, eg, A, B, L, R1-R ³ and L have the following definitions. The description includes all combinations of these definitions resulting in stable compounds.

For example, the disclosure includes compounds and salts of Formulas II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI and XXII, which are within the scope of Formula I. The variables specified in Formulas II-XXIV have the definitions set forth in the Summary of the invention for Formula I or any of the definitions set forth herein.

r ₃ ; ^r3 in -ή3 ² - / H> 0 A Formula II 2 r ^2, -η \ fl _r An ^Η A Formula V R ³ B o R ³ _r An o R ' ⁸ A ⁰ ) = 0 A A Formula III Formula IV R ^{3 R} \ Ji f s ^r2 ^ T) _ _l / r ² ^ ^{b R} \ ^r8 </ ° rS / ^{0 R14} R ⁸ '1 r13 R ⁸ \ _X 14 * ^ V \ _X " ^X R ⁸ R" R ⁶ Formula VI Formula VII

- 132 038607

w is 0 or 1.

w is 0 or 1.

Formula XIV Formula XV Formula XVI

m is 0 or 1.

Formula XVII Formula XVIII Formula XIX

w is 0 or 1.m is 0 or 1

Formula XX Formula XXI

In addition, the invention includes compounds and salts of Formula I and any of its sub-formulas (II-XXIV) in which at least one of the following conditions is fulfilled.

R ¹ , R ¹ , R ² , R ³ and R ³ , if present, are all hydrogen; and R ² is

- 133 038607 fluorine.

R ¹ , R ¹ , R ² and R ³ , if present, are all hydrogen; and R ² is fluoro and R ³ is —C ₀ -C4 alkyl (C ₃ -C ₇ cycloalkyl) or —O — C ₀ -C4 alkyl (C ₃ -C ₇ cycloalkyl.

R ¹ and R ² taken together form a 3- to 6-membered cycloalkyl group, and R ¹ , R ² , R ³ and R ³ , where present, are all hydrogen.

R ¹ , R ¹ , R ³ and R ³ , if present, are all hydrogen, and R ² and R ² taken together form a 5 or 6 membered heterocycloalkyl group having 1 or 2 oxygen atoms.

-L-B- is

where R ²⁶ and R ^{27 are} independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -αalkoxy , C ₁ -C ₆ -thioalkyl, -C ₀ -C4-alkyl (mono- and di-C ₁ -C ₆ alkylamino), -C ₀ -C4-alkyl (C ₃ -C ₇ -cycloalkyl), -C ₀ -C4-alkoxy- (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₂ -haloalkyl, C ₁ -C ₂ -haloalkoxy and C ₁ -C ₂ -haloalkylthio.

(f) -L-B- is;

where R ¹⁸ and R ^{18 are} independently selected from hydrogen, halogen and methyl; and m is 0 or 1;

and

R ²⁶ , R ²⁷ and R ^{28 are} independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C1-C6-αalkyl, C2-C6-alkenyl, C2-C6-alkanoyl, C1-C6-alkoxy, C1-C6-thioαalkyl , (mono- and di-C1-C6 alkylamino) C0-C4 alkyl, (C3-C7 cycloalkyl) C0-C4 alkyl and -C0-C4 alkoxy (C3-C7 cycloalkyl); each of R ²⁶ , R ²⁷ and R ²⁸ other than hydrogen, halogen, hydroxyl, nitro, cyano is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, amino, C1-C2 alkoxy, C1-C2-haloalkyl and C _g C ₂ -haloalkoxy; and

R ²⁹ represents hydrogen, _{C1-C2-alkyl, C1-C2} haloalkyl, or Si (CH _{3) 2} C (CH _{3) 3.}

(g) R ⁸ and R ^{8 are} independently hydrogen or methyl.

(h) R ⁸ and R ⁸ are hydrogen.

(i) R ⁷ is hydrogen or methyl.

(j) R ⁷ is hydrogen.

(k) One of R ¹² and R ^{13 is} selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ -αalkoxy, C ₁ -C ₆ -thioalkyl, -C ₀ -C ₄ -alkyl (mono- and di-C ₁ -C ₆ alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -OC ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C1-C ₂ -haloalkyl and C ₁ -C ₂ -haloalkoxy.

(l) R ¹ , R ¹ , R ² and R ^{3 are} all hydrogen.

R ² is fluorine and R ³ is hydrogen, —C0 — C4 alkyl (C3 — C7 cycloalkyl) or O — C ₀ —C ₄ —αalkyl (C ₃ —C ₇ cycloalkyl);

R ⁵ represents hydrogen, halogen or _C1-C2 alkyl;

R ^11, R ^13, R ¹⁴ and R ^15, if present, are independently selected at each occurrence from hydrogen, halogen, hydroxyl, amino, _C1-C4 alkyl, _C1-C4 alkoxy, -C ₀ -C ₂ alkyl (mono- and di-C _g C ₂ -alkylamino), trifluoromethyl and trifluoromethoxy;

X ¹² represents CR ¹² ; and

R ¹² is -JNR ⁹ C (O) OR ¹⁰ , -JNR ⁹ C (O) OR ²³ , -JOC (O) NR ²¹ R ²² , -JOC (O) NR ²⁴ R ²⁵ , -JNR ⁹ C (O ) NR ¹⁰ R ²³ or -JNR ⁹ C (O) NR ²⁴ R ²⁵ .

(m) J is a bond.

(n) One of R ¹² and R ^{13 is} selected from

- 134 038607

⁰ А ΑΛν ^ НН ^F , O O A / y n I 1 F F, About AA ^ ⁿ O with О Λ _Μ Λ _Ν ^H ΐί O Aiau О F νχ Oh ⁿ 'n y О AML-LY ^ ^HH V, ⁰ A H, ⁰ Л F ζ Л Αν WW Н, ° chap 7 about GU ⁰ / ⁰ hl AL ₀ A> x a JL V AAA a _n a ₀ V H, n, H, H, O About F O at o AAAv ~ ^H N-NH, if / A ^F II n 1 V and, o ⁿ 1 О AL ^ у Н / \ Oh ⁿ ff About AAvy n / a and О Ζ 1 / к О CF ₃ n.

where p is 0, 1, 2, 3, or 4.

(o) Disclosure includes compounds and salts for Formula VII

where R ¹ , R ² , R ² and R ^{3 are} independently selected from hydrogen, halogen, C1-C4-alkyl, C1-C4-α-alkoxy, -C0-C2 alkyl NR9R ¹⁰ , -C0-C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), —O — C ₀ —C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl, C _{1 -C 2} -haloalkyl and C 1 -C ₂ -haloalkoxy;

R ⁸ and R ^{8 are} independently selected from hydrogen, halogen and methyl;

R ⁵ is hydrogen, hydroxyl, cyano, -COOH, C ₁ -C ₆ -αalkyl, C ₁ -C ₆ -alkoxy, C ₂ -C ₆ alkanoyl -C ₀ -C ₄ -alkyl (C ₃ -C ₇ - cycloalkyl), -C (O) C ₀ -C ₄ alkyl (C ₃ -C ₇ -cycloalkyl, _C1-C2 haloalkyl or C 1 -C ₂ -galogenalkoksi;

R ⁶ is —C (O) CH ₃ , —C (O) NH ₂ , —C (O) CF ₃ , —C (O) (cyclopropyl), or —ethyl (cyanoimino);

and

R ¹¹ and R ¹⁴ are independently selected from hydrogen, halogen, hydroxyl, amino, nitro, cyano, C1-C ₆ alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ alkanoyl, _C1-C6 alkoxy, C1 -C ₆ -thioalkyl, -C ₀ -C ₄ -alkyl (mono- and di-C1C ₆ -alkylamino), -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -OC ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), C ₁ -C ₂ haloalkyl and C1-C ₂ -haloalkoxy.

(p) B is selected from

- 135 038607

where R ²⁷ represents hydrogen, methyl or trifluoromethyl; R ²⁸ is hydrogen or halogen; and R ²⁹ is hydrogen, methyl, trifluoromethyl, or —Si (CH ₃ ) ₂ C (CH ₃ ) ₃ .

(q) B is phenyl, pyridyl or indanyl, each of which is unsubstituted or substituted with one or more substituents independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ - alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -thioalkyl, (mono- and di-C1-C ₆ alkylamino) C ₀ -C4-alkyl, (C ₃ -C ₇ -cycloalkyl) C ₀ -C4 -alkyl, -C ₀ -C4-alkoxy (C ₃ -C ₇ -cycloalkyl), (phenyl) C ₀ -C ₂ -alkyl, (pyridyl) C ₀ -C ₂ -alkyl; each of substituents other than hydrogen, halogen, hydroxyl, nitro, cyano is unsubstituted or substituted by one or more substituents independently selected from halogen, hydroxyl, amino, C ₁ -C ₂ -alkyl, _{C 1 -C 2} -alkoxy, - OSi (CH ₃ ) ₂ C (CH ₃ ) ₃ , —Si (CH ₃ ) ₂ C (CH ₃ ) ₃ , C1 — C ₂ haloalkyl and C ₁ —C ₂ haloalkoxy.

(r) B is phenyl or pyridyl substituted with 1, 2 or 3 substituents selected from chlorine, bromine, hydroxyl, —SCF ₃ , C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy, trifluoromethyl, and trifluoromethoxy.

(s) A is a group of the formula

(t) -L-B represents a bond and an indanyl group of the formula

The present invention further includes embodiments of the invention in which m is 0 or 1;

R ² is halogen, R ² is hydrogen or halogen, and R ³ is hydrogen, halogen, —C ₀ -C4 alkyl (C ₃ -C ₇ cycloalkyl) or —O — C ₀ -C4 alkyl ( C ₃ -C ₇ -cycloalkyl;

R ⁶ is -C (O) C ₁ -C4-alkyl, -C (O) NH ₂ , -C (O) CF ₃ , -C (O) (C ₃ -C ₇ -cycloalkyl) or -ethyl ( cyanoimino);

one of R ¹² and R ¹³ is selected from hydrogen, halogen, _C1-C4 alkyl, _C1-C4 alkoxy, trifluoromethyl and trifluoromethoxy; the other of R ¹² and R ¹³ is selected from (s), where (s) is C ₂ -C ₆ alkynyl, -C ₂ -C ₆ -alkynyl R ²³ , C ₂ -C ₆ -alkanoyl, -JC ₃ - C ₇ -cycloalkyl, -B (OH) 2, -JC (O) NR ⁹ R ²³ , -JOSO2OR ²¹ , -C (O) (CH2) 1.4S (O) R ²¹ , -O (CH2) 1.4S ( O) NR ²¹ NR ²² , -JOP (O) (OR ²¹ ) (OR ²² ), -JP (O) (OR ²¹ ) (OR ²² ), -JOP (O) (OR ²¹ ) R ²² , JP (O ) (OR ²¹ ) R ²² , -JOP (O) R ²¹ R ²² , -JP (O) R ²¹ R ²² , -JSP (O) (OR ²¹ ) (OR ²² ), -JSP (O) (OR ²¹ ) (R ²² ), -JSP (O) (R ²¹ ) (R ²² ), -JNR ⁹ P (O) (NHR ²¹ ) (NHR ²² ), -JNR ⁹ P (O) (OR ²¹ ) (NHR ²² ),

JNR ⁹ P (O) (OR ²¹ ) (OR ²² ), -JC (S) R ²¹ , -JNR ²¹ SO2R ²² , -JNR ⁹ S (O) NR ¹⁰ R ²² , JNR ⁹ SO2NR ¹⁰ R ²² , -JSO2NR ⁹ COR ²² , -O (CH2) 1-4SO2NR ²¹ R ²² , -JSO2NR ⁹ CONR ²¹ R ²² , -JNR ²¹ SO2R ²² , JC (O) NR ²¹ SO2R ²² , -JC (NH2) NCN, -JC (NH2 ) NR ²² , -JC (NH2) NS (O) 2R ²² , -JOC (O) NR ²¹ R ²² , -JOC (O) NR ²⁴ R ²⁵ , -JNR ⁹ C (O) OR ¹⁰ , -JNR ⁹ C (O) OR ²³ , -JNR ²¹ OC (O) R ²² , - (CH2) 1-4C (O) NR ²¹ R ²² , -JNR ⁹ C (O) R ²¹ , -JC (O) R ²¹ , - JNR ⁹ C (O) NR ⁹ R ¹⁰ , -JNR ⁹ C (O) NR ¹⁰ R ²³ , -JNR ⁹ C (O) NR ²⁴ R ²⁵ , -CCR ²¹ , - (CH2) 1-4OC (O) R ²¹ , -JC (O) OR ²³ , -C2-C ₄ -αalkyl R ²³ and -J paracyclophane; where J is independently selected at each occurrence and represents a covalent bond, C1C ₄ alkylene, C ₂ -C ₄ alkenylene or C ₂ -C ₄ alkynylene;

R ²¹ and R ^{22 are} independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C ₆ alkyl, C1-C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl) C ₀ -C _4-alkyl, (phenyl) C ₀ -C ₄ alkyl, _-C1-C4 alkyl, OC (O) OC ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkilOS (O) C ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkylC (O) OC ₁ -C ₆ -alkyl, (4-7-membered heterocycloalkyl) C ₀ -C ₄ -alkyl having 1, 2 or 3 heteroatoms independently selected from N , O and S, and (5- or 6-membered unsaturated or aromatic heterocycloalkyl) C ₀ -C ₄ -alkyl having 1, 2 or

- 136 038607 heteroatoms independently selected from N, O and S;

R ^{23 is} independently selected at each occurrence from (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, (4-7 membered heterocycloalkyl) C ₀ -C ₄ - alkyl having 1, 2 or 3 heteroatoms independently selected from N, O and S, and (5- or 6-membered unsaturated or aromatic heterocycle) C ₀ -C ₄ -alkyl having

1, 2 or 3 heteroatoms independently selected from N, O and S;

R ²⁴ and R ²⁵ , taken together with the nitrogen atom to which they are attached, form a 4 to 7 membered monocyclic heterocycloalkyl group or a 6-10 membered bicyclic heterocycloalkyl group having fused, spiro or bridged rings; each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B (OH) ₂ , -Si (CH ₃ ) ₃ , -COOH, -CONH2 , -P (O) (OH) ₂ , C1-C ₆ -alkyl, Cl-C ₆ -alkoxy, -C ₀ -C ₂ -alkyl (mono- and di-C ₁ -C ₄ -alkylamino), C ₁ -C ₆ alkyl esters, C ₁ -C ₄ -alkylamino, C 1-C ₄ hydroxyalkyl, C ₁ -C ₂ -haloalkyl and C ₁ -C ₂ -galogenalkoksi.

(r) The present invention includes compounds and salts in which one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other

R ¹² and R ^{13 are} independently selected from (s), where (s) is C2-C6 alkynyl, -C2-C6 alkynyl R ²³ , C2-C ₆ alkanoyl, -JC ₃ -C ₇ cycloalkyl, - JC (O) NR ⁹ R ²³ , -C (O) (CH ₂ ) _1-4 S (O) R ²¹ , -JP (O) (OR ²¹ ) (OR ²² ),

-JOP (O) (OR ²¹ ) R ²² , -JP (O) (OR ²¹ ) R ²² , -JOP (O) R ²¹ R ²² , -JP (O) R ²¹ R ²² , -JNR ²¹ SO2R ²² , -JNR ²¹ SO2R ²² , -JC (O) NR ²¹ SO2R ²² , -JC (NH2) NCN, -JC (NH2) NR ²² , -JC (NH2) NS (O) 2R ²² , -JOC (O) NR ²¹ R ²² , -JOC (O) NR ²⁴ R ²⁵ , -JNR ⁹ C (O) OR ¹⁰ , -JNR ⁹ C (O) OR ²³ , -JNR ²¹ OC (O) R ²² , -JC (O) R ²¹ , —JNR ⁹ C (O) NR ⁹ R ¹⁰ , —JNR ⁹ C (O) NR ¹⁰ R ²³ , —JNR ⁹ C (O) NR ²⁴ R ²⁵ and —J paracyclophane; wherein J is independently selected at each occurrence and represents a covalent bond, C1-C ₄ alkylene, C ₂ -C ₄ alkenylene or C ₂ -C ₄ -alkynylene;

R ²¹ and R ^{22 are} independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ - cycloalkyl) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, -C1-C ₄ -alkyl OC (O) OC1 -C ₆ -alkyl, -C -C ₄ -alkylOS (O) C1 _C6 alkyl, -C1 ₄ -alkilS -C (O) OC 1 -C ₆ -alkyl, (pyrrolidinyl) C0-C4alkyl, ((morpholinyl) C0-C4alkyl, (thiomorpholinyl) C0-C4alkyl , (piperidinyl) C0-C4 alkyl, (piperazinyl) C ₀ -C ₄ -alkyl, (tetrahydrofuranyl) C ₀ -C ₄ -alkyl, pyrazolyl) C ₀ -C ₄ -alkyl, (thiazolyl) C ₀ -C ₄ -alkyl , (triazolyl) C ₀ -C ₄ -alkyl, (tetrazolyl) C ₀ -C ₄ -alkyl, (imidazolyl) C ₀ -C ₄ -alkyl, (oxazolyl) C ₀ -C ₄ -alkyl, (furanyl) C ₀ -C ₄ -alkyl, (pyridinyl) C ₀ -C ₄ -alkyl, (pyrimidinyl) C ₀ -C ₄ -alkyl, (pyrazinyl) C ₀ -C ₄ -alkyl, (pyridisinyl) C ₀ -C ₄ -alkyl and (tetrahydropyridinyl) C ₀ -C ₄ -alkyl;

R ^{23 is} independently selected at each occurrence from (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, (pyrrolidinyl) C ₀ -C ₄ -alkyl, (morpholinyl) C ₀ -C ₄ -alkyl, (thiomorpholinyl) C ₀ -C ₄ -alkyl, (piperidinyl) C0-C4-alkyl, (piperazinyl) C0-C4-alkyl, (tetrahydrofuranyl) C0-C4-alkyl, (pyrazolyl) C0 -C4alkyl, (thiazolyl) C0-C4-alkyl, (triazolyl) C0-C4-alkyl, (tetrazolyl) C0-C4-alkyl, (imidazolyl) C0-C4-alkyl, (oxazolyl) C0-C4-alkyl, (furanyl) C0 -C4-alkyl, (pyridinyl) C0-C4-alkyl, (pyrimidinyl) C0C4-alkyl, (pyrazinyl) C0-C4-alkyl, (pyridizinyl) C0-C4-alkyl and (tetrahydropyridinyl) C0-C4-alkyl;

R ²⁴ and R ²⁵ taken together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl group, each optionally bridged to a methylene or ethylene group or spiro to a C ₃ -C ₆ cycloalkyl group;

each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B (OH) ₂ , -Si (CH ₃ ) ₃ , -COOH, -CONH _2, -P (O) (OH) _{2, C1-C6} alkyl, _C1-C6 alkoxy, -C ₀ -C ₂ alkyl (mono- and _di-C1-C4 alkylamino) C1 C ₆ alkyl esters, _C1-C4 alkylamino, _C1-C4 -gidroksilalkila, C1-C ₂ -haloalkyl and C 1 C ₂ -galogenalkoksi.

The present disclosure includes compounds and salts in which one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R ¹² and R ^{13 is} selected from (s), where (s) is -JP (O) (OR ²¹ ) (OR ²² ), -JOP (O) (OR ²¹ ) R ²² , -JP (O ) (OR ²¹ ) R ²² , -JOP (O) R ²¹ R ²² or -JP (O) R ²¹ R ²² ;

where J is independently selected at each occurrence and represents a covalent bond, C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene;

R ²¹ and R ^{22 are} independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C1-C ₆ alkyl, C1-C ₆ alkyl, C1-C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl) C ₀ -C ₄ alkyl, (phenyl) C ₀ -C ₄ alkyl and _-C1-C4 alkilOS (O) OC ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkilOS (O) C ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkylC (O) OC ₁ -C ₆ -alkyl;

each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, —B (OH) ₂ , —Si (CH ₃ ) ₃ , —COOH, CONH ₂ , -P (O) (OH) _{2, C1-C6} alkyl, _C1-C6 alkoxy, -C ₀ -C ₂ alkyl (mono- and _di-C1-C4 alkylamino) C1-S6alkilefira, _C1-C4 alkylamino, _C1-C4 -gidroksilalkila, C1-C ₂ -haloalkyl and C 1 C ₂ -galogenalkoksi.

The present disclosure includes compounds and salts in which one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R ¹² and R ¹³ is C ₂ -C ₆ alkynyl R; where

R ²³ is (C3-C7 cycloalkyl) C0-C4-alkyl, (phenyl) C0-C4-alkyl, (pyrrolidinyl) C0-C4 alkyl, (morpholinyl) C0-C4-alkyl, (thiomorpholinyl) C0-C4-alkyl , (piperidinyl) C0-C4-alkyl, (piperazinyl) C ₀ -C ₄ -alkyl, (tetrahydrofuranyl) C ₀ -C ₄ -alkyl, (pyrazolyl) C ₀ -C ₄ -alkyl, (thiazolyl) C ₀ -C ₄ -alkyl, (triazolyl) C ₀ -C ₄ -alkyl, (tetrazolyl) C ₀ -C ₄ -alkyl, (imidazolyl) C ₀ -C ₄ -alkyl, (oxazolyl) C ₀ -C ₄ -alkyl, (fura - 137 038607 nyl) C ₀ -C4-alkyl, (pyridinyl) C ₀ -C4-alkyl, (pyrimidinyl) C ₀ -C4-alkyl, (pyrazinyl) C ₀ -C4-alkyl, (pyridizinyl) C ₀ -C4- alkyl and (tetrahydropyridinyl) C ₀ -C 4 alkyl; which may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B (OH) 2, -Si (CH3) 3, -COOH, -CONH2, -P (O ) (OH) 2, C _g C6-alkyl, ^^ -alkoxy, -C0-C2alkyl (mono- and di-C ₁ -C ₄ -alkylamino), C ₁ -C ₆ -alkylether, C1-C ₄ -alkylamino , _C1-C4 -gidroksilalkila, C1S ₂ -haloalkyl and C 1 C ₂ -galogenalkoksi.

The present disclosure includes compounds and salts in which one of R ¹² and R ¹³ is hydrogen, hydroxyl, halogen, methyl, or methoxy; and the other of R ¹² and R ^{13 is} selected from (s), where (s) is selected from -JNR ⁹ C (O) OR ^{B * 10} , -JNR ⁹ C (O) OR ²³ , -JOC (O) NR ²¹ R ²² , JOC (O) NR ²⁴ R ²⁵ , JNR ⁹ C (O) NR ¹⁰ R ²³ and —JNR ⁹ C (O) NR ²⁴ R ²⁵ ;

R ²¹ and R ^{22 are} independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, (C ₃ -C ₇ cycloalkyl ) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, -C1-C4 alkylOS (O) OC1-C ₆ -alkyl, -C ₁ -C ₄ -alkylOS (O) C ₁ -C ₆ -alkyl, -C ₁ -C ₄ -alkylC (O) OC ₁ -C ₆ -alkyl, (pyrrolidinyl) C ₀ -C ₄ -alkyl, (morpholinyl) C ₀ -C ₄ -alkyl, (thiomorpholinyl) C ₀ - C ₄ -alkyl, (piperidinyl) C ₀ -C ₄ alkyl, (piperazinyl) C ₀ -C ₄ -alkyl, (tetrahydrofuranyl) C ₀ -C ₄ -alkyl, (pyrazolyl) C ₀ -C ₄ -alkyl, (thiazolyl ) C ₀ -C ₄ -alkyl, (triazolyl) C ₀ -C ₄ -alkyl, (tetrazolyl) C ₀ -C ₄ -alkyl, (imidazolyl) C ₀ -C ₄ -alkyl, (oxazolyl) C ₀ -C ₄ -alkyl, (furanyl) C ₀ -C ₄ -alkyl, (pyridinyl) C ₀ -C ₄ -alkyl, (pyrimidinyl) C ₀ -C ₄ -alkyl, (pyrazinyl) C ₀ -C ₄ -alkyl, (pyridizinyl) C ₀ -C ₄ -alkyl and (tetrahydropyridinyl) C ₀ -C ₄ -alkyl;

R ^{23 is} independently selected at each occurrence from (C ₃ -C ₇ -cycloalkyl) C ₀ -C ₄ -alkyl, (phenyl) C ₀ -C ₄ -alkyl, (pyrrolidinyl) C ₀ -C ₄ -alkyl, (morpholinyl ) C ₀ -C ₄ -alkyl, (thiomorpholinyl) C ₀ -C ₄ -alkyl, (piperidinyl) C ₀ -C ₄ -alkyl, (piperazinyl) C ₀ -C ₄ -alkyl, (tetrahydrofuranyl) C ₀ -C ₄ -alkyl, (pyrazolyl) C ₀ -C ₄ alkyl, (thiazolyl) C ₀ -C ₄ -alkyl, (triazolyl) C ₀ -C ₄ -alkyl, (tetrazolyl) C ₀ -C ₄ -alkyl, (imidazolyl) C ₀ -C ₄ alkyl, (oxazolyl) C ₀ -C ₄ -alkyl, (furanyl) C ₀ -C ₄ -alkyl, (pyridinyl) C ₀ -C ₄ -alkyl, (pyrimidinyl) C ₀ C ₄ -alkyl, ( pyrazinyl) C ₀ -C ₄ -alkyl, (pyridisinyl) C ₀ -C ₄ -alkyl and (tetrahydropyridinyl) C ₀ -C ₄ -alkyl;

R ²⁴ and R ²⁵ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl group, each optionally bridged to a methylene or ethylene group or spiro to a C ₃ -C ₆ cycloalkyl group; each of (s) may be unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, oxo, -B (OH) ₂ , -Si (CH ₃ ) ₃ , -COOH, -CONH2 , -P (O) (OH) ₂ , C ₁ -C ₆ -alkyl, C1-C ₆ -alkoxy, -C ₀ -C ₂ -alkyl (mono- and di-C ₁ -C ₄ -alkylamino), C ₁ -C ₆ alkyl esters, _C1-C4 alkylamino, _C1-C4 -gidroksilalkila, C ₁ -C ₂ -haloalkyl and C 1 C ₂ -galogenalkoksi.

The present invention includes compounds and salts of formula IA:

where B may have any of the definitions set forth herein for this variable. In some embodiments, B is 2-fluoro-3-chlorophenyl or 2-fluoro-3-trifluoromethoxyphenyl. Examples of such compounds include compounds shown in table. 1. In any of the compounds shown in table. The 1,2-fluoro-3-chlorophenyl group can be replaced with 2-fluoro-3-trifluoromethoxyphenyl.

The present disclosure includes compounds and salts of formula IB, IC and ID.

In formula IB, IC and ID variables can include any of the definitions set forth herein, which leads to the formation of a stable compound. In some embodiments, the following conditions apply to Formula IB, IC, and ID.

R ¹ is hydrogen and R 2 is fluoro.

R ¹ and R2 are connected to form a 3-membered ring.

m is 0.

B is pyridyl optionally substituted with halogen, C ₁ -C ₂ alkoxy and trifluoromethyl.

B represents phenyl substituted with 1, 2 or 3 substituents independently selected from gas-138 038 607 logena, _{C1-C2-alkyl, C1-C2} alkoxy, trifluoromethyl, and optionally substituted phenyl.

R ¹³ is hydrogen and R ¹² is —NHC (O) NR ²⁴ R ²⁵ .

R ¹³ is hydrogen and R ¹² is —CCR ²³ .

R ¹³ is hydrogen and R ¹² is —NHC (O) NHR ²³ .

R ¹³ is hydrogen and R ¹² is —C (O) R ²³ .

This specification has been described with reference to embodiments of the invention. However, it will be apparent to one of ordinary skill in the art that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. Accordingly, the description is to be considered in an illustrative and not restrictive sense, and all such modifications are to be included within the scope of the invention.

Claims (32)

CLAIM 1. Compound of formula I or a pharmaceutically acceptable salt thereof, where Q ¹ is C (R1R1); Q ² represents C (R2R ² ); Q ³ represents C (R ³ R ³ ); X ¹ represents N; X ² represents CH; R ² and R ^{2 are} independently selected from hydrogen and halogen; R ¹ , R ¹ , R ³ and R ³ are hydrogen; R ⁹ and R ^{10 are} independently selected from hydrogen and C ₁ -C ₆ alkyl; A represents a group selected from R ⁵ is hydrogen; R ⁶ is —C (O) NH2 or C ₂ -C ₆ alkanoyl; R ⁸ and R ⁸ are hydrogen; X ¹¹ represents CR ¹¹ ; X ¹² represents CR ¹² ; X ¹³ represents CR ¹³ ; X ¹⁴ represents CR ¹⁴ ; one of R ¹² and R ^{13 is} selected from R ³¹ and the other of R ¹² and R ^{13 is} selected from R ³² ; R ³¹ is hydrogen; R ^{32 is} selected from 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O and S; phenyl; and a saturated or unsaturated 6-membered heterocycle containing 1 or 2 nitrogen atoms, where the heterocycle is linked through a carbon atom in the heterocyclic ring to a carbon atom of ring A; and where each R ^{32 is} optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, hydroxyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ - C ₂ haloalkyl, C ₁ -C ₆ -alkylsulfonyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 6-membered heterocycle containing 1 or 2 heteroatoms independently selected of N, O and S; R ¹¹ and R ¹⁴ are hydrogen; L represents R ¹⁷ is hydrogen; m is 0; B is a monocyclic or bicyclic carbocyclic group containing - 139 038607 containing from 3 to 6 ring atoms per ring; a monocyclic or bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S and 4 to 7 ring atoms per ring; - (C ₀ -C ₄ -alkyl) (monocyclic or bicyclic aryl containing 6 ring atoms per ring); - (C ₀ -C ₄ -alkyl) (monocyclic or bicyclic heteroaryl group containing from 1 to 3 heteroatoms independently selected from N, O and S, and from 5 to 6 ring atoms per ring); or - (C ₀ -C ₄ -alkyl) (biphenyl), each of B is unsubstituted or substituted with one to four substituents independently selected from R ³³ and R ³⁴ , and 0 or 1 substituent selected from R ³⁵ and R ³⁶ ; R ^{33 is} independently selected from halogen, hydroxyl, C1-C6-α-alkyl, C1-C6-α-alkoxy, -C0-C4 -alkyl NR9R ¹⁰ , C1-C ₂ -haloalkyl and C1-C ₂ -haloalkoxy; R ³⁴ is —JC ₃ —C ₇ cycloalkyl; R ^{35 is} independently selected from naphthyl and (4-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S) C 0 -C 4 -alkyl, each of R ³⁵ is unsubstituted or substituted with one substituent independently selected from halogen , hydroxyl, nitro, cyano, C1-C6-alkyl, C ^ Qs alkenyl, C2-C6-alkanoyl, C1-C6-α-alkoxy, (mono- and di-C1-C6-alkylamino) C0-C4-alkyl, complex C1- S6alkilovogo ether -c0-C4-alkyl (C3-C7 cycloalkyl), -SO2R ^{6 7 8 9} C1-C2 haloalkyl and _C1-C2 -galogenalkoksi; R ^{36 is} independently selected from (phenyl) C0-C2-alkyl, (phenyl) C1-C2-alkoxy and 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, B and S, each of R ³⁶ is unsubstituted or substituted with one to two substituents independently selected from halogen, hydroxyl, nitro, cyano, C1-C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl, C ₁ - C ₆ -αalkoxy, (mono- and di-C ₁ -C ₆ alkylamino) C ₀ -C ₄ -alkyl, -C ₀ -C ₄ -alkyl (C ₃ -C ₇ -cycloalkyl), -SO2 alkyl, C1- C ₂ -haloalkyl and C ₁ -C ₂ haloalkoxy; and J is independently selected from a covalent bond, C1-C ₄ -alkylene, -OS1-C ₄ -alkylene, C ₂ -C ₄ -alkenyl and C ₂ -C ₄ -alkynylene. 2. A compound according to claim 1, wherein the ring is selected from 3. The connection according to claim 1, where the ring selected from 4. A compound according to claim 1, wherein R ² is halogen. 5. A compound according to claim 1, wherein A is 6. A compound according to claim 1, wherein the R ³² moiety is a 5-6 membered heteroaryl containing 1, 2 or 3 nitrogen heteroatoms. 7. A compound according to claim 1, wherein B is a monocyclic carbocyclic or bicyclic carbocyclic group containing from 3 to 6 ring atoms per ring, each of B is unsubstituted or substituted with one to four substituents independently selected from R ³³ and R ³⁴ , and 0 or 1 substituent selected from R ³⁵ and R ³⁶ . 8. A compound according to claim 7, wherein the monocyclic carbocyclic group is selected from cyclohexenyl, cyclohexyl, cyclopentenyl, cyclopentyl, cyclobutenyl, cyclobutyl or cyclopropyl optionally substituted with halogen, cyano, hydroxyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ - alkoxy or phenyl. - 140 038607 9. The compound according to claim 1, where B is selected from a monocyclic or bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and from 4 to 7 ring atoms per ring; where B is unsubstituted or substituted with one to four substituents independently selected from R ³³ and R ³⁴ , and 0 or 1 substituent selected from R ³⁵ and R ³⁶ . 10. A compound according to claim 9, wherein the monocyclic or bicyclic heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and from 4 to 7 ring atoms per ring, is selected from pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl or piperazinyl optionally substituted with halogen, cyano, hydroxyl, C ₁ -C ₆ -αalkyl, C ₁ -C ₆ alkoxy or phenyl. 11. The compound according to claim 1, where B is selected from - (C ₀ -C ₄ -alkyl) (monocyclic or bicyclic aryl containing 6 ring atoms per ring); - (C ₀ -C ₄ -alkyl) (monocyclic or bicyclic heteroaryl group containing from 1 to 3 heteroatoms independently selected from N, O and S and from 5 to 6 ring atoms per ring); or - (C ₀ -C ₄ -alkyl) (biphenyl), where B is unsubstituted or substituted with one to four substituents independently selected from R ³³ and R ³⁴ , and 0 or 1 substituent selected from R ³⁵ and R ³⁶ . 12. The compound according to claim 11, where - (C ₀ -C ₄ -alkyl) (monocyclic or bicyclic aryl containing 6 ring atoms per ring) the group is phenyl or benzyl, optionally substituted with halogen, hydroxyl, -COOH, cyano, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkanoyl, C ₁ -C ₆ -alkoxy, -C ₀ -C ₄ -alkyl NR ⁹ R ¹⁰ , -SO ₂ -alkyl, C1-C ₂ -halogenoalkyl and C ₁ -C ₂ -halogenoalkoxy, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -thioalkyl or -JC ₃ -C ₇ -cycloalkyl. 13. A compound according to claim 11, wherein - (C ₀ -C ₄ -alkyl) (monocyclic or bicyclic heteroaryl group containing from 1 to 3 heteroatoms independently selected from N, O and S, and from 5 to 6 atoms per ring ) the group is imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl or pyrrolyl optionally substituted with halogen, hydroxyl, C ₁ -C ₆ -alkyl, C ₁ -C 6 _6- alkoxy, -C ₀ -C ₄ -alkyl NR9R ¹⁰ , -SO ₂ -alkyl, C ₁ -C ₂ -haloalkyl, C1-C ₂ -haloalkoxy or -JC ₃ -C ₇ -cycloalkyl. 14. A compound according to claim 11, wherein the - (C ₀ -C ₄ -alkyl) (biphenyl) group is biphenyl optionally substituted with halogen, hydroxyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -αalkoxy, - C ₀ -C ₄ alkyl NR9R ¹⁰ , C1-C2 haloalkyl, C1-C ₂ haloalkoxy or —JC ₃ -C ₇ cycloalkyl. 15. A compound according to claim 1, wherein B is selected from 16. The connection according to claim 1, where B is selected from 17. A compound according to claim 1, wherein B is selected from - 141 038607 18. A compound according to claim 1, wherein R ³² is pyrimidine substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, hydroxyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ -alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₂ -halogenoalkyl, C ₁ -C ₆ -alkylsulfonyl, 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and a 6-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O and S. 19. A compound according to claim 1 of the formula or a pharmaceutically acceptable salt thereof. 20. A compound according to claim 1 of the formula, or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition for the treatment of a complement factor D mediated disorder, comprising an effective amount of a compound selected from any of claims 1-20 in a pharmaceutically acceptable carrier. 22. A method of treating a disorder mediated by complement factor D, which comprises administering an effective amount to a host in need of such treatment, a compound selected from any one of claims. 1 -20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 21. 23. The method of claim 22, wherein the disorder is age-related macular degeneration (AMD). 24. The method of claim 22, wherein the disorder is retinal degeneration, ocular disease, multiple sclerosis, arthritis, or COPD. 25. The method of claim 22, wherein the disorder is an ocular disorder. 26. The method of claim 20, wherein the disorder is paroxysmal nocturnal hemoglobinuria (PNH). 27. The method of claim 22, wherein the disorder is a respiratory disease. 28. The method of claim 22, wherein the disorder is cardiovascular disease. 29. The method of claim 22, wherein the disorder is atypical or typical hemolytic uremic syndrome. 30. The method of claim 22, wherein the disorder is rheumatoid arthritis. 31. The method of claim 22, wherein the disorder is C3 glomerulonephritis. 32. A method according to any one of claims 22 to 31, wherein the host is a human.